WO2022206939A1

WO2022206939A1 - Heterocyclic compound serving as fgfr inhibitor and application thereof

Info

Publication number: WO2022206939A1
Application number: PCT/CN2022/084728
Authority: WO
Inventors: 祝伟; 邹昊; 麦万笋; 汪涛; 陈祥; 李正涛
Original assignee: 海南耀臻生物医药科技有限公司
Priority date: 2021-04-03
Filing date: 2022-04-01
Publication date: 2022-10-06
Also published as: CN117222640A; TW202304889A

Abstract

Provided is a heterocyclic compound serving as an FGFR inhibitor, and specifically, disclosed are a compound represented by formula (I), and a stereoisomer or pharmaceutically acceptable salt thereof.

Description

Heterocyclic compounds as FGFR inhibitors and their applications

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the rights and priority of the following two Chinese invention patent applications, the entire contents of which are hereby incorporated by reference in their entirety:

Patent Application No. 202110380922.X filed with the State Intellectual Property Office of China on April 3, 2021; and

Patent application No. 202210224490.8 submitted to the State Intellectual Property Office of China on March 7, 2022.

technical field

The invention belongs to the technical field of medicine, and relates to a heterocyclic compound of an FGFR inhibitor and a preparation method and application thereof.

Background technique

FGFR (Fibroblast Growth Factor Receptor, fibroblast growth factor receptor) is a transmembrane receptor tyrosine kinase, the family mainly includes four members FGFR1, 2, 3 and 4. After FGFR binds to its ligand FGF (Fibroblast growth factor), it causes receptor dimerization and then phosphorylates tyrosine residues in the kinase domain to activate the receptor, and then the activated FGFR further activates the downstream Signaling pathways such as RAS/RAF, PI3K/AKT, JAK/STAT, and PLCγ are involved in the regulation of cell proliferation, apoptosis, migration, repair of damaged tissue, and angiogenesis. Under normal physiological conditions, the FGFR signaling pathway is tightly regulated and is at a weakly activated level. And its excessive activation often leads to the occurrence and development of tumors. The molecular mechanisms of abnormal activation of FGFR mainly include 1) gene amplification; 2) gene mutation; 3) gene fusion caused by gene translocation. For example, FGFR2 gene amplification occurs in gastric cancer (5-10%), FGFR2 gene translocation occurs in intrahepatic cholangiocarcinoma (14%), and FGFR2 gene mutation occurs in endometrial cancer (12-14%). FGFR3 genetic abnormalities are most commonly found in bladder cancer, including gene mutations (60-80% of non-muscle-invasive bladder cancers and 15-20% of muscle-invasive bladder cancers), gene translocations (3-6%), and gene Amplification (incidence not reported); followed by myeloma, with FGFR3 translocations in 15-20% of myeloma patients. Some of the above FGFR gene abnormalities have been confirmed to be associated with poor prognosis of patients.

In view of the importance of the FGFR signaling pathway in tumor therapy, targeted therapy targeting the FGFR signaling pathway has become a research hotspot in the field of tumor therapy in recent years. This patent application has discovered a class of heterocyclic compounds that can selectively inhibit FGFR proteins, such as FGFR2, and have a killing effect on related tumor cells.

SUMMARY OF THE INVENTION

The present invention provides a class of heterocyclic compounds of formula, and stereoisomers and pharmaceutically acceptable salts thereof. These compounds can inhibit the activity of FGFR, thereby affecting biological function.

Specifically, the present invention provides a compound represented by formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof,

X, Z are each independently selected from CR ⁹ or N;

W is selected from O or C (=O);

Y is selected from C(=O), NHC(=O), C(=O)NH, N( _CH3 ) or a bond;

Ring A is selected from 5-10 membered heteroaryl or 5-10 membered heterocyclyl;

Ring B is selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl or C ₃ -C ₁₀ cyclic hydrocarbon group;

E is selected from C ₃ -C ₁₀ cyclic hydrocarbon group, C ₆ -C ₁₀ aryl group, 3-12 membered heterocyclic group or 5-12 membered heteroaryl group, said C ₃ -C ₁₀ cyclic hydrocarbon group C ₆ -C ₁₀ aryl group radical, 3-12 membered heterocyclyl or 5-12 membered heteroaryl optionally substituted with one or more R ^1a ;

R ^1a is independently selected from halogen, CN, NH ₂ , OH, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3-6 membered heterocyclyl, C ₁ -C ₆ alkoxy, -S (=O)-C ₁ -C ₄ alkyl, -S(=O) ₂ -C ₁ -C ₄ alkyl,

-S(=O)(=NR ^8a )R ^8b , -N=S(=O)R ^8a R ^8b , -NR ^8a R ^8b , -C(=O)NR ^8a R ^8b or -NR ⁷ C(= O)R ^8b , the C ₁ -C ₆ alkyl group, C ₃ -C ₈ cyclic hydrocarbon group, 3-6 membered heterocyclic group, C ₁ -C ₆ alkoxy group, -S(=O)-C ₁ - C4alkyl or -S(=O) ₂ _- _C1 _- C4alkyl is optionally substituted with one or more groups independently selected from halogen, OH, _C1 _- C3alkoxy or CN ;

R ¹ is selected from -CN, -(CH ₂ ) _q CN, -C≡CR ⁵ , -C(=O)C≡CR ⁵ , -C(=O)CR ⁶ =C(R ⁵ ) ₂ , -R ⁷ C(=O)CH=C(R ⁵ ) ₂ , -NHC(=O)CR ⁶ =C(R ⁵ ) ₂ , -R ⁷ NHC(=O)CH=C(R ⁵ ) ₂ , -NHC (=O)C≡CR ⁵ , -S(=O)CR ⁶ =C(R ⁵ ) ₂ , -S(=O) ₂ CR ⁶ =C(R ⁵ ) ₂ , -NHS(=O)CR ⁶ =C(R ⁵ ) ₂ , -NHS(=O) ₂ CR ⁶ =C(R ⁵ ) ₂ , -NR ⁶ C(=O)CR ⁶ =C(R ⁵ ) ₂ or NHC(=O)R ⁵ ;

R ⁵ is independently selected from H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, 3-12 membered heterocyclyl or C ₆ -C ₁₀ aryl , the C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₈ cyclic hydrocarbon group, 3-12-membered heterocyclic group or C ₆ -C ₁₀ aryl group are optionally replaced by one or more R ^5a substitutions;

R ^5a is independently selected from halogen, CN, N(R ^5b ) ₂ , OH, NO ₂ , C ₃ -C ₈ cycloalkyl, or 3-12 membered heterocyclyl;

R ^5b is independently selected from H or C ₁ -C ₆ alkyl;

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

R ⁷ is selected from C ₁ -C ₆ alkylene, C ₃ -C ₈ cycloalkylene or 3-12 membered heterocyclylene;

R ² is selected from H, NH ₂ , C ₁ -C ₆ alkyl, OH or halogen;

R ³ is independently selected from halogen, CN, NH ₂ , OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy or C _3-8 _cycloalkyl ;

R ⁴ is independently selected from halogen, CN, NH ₂ , OH, NO ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, 3-10 membered heterocycle base, -C(=O)R ^8a , -C(=O)OR ^8a , -NR ^8a R ^8b , -C(=O)NR ^8a R ^8b or -NR ⁷ C(=O)R ^8b , the C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl or 3-10 membered heterocyclyl optionally substituted with one or more R ^4a ;

R ^4a is independently selected from halogen, CN, NH ₂ , OH or C ₁ -C ₆ alkyl;

R ^8a and R ^8b are each independently selected from H, halogen, CN, NH ₂ , OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkyl;

R ⁹ is selected from H, CN, OH, NH ₂ , -NHR ¹⁰ , -NH-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₃ -C ₈ Cycloalkyl, said _C1 - _C6 alkyl, -NH- _C1 - _C6 alkyl, _C1 - _C6 alkoxy, or C3 _- _C8 cycloalkyl optionally surrounded by one or more R ¹⁰ substituted;

R ¹⁰ is independently selected from halogen, NH ₂ , C ₃ -C ₈ cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl, the NH ₂ , C ₃ - _C8 cycloalkyl, 3-10 membered heterocyclyl, _C6 - _C10 membered aryl or 5-10 membered heteroaryl optionally substituted with one or more ^R11 ;

R ¹¹ is independently selected from C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl or 3-10 membered heterocyclyl, said C ₁ -C ₆ alkane group, C ₃ -C ₈ cycloalkyl or 3-10 membered heterocyclyl optionally by C ₁ -C ₆ alkyl, halogen, OH, -NH-C ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ substituted;

n and m are each independently selected from 0, 1, 2 or 3;

q is selected from 1, 2 or 3.

In some embodiments, Ring A is selected from 5-10 membered heteroaryl.

In some embodiments, Ring A is selected from 5-6 membered heteroaryl.

In some embodiments, Ring A is selected from 5-6 membered heteroaryl or 5-6 membered heterocyclyl.

In some embodiments, Ring A is selected from pyrimidinyl, pyridyl, or tetrahydropyrrolyl.

In some embodiments, Ring A is selected from pyrimidinyl or tetrahydropyrrolyl.

In some embodiments, Ring A is selected from pyridyl or pyrimidinyl.

In some embodiments, Ring A is selected from pyrimidinyl.

In some embodiments, Ring B is selected from _C6 - _C10 aryl or 5-10 membered heteroaryl.

In some embodiments, Ring B is selected from C ₆ -C ₁₀ aryl or C ₃ -C ₁₀ cyclohydrocarbyl.

In some embodiments, Ring B is selected from phenyl or cyclohexenyl.

In some embodiments, Ring B is selected from phenyl.

In some embodiments, W is selected from O.

In some embodiments, Y is selected from C(=O), NHC(=O), C(=O)NH, or a bond.

In some embodiments, Y is selected from N( _CH3 ) or a bond.

In some embodiments, Z is selected from ^CR9 .

In some embodiments, E is selected from C3 _- _C6 cycloalkyl, _C6 - _C10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, the C3 _- _C6 cycloalkyl , C ₆ -C ₁₀ aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R ^1a .

In some embodiments, E is selected from C ₆ -C ₁₀ aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, said C ₆ -C ₁₀ aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl optionally substituted with R ^1a .

In some embodiments, E is selected from C ₆ -C ₁₀ aryl, 3-10 membered heterocyclyl, or 5-6 membered heteroaryl, said C ₆ -C ₁₀ aryl, 3-10 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with R ^1a .

In some embodiments, E is selected from the following groups optionally substituted with R ^1a : phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thienyl, pyrrolyl , pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, Tetrahydropyrrolyl, tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2-pyridine Keto, 2-piperazinone, azetidinyl, 1,4-diazepanyl, bicyclo[1.1.1]pentanyl, 2,7-diazaspiro[4.4 ]nonyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.5]nonyl Alkyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 2,5-diazaspiro[3.4]octyl , 4,7-diazaspiro[2.5]octyl, 2,5-diazabicyclo[2.2.1]heptyl, 5,8-diazaspiro[3.5]nonyl , 3,8diazabicyclo[3.2.1]octyl or dihydropyrrolyl.

In some embodiments, E is selected from the following groups optionally substituted with R ^1a : phenyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thienyl, pyrrolyl , pyrazolyl, thiazolyl, imidazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxazolyl, benzothiazolyl, indolyl, quinolinyl, isoquinolinyl, Tetrahydropyrrolyl, tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2-pyridine Keto, 2-piperazinone, azetidinyl, 1,4-diazepanyl, bicyclo[1,1,1]pentanyl, 2,7-diazaspiro [4.4] Nonyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.5 ]nonyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl or 2,5-diazaspiro[3.4]octane alkyl.

In some embodiments, E is selected from the following groups optionally substituted with R ^1a : phenyl, pyridyl, thienyl, pyrazolyl, imidazolyl, azetidinyl, tetrahydropyrrolyl, piperidine base, piperazinyl, tetrahydropyridyl, cyclohexyl, cyclohexenyl, morpholinyl, 2-piperazinone, 2-pyridone, 1,4-diazepanyl, bicyclic [1,1,1]Pentyl, 2,7-diazaspiro[4.4]nonanyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.5]decyl Spiro[3.5]nonanyl, 2,6-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro [3.4]octyl, 2,5-diazaspiro[3.4]octyl, 4,7-diazaspiro[2.5]octyl, 2,5diazabicyclo[2, 2,1]heptyl, 5,8-diazaspiro[3.5]nonyl, 3,8diazabicyclo[3,2,1]octyl or dihydropyrrolyl.

In some embodiments, E is selected from the following groups optionally substituted with R ^1a : phenyl, pyridyl, thienyl, pyrazolyl, imidazolyl, azetidinyl, tetrahydropyrrolyl, piperidine base, piperazinyl, tetrahydropyridyl, cyclohexyl, cyclohexenyl, morpholinyl, 2-piperazinone, 2-pyridone, 1,4-diazepanyl, bicyclic [1,1,1]Pentyl, 2,7-diazaspiro[4.4]nonanyl, 2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.5]decyl Spiro[3.5]nonanyl, 2,6-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro [3.4]octyl or 2,5-diazaspiro[3.4]octyl.

In some embodiments, R ^1a is independently selected from halogen, CN, NH ₂ , OH, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3-6 membered heterocyclyl, C ₁ -C ₆ Alkoxy, -S(=O)-C ₁ -C ₄ alkyl, -S(=O) ₂ -C ₁ -C ₄ alkyl,

-S(=O)(=NR ^8a )R ^8b , -N=S(=O)R ^8a R ^8b , -NR ^8a R ^8b , -C(=O)NR ^8a R ^8b or -NR ⁷ C(= O)R ^8b , the C ₁ -C ₆ alkyl group, C ₃ -C ₈ cyclic hydrocarbon group, 3-6 membered heterocyclic group, C ₁ -C ₆ alkoxy group, -S(=O)-C ₁ - C4alkyl or -S(=O) ₂ _- _C1 _- C4alkyl is optionally substituted with one or more groups independently selected from halogen, OH or _C1 _- C3alkoxy.

In some embodiments, R ^1a is independently selected from halogen, CN, NH ₂ , OH, -NR ^8a R ^8b , C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3-6 membered heterocyclyl , C ₁ -C ₆ alkoxy, the C ₁ -C ₆ alkyl, C ₃ -C ₈ cyclic hydrocarbon group, 3-6 membered heterocyclic group, C ₁ -C ₆ alkoxy optionally by one or Substituted with groups independently selected from halogen, OH, or _C1 _- C3alkoxy.

In some embodiments, R ^1a is independently selected from halogen, CN, NH ₂ , OH, C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, 3-6 membered heterocyclyl, C ₁ -C ₆ Alkoxy, the C ₁ -C ₆ alkyl group, C ₃ -C ₈ cyclic hydrocarbon group, 3-6 membered heterocyclyl group, C ₁ -C ₆ alkoxy group are optionally selected by one or more independently selected from Group substitution with halogen, OH or _C1 _- C3alkoxy.

In some embodiments, R ^1a is independently selected from halogen, -NR ^8a R ^8b , C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy, said C ₁ -C ₆ alkyl optionally being Substituted with one or more groups independently selected from halogen, OH, CN or _C1 _- C3alkoxy.

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

In some embodiments, R ^1a is independently selected from Cl, F, CH ₃ , -OCH ₃ , CF ₃ , -N(CH ₃ ) ₂ or CH ₂ CN.

In some embodiments, R ^1a is independently selected from CH ₃ or -OCH ₃ .

^In some embodiments, R1 is selected from -CN, -( _CH2 ) _qCN , ^-C≡CH , -C(=O) ^C≡CR5 , -C(=O)CR6=C( ^R5 ) ₂ , -R ⁷ C(=O)CH=C(R ⁵ ) ₂ , -NHC(=O)CR ⁶ =C(R ⁵ ) ₂ , -R ⁷ NHC(=O)CH=C(R ⁵ ) ₂ , -NHC(=O)C≡CR ⁵ , -S(=O)CR ⁶ =C(R ⁵ ) ₂ , -S(=O) ₂ CR ⁶ =C(R ⁵ ) ₂ , -NHS( =O)CR ⁶ =C(R ⁵ ) ₂ or -NHS(=O) ₂ CR ⁶ =C(R ⁵ ) ₂ .

In some embodiments, R ¹ is selected from -C≡CR ⁵ , -C(=O)C≡CR ⁵ , -C(=O)CR ⁶ =C(R ⁵ ) ₂ , -R ⁷ C(=O )CH=C(R ⁵ ) ₂ , -NHC(=O)CR ⁶ =C(R ⁵ ) ₂ , -R ⁷ NHC(=O)CH=C(R ⁵ ) ₂ , -NHC(=O)C ≡CR ⁵ , -S(=O)CR ⁶ =C(R ⁵ ) ₂ , -S(=O) ₂ CR ⁶ =C(R ⁵ ) ₂ , -NHS(=O)CR ⁶ =C(R ⁵ ) ₂ , -NHS(=O) ₂ CR ⁶ =C(R ⁵ ) ₂ , -NR ⁶ C(=O)CR ⁶ =C(R ⁵ ) ₂ or NHC(=O)R ⁵ .

^In some embodiments, R1 is selected from -CN, -( _CH2 ) _qCN , ^-C≡CR5 , -C(=O) ^C≡CR5 , -C(=O) ^CR6 =C(R ⁵ ) ₂ , -R ⁷ C(=O)CH=C(R ⁵ ) ₂ , -NHC(=O)CR ⁶ =C(R ⁵ ) ₂ , -R ⁷ NHC(=O)CH=C(R ⁵ ) ₂ , -NHC(=O)C≡CR ⁵ , -NHS(=O) ₂ CR ⁶ =C(R ⁵ ) ₂ , -NR ⁶ C(=O)CR ⁶ =C(R ⁵ ) ₂ or NHC(=O) ^R5 .

In some embodiments, R ¹ is selected from -(CH ₂ ) _q CN, -C≡CH, -C(=O)C≡CR ⁵ , -C(=O)CR ⁶ =C(R ⁵ ) ₂ , -R ⁷ C(=O)CH=C(R ⁵ ) ₂ , -NHC(=O)CR ⁶ =C(R ⁵ ) ₂ , -R ⁷ NHC(=O)CH=C(R ⁵ ) ₂ , -NHC(=O)C≡CR ⁵ or -NHS(=O) ₂ CR ⁶ =C(R ⁵ ) ₂ .

In some embodiments, R ¹ is selected from -C≡CR ⁵ , -C(=O)C≡CR ⁵ , -C(=O)CR ⁶ =C(R ⁵ ) ₂ , -R ⁷ C(=O )CH=C(R ⁵ ) ₂ , -NHC(=O)CR ⁶ =C(R ⁵ ) ₂ , -R ⁷ NHC(=O)CH=C(R ⁵ ) ₂ , -NHC(=O)C ≡CR ⁵ , -NHS(=O) ₂ CR ⁶ =C(R ⁵ ) ₂ , -NR ⁶ C(=O)CR ⁶ =C(R ⁵ ) ₂ or NHC(=O)R ⁵ .

In some embodiments, R ⁶ is selected from H, F, Cl, CN or CH ₃ .

_In some embodiments, R6 is selected from H, F, CN or ^CH3 .

In some embodiments, R ⁵ is independently selected from H, C ₁ -C ₃ alkyl or C ₃ -C ₆ cycloalkyl, said C ₁ -C ₃ alkyl or C ₃ -C ₆ cycloalkyl being any optionally substituted with one or more R ^5a .

In some embodiments, R ⁵ is independently selected from H or C ₁ -C ₃ alkyl optionally substituted with _one or more _R ^5a .

In some embodiments, R ^5a is independently selected from halogen, CN, N(R ^5b ) ₂ or 3-12 membered heterocyclyl.

In some embodiments, R ^5a is independently selected from halogen, CN, N(R ^5b ) ₂ or 3-6 membered heterocyclyl.

In some embodiments, R ^5a is independently selected from N(R ^5b ) ₂ or 3-6 membered heterocyclyl.

In some embodiments, R ^5a is independently selected from halogen, CN, N(CH ₃ ) ₂ , piperidinyl, or morpholinyl.

In some embodiments, R ^5a is independently selected from N(R ^5b ) ₂ , piperidinyl, or morpholinyl.

In some embodiments, R ^5b is independently selected from C ₁ -C ₆ alkyl.

In some embodiments, R ^5b is independently selected from CH ₃ .

In some embodiments, R ⁷ is selected from C ₁ -C ₆ alkylene, C ₃ -C ₆ cycloalkylene, or 3-6 membered heterocyclylene.

In some embodiments, ^R7 is selected from the following groups: _-CH2- , -CH( _CH3 )-, -C( _CH3 ) _2- ,

In some embodiments, R ¹ is selected from the following groups:

In some embodiments, R ¹ is selected from the following groups:

In some embodiments, R ² is selected from H, NH ₂ , CH ₃ , OH or halogen.

In some embodiments, R ² is selected from H, NH ₂ , CH ₃ or halogen.

In some embodiments, R ² is selected from H, NH ₂ or halogen.

In some embodiments, R ² is selected from H or NH ₂ .

In some embodiments, R ³ is independently selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ haloalkyl.

In some embodiments, R ³ is independently selected from halogen or C ₁ -C ₆ alkoxy.

In some embodiments, ^R3 is selected from F and _-OCH3 .

In some embodiments, ^R3 is selected from halogen.

In some embodiments, ^R3 is selected from F.

In some embodiments, m is selected from 0 or 1.

In some embodiments, R ⁴ is independently selected from halogen, CN, NH ₂ , OH, NO ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, 3-10 membered heterocyclic group, the C ₁ -C ₆ alkyl group, C ₁ -C ₆ alkoxy group, C ₃ -C ₈ cycloalkyl group, 3-10 membered heterocyclic group are optionally replaced by one or more R ^4a is substituted.

In some embodiments, R ⁴ is independently selected from CN, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy.

In some embodiments, R ⁴ is independently selected from halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy.

In some embodiments, R ⁴ is independently selected from CN or C ₁ -C ₆ alkyl.

^In some embodiments, R4 is independently selected from CN or _CH3 .

In some embodiments, R ⁴ is independently selected from C ₁ -C ₆ alkyl.

^In some embodiments, R4 is independently selected from _CH3 .

In some embodiments, n is selected from 0 or 1.

In some embodiments, R ⁹ is selected from H, NH ₂ , -NHR ¹⁰ , -NH-C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl, said C ₁ -C ₆ alkyl or -NH -C ₁ -C ₆ alkyl is optionally substituted with one or more R ¹⁰ .

In some embodiments, R ⁹ is selected from H, _CN , OH, NH ₂ , -NHR ¹⁰ or -NH _- C ₁ -C ₆ alkyl, optionally by One or more R ¹⁰ substitutions.

In some embodiments, R ¹⁰ is independently selected from halogen, NH ₂ , C ₃ -C ₈ cycloalkyl or 3-10 membered heterocyclyl, said NH ₂ , C ₃ -C ₈ cycloalkyl or 3- The 10-membered heterocyclyl is optionally substituted with one or more R ¹¹ .

In some embodiments, R ¹⁰ is independently selected from halogen, NH ₂ , C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl, C ₆ -C ₁₀ aryl, or 5-6 membered heteroaryl, Said _NH2 , C3 _- _C6 cycloalkyl, 5-6 membered heterocyclyl, _C6 - _C10 aryl or 5-6 membered heteroaryl is optionally substituted with one or more ^R11 .

In some embodiments, R ¹⁰ is independently selected from NH ₂ , C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl, C ₆ -C ₁₀ aryl, or 5-6 membered heteroaryl, the NH ₂ , C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-6 membered heteroaryl are optionally substituted with one or more R ¹¹ .

In some embodiments, R ¹⁰ is independently selected from NH ₂ , 3-10 membered heterocycle, C ₆ -C ₁₀ aryl, or 5-10 membered heteroaryl, said NH ₂ , 3-10 membered heterocycle , C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl optionally substituted with one or more R ¹¹ .

In some embodiments, R ¹⁰ is independently selected from the following groups optionally substituted with one or more R ¹¹ : pyrazolyl, NH ₂ , phenyl, pyridyl, pyrrolyl, tetrahydropyrrolyl, or Morpholine.

In some embodiments, R ¹¹ is independently selected from C ₁ -C ₆ alkyl, halogen, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, or 5-6 membered heterocyclyl, the C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or 5-6 membered heterocyclyl optionally by C ₁ -C ₆ alkyl, halogen, OH, -NH-C ₁ -C ₆ alkyl or -N(C ₁ -C ₆ alkyl) ₂ substituted.

In some embodiments, R ¹¹ is independently selected from optionally C ₁ -C ₆ alkyl, halogen, OH, -NH-C ₁ -C ₆ alkyl, or -N(C ₁ -C ₆ alkyl ) ₂ substituted with the following groups: methyl, ethyl, tetrahydropyrrolyl, piperidinyl, _-OCH3 , F, piperazinyl, cyclopropyl or isopropyl.

In some embodiments, R ¹¹ is independently selected from the following groups optionally substituted with methyl, ethyl, OH, -N(CH ₃ ) ₂ or F: methyl, ethyl, tetrahydropyrrolyl , piperidinyl, _-OCH3 , F, piperazinyl, cyclopropyl or isopropyl.

In some embodiments, R ¹¹ is independently selected from C ₁ -C ₆ alkyl.

In some embodiments, R ⁹ is selected from the following groups: H, CN, OH, NH ₂ ,

In some embodiments, the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, is selected from the compound of formula (II), or a stereoisomer or pharmaceutically acceptable salt thereof ,

wherein Rings A, X, Y, Z, E, R ¹ , R ² , R ³ , R ⁴ , n, m are as defined above. It is to be understood that in claim 14 relating to formula (II), when claim 14 refers to the preceding claim x, the rings A, X, Y, Z, E, R ¹ , R ² in said formula (II) , R ³ , R ⁴ , n, m are as defined in claim x. For example, when claim 14 refers to claim 1, the rings A, X, Y, Z, E, R ¹ , R ² , R ³ , R ⁴ , n, m in the formula (II) are as claimed in claim 1 Definition; when claim 14 refers to claim 2, the rings A, X, Y, Z, E, R ¹ , R ² , R ³ , R ⁴ , n, m in said formula (II) are as claimed in claim 2 definition, and so on.

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

wherein Rings B, X, Y, Z, E, R ¹ , R ² , R ³ , R ⁴ , n, m are as defined above. It is to be understood that in claim 15 referring to formula (III), when claim 15 refers to the preceding claim x, rings B, X, Y, Z, E, R ¹ , R ² in said formula (III) are to be understood , R ³ , R ⁴ , n, m are as defined in claim x. For example, when claim 15 refers to the preceding claim 1, the rings B, X, Y, Z, E, R ¹ , R ² , R ³ , R ⁴ , n, m in said formula (III) are as claimed in 1 Definition; when claim 15 refers to the preceding claim 2, the rings B, X, Y, Z, E, R ¹ , R ² , R ³ , R ⁴ , n, m in said formula (III) are as claimed Requirement 2 definition, and so on.

In some embodiments, the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, is selected from the compound of formula (IV), or a stereoisomer or pharmaceutically acceptable salt thereof ,

wherein X, Y, Z, E, R ¹ , R ² , R ³ , R ⁴ , n, m are as defined above.

It is to be understood that in claim 16 relating to formula (IV), when claim 16 refers to the preceding claim x, X, Y, Z, E, R ¹ , R ² , R ³ in said formula (IV) , R ⁴ , n, m are as defined in claim x. For example, X, Y, Z, E, R ¹ , R ² , R ³ , R ⁴ , n, m in said formula (IV) are as defined in claim 1 when claim 16 refers to the preceding claim 1; When claim 16 refers to the preceding claim 2, X, Y, Z, E, R ¹ , R ² , R ³ , R ⁴ , n, m in said formula (IV) are as defined in claim 2, whereby analogy.

In some embodiments, the compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, is selected from the compound of formula (V), or a stereoisomer or pharmaceutically acceptable salt thereof ,

wherein Ring A, Ring B, Y, W, E, R ¹ , R ² , R ³ , R ⁴ , n, m are as defined above.

It is to be understood that in claim 17 relating to formula (V), when claim 17 refers to the preceding claim x, ring A, ring B, Y, W, E, R ¹ , R in said formula (V) ² , ^R3 , ^R4 , n, m are as defined in claim x. For example, when claim 17 refers to the preceding claim 1, the ring A, ring B, Y, W, E, R ¹ , R ² , R ³ , R ⁴ , n, m in said formula (V) are as claimed As defined in claim 1; when claim 17 refers to the preceding claim 2, ring A, ring B, Y, W, E, R ¹ , R ² , R ³ , R ⁴ , n, m in said formula (V) As defined in claim 2, and so on.

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

Further, the present invention also provides a pharmaceutical composition comprising the compound represented by formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary material.

Further, the present invention relates to the use of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating FGFR-related diseases.

Further, the present invention relates to the use of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of FGFR-related diseases.

Further, the present invention relates to a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prevention or treatment of FGFR-related diseases.

The present invention also relates to a method of preventing or treating FGFR-related diseases, the method comprising administering to a subject a therapeutically effective dose of a compound of formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, according to the present invention , its pharmaceutical composition, or the pharmaceutical preparation comprising the compound of formula (I) described in the present invention, or its stereoisomer or pharmaceutically acceptable salt.

Further, the FGFR-related disease is selected from cancer.

In some embodiments of the present application, the cancer is, for example, a solid tumor, such as gastric cancer.

In another aspect, the present invention provides use of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating cancer diseases.

In another aspect, the present invention provides the use of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of cancer diseases.

In another aspect, the present invention provides a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prevention or treatment of cancer diseases.

In another aspect, the present invention provides a method of treating a cancerous disease in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

Definition and Explanation of Terms

Unless otherwise stated, definitions of groups and terms set forth in the present specification and claims, including their definitions as examples, exemplary definitions, preferred definitions, definitions set forth in the tables, definitions of specific compounds in the examples etc., can be arbitrarily combined and combined with each other. Such combinations, group definitions and compound structures after the combination should fall within the scope described in the specification of the present invention.

in this article

Indicates the attachment site.

In this paper, the double arrow in the synthetic route

or multiple arrows

represents a multi-step reaction.

The term "pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.

The compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.

A schematic representation of racemate or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise stated, wedge and dashed bonds are used to indicate the absolute configuration of a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include E, Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the present invention.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

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

The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the ketone form predominates; in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

The term "pharmaceutical composition" means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, so long as the valence of the specified atom is normal and the compound after substitution is stable. When the substituent is oxo (ie =O), it means that two hydrogen atoms are substituted and oxo does not occur on an aromatic group.

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and the non-occurrence of said event or circumstance. For example, an ethyl group "optionally" substituted with halogen means that the ethyl group can be unsubstituted ( _CH2CH3 ₎ , monosubstituted (eg CH2CH2F ₎ , polysubstituted (eg _CHFCH2F , _CH ₂ CHF ₂ etc.) or fully substituted (CF ₂ CF ₃ ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.

The term "C ₁ -C ₆ alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, 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 and the like. The term "C ₁ -C ₃ alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3 carbon atoms.

The term "alkoxy" refers to a group resulting from the loss of a hydrogen atom on the hydroxyl group of a straight or branched chain alcohol, and may be understood as "alkyloxy" or "alkyl-O-", where alkyl is as defined above . The term "C ₁ -C ₆ alkoxy" is to be understood as "C ₁ -C ₆ alkyloxy" or "C ₁ -C ₆ alkyl-O-". The "C ₁ -C ₆ alkoxy group" may include a range such as "C ₁ -C ₃ alkoxy group".

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

The term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C ₁ -C ₆ haloalkyl" means a C ₁ -C ₆ alkyl group as defined above substituted with one or more halogens, including but not limited to trifluoromethyl, 2,2,2-trifluoromethyl, Fluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl and pentachloroethyl and the like.

The term "haloalkoxy" is intended to include monohaloalkoxy and polyhaloalkoxy wherein the halogen is substituted on the alkyl portion of the alkoxy. For example, the term "C ₁ -C ₆ haloalkoxy" means a C ₁ -C ₆ alkoxy group as defined above substituted with one or more halogens.

The term "C ₃ -C ₁₀ cyclohydrocarbyl" is understood to mean a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms. It includes C ₃ -C ₁₀ cycloalkyl and C ₃ -C ₁₀ partially saturated cyclic hydrocarbon groups (eg cycloalkenyl, cycloalkynyl, etc.), the term "C ₃ -C ₁₀ cycloalkyl" means saturated monocyclic or bicyclic A hydrocarbon ring having 3 to 10 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as decalin ring. The C3 _- _C10 partially saturated cyclic hydrocarbon group represents a partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 10 carbon atoms. For example cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl. According to the present invention, the bicyclic hydrocarbon ring includes a bridged ring, a spirocyclic ring or a paracyclic ring structure. The term "C ₃ -C ₈ cyclohydrocarbyl" is understood to mean a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 8 atoms, which includes C ₃ -C ₈ cycloalkyl and C ₃ -C ₈ Partially saturated cyclic hydrocarbon group, the term "C ₃ -C ₈ cycloalkyl" denotes a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 8 carbon atoms. The term "C ₃ -C ₆ cyclohydrocarbyl" is understood to mean a saturated or partially saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 atoms, which includes C ₃ -C ₆ cycloalkyl and C ₃ -C ₆ Partially saturated cyclic hydrocarbon group, the term "C ₃ -C ₆ cycloalkyl" denotes a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms.

The term "C6 _- _C10 aryl" is to be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10 carbon atoms, in particular having 6 A ring of 1 carbon atoms ("C ₆ aryl"), such as phenyl; or a ring of 9 carbon atoms ("C ₉ aryl"), such as indanyl or indenyl, or a ring of 10 carbon atoms Ring (" _Cio aryl") such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.

The term "3-12 membered heterocyclyl" is to be understood as a saturated or partially unsaturated monovalent monocyclic or bicyclic ring having 3 to 12 ring atoms. The bicyclic rings include bridged rings, spiro rings, and fused rings. "Hetero" in the heterocyclyl group includes, but is not limited to, atoms independently selected from N, O, S, C(=O), C(=S), S(=O), S(O) ₂ and /or atomic group, the number of heteroatoms can be, for example, 1-6 (eg, 1, 2, 3, 4, 5, or 6). In particular, the heterocyclyl group may be monocyclic, including but not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxane Pentenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholine group, 1,1-dioxothiomorpholinyl, piperazinyl, 2-piperazinone, or trithianyl; or a 7-membered ring such as diazepanyl. Optionally, the heterocyclyl group may be bicyclic, such as, but not limited to, a 5,5 membered ring, such as a hexahydrocyclopento[c]pyrrol-2(1H)-yl ring, or a 5,6 membered bicyclic ring, Such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The ring may be partially unsaturated, i.e. it may contain one or more double bonds such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazine , 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, alternatively, it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl. The term "3-8 membered heterocyclyl" is to be understood as a saturated or partially unsaturated monovalent monocyclic or bicyclic ring having 3 to 8 ring atoms. The term "3-6 membered heterocyclyl" is to be understood as a saturated or partially unsaturated monovalent monocyclic or bicyclic ring having 3 to 6 ring atoms.

The term "5-12 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems, in particular 5 or 6 or 9 or 10 ring atoms, and in each case may be Benzo-fused. "Hetero" in the heteroaryl group means that the aromatic ring includes but is not limited to independently selected from N, O, S, C(=O), C(=S), S(=O), S(O) ₂ atoms and/or atomic groups, the number of heteroatoms can be, for example, 1-6 (eg, 1, 2, 3, 4, 5, or 6). In particular, heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl Diazolyl and the like and their benzo derivatives such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinoline oxazolinyl, isoquinolinyl, etc; Naphthyridinyl, pteridyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl or

Wait.

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

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

(ii) Alleviation of the disease or disease state, even if the disease or disease state resolves.

The term "therapeutically effective amount" means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the invention to be used for the onset of one or more symptoms of a particular disease, condition or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to its own knowledge and the present 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 (eg, chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals , such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal may be a human.

The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of classes of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flowability and/or stickiness. Examples of typical "pharmaceutically acceptable carriers" suitable for the above-mentioned preparations are: carbohydrates, starches, cellulose and their derivatives and other commonly used adjuvants in pharmaceutical preparations.

The term "pharmaceutically acceptable excipients" refers to those excipients which are not significantly irritating to the organism and which do not impair the biological activity and properties 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, and the like.

The words "comprise", "comprise" or "comprise" and their English variants such as comprises or comprising are to be understood in an open, non-exclusive sense, ie, "including but not limited to".

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.

The chemical reactions of specific embodiments of the present invention are carried out in suitable solvents suitable for the chemical changes of the present invention and their required reagents and materials. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthetic steps or reaction schemes on the basis of the existing embodiments.

Detailed ways

The following examples illustrate the technical solutions of the invention in detail, but the protection scope of the present invention includes but is not limited thereto.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The units of NMR shifts are ^10-6 (ppm). The solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).

Abbreviations:

DMAP: 4-dimethylaminopyridine; Et3N or TEA: triethylamine; THF: tetrahydrofuran; MeCN or ACN: acetonitrile; 18-crown-6 or 18-crown-6: 1,4,7,10,13,16 - Hexacyclooctadecane; Pd(dppf)Cl ₂ : [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; dioxane: dioxane; Pd(PPh ₄ ) ₃ : Tetrakis(triphenylphosphine) palladium; DIEA or DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; HATU: 2-(7-azobenzotrimine azole)-N,N,N',N'-tetramethylurea hexafluorophosphate; NMP: N-methylpyrrolidone; BOP-Cl: bis(2-oxo-3-oxazolidinyl) times Phosphorus oxychloride; Pyridine: pyridine; Pd(OAc) ₂ : palladium acetate; S-phos: 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl; DCM: dichloromethane; BINAP: 1, 1'-Binaphthalene-2,2'-bisdiphenylphosphine; TCHP: tricyclohexylphosphorus; TFA: trifluoroacetic acid; LiHMDS: lithium hexamethyldisilazide; TsCl: p-toluenesulfonyl; MeAC: Acetic acid; TBAF: tetrabutylammonium fluoride; TsOH: p-toluenesulfonic acid; LAH: lithium aluminum hydride.

Example 1

N-(4-(6-Amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)acryloylamide (1 )

The first step N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acryloylamide (1B)

4,4,5,5-Tetramethyl-2-(4-aminophenyl)-1,3,2-dioxaborolane (5.0 g, 23 mmol, 1 eq), 4-dimethylaminopyridine ( 0.70g, 5.7mmol, 0.25eq) and triethylamine (4.6g, 46mmol, 6.3mL, 2eq) were dissolved in tetrahydrofuran (50mL), and acryloyl chloride (2.5g, 27mmol, 2.2mL) was slowly added dropwise at 0 degrees Celsius , 1.2eq) in tetrahydrofuran (5mL). The resulting mixture was stirred at 20 degrees Celsius for 5 hours. The reaction solution was evaporated under reduced pressure to remove the solvent, and water (100 mL) was added to the obtained residue. The resulting mixture was extracted with ethyl acetate (100 mL×3 times). The organic phases were mixed, washed with saturated brine (100 mL×3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column (the elution phase was a mixed solvent of petroleum ether containing 16-18% ethyl acetate) to obtain the title compound 1B (2.3 g, 8.3 mmol, yield: 36%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.24 (s, 1H), 7.73-7.66 (m, 2H), 7.65-7.59 (m, 2H), 6.50-6.39 (m, 1H), 6.31- 6.22(m, 1H), 5.77(d, J=10.8Hz, 1H), 1.28(s, 12H).

Step 2 2-(4-Bromo-2-fluorophenoxy)-4-methylpyrimidine (1E)

4-Bromo-2fluorophenol (5.0g, 26mmol, 1.0eq) and 2-chloro-4-methylpyrimidine (3.7g, 29mmol, 1.1eq) were dissolved in acetonitrile (30mL), potassium carbonate (7.2g) was added , 52mmol, 2.0eq) and 18-crown-6 (0.69g, 2.6mmol, 0.10eq). The resulting mixture was stirred at 85 degrees Celsius for 12 hours, cooled, water (100 mL) was added and extracted with ethyl acetate (100 mL x 3 times). The obtained organic phases were mixed, washed with saturated brine (100 mL×3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column (the elution phase was a mixed solvent of petroleum ether containing 0-15% ethyl acetate) to obtain the title compound 1E (7.2 g, yield: 97%) as a white solid.

¹ H NMR (400MHz, CDCl ₃ ): δ=8.35 (d, J=5.2Hz, 1H), 7.42-7.28 (m, 2H), 7.22-7.10 (m, 1H), 6.95 (d, J=5.2Hz) ,1H),2.50(s,3H).

The third step 2-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropenan-2-yl)phenoxy)-4-methyl Pyrimidine (1G)

Compound 1E (4.7g, 17mmol, 1.0eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- Dioxaborolane) (5.1g, 20mmol, 1.2eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.2g, 1.7mmol, 0.1eq), potassium acetate (4.9 g, 50 mmol, 3 eq) were mixed in dioxane (100 mL). The mixture was stirred at 80 degrees Celsius under nitrogen atmosphere for 3 hours. Acetonitrile (100 mL) was added to the mixture, stirred for 30 minutes, and then filtered. The filtrate was concentrated to give a black solid as the title compound 1G (10 g, crude).

MS(ESI+)m/z=331.0[M+H].

The fourth step 6-chloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-amine (1I)

6-Chloro-5-iodo-4-aminopyrimidine (1.7g, 6.7mmol, 1.0eq), compound 1G (2.2g, 6.7mmol, 1.0eq), [1,1'-bis(diphenylphosphine) [Ferrocene]palladium dichloride (0.49 g, 0.67 mmol, 0.10 eq) and potassium phosphate (2.8 g, 13 mmol, 2.0 eq) were mixed in dioxane (40 mL) and water (4 mL). The resulting mixture was stirred under nitrogen at 85 degrees Celsius for 2 hours. The yellow reaction solution was distilled under reduced pressure to remove the solvent, and the obtained 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 1I as a pale yellow solid (1.10 g, yield : 50%).

1H NMR (400 MHz, DMSO-d ₆ ): δ=8.49 (d, J=5.2 Hz, 1H), 8.23 (s, 1H), 7.48 (t, J=8.4 Hz, 1H), 7.37 (d, J= 11.2Hz, 1H), 7.21 (d, J=5.2Hz, 1H), 7.17 (d, J=8.0Hz, 1H), 2.45 (s, 3H).

The fifth step N-(4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)acryloyl Amide (1)

Compound 1I (0.24g, 0.72mmol, 1.0eq), compound 1B (0.19g, 0.72mmol, 1.0eq), tetrakistriphenylphosphine palladium (84mg, 0.073mmol, 0.10eq) and potassium carbonate (0.20g, 1.5 mmol, 2.0 eq) was mixed in dioxane (10 mL) and water (1 mL). The resulting mixture was stirred under nitrogen at 85 degrees Celsius for 18 hours. Saturated ammonium chloride solution (20 mL) was added to the reaction solution and extracted with dichloromethane (30 mL×3 times). The obtained organic phases were mixed, washed with saturated brine (100 mL×3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative chromatography and lyophilized to give the title compound 1 (0.15 g, yield: 46%) as a white solid.

MS(ESI+)m/z=443.1[M+H].

¹ H NMR (400MHz, DMSO-d6): δ=10.20(s, 1H), 8.50(d, J=5.2Hz, 1H), 8.46(s, 1H), 7.55(d, J=8.4Hz, 2H) ,7.34(t,J=8.4Hz,1H),7.29-7.14(m,4H),7.00(dd,J1 ₌ 8.4Hz,J2=1.2Hz,1H), _6.74-6.29 (m,3H), 6.29-6.19(m, 1H), 5.76(dd, J ₁ =10.0Hz, J ₂ =2.0Hz, 1H), 2.43(s, 3H).

Example 2

N-(4-(6-Amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)methacryloylamide (2)

The first step N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacryloylamide (2B)

Combine 4,4,5,5-tetramethyl-2-(4-aminophenyl)-1,3,2-dioxaborolane (0.20g, 0.91mmol, 1eq), methacrylic acid (0.16g) , 1.8mmol, 2.0eq), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.69g, 1.8mmol, 2eq) and N,N-Diisopropylethylamine (0.24 g, 0.18 mmol, 2.0 eq) was dissolved in acetonitrile (50 mL) and the resulting mixture was stirred at 25 degrees Celsius under nitrogen atmosphere for 2 hours. The reaction solution was evaporated under reduced pressure to remove the solvent, and water (30 mL) was added to the obtained residue. The resulting mixture was extracted with ethyl acetate (30 mL x 3 times). The organic phases were mixed, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column (the elution phase was a mixed solvent of petroleum ether containing 0-50% ethyl acetate) to obtain the title compound 2B (0.20 g, yield: 76%) as a pale yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ=7.79 (d, J=8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 5.80 (s, 1H), 5.48 (d, J=1.2 Hz, 1H), 2.07(s, 3H), 1.35(s, 12H)

The second step N-(4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)methyl Acryloylamide (2)

Compound 1I (0.030g, 0.090mmol, 1.0eq), compound 2B (0.029g, 0.099mmol, 1.0eq), tetrakistriphenylphosphine palladium (0.010mg, 9.4μmol, 0.10eq) and potassium carbonate (0.025g, 0.18 mmol, 2.0 eq) in dioxane (5 mL) and water (0.5 mL). The resulting mixture was stirred at 80 degrees Celsius under nitrogen atmosphere for 2 hours. Saturated ammonium chloride solution (20 mL) was added to the reaction solution and extracted with dichloromethane (30 mL×3 times). The obtained organic phases were mixed, washed with saturated brine (20 mL×3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative chromatography and lyophilized to give the title compound 2 (3.9 mg, yield: 9.2%) as a white solid.

MS(ESI+)m/z=457.2[M+1].

¹ H NMR (400 MHz, MeOD-d ₄ ): δ=9.50-9.40 (m, 2H), 8.61-8.56 (m, 2H), 8.37-8.30 (m, 3H), 8.19-8.14 (m, 2H), 8.12-8.08(m,1H),6.79(s,1H),6.52(s,1H),3.51(s,3H),3.02(s,3H)

Example 3

6-(6-Ethynyl-4-methylpyridin-3-yl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-amine (3)

The first step 5-bromo-4-methyl-2-((triisopropylsilyl)ethynyl)pyridine (3C)

Compound 3A (10g, 40mmol, 1.0eq), compound 3B (7.3g, 40mmol, 9.0mL, 1.0eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium (2.9 g, 4.0mmol, 0.10eq), cuprous iodide (0.76g, 4.0mmol, 0.10eq) and triethylamine (8.1g, 80mmol, 11mL, 2.0eq) were mixed in N,N-dimethylformamide ( 50mL). The resulting mixture was stirred under nitrogen at 85 degrees Celsius for 2 hours. Saturated ammonium chloride solution (100 mL) was added to the reaction solution and extracted with dichloromethane (100 mL×3 times). The obtained organic phases were mixed, washed with saturated brine (50 mL×3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column (the elution phase was a mixed solvent of petroleum ether containing 5-12% ethyl acetate) to obtain the title compound 3C (8.5 g, yield: 61%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ=8.56-8.47 (m, 1H), 7.26 (s, 1H), 2.30 (s, 3H), 1.08-1.06 (m, 21H)

The second step 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-2-((triisopropylsilane yl)ethynyl)pyridine (3D)

Compound 3C (4.0g, 11mmol, 1.0eq), compound 1F (5.8g, 23mmol, 2.0eq), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.83g, 1.1mmol, 0.10eq), potassium acetate (2.2g, 23mmol, 2.0eq) were mixed in 1,4-dioxane (40mL). The resulting mixture was stirred under a nitrogen atmosphere at 80 degrees Celsius for 3 hours. The reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by C18 reverse-phase silica gel column (the elution phase was an aqueous solution containing 20-100% acetonitrile) and lyophilized to obtain the title compound 3D as a white solid (0.80 g, yield: 16%)

¹ H NMR (400MHz, DMSO-d ₆ ): δ=8.61(s,1H), 7.38(s,1H), 2.45(s,3H), 1.31(s,12H), 1.18-1.04(m,21H)

The third step 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(4-methyl-6-((triisopropylsilyl) Ethynyl)pyridin-3-yl)pyrimidin-4-amine (3E)

Compound 1I (0.060g, 0.18mmol, 1.0eq), compound 3D (0.073g, 0.18mmol, 1.0eq), tetrakistriphenylphosphine palladium (0.021mg, 18μmol, 0.10eq) and potassium carbonate (0.075g, 0.54 mmol, 3.0 eq) was mixed in dioxane (3 mL) and water (0.3 mL). The resulting mixture was stirred under nitrogen at 85 degrees Celsius for 12 hours. The reaction solution was distilled under reduced pressure to remove the solvent, and the obtained residue was purified by preparative chromatography and lyophilized to obtain the title compound 3E (75 mg, yield: 73%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ=8.59 (s, 1H), 8.26 (d, J=5.2 Hz, 1H), 8.13 (s, 1H), 7.19-7.14 (m, 2H), 6.92-6.82 (m,3H),5.29-5.07(m,2H),2.40(s,3H),2.13(s,3H),1.10-1.03(m,21H)

The fourth step 6-(6-ethynyl-4-methylpyridin-3-yl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidine- 4-Amine (3)

Compound 3E (70 mg, 0.12 mmol, 1.0 eq) was dissolved in 2 mL of tetrahydrofuran, and triethylamine trihydrofluoride (0.20 g, 1.2 mmol, 0.20 mL, 10 eq) was added. The resulting mixture was stirred under a nitrogen atmosphere at 40 degrees Celsius for 3 hours. The reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by preparative chromatography and lyophilized to obtain the title compound 3 (24 mg, yield: 47%) as a white solid.

MS(ESI+)m/z=413.1[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ): δ=8.45(d, J=5.2Hz, 1H), 8.48(s, 1H), 8.16(s, 1H), 7.40(s, 1H), 7.28-7.21 (m, 2H), 7.16(d, J＝5.2Hz, 1H), 7.04-6.45(m, 3H), 4.29(s, 1H), 2.38(s, 3H), 2.14(s, 3H)

Example 4

N-(1-(6-Amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)piperidin-4-yl)propene Acylamide (4)

The first step 1-tert-butyloxycarbonyl 4-acryloyl amidopiperidine (4C)

1-tert-Butyloxycarbonyl 4-aminopiperidine (3.0g, 15mmol, 1.0eq) and N,N-diisopropylethylamine (3.9g, 30mmol, 6.3mL, 2.0eq) were dissolved in dichloromethane In methane (40 mL), a solution of acryloyl chloride (2.0 g, 22 mmol, 1.8 mL, 1.5 eq) in dichloromethane (5 mL) was slowly added dropwise at 0 degrees Celsius. The resulting mixture was stirred at 20 degrees Celsius for 3 hours. The reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column (the elution phase was a mixed solvent of petroleum ether containing 0-50% ethyl acetate) to obtain the title compound 4C (2.5 g, yield: 66%) as a white solid. ).

¹ H NMR (400 MHz, CDCl ₃ ): δ=6.29 (dd, J=1.3, 16.0 Hz, 1H), 6.12-6.03 (m, 1H), 5.65 (dd, J=1.3, 10.4 Hz, 1H), 5.57 (br d, J=8.0Hz, 1H), 4.15-3.91(m, 3H), 2.87(t, J=12.0Hz, 2H), 2.00-1.87(m, 2H), 1.46(s, 9H), 1.39 -1.30(m,2H).

The second step 4-Acryloyl amido piperidine hydrochloride (4D)

Compound 4C (2.0 g, 7.9 mmol, 1.0 eq) was dissolved in dichloromethane (15 mL), and 4M hydrochloric acid dioxane solution (7.86 mL, 4.0 eq) was slowly added dropwise at 0 degrees Celsius. The resulting mixture was stirred at 20 degrees Celsius for 2 hours. The reaction solution was evaporated under reduced pressure to remove the solvent to obtain the title compound 4D (2.5 g, crude product) as a solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.30 (d, J=7.2 Hz, 1H), 6.28-6.19 (m, 1H), 6.14-6.06 (m, 1H), 5.60 (dd, J= 2.3,10.0Hz,1H),3.30-3.19(m,2H),3.03-2.86(m,2H),1.92(dd,J=3.0,

13.6Hz, 2H), 1.72-1.56(m, 2H).

The third step N-(1-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)piperidine-4- base) acrylamide (4)

Compound 4D (0.50g, 3.2mmol, 1eq), compound 1I (0.11mg, 0.32mmol, 0.1eq) and N,N-diisopropylethylamine (0.84g, 6.5mmol, 1.1mL, 2.0eq) Dissolved in N-methylpyrrolidone (3 mL). The resulting mixture was microwaved at 120 degrees Celsius under nitrogen and stirred for 1 hour. The resulting reaction solution was purified by preparative chromatography (Waters Xbridge C18, 20-70% aqueous acetonitrile (containing 0.01% aqueous ammonia)) and lyophilized to give the title compound 4 (1.6 mg, yield: 1.0%) as a white solid.

MS(ESI+)m/z=450.1[M+H].

¹ H NMR (400 MHz, MEOD-d ₄ ): δ=8.43 (d, J=5.2 Hz, 1H), 8.25 (s, 1H), 7.53 (t, J=8.2 Hz, 1H), 7.38 (dd, J =1.8,10.8Hz,1H),7.30(d,J=7.6Hz,1H),7.18(d,J=5.2Hz,1H),6.20(d,J=6.4Hz,2H),5.64(t,J =6.0Hz,1H),4.07(br d,J=13.6Hz,2H),3.98-3.89(m,1H),3.31(s,10H),3.04(t,J=11.6Hz,2H),2.48( s,3H),1.83(d,J＝10.8Hz,2H),1.46-1.36(m,2H)

Example 5

1-(4-(6-Amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-3,6-dihydropyridine -1(2H)-yl)-2-methylprop-2-en-1-one (5)

The first step 4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-3,6-dihydropyridine -1(2H)-Carboxylic acid tert-butyl ester (5B)

Compound 1I (1.1g, 3.32mmol, 1.0eq), compound 5A (1.1g, 3.5mmol, 1.1eq), tetrakistriphenylphosphine palladium (0.24g, 0.33mmol, 0.10eq) and potassium carbonate (1.4g, 10 mmol, 3.0 eq) was mixed in dioxane (30 mL) and water (3 mL). The resulting mixture was stirred under nitrogen at 85 degrees Celsius for 12 hours. The reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (the elution phase was a mixed solvent of dichloromethane containing 0-10% methanol) to obtain the title compound 5B (0.70 g, yield: 44%) as a brown solid. ).

¹ H NMR (400 MHz, CDCl ₃ ): δ=8.56 (s, 1H), 8.38 (d, J=5.2 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.17-7.06 (m, 2H) ),6.96(d,J＝5.2Hz,1H),5.84(s,1H),5.31(s,1H),5.00(s,2H),3.90(s,2H),3.49-3.33(m,2H) ,2.51(s,3H),1.45(s,9H)

The second step 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine -4-Amine hydrochloride (5C)

Compound 5B (0.20 g, 0.42 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and 4M hydrochloric acid dioxane solution (1.04 mL, 10 eq) was slowly added dropwise at 0 degrees Celsius. The resulting mixture was stirred at 25 degrees Celsius for 1 hour. The reaction solution was evaporated under reduced pressure to remove the solvent to obtain the title compound 5C (0.18 g, crude product) as a solid.

MS(ESI+)m/z=378.9[M+H].

The third step 1-(4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-3,6- Dihydropyridin-1(2H)-yl)-2-methylprop-2-en-1-one (5)

Compound 5C (0.16g, 0.39mmol, 1.0eq) and triethylamine (0.12g, 1.2mmol, 0.16mL, 3.0eq) were dissolved in dichloromethane (5mL), and methpropylene was slowly added dropwise at 0 degrees Celsius Acid chloride (42 mg, 0.40 mmol, 1.0 eq). The resulting mixture was stirred at 25 degrees Celsius for 1 hour. The reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by preparative chromatography (Waters Xbridge C18, 20-70% acetonitrile aqueous solution (containing 0.01% ammonia water)) to obtain the title compound 5 (0.070 g, yield: 39%) as a white solid ).

MS(ESI+)m/z=447.2[M+H].

¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.46 (d, J=4.8 Hz, 1H), 8.37 (s, 1H), 7.38 (t, J=8.2 Hz, 1H), 7.24 (dd, J ₁ = _11.2Hz , J2=2.0Hz, 1H), 7.17(d, J=5.2Hz, 1H), 7.10(td, J=8.4, 0.8Hz, 1H), 6.17(s, 2H), 5.61(s ,1H),5.20-5.03(m,1H),4.90(s,1H),3.89(q,J=2.8Hz,2H),3.49(t,J=5.6Hz,2H),2.43(s,3H) ,2.22(d,J＝2.0Hz,2H),1.79(s,3H).

Example 6

1-(2-Methacryloyl)-(4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl ) piperidine (6)

The first step 4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)piperidine-1-carboxylic acid tertiary Butyl ester (6A)

Compound 5B (0.40 g, 0.84 mmol, 1.0 eq) was dissolved in methanol (20 mL), and 10% palladium on carbon (0.050 g) was added. The resulting mixture was stirred under a hydrogen atmosphere at 30 degrees Celsius for 12 hours. The reaction solution was filtered to remove palladium carbon, and the solvent was distilled off under reduced pressure. The obtained residue was slurried with a petroleum ether solution containing 10% ethyl acetate and filtered to obtain the solid title compound 6A (0.34 g, yield: 85%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.51 (d, J=5.2 Hz, 1H), 8.40-8.31 (m, 1H), 7.52-7.43 (m, 1H), 7.31 (dd, J= 11.2Hz, 1.2Hz, 1H), 7.22(d, J=5.2Hz, 1H), 7.12(d, J=8.0Hz, 1H), 6.24(s, 2H), 4.18-3.81(m, 4H), 3.17 (s,1H),2.44(s,3H),1.70-1.59(m,2H),1.53(d,J=12.8Hz,2H),1.40(s,9H)

The second step 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(piperidin-4-yl)pyrimidin-4-amine hydrochloride (6B )

Compound 6A (0.30 g, 0.62 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), and 4M hydrochloric acid dioxane solution (1 mL) was slowly added dropwise at 0 degrees Celsius. The resulting mixture was stirred at 25 degrees Celsius for 1 hour. The reaction solution was evaporated under reduced pressure to remove the solvent to obtain the title compound 6B (0.39 g, crude product) as a solid.

MS(ESI+)m/z=381.2[M+H].

The third step 1-(2-methacryloyl)-(4-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidine- 4-yl)piperidine (6)

Compound 6B (0.39g, 0.94mmol, 1.0eq) and triethylamine (0.28g, 1.2mmol, 0.16mL, 3.0eq) were dissolved in dichloromethane (5mL), and methpropylene was slowly added dropwise at 0 degrees Celsius Acid chloride (98 mg, 0.94 mmol, 1.0 eq). The resulting mixture was stirred at 25 degrees Celsius for 1 hour. The reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by preparative chromatography (Waters Xbridge C18, 20-70% acetonitrile aqueous solution (containing 0.01% ammonia water)) to obtain the title compound 6 (0.075 g, yield: 18%) as a white solid. .

MS(ESI+)m/z=449.2[M+H].

¹ H NMR (400 MHz, DMSO-d ₆ ): δ=8.51 (d, J=5.2 Hz, 1H), 8.37 (s, 1H), 7.49 (t, J=8.4 Hz, 1H), 7.38-7.27 (m ,1H),7.22(d,J＝5.2Hz,1H),7.13(d,J＝8.0Hz,1H),6.28(s,2H),5.14(s,1H),4.93(s,1H),4.37 (s,1H),3.87(s,1H),2.99-2.74(m,1H),2.64-2.55(m,1H),2.45(s,3H),1.85(s,3H),1.76-1.54(m ,5H)

Example 7

6-(4-Propynamidophenyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-aminopyrimidine (7)

The first step 6-(4-aminophenyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-aminopyrimidine (7A)

Compound 1I (6.0 g, 18.1 mmol), compound 1A (4.0 g, 18.1 mmol), palladium tetrakistriphenylphosphine (2.1 g, 1.81 mmol) and potassium carbonate (5.0 g, 36.2 mmol) were mixed in dioxane (80 mL) and water (8 mL). The resulting mixture was stirred under a nitrogen atmosphere at 100 degrees Celsius for 2 hours. The reaction solution was cooled and evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (the elution phase was a mixed solvent of dichloromethane containing 0-10% methanol) to obtain the title compound 7A (6.0 g, yield: 85%) as a brown solid. %). MS(ESI+)m/z=389.2[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ): δ=8.56-8.46 (m, 1H), 8.38 (s, 1H), 7.69-7.49 (m, 1H), 7.35 (t, J=8.4Hz, 1H) ,7.22-7.15(m,2H),7.01(d,J=8.4Hz,2H),6.37(d,J=8.4Hz,2H),5.33(s,2H),2.44(s,3H)

The second step 6-(4-Propynamidophenyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-aminopyrimidine (7)

Compound 7B (54 mg, 0.77 mmol) was dissolved in dichloromethane (5 mL), and bis(2-oxo-3-oxazolidinyl)phosphine chloride (0.26 g, 1.0 mmol) was slowly added dropwise at 0 degrees Celsius, Compound 7A (0.20 g, 0.51 mmol) and N,N-diisopropylethylamine (0.26 g, 2.0 mmol). The resulting mixture was stirred at 0 degrees Celsius for 1 hour. The reaction solution was distilled under reduced pressure to remove the solvent, and the obtained crude product was purified by preparative chromatography (Waters Xbridge C18, 20-70% acetonitrile aqueous solution (containing 0.01% ammonia water)) to obtain the title compound 7 (23 mg, yield: 10%).

MS(ESI+)m/z=441.1[M+H].

¹ H NMR (400 MHz, DMSO-d ₆ ): δ=10.85 (s, 1H), 8.49 (d, J=5.2 Hz, 1H), 8.45 (s, 1H), 7.47 (d, J=8.8 Hz, 2H) ),7.33(t,J＝8.4Hz,1H),7.27-7.14(m,4H),6.98(dd,J＝8.4,1.6Hz,1H),6.52(s,2H),4.43(s,1H) ,2.42(s,3H).

Example 8

The following compounds 8-14 can be synthesized through the similar synthetic route and procedure of Example 7, in the second step, the starting material A in the table below is used to replace the starting material 7B.

Example 9

Through the similar synthetic route and procedure of Example 7, in the first step, the starting material B in the following table is used to replace the starting material 1A, and the starting material C is used to replace the propynoic acid 7B in the second step to synthesize the corresponding compounds 15-26 below.

Wherein the synthetic route of compound 23A is as follows:

Compound 23A can be synthesized using a similar synthetic procedure to compound 3D in the second step in Example 3. MS(ESI+)m/z=263.2[M+H].

Example 10

Through the similar synthetic route and steps of Example 5, in the first step, replace 5A with different raw materials D in the following table, and in the third step, replace methacryloyl chloride with acryloyl chloride, the corresponding compound 27 in the following table can be synthesized -29.

Example 11

N-(4-(6-Amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)ethylenesulfonamide (30 )

Compound 7A (150 mg, 0.39 mmol) and pyridine (122 mg, 1.54 mmol) were dissolved in dichloromethane (5 mL), and chloroethylsulfonyl chloride 30A (69 mg, 0.42 mmol) was slowly added dropwise at 0 degrees Celsius. The resulting mixture was stirred at 0 degrees Celsius for 3 hours. The reaction solution was distilled under reduced pressure to remove the solvent, and the obtained crude product was purified by preparative chromatography (Phenomenex Luna C ₁₈ 100*30mm*5um, 5-35% acetonitrile aqueous mobile phase) to obtain the title compound 30 (13 mg, yield: 7.3%).

MS(ESI+)m/z=479.2[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.17(s, 1H), 8.49(d, J=5.2Hz, 1H), 8.43(s, 1H), 7.32(t, J=8.4Hz, 1H) ,7.23-7.17(m,4H),7.01-6.94(m,3H),6.74(dd,J=16.4,9.6Hz,1H),6.50(s,2H),6.06(d,J=16.4Hz,1H ), 5.97(d, J=9.6Hz, 1H), 2.43(s, 3H).

Example 12

1-(2-(6-Amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-2,7-diaza Spiro[3.5]nonan-7-yl)prop-2-en-1-one (31)

The first step 2-(6-Amino-5-iodopyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (31C)

Compound 31A (0.50 g, 2.2 mmol), compound 31B (1.1 g, 2.3 mmol) and potassium carbonate (0.61 g, 4.4 mmol) were mixed in dioxane (30 mL). The resulting mixture was stirred at 80 degrees Celsius under nitrogen atmosphere for 4 hours. The reaction solution was distilled under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (the elution phase was a mixed solvent of petroleum ether containing 25-50% ethyl acetate) to obtain the title compound 31C (1.04 g, yield: 31C) as a pale yellow solid. 97%).

MS(ESI+)m/z=446.3[M+H].

The second step 2-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-2,7-diaza Spiro[3.5]nonane-7-carboxylate tert-butyl ester (31D)

Compound 31C (0.50 g, 0.92 mmol), compound 1G (0.36 g, 1.1 mmol), palladium acetate (10 mg, 46 μmol), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (38 mg , 92 μmol) and potassium carbonate (0.25 g, 1.84 mmol) were mixed in dioxane (7.5 mL) and water (0.75 mL). The resulting mixture was stirred under nitrogen at 85 degrees Celsius for 12 hours. The reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (the elution phase was a mixed solvent of dichloromethane containing 0-10% methanol) to obtain the title compound 31D (60 mg, yield: 12%) as a brown solid. .

MS(ESI+)m/z=522.1[M+H].

The third step 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(2,7-diazaspiro[3.5]nonan-2-yl )-4-aminopyrimidine (31E)

Compound 31D (60 mg, 0.11 mmol) was dissolved in dichloromethane (2 mL), and 4M hydrochloric acid dioxane solution (1.0 mL) was slowly added dropwise at 0 degrees Celsius. The resulting mixture was stirred at 25 degrees Celsius for 1 hour. The reaction solution was evaporated under reduced pressure to remove the solvent to obtain a solid hydrochloride of the title compound 31E (80 mg, crude product).

MS(ESI+)m/z=422.1[M+H].

The fourth step 1-(2-(6-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-2,7- Diazaspiro[3.5]nonan-7-yl)prop-2-en-1-one (31)

Compound 31E (32 mg, 75 μmol) and triethylamine (32 mg, 0.32 mmol) were dissolved in dichloromethane (5 mL), and a dichloromethane solution of acryloyl chloride 4B (5.8 mg, 64 μmol, 64 uL) was slowly added dropwise at 0 degrees Celsius. , 1.0mol/L). The resulting mixture was stirred at 25 degrees Celsius for 1 hour. The reaction solution was distilled under reduced pressure to remove the solvent, and the obtained residue was purified by preparative chromatography (Phenomenex Luna C ₁₈ 150*25mm*10um, the elution phase was 3%-33% acetonitrile-water (containing 0.1% TFA)) to obtain a white solid The title compound 31 (11 mg, yield: 30%).

MS(ESI+)m/z=476.2[M+H].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.47 (d, J=5.2 Hz, 1H), 7.98 (s, 1H), 7.40 (t, J=8.4 Hz, 1H), 7.27 (dd, J= 11.2,1.6Hz,1H),7.18(d,J=5.2Hz,1H),7.12(dd,J=8.4,1.2Hz,1H),6.76(dd,J=16.4,10.4Hz,1H),6.05( dd, J=16.4, 2.4Hz, 1H), 5.79(br s, 2H), 5.65-5.60(m, 1H), 3.41-3.34(m, 8H), 2.37(s, 3H), 1.55(br s, 4H).

Example 13

Through the similar synthetic route and steps of Example 12, in the first step, the different starting materials E in the following table are used to replace 31A, and the corresponding compounds 32-43 in the following table can be synthesized.

Example 14

N-(1-(6-Amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)azetidin-3- base) ethylene sulfonamide (44)

Compound 44 was synthesized via a synthetic route and procedure analogous to Example 12, substituting 34A for 31A in the first step and 2-chloroethylsulfonyl chloride 30A for acryloyl chloride 4B in the fourth step.

MS(ESI+)m/z=458.1[M+H].

¹ HNMR (400MHz, DMSO-d ₆ )δ8.48(d,J=5.2Hz,1H),8.24-7.72(m,2H),7.41(t,J=8.4Hz,1H),7.33-7.16(m ,2H),7.09(d,J＝8.8Hz,1H),6.67(dd,J＝16.8,9.6Hz,1H),5.99(d,J＝16.4 Hz,1H),5.91(d,J＝9.6Hz ,1H),5.85(s,2H),3.89(d,J=4.8Hz,1H),3.71(t,J=8.0Hz,2H),3.56-3.45(m,2H),2.41(s,3H) .

Example 15

Using compound 34E as a raw material, the synthesis method of the second step in Example 7 was adopted, and 7B was replaced with the raw material C in the following table to synthesize the corresponding compounds 45-48.

Example 16

The corresponding compounds 49-55 were synthesized by the similar synthetic methods and steps in Example 1, replacing 1H in the fourth step with the starting material F in the following table.

The raw material 54B of compound 54 was synthesized from 54A by the following steps.

54A (500 mg, 3.3 mmol) was dissolved in 10 mL of dichloromethane, and iodine chloride (1.6 g, 10 mmol) was slowly added dropwise at 0 degrees Celsius under nitrogen atmosphere. The resulting reaction solution was reacted at room temperature for 1 hour, quenched by adding 5 mL of saturated sodium sulfite solution, and extracted by adding 25 mL of dichloromethane. The organic phase was dried with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column (the elution phase was 0-100% ethyl acetate in petroleum ether) to obtain compound 54B (410 mg, yield: 45%). %).

Example 17

N-(4-(6-Amino-5-(4-((S)-2-cyanopyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)pyrimidin-4-yl)phenyl )-2-butynamide (55)

The first step Ethyl 4-(4-amino-6-chloropyrimidin-5-yl)cyclohex-3-ene-1-carboxylate (55B)

4-Amino-6-chloro-5-iodopyrimidine 1H (2.0 g, 7.8 mmol), compound 55A (2.6 g, 9.4 mmol), [1,1'-bis(diphenylphosphino)ferrocene]bis Palladium chloride (0.57 g, 0.78 mmol) and potassium carbonate (2.2 g, 16 mmol) were dissolved in dioxane (20 mL) and water (2 mL), and the reaction was stirred at 100° C. for 2 hours after nitrogen replacement three times. After cooling the reaction solution, 20 mL of saturated ammonium chloride solution was added and extracted with 40 mL of ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by column chromatography (elution phase was petroleum ether containing 50% ethyl acetate) to obtain solid compound 55B (1.1 g, yield : 50%).

¹ H NMR (400MHz, DMSO-d ₆ )δ8.09(s,1H),7.56-6.28(m,2H),5.67(s,1H),4.16-4.03(m,2H),2.99-2.57(m ,1H),2.41-1.87(m,6H),1.20(t,J＝7.2Hz,3H)

The second step 4-(4-amino-6-(4-nitrophenyl)pyrimidin-5-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester (55D)

Compound 55B (1.1 g, 3.9 mmol), 4-nitrophenylboronic acid 55C (0.78 g, 4.7 mmol), tetrakis(triphenylphosphine)palladium (0.45 g, 0.39 mmol) and potassium carbonate (1.1 g, 7.8 mmol) were combined ) was dissolved in dioxane (15 mL) and water (1.5 mL), replaced with nitrogen three times, and then placed at 100° C. to stir for 2 hours. After cooling the reaction solution, 20 mL of saturated ammonium chloride solution was added and extracted with 40 mL of ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (elution phase was 50% ethyl acetate in petroleum ether) to obtain compound 55D (0.39 g, yield: 27%).

MS(ESI+)m/z=368.2[M+H].

The third step 4-(4-amino-6-(4-aminophenyl)pyrimidin-5-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester (55E)

Compound 55D (0.36 g, 1.0 mmol) was dissolved in 10 mL of methanol, iron powder (0.56 g, 10 mmol) and 2 mL of saturated ammonium chloride solution were added. The mixture was stirred at room temperature under nitrogen for 16 hours. The resulting mixture was filtered through celite, and the filter cake was washed with 40 mL of ethyl acetate. To the obtained filtrate, 20 mL of saturated sodium chloride solution was added, and another 20 mL of ethyl acetate was added for extraction. The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (elution phase was 50%-100% ethyl acetate in petroleum ether) to give solid 55E (0.21 g, yield: 62%).

MS(ESI+)m/z=339.2[M+H].

The fourth step 4-(4-amino-6-(4-(-2-butynoylamino)phenyl)pyrimidin-5-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester (55G)

Compound 55E (0.21 g, 0.58 mmol) and N,N-diisopropylethylamine (0.23 g, 1.8 mmol) were dissolved in 3 mL of dichloromethane, and 2-butynoyl chloride 55F (55 mg) was added at 0 degrees Celsius , 0.55mmol). The resulting mixture was stirred at 0 degrees Celsius for 1 hour. The obtained reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by C ₁₈ reverse-phase chromatography (the elution phase was an aqueous solution containing 5-80% acetonitrile), and lyophilized to remove the solvent to obtain compound 55G (0.19 g, yield: 81%) ).

MS(ESI+)m/z=405.2[M+H].

The fifth step 4-(4-amino-6-(4-(-2-butynoylamino)phenyl)pyrimidin-5-yl)cyclohex-3-ene-1-carboxylic acid (55H)

Compound 55G (0.19 g, 0.47 mmol), lithium hydroxide (23 mg, 0.95 mmol) were mixed in tetrahydrofuran (2 mL) and water (0.5 mL). After the resulting mixture was stirred at room temperature for 1 hour, dry ice (5 g) was added to the reaction solution. The resulting mixture was concentrated under reduced pressure to give crude compound 55H (0.24 g).

MS(ESI+)m/z=377.2[M+H].

The sixth step N-(4-(6-amino-5-(4-((S)-2-cyanopyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)pyrimidin-4-yl )phenyl)-2-butynamide (55)

2-(7-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (57 mg, 0.15 mmol) was added to crude 55H (48 mg, about 0.1 mmol) of N,N-dimethylformamide (1 mL), then N,N-diisopropylethylamine (39 mg, 0.3 mmol) and (S)-2-cyanopyrrolidine 55I (20 mg, 0.21 mmol) were added. mmol). The resulting solution was stirred at room temperature for 2 hours. The mixture was filtered and purified by preparative high performance liquid phase (Waters Xbridge C18, 20-60% acetonitrile in water containing 0.01% ammonia) to give the title compound 55 (3.6 mg, yield: 7.9%).

MS(ESI+)m/z=455.2[M+H].

¹ H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.31(s,1H),7.62(d,J=8.6Hz,4H),6.63(s,2H),5.76(s,1H) ), 4.72(dt, J＝7.6, 3.9Hz, 1H), 3.69(s, 4H), 2.34-2.10(m, 4H), 2.06(m, 4H), 1.71(m, 2H), 1.24(m, 2H),0.96(m,2H).

Example 18-1

Following a similar route and procedure in Example 17, compound 55A in the first step was replaced with different starting materials G in the following table, 2-butynoyl chloride 55F was replaced with acryloyl chloride 4B in the fourth step, and 2-butynoyl chloride 55F was replaced in the sixth step with Substituting starting material H in the table below for 55I, the corresponding compounds 56-59 in the table were synthesized.

Example 18-2

N-(3-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl )amino)pyrimidin-4-yl)phenyl)acryloylamide (60)

The first step 2,4-dichloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidine (60B)

2,4-Dichloro-5-iodopyrimidine 60A (5.0 g, 18 mmol), compound 1G (6.0 g, 18 mmol), potassium carbonate (5.0 g, 36 mmol) and (diphenylphosphinoferrocene) dichloride Palladium (0.70 g, 0.91 mmol) was added to a mixed solvent of dioxane (50 mL) and water (5 mL), and the reaction was stirred at 100° C. for 2 hours after nitrogen replacement three times. The reaction solution was quenched with 20 mL of ammonium chloride and then extracted with 100 mL of ethyl acetate. The separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=4/1-2/1) to obtain compound 60B (2.9 g, yield: 45%).

MS(ESI+)m/z=351.0[M+H].

The second step 2-chloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-(3-nitrophenyl)pyrimidine (60D)

Compound 60B (2.1 g, 6.0 mmol), 3-nitrophenylboronic acid 60C (1.0 g, 6.0 mmol), potassium carbonate (1.7 g, 12.0 mmol) and tetrakistriphenylphosphonium palladium (0.35 g, 0.30 mmol) were added It was placed in a mixed solvent of dioxane (20 mL) and water (2 mL), replaced with nitrogen three times, and then stirred at 100° C. for 2 hours. The reaction solution was quenched with 20 mL of ammonium chloride, and then 50 mL of ethyl acetate was added for extraction, and the obtained organic phase was separated and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=2/1-1/1) to obtain compound 60D (1.0 g, yield: 38%).

MS(ESI+)m/z=438.1[M+H].

¹ H NMR (400MHz, DMSO-d ₆ )δ9.05(s, 1H), 8.52(d, J=5.2Hz, 1H), 8.39-8.31(m, 2H), 7.87(d, J=8.0Hz, 1H), 7.79-7.71(m, 1H), 7.53-7.43(m, 2H), 7.30-7.20(m, 2H), 2.48-2.44(m, 3H).

The third step 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)-4- (3-Nitrophenyl)pyrimidin-2-amine (60F)

Compound 60D (0.40 g, 0.91 mmol), 1-methyl-1H-pyrazol-4-amine 60E (0.17 g, 1.8 mmol), cesium carbonate (0.88 g, 2.7 mmol), 1,1'-binaphthyl -2,2'-Bisdiphenylphosphine (57 mg, 0.091 mmol) and palladium acetate (20 mg, 0.091 mmol) were added to dioxane (20 mL), nitrogen was replaced three times, and the reaction was stirred at 100° C. for 2 hours. The reaction solution was quenched with 20 mL of ammonium chloride, and then 50 mL of ethyl acetate was added for extraction, and the obtained organic phase was separated and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=2/1-0/1) to obtain compound 60F (0.20 g, yield: 44%)

MS(ESI+)m/z=499.1[M+H].

The fourth step 4-(3-aminophenyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-(1-methyl-1H- Pyrazol-4-yl)pyrimidin-2-amine (60G)

Compound 60F (0.18 g, 0.36 mmol) was dissolved in 5 mL of methanol, iron powder (0.2 g, 3.6 mmol) and 1 mL of saturated ammonium chloride solution were added. The mixture was stirred at room temperature under nitrogen for 16 hours. The resulting mixture was filtered through celite, and the filter cake was washed with 20 mL of ethyl acetate. 10 mL of saturated sodium chloride solution was added to the obtained filtrate, and another 20 mL of ethyl acetate was added for extraction. The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by _C18 reverse phase column (mobile phase was 5-80% acetonitrile in water) and lyophilized to remove solvent to give solid 60G (80 mg, yield: 47%). MS(ESI+)m/z=469.2[M+H].

The fifth step N-(3-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazole- 4-yl)amino)pyrimidin-4-yl)phenyl)acrylamide (60)

Compound 60G (70 mg, 0.15 mmol) and triethylamine (45 mg, 0.45 mmol) were dissolved in dichloromethane (5 mL), and a dichloromethane solution of acryloyl chloride 4B (13 mg, 0.15 mmol, 150uL, 1.0mol/L). The resulting mixture was stirred at 0 degrees Celsius for 1 hour. The reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by preparative chromatography (Phenomenex Luna C18 150*25mm*10um, the elution phase was 3%-55% acetonitrile-water) to obtain the title compound 60 (20 mg, collected as a white solid). rate: 26%).

MS(ESI+)m/z=523.2[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.27(s, 1H), 9.75(s, 1H), 8.53(s, 1H), 8.46(d, J=4.8Hz, 1H), 8.43-7.80( m, 2H), 7.60(s, 1H), 7.53(s, 1H), 7.33-7.20(m, 3H), 7.18(d, J=5.2Hz, 1H), 7.03(d, J=8.0Hz, 1H) ),6.91(d,J＝7.6Hz,1H),6.53-6.39(m,1H),6.35-6.19(m,1H),5.77(d,J＝11.2Hz,1H),3.84(s,3H) ,2.41(s,3H).

Example 19

N-(3-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl )amino)pyrimidin-4-yl)phenyl)methacryloylamide (61)

Using compound 60G as raw material, compound 61 was synthesized by a similar synthetic method as in the fifth step in Example 18-2, substituting 61A for acryloyl chloride 4B.

MS(ESI+)m/z=537.1[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.94(s, 1H), 9.76(s, 1H), 8.52(s, 1H), 8.46(d, J=5.2Hz, 1H), 8.0(s, 2H), 7.60(s, 1H), 7.51(s, 1H), 7.32-7.16(m, 4H), 7.03(d, J=8.0Hz, 1H), 6.86(d, J=6.8Hz, 1H), 5.82(s, 1H), 5.54(s, 1H), 3.85(s, 3H), 2.41(s, 3H), 1.96(s, 3H).

Example 20

N-(3-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl )amino)pyrimidin-4-yl)phenyl)propionylamide (62)

Using compound 60G as raw material, compound 62 was synthesized by a similar synthetic method as in the fifth step in Example 18-2, substituting 62A for acryloyl chloride 4B.

MS(ESI+)m/z=525.1[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.98(s, 1H), 9.73(s, 1H), 8.52(s, 1H), 8.47(d, J=5.2Hz, 1H), 8.09(s, 2H), 7.52-7.51(m, 1H), 7.52(s, 1H), 7.36-7.13(m, 4H), 7.02(d, J=8.0Hz, 1H), 6.84(d, J=7.2Hz, 1H) ),3.84(s,3H),2.42(s,3H),2.38-2.29(m,2H),1.19-1.04(m,3H).

Example 21

2-Fluoro-N-(3-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazole -4-yl)amino)pyrimidin-4-yl)phenyl)acrylamide (63)

Using compound 60G as raw material, adopt the similar synthetic method of the second step in Example 7, replace 7B with 63A, and use 2-(7-azabenzotriazole)-N,N,N',N'-tetrazolium Methylurea hexafluorophosphate was used to replace bis(2-oxo-3-oxazolidinyl)phosphine chloride, and the reaction was carried out at room temperature for 1 hour to synthesize compound 63.

MS(ESI+)m/z=541.1[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.44 (d, J=4.4 Hz, 1H), 9.77 (s, 1H), 8.53 (s, 1H), 8.46 (d, J=5.2 Hz, 1H) ,8.13(s,2H),7.66(d,J=7.2Hz,1H),7.53(s,1H),7.34-7.15(m,4H),7.09-6.90(m,2H),5.83-5.63(m ,1H),5.45(dd,J=3.6,15.5Hz,1H),3.84(s,3H),2.41(s,3H).

Example 22

N-(3-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl )amino)pyrimidin-4-yl)2-methylphenyl)acryloylamide (64)

Compound 64 was synthesized using a similar synthetic procedure and method following the second step in Example 18-2, substituting 64A for 60C.

MS(ESI+)m/z=537.2[M+H].

¹ H NMR (400MHz, DMSO-d ₆ )δ9.76(s,1H), 9.52(s,1H), 8.59(s,1H), 8.44(d, J=5.2Hz,1H), 8.02-7.70( m, 1H), 7.64-7.43(m, 2H), 7.28-7.19(m, 2H), 7.16(d, J=5.2Hz, 1H), 7.14-7.05(m, 2H), 6.94(d, J= 8.0Hz, 1H), 6.52(dd, J＝10.4, 16.6Hz, 1H), 6.23(d, J＝17.2Hz, 1H), 5.73(d, J＝10.4Hz, 1H), 3.80(s, 3H) ,2.39(s,3H),1.92(s,3H).

Example 23

N-(3-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl )amino)pyrimidin-4-yl)2-methoxyphenyl)acryloylamide (65)

Compound 65 was synthesized using a similar synthetic procedure and method following the second step in Example 18-2, substituting 65A for 60C.

MS(ESI+)m/z=553.2[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.79(s, 1H), 9.57(s, 1H), 8.59(s, 1H), 8.44(d, J=5.2Hz, 1H), 8.18(d, J=6.3Hz, 1H), 7.88(s, 1H), 7.53(s, 1H), 7.24-7.14(m, 5H), 6.97(dd, J=1.6, 8.4Hz, 1H), 6.75(dd, J =10.0,17.0Hz,1H),6.25(dd,J=1.8,16.8Hz,1H),5.75-5.68(m,1H),3.81(s,3H),3.44(s,3H),2.38(s, 3H).

Example 24

N-(3-(2-((1-(2-(Dimethylamino)ethyl)-1H-pyrazol-4-yl)amino)-5-(3-fluoro-4-((4-methyl) pyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)acryloylamide (66)

Compound 66 was synthesized using a similar synthetic procedure and method following the third step in Example 18-2, substituting 66A for 60E.

MS(ESI+)m/z=580.3[M+H].

Example 25

N-(3-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-(1-methylpyrrolidin-3-yl) )-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)acryloylamide (67)

Compound 67 was synthesized using a similar synthetic procedure and method following the third step in Example 18-2, substituting 67A for 60E.

MS(ESI+)m/z=592.3[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.27(t, J=5.2Hz, 1H), 9.77(s, 1H), 8.55(s, 1H), 8.47(d, J=5.2Hz, 1H) ,8.22(s,1H),7.67-7.59(m,1H),7.57(s,1H),7.32-7.21(m,3H),7.19(d,J＝4.8Hz,1H),7.03(d,J =6.8Hz,1H),6.94(d,J=8.0Hz,1H),6.52-6.40(m,1H),6.33-6.24(m,1H),5.78(d,J=11.6Hz,1H),4.91 (s, 1H), 2.87-2.80(m, 4H), 2.41(s, 3H), 2.26(s, 5H), 2.05(d, J=6.4Hz, 1H).

Example 26

N-(3-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-(1-methylpiperidin-4-yl) )-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)acryloylamide (68)

Compound 68 was synthesized using a similar synthetic procedure and method following the third step in Example 18-2, substituting 68A for 60E.

MS(ESI+)m/z=605.3[M+H].

Example 27

N-(4-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl )amino)pyrimidin-4-yl)phenyl)acryloylamide (69)

The first step 2,5-dichloro-4-(4-nitrophenyl)pyrimidine (69B)

2,4,5-Trichloropyrimidine 69A (1.8g, 10mmol), p-nitrophenylboronic acid 55C (1.7g, 10mmol), potassium carbonate (2.8g, 20mmol) and (diphenylphosphinoferrocene)di Palladium chloride (0.35 g, 0.46 mmol) was added to a mixed solvent of dioxane (20 mL) and water (2 mL), and after nitrogen replacement three times, the reaction was stirred at 70° C. for 2 hours. The reaction solution was quenched with 20 mL of ammonium chloride and then extracted with 100 mL of ethyl acetate. The separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=4/1-2/1) to obtain compound 69B (1.7 g, yield: 63%).

MS(ESI+)m/z=270.0[M+H].

The second step 5-chloro-N-(1-methyl-1H-pyrazol-4-yl)-4-(4-nitrophenyl)pyrimidin-2-amine (69C)

Compound 69B (0.24 g, 0.91 mmol), 1-methyl-1H-pyrazol-4-amine 60E (0.17 g, 1.8 mmol), cesium carbonate (0.88 g, 2.7 mmol), 1,1'-binaphthyl -2,2'-bisdiphenylphosphine (57 mg, 0.091 mmol) and palladium acetate (20 mg, 0.091 mmol) were added to dioxane (20 mL), nitrogen was replaced three times, and the reaction was stirred at 100° C. for 2 hours. The reaction solution was quenched with 20 mL of ammonium chloride, and then 50 mL of ethyl acetate was added for extraction, and the obtained organic phase was separated and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=2/1-0/1) to obtain compound 69C (0.20 g, yield: 67%)

MS(ESI+)m/z=331.0[M+H].

The third step 5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)-4- (4-Nitrophenyl)pyrimidin-2-amine (69D)

Compound 69C (0.20 g, 0.61 mmol), compound 1G (0.20 g, 0.61 mmol), potassium carbonate (170 mg, 1.2 mmol), palladium acetate (13 mg, 0.06 mmol) and tricyclohexylphosphorus (34 mg, 0.12 mmol) were added It was placed in a mixed solvent of dioxane (20 mL) and water (2 mL), replaced with nitrogen three times, and then stirred at 100° C. for 2 hours. The reaction solution was quenched with 20 mL of ammonium chloride, and then 50 mL of ethyl acetate was added for extraction, and the obtained organic phase was separated and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=2/1-0/1) to obtain compound 69D (0.13 g, yield: 41%).

MS(ESI+)m/z=499.1[M+H].

The fourth step 4-(4-aminophenyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-(1-methyl-1H- Pyrazol-4-yl)pyrimidin-2-amine (69E)

Compound 69D (0.13 g, 0.26 mmol) was dissolved in 5 mL of methanol, iron powder (0.2 g, 3.6 mmol) and 1 mL of saturated ammonium chloride solution were added. The mixture was stirred at room temperature under nitrogen for 16 hours. The resulting mixture was filtered through celite, and the filter cake was washed with 20 mL of ethyl acetate. 10 mL of saturated sodium chloride solution was added to the obtained filtrate, and another 20 mL of ethyl acetate was added for extraction. The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by C18 reverse phase column (mobile phase was 5-80% acetonitrile in water) and lyophilized to remove the solvent to give solid 69E (42 mg, yield: 34%). MS(ESI+)m/z=469.2[M+H].

The fifth step N-(4-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazole- 4-yl)amino)pyrimidin-4-yl)phenyl)acrylamide (69)

Compound 69E (42 mg, 0.09 mmol) and triethylamine (18 mg, 0.18 mmol) were dissolved in dichloromethane (5 mL), and a solution of acryloyl chloride 4B in dichloromethane (7.6 mg, 0.085 mmol) was slowly added dropwise at 0 degrees Celsius. , 85uL, 1.0mol/L). The resulting mixture was stirred at 0 degrees Celsius for 1 hour. The reaction solution was distilled under reduced pressure to remove the solvent, and the obtained residue was purified by preparative chromatography (Phenomenex Luna C18 150*25mm*10um, the elution phase was 3%-55% acetonitrile-water) to obtain the title compound 69 (18 mg, yield) as a white solid. rate: 38%).

MS(ESI+)m/z=523.2[M+H].

¹ H NMR (400MHz, DMSO-d ₆ )δ 10.30(s, 1H), 9.72(s, 1H), 8.49(s, 1H), 8.48(d, J=5.0Hz, 1H), 7.92(s, 1H), 7.67(d, J＝8.4Hz, 2H), 7.49(d, J＝60.8Hz, 3H), 7.31(t, J＝8.4Hz, 1H), 7.26-7.21(m, 1H), 7.19( d,J＝5.1Hz,1H),7.05-6.98(m,1H),6.44(dd,J＝16.9,10.1Hz,1H),6.27(dd,J＝16.9,2.0Hz,1H),5.78(dd , J=10.0, 2.1Hz, 1H), 3.82(s, 3H), 2.43(s, 3H).

Example 28

N-(4-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-methyl-2-((1-methyl-1H-pyridine Azol-4-yl)amino)pyrimidin-4-yl)phenyl)acryloylamide (70)

Compound 70 was synthesized using analogous synthetic procedures and methods following the third step in Example 27, substituting 70A for 69A.

MS(ESI+)m/z=537.2[M+H].

¹ H NMR (400MHz, DMSO-d ₆ )δ 10.17(s, 1H), 9.54(s, 1H), 8.43(d, J=5.0Hz, 1H), 7.57-7.50(m, 2H), 7.48( s, 1H), 7.24 (t, J=8.3Hz, 1H), 7.18 (dd, J=11.4, 2.0Hz, 1H), 7.13 (d, J=5.1Hz, 1H), 6.95 (d, J=8.1 Hz,1H),6.35(dd,J=16.8,10.1Hz,1H),6.19(dd,J=17.0,2.0Hz,1H),5.70(dd,J=10.1,2.1Hz,1H),3.74(s ,3H),2.35(s,3H),2.22(s,3H).

Example 29

N-(4-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-amino-2-((1-methyl-1H-pyrazole -4-yl)amino)pyrimidin-4-yl)phenyl)acrylamide (71)

Compound 71 was synthesized using analogous synthetic procedures and methods following the third step in Example 27, substituting 71A for 69A.

MS(ESI+)m/z=538.2[M+H].

1H NMR (400MHz, DMSO-d6) δ10.22(s,1H), 8.50-8.48(m,1H), 8.19-8.08(m,1H), 7.74-7.51(m,4H), 7.33-7.25(m ,3H),7.20-7.19(m,2H),6.98-6.96(m,1H),6.69-6.66(m,2H),6.45-6.38(m,1H),6.28-6.23(m,1H),5.57 -5.76(m, 1H), 3.80(s, 3H), 2.42(s, 3H).

Example 30

N-(4-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl )amino)pyrimidin-4-yl)phenyl)but-2-ynamide (72)

Using compound 69E as a raw material, a method similar to the fifth step in Example 27 was adopted, and acryloyl chloride 4B was replaced with 2-butynoyl chloride 55F to synthesize compound 72.

MS(ESI+)m/z=535.2[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.71(s, 1H), 9.65(s, 1H), 8.41(d, J=5.0Hz, 2H), 7.85(s, 1H), 7.57-7.44( m, 3H), 7.32(s, 2H), 7.23(t, J=8.4Hz, 1H), 7.19-7.08(m, 2H), 6.97-6.89(m, 1H), 3.75(s, 3H), 2.36 (s,3H),1.98(s,3H).

Example 31

2-Fluoro-N-(4-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazole -4-yl)amino)pyrimidin-4-yl)phenyl)acrylamide (73)

Using compound 69E as starting material, a similar synthetic method as in the second step in Example 7 was adopted, 63A was used instead of 7B, and 2-(7-azabenzotriazole)-N,N,N',N'-tetrazolium was used. Methylurea hexafluorophosphate was substituted for bis(2-oxo-3-oxazolidinyl)phosphine chloride to synthesize compound 73.

MS(ESI+)m/z=541.1[M+H].

¹ H NMR (400MHz, DMSO-d ₆ )δ 10.43(s, 1H), 9.74(s, 1H), 8.51(s, 1H), 8.48(d, J=5.0Hz, 1H), 7.92(s, 1H), 7.74(d, J=8.4Hz, 2H), 7.57(s, 1H), 7.43(s, 2H), 7.31(t, J=8.4Hz, 1H), 7.26-7.21(m, 1H), 7.19(d,J＝5.1Hz,1H),7.01(dd,J＝8.1,1.8Hz,1H),5.73(dd,J＝47.6,3.7Hz,1H),5.46(dd,J＝15.6,3.7Hz ,1H),3.82(s,3H),2.43(s,3H).

Example 32

N-(4-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-(piperidin-4-yl)-1H- Pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)acryloylamide (74)

Compound 74B was synthesized using a similar route and procedure as in Example 27, substituting 74A for 60E in the second step.

Compound 74B (27 mg, 0.039 mmol) was dissolved in 2 mL of dichloromethane and 1 mL of trifluoroacetic acid was added at 0 degrees Celsius. The resulting mixed solution was stirred at 0 degrees Celsius for 1 hour. The solvent and trifluoroacetic acid were removed by concentration under reduced pressure, and the obtained crude product was purified by preparative chromatography (Phenomenex Luna C ₁₈ 150*25mm*10um, elution phase was 3%-55% acetonitrile-water) to obtain compound 74 (8.7 mg, yield : 37%).

MS(ESI+)m/z=592.3[M+H].

Example 33

2-Fluoro-N-(4-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-(piperidin-4-yl )-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)acryloylamide (75)

Compound 75B can be synthesized using a similar route and procedure in Example 27, substituting 74A for 60E in the second step. Compound 75 can be synthesized from compound 75B through two-step reaction.

The first step 4-(4-((5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-(4-(2-fluoroacrylamido) )Phenyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate tert-butyl ester (75C)

Compound 75B (56 mg, 0.088 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (38 mg, 0.10 mmol) and 2 - Fluoroacrylic acid (18 mg, 0.20 mmol) was mixed in a dichloromethane solution, then N,N-diisopropylethylamine (39 mg, 0.30 mmol) was added. The resulting solution was stirred at 0 degrees Celsius for 1 hour. The mixture was filtered and purified by _C18 reverse phase chromatography (elution phase was 20-80% acetonitrile in water) to give compound 75C (26 mg, yield: 42%).

MS(ESI+)m/z=710.3[M+H].

The second step 2-fluoro-N-(4-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-(piperidine- 4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)acryloylamide (75)

Compound 75C (26 mg, 0.037 mmol) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added at 0 degrees Celsius. The resulting mixed solution was stirred at 0 degrees Celsius for 1 hour. The solvent and trifluoroacetic acid were removed by concentration under reduced pressure, and the obtained crude product was purified by preparative chromatography (Phenomenex Luna C ₁₈ 150*25mm*10um, elution phase was 3%-55% acetonitrile-water) to obtain compound 75 (6.1 mg, yield : 27%).

MS(ESI+)m/z=610.2[M+H].

Example 34

N-(4-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl ) amino)pyrimidin-4-yl)-3-methylphenyl)acryloylamide (76)

Referring to the synthetic route and method of Example 27, substituting 76A for 55C, compound 76 was synthesized.

MS(ESI+)m/z=537.2[M+H].

1H NMR (400MHz, DMSO-d6)δ10.19(s,1H), 9.73(s,1H), 8.58(s,1H), 8.46(d,J=5.0Hz,1H), 7.70(m,1H) ,7.49(m,3H),7.23(t,J=8.4Hz,1H),7.15(m,2H),7.12(dd,J=11.7,1.8Hz,1H),6.89(m,1H),6.43( dd,J＝17.0,10.1Hz,1H),6.26(d,J＝18.8Hz,1H),5.76(d,J＝12.0Hz,1H),3.80(s,3H),2.40(s,3H), 2.03(s,3H).

Example 35

N-(4-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl )amino)pyrimidin-4-yl)-3-fluorophenyl)acryloylamide (77)

Referring to the synthetic route and method of Example 27, substituting 77A for 55C, compound 77 was synthesized.

MS(ESI+)m/z=541.2[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.40 (s, 1H), 9.20 (s, 1H), 9.07 (d, J=6.6 Hz, 1H), 8.49 (d, J=5.0 Hz, 1H) ,7.92(s,1H),7.83-7.55(m,2H),7.39(t,J＝8.4Hz,1H),7.32(dd,J＝11.5,2.1Hz,1H),7.24-7.13(m,2H) ), 5.58 (d, J＝3.5Hz, 0.5H), 5.46 (d, J＝3.5Hz, 0.5H), 5.27 (dd, J＝15.6, 3.5Hz, 1H), 4.58–4.51 (m, 1H) ,4.12–4.00(m,2H),3.86–3.74(m,2H),2.42(s,3H).

Example 36

2-Fluoro-N-(4-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazole -4-yl)amino)pyrimidin-4-yl)-3-methylphenyl)acryloylamide (78)

Referring to the synthetic route and method of Example 27, substituting 76A for 55C, and substituting 2-fluoroacryloyl chloride for acryloyl chloride 4B, compound 78 was synthesized.

MS(ESI+)m/z=555.2[M+H].

1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),9.75(s,1H),8.59(s,1H),8.47-8.45(m,1H),7.61-7.9(m,2H), 7.52(s, 1H), 7.25-7.11(m, 5H), 6.94-6.92(m, 1H), 5.78-5.77(m, 0.5H), 5.66-5.65(m, 0.5H), 5.47-5.42(m ,1H),3.80(s,3H),2.40(s,3H).

Example 37

N-(4-(5-(4-((S)-2-cyanopyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-2-((1-methyl-1H- Pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)acryloylamide (79)

Referring to the synthetic route and method of Example 27, substituting 55A for 1G, compound 79A was synthesized. Then, compound 79A was used to replace 55G in Example 17, and compound 79 was synthesized through the synthesis steps and methods of the fifth step and the sixth step in Example 17.

MS(ESI+)m/z=523.2[M+H].

¹ H NMR (400MHz, DMSO-d ₆ )δ10.36(d,J=3.5Hz,1H),9.49(s,1H),8.20(s,1H),7.88(d,J=4.7Hz,1H) ,7.84-7.70(m,4H),7.52(s,1H),6.54-6.38(m,1H),6.35-6.20(m,1H),5.86-5.73(m,2H),4.73(ddd,J= 7.4, 5.2, 3.6Hz, 1H), 3.80(s, 3H), 3.74-3.61(m, 1H), 3.51(dt, J=16.3, 7.6Hz, 1H), 2.68(d, J=9.1Hz, 1H) ),2.41-1.63(m,10H).

Example 38

N-(3-(5-(4-((S)-2-cyanopyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)-2-((1-methyl-1H- Pyrazol-4-yl)amino)pyrimidin-4-yl)phenyl)acryloylamide (80)

Referring to the synthetic route and method of Example 18-2, substituting 55A for 1G, compound 80A can be synthesized. Then, compound 80A was replaced by 55G in Example 17, and compound 80 was synthesized through the synthesis steps and methods of the fifth step and the sixth step in Example 17.

MS(ESI+)m/z=523.2[M+H].

Example 39

N-(1-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl ) amino)pyrimidin-4-yl)azetidin-3-yl)acryloylamide (81)

The first step (1-(2-chloro-5-bromopyrimidin-4-yl) azetidine-3-yl) tert-butyl carbamate (81C)

2,4-Dichloro-5-bromopyrimidine 81A (2.3 g, 10 mmol), 3-tert-butoxycarbonyl-aminoazetidine 81B (1.7 g, 10 mmol) and N,N-diisopropylethyl The amine (2.6 g, 20 mmol) was mixed in 25 mL of dioxane. The resulting mixture was stirred at 80°C for 1 hour and then concentrated under reduced pressure, and the resulting crude product 81C (6.6 g, about 10 mmol) was directly used in the next step.

MS(ESI+)m/z=363.1,365.1[M+H].

The second step (1-(2-chloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)azetidine-3 -yl) tert-butyl carbamate (81D)

Compound 81C (3.3 g, crude product, about 5.0 mmol), compound 1G (2.0 g, 6.0 mmol), potassium carbonate (2.8 g, 20 mmol) and (diphenylphosphinoferrocene) palladium dichloride (0.38 g, 0.5 mmol) was added to a mixed solvent of dioxane (30 mL) and water (3 mL), and the reaction was stirred at 100° C. for 2 hours after nitrogen replacement three times. The reaction solution was quenched with 20 mL of ammonium chloride, and then extracted with 100 mL of ethyl acetate. The separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=4/1-2/1) to obtain compound 81D (1.7 g, yield: 71%).

MS(ESI+)m/z=487.1[M+H].

The third step (1-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazole-4- (81E)

Compound 81D (0.49 g, 1.0 mmol), 1-methyl-1H-pyrazol-4-amine 60E (0.17 g, 1.8 mmol), cesium carbonate (0.88 g, 2.7 mmol), 1,1'-binaphthyl -2,2'-bisdiphenylphosphine (62 mg, 0.10 mmol) and palladium acetate (22 mg, 0.10 mmol) were added to dioxane (20 mL), nitrogen was replaced three times, and the reaction was stirred at 100 °C for 2 hours. The reaction solution was quenched with 20 mL of ammonium chloride, and then 50 mL of ethyl acetate was added for extraction, and the obtained organic phase was separated and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=2/1-0/1) to obtain compound 81E (0.37 g, yield: 67%).

MS(ESI+)m/z=548.2[M+H].

The fourth step 4-(3-aminoazetidine-1-yl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-( 1-Methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (81F)

Compound 81E (0.37 g, 0.67 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was slowly added at 0 degrees Celsius. The resulting solution was stirred at 0°C for 1 hour and then concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase C ₁₈ column chromatography (elution phase was 5-75% acetonitrile in water (containing 8 mmol/L NH ₃ )) to obtain compound 81F (0.26 g, yield: 87%). MS(ESI+)m/z=448.2[M+H].

The fifth step N-(1-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazole- 4-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acryloylamide (81)

Compound 81F (45 mg, 0.10 mmol) and triethylamine (20 mg, 0.20 mmol) were dissolved in dichloromethane (2 mL), and a dichloromethane solution of acryloyl chloride 4B (9.0 mg, 0.1 mmol) was slowly added dropwise at 0 degrees Celsius. , 100uL, 1.0mol/L). The resulting mixture was stirred at 0 degrees Celsius for 1 hour. The reaction solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was purified by preparative chromatography (Phenomenex Luna C ₁₈ 150*25mm*10um, elution phase was 5%-75% acetonitrile-water) to obtain the title compound 81 (26 mg, 5%-75%) as a white solid. Yield: 52%).

MS(ESI+)m/z=502.2[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.21(s, 1H), 8.72(d, J=6.8Hz, 1H), 8.49(d, J=5.0Hz, 1H), 7.92(s, 1H) ,7.83(s,1H),7.49(s,1H),7.39(t,J=8.3Hz,1H),7.32(dd,J=11.4,2.0Hz,1H),7.24-7.13(m,2H), 6.23-6.01(m, 2H), 5.61(dd, J=9.6, 2.6Hz, 1H), 4.51(d, J=7.4Hz, 1H), 4.08(s, 2H), 3.80(s, 3H), 3.66 (s, 2H), 2.42(s, 3H).

Example 40

N-(1-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl )amino)pyrimidin-4-yl)azetidin-3-yl)-2-butynamide (82)

Using compound 81F as a raw material, a method similar to the fifth step in Example 27 was adopted, and acryloyl chloride 4B was replaced with 2-butynoyl chloride 55F to synthesize compound 82.

MS(ESI+)m/z=514.2[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.13 (s, 1H), 9.05 (d, J=6.7 Hz, 1H), 8.42 (d, J=5.0 Hz, 1H), 7.84 (s, 1H) ,7.75(s,1H),7.42(s,1H),7.31(t,J=8.4Hz,1H),7.24(dd,J=11.5,2.1Hz,1H),7.14-7.06(m,2H), 4.37(s,1H),4.07-3.82(m,2H),3.73(s,3H),3.67-3.44(m,2H),2.35(s,3H),1.88(s,3H).

Example 41

2-Fluoro-N-(1-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazole -4-yl)amino)pyrimidin-4-yl)azetidin-3-yl)acryloylamide (83)

Compound 81F (40 mg, 0.088 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (38 mg, 0.10 mmol) and 2 - Fluoroacrylic acid 63A (18 mg, 0.20 mmol) was mixed in a dichloromethane solution, then N,N-diisopropylethylamine (39 mg, 0.30 mmol) was added. The resulting solution was stirred at 0 degrees Celsius for 1 hour. The mixture was filtered and purified by _C18 reverse phase chromatography (elution phase: 20-70% acetonitrile in water) to give compound 83 (21 mg, yield: 46%). MS(ESI+)m/z=520.2[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.20(s, 1H), 9.07(d, J=6.9Hz, 1H), 8.48(d, J=5.0Hz, 1H), 7.92(s, 1H) ,7.83(s,1H),7.49(s,1H),7.39(t,J=8.4Hz,1H),7.31(dd,J=11.4,2.0Hz,1H),7.23-7.13(m,2H), 5.52(dd,J＝47.9,3.5Hz,1H),5.27(dd,J＝15.6,3.5Hz,1H),4.58(d,J＝7.4Hz,1H),4.06(s,2H),3.94-3.46 (m,5H),2.42(s,3H).

Example 42

The corresponding compounds 84-117 in the table can be synthesized by the similar route and procedure of Example 39, substituting the starting material I in the table below for compound 81B in the first step. Through the similar route and steps of Example 39, when the corresponding compounds 118-119 in the table are synthesized by replacing the compound 81B in the first step with 118A and 119A in the raw material I, it is necessary to replace the trifluoroacetic acid in the reaction solution in the fourth step. The concentration was increased to 50%.

117A and 118A in the raw material I can be synthesized by the following steps:

The first step 1-(tert-butyl) 3-methyl 3-((S)-1-(((R)-tert-butylsulfinyl)amino)ethyl)azetidinyl-1,3 -Dicarboxylate (117D)

Compounds 117B (4.4 g, 20 mmol) and 117C (1.5 g, 10 mmol) were dissolved in 50 mL of anhydrous tetrahydrofuran, and the resulting solution was cooled to minus 78 degrees Celsius. A solution of lithium hexamethyldisilazide (1.0 M solution in tetrahydrofuran, 20 mL, 20 mmol) was slowly added dropwise with stirring, and stirring was continued at minus 78 degrees Celsius for 3 hours. After adding 10 mL of saturated ammonium chloride aqueous solution to the reaction solution to quench, the temperature was slowly raised to room temperature. To the obtained mixture, 100 mL of ethyl acetate and 50 mL of saturated aqueous ammonium chloride solution were added, the separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1-1/1) to obtain compound 117D (2.1 g, yield: 58%). MS(ESI+)m/z=363.2[M+H].

The second step Ester (117E)

Compound 117D (2.1 g, 5.8 mmol) was dissolved in 40 mL of anhydrous tetrahydrofuran, and the resulting solution was cooled to 0 degrees Celsius. Lithium aluminum hydride (0.38 g, 10 mmol) was slowly added to the reaction solution, and the reaction was stirred at 0 degrees Celsius for 2 hours. 10 g of sodium sulfate decahydrate was added to the obtained reaction solution, and the reaction was stirred at 0 degrees Celsius for 1 hour and slowly raised to room temperature, and the stirring was continued for 16 hours. The obtained mixture was filtered under reduced pressure, the filter cake was washed with 50 mL of ethyl acetate, the obtained filtrate was concentrated to obtain the crude product, and the crude product was purified by silica gel column (the elution phase was dichloromethane containing 3% methanol) to obtain the main product 117E (1.2 g, yield 62%).

MS(ESI+)m/z=335.2[M+H].

The third step (S)-6-((R)-tert-butylsulfinyl)-5-methyl-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl ester (117F )

Crude compound 117E (1.2 g, 3.6 mmol) and p-toluenesulfonyl chloride (1.03 g, 5.4 mmol) were dissolved in 20 mL of anhydrous tetrahydrofuran, and sodium hydride (0.7 g, 60%, 17.4 mmol) was slowly added at 0 degrees Celsius. The resulting mixture was stirred at 0 degrees Celsius for 2 hours and then quenched by the slow addition of 20 mL of water. The obtained reaction solution was extracted three times with 30 mL of ethyl acetate, the separated organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1-1/1) to obtain compound 117F (1.0 g, yield: 88%).

MS(ESI+)m/z=317.2[M+H].

The fourth step (R)-5-methyl-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl ester (117A) and (R)-2-((S)-tert-butyl sulfinyl)-1-methyl-2,6-diazaspiro[3.3]heptane (118A)

Compound 117F (0.63 g, 2.0 mmol) was dissolved in 5 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added at 0 degrees Celsius. The resulting reaction solution was stirred at 0 degrees Celsius for 1 hour. The reaction solution was concentrated under reduced pressure at 0 degrees Celsius, and the obtained crude product was purified by C ₁₈ reverse phase column (mobile phase was 0-60% acetonitrile aqueous solution) to obtain compound 117A (63 mg, yield: 15%) and 118A (122 mg, Yield: 28%).

Compound 117A MS (ESI+) m/z=213.2[M+H].

Compound 118A MS (ESI+) m/z=217.2[M+H].

119A was synthesized via a similar synthetic method and procedure to compound 118A, using 119C in place of 117C.

MS(ESI+)m/z=217.2[M+H].

Example 43

Through the similar method and procedure in the first to fourth step in Example 39, the compound 81B in the first step was replaced with the starting material I in the following table, and the similar method and procedure in Example 41 was adopted in the fifth step , the corresponding compounds 120-125 in the table can be synthesized.

Example 44

Through similar methods and steps in Example 39, using the raw material I in the following table to replace the compound 81B in the first step, and using the raw material J in the following table to replace the 60E in the third step, the corresponding compounds in the following table can be synthesized. 126-154.

Example 45

Through similar methods and steps in Example 39, using the raw material I in the following table to replace the compound 81B in the first step, and using the raw material K in the following table to replace the 1G in the second step, the corresponding compound 156- 159.

The synthetic route of compound 158A is as follows

The synthetic steps similar to compound 1G in Example 1 were adopted, in step 1, compound 158B was used to replace compound 1C, compound 158C was replaced with 1D, the reaction solvent was replaced with N,N-dimethylformamide, and the reaction temperature was increased to 130 degrees Celsius After 12 hours of reaction, compound 158A can be synthesized by following a similar step 2. MS(ESI+)m/z=342.0[M+H].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.66 (t, J=7.6 Hz, 1H), 7.36-7.24 (m, 2H), 7.09 (d, J=8.0 Hz, 1H), 6.92 (d, J=7.2Hz, 1H), 6.69(d, J=8.0Hz, 1H), 3.70(s, 3H), 2.26(s, 3H), 1.31(s, 12H).

The synthetic route of compound 159A is as follows

Compound 159A can be synthesized by using a similar synthetic procedure for compound 1G in Example 1, substituting compound 159B for compound 1D in step 1. MS(ESI+)m/z=234.9[M+H].

¹ H NMR (400 MHz, DMSO-d ₆ ) δ=8.66 (d, J=4.8 Hz, 2H), 7.55 (d, J=8.0 Hz, 1H), 7.51 (d, J=11.2 Hz, 1H), 7.41 (t, J=7.2Hz, 1H), 7.32 (t, J=4.8Hz, 1H), 1.31 (s, 12H).

Example 46

(2S)-1-(4-(4-((2S,5R)-4-acryloyl-2,5-dimethylpiperazin-1-yl)-2-((1-methyl-1H- Pyrazol-4-yl)amino)pyrimidin-5-yl)cyclohex-3-ene-1-carbonyl)pyrrolidine-2-carbonitrile (162)

Referring to the synthetic route and method of Example 39, substituting 162A for 81B and substituting 55A for 1G, compound 162F was synthesized.

Then, compound 162F was used to replace 55G in Example 17, and compound 162 was synthesized through the synthesis steps and methods of the fifth step and the sixth step in Example 17.

MS(ESI+)m/z=544.3[M+H].

¹ H NMR(400MHz, DMSO-d6)δ9.01(s,1H),7.74-7.72(m,2H),7.44-7.43(m,1H),6.89-6.76(m,1H),6.18-6.13( m,1H),5.76-5.68(m,2H),4.77-4.72(m,1H),4.60-4.41(m,3H),4.16-4.12(m,1H),3.91-3.87(m,1H), 3.79(s, 3H), 3.74-3.70(m, 2H), 3.62-3.55(m, 2H), 2.77-2.58(m, 2H), 2.32-2.26(m, 3H), 2.21-2.15(m, 2H) ),2.05-1.91(m,5H),1.16-1.09(m,3H),1.04-0.96(m,3H).

Example 47

(R)-4-Acryloyl-1-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H- Pyrazol-4-yl)amino)pyrimidin-4-yl)-5-methylpiperazin-2-one (163)

The first step (R)-4-(5-bromo-2-chloropyrimidin-4-yl)-2-methyl-5-carbonylpiperazine-1-carboxylate tert-butyl ester (163B)

Compound 163A (84 mg, 0.4 mmol) was dissolved in 3 mL of dioxane, and sodium hydride (32 mg, 60%, 0.8 mmol) was added with stirring at 0 degrees Celsius. After the resulting mixture was stirred at 0 degrees Celsius for 30 minutes, 2,4-dichloro-5-bromopyrimidine 81A (123 mg, 0.5 mmol) was added and stirring was continued at 0 degrees Celsius for 1 hour. After the reaction solution was quenched with 1 mL of saturated ammonium chloride solution, 20 mL of saturated sodium chloride solution was added, and extracted three times with 20 mL of ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=10/1-1/2) to obtain compound 163B (89 mg, yield: 55%).

MS(ESI+)m/z=405.0,407.0[M+H].

Substituting compound 163B for 81C, and using similar experimental methods and procedures in the second to fifth steps of Example 39, compound 163 was synthesized.

MS(ESI+)m/z=544.2[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.83(s, 1H), 8.54-8.45(m, 2H), 7.87(s, 1H), 7.54(s, 1H), 7.35(d, J=11.6 Hz, 1H), 7.28(s, 1H), 7.19(d, J=5.0Hz, 2H), 6.72(d, J=64.7Hz, 1H), 5.65(s, 1H), 4.73(d, J=57.0 Hz, 1H), 4.20(d, J=84.4Hz, 3H), 3.86–3.78(m, 3H), 3.70(t, J=20.6Hz, 1H), 2.42(s, 3H), 1.22(s, 4H) ).

Example 48

1-(4-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazol-4-yl )amino)pyrimidin-4-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one (164)

The first step 4-(2-chloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-3,6-dihydropyridine -1(2H)-tert-Butyl carboxylate (164B)

Compound 60B (0.35 g, 1.0 mmol), compound 164A (0.40 g, 1.3 mmol), potassium carbonate (0.34 g, 2.4 mmol) and (diphenylphosphinoferrocene) palladium dichloride (70 mg, 0.10 mmol) were combined It was added to a mixed solvent of dioxane (5 mL) and water (0.5 mL), and the mixture was replaced with nitrogen three times and then placed at 100° C. to stir and react for 2 hours. The reaction solution was quenched with 10 mL of ammonium chloride, and then extracted with 20 mL of ethyl acetate. The organic phase was separated and concentrated to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=2/1-1/1) to obtain compound 164B (270 mg, yield: 54%).

MS(ESI+)m/z=498.2[M+H].

Compound 164 can be synthesized by substituting compound 164B for 81D, and using similar experimental methods and procedures in the third to fifth steps of Example 39.

MS(ESI+)m/z=513.2[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.65(s, 1H), 8.49(d, J=5.0Hz, 1H), 8.42(s, 1H), 7.88(s, 1H), 7.53(s, 1H), 7.39(t, J＝8.3Hz, 2H), 7.30–7.14(m, 2H), 6.86(dd, J＝16.6, 10.4Hz, 1H), 6.12(dd, J＝16.6, 2.4Hz, 1H) ), 5.86(s, 1H), 5.68(d, J=10.4Hz, 1H), 4.16–3.97(m, 2H), 3.82(s, 3H), 3.66(s, 2H), 2.48–2.29(m, 5H).

Example 49

Through the similar method and steps in the synthesis of compound 164, the corresponding compounds 165-166 in the following table were synthesized by substituting the starting material L in the following table for 164A in the first step.

Example 50

N-(3-(2-Amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)acryloylamide (167 )

The first step: 3-(2-chloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)aniline (167B)

Compound 60B (3.0 g, 8.5 mmol), compound 167A (1.9 g, 8.5 mmol) and (diphenylphosphinoferrocene) palladium dichloride (0.38 g, 0.51 mmol), potassium carbonate (2.4 g, 17 mmol) Dissolved in dioxane (35 mL) and water (3.5 mL). The resulting mixture was reacted at 100°C for 2 hours in a nitrogen atmosphere, and then concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=4/1-2/1) to obtain compound 167B (0.40 g, 0.98 mmol, yield: 11%).

MS(ESI+)m/z=407.9[M+H].

Step 2: 4-(3-Aminophenyl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-2-amine (167C)

Compound 167B (0.4 g, 0.98 mmol) was placed in a pressure-resistant reaction tube, and a methanol solution of ammonia (7 mol/L, 6 mL) was added. The resulting solution was reacted under closed stirring at 60 degrees Celsius for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate=3/1-1/2) to obtain compound 167C (0.11 g, 0.28 mmol, yield: 29%).

MS(ESI+)m/z=389.2[M+H].

The third step: N-(3-(2-amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)propene Acylamide (167)

Compound 167C (0.10 g, 0.26 mmol) was dissolved in dichloromethane (3 mL) and triethylamine (78 mg, 0.77 mmol) was added. Acryloyl chloride (19 mg, 0.21 mmol) was added at 0°C. The reaction was stirred at 0°C for 1 hour. The reaction solution was concentrated, and the crude product was purified by preparative high performance liquid chromatography (mobile phase was 25%-55% acetonitrile aqueous solution (containing 0.1% formic acid)) to obtain solid compound 167 (17 mg, yield: 15%).

MS(ESI+)m/z=443.0[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.20(s, 1H), 8.45(d, J=5.2Hz, 1H), 8.36(s, 1H), 7.83(s, 1H), 7.72-7.66( m,1H),7.23(dt,J=8.2,6.4Hz,2H),7.19-7.11(m,2H),6.98-6.85(m,4H),6.47-6.38(m,1H),6.29-6.20( m,1H),5.78-5.72(m,1H),2.40(s,3H).

Example 51

N-(3-(2-Amino-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)-2-methylphenyl) Acryloylamide (168)

Compound 168 was synthesized using a synthetic method and procedure similar to Example 50, substituting compound 168A for compound 167A.

MS(ESI+)m/z=457.0[M+H].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.49(s, 1H), 8.46(d, J=5.2Hz, 1H), 8.33(s, 1H), 7.72(s, 1H), 7.26(t, J=8.4Hz, 1H), 7.21-7.09(m, 3H), 6.96(d, J=8.2Hz, 1H), 6.92(d, J=8.0Hz, 1H), 6.87(s, 2H), 6.52( dd,J＝17.6,10.4Hz,1H),6.23(dd,J＝16.8,1.6Hz,1H),5.74(d,J＝9.6Hz,1H),2.41(s,3H),2.20(s,3H ).

Example 52

N-(3-(2-Hydroxy-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)phenyl)acryloylamide (169 )

Adopt the synthetic method and steps similar to the second step and the third step of Example 50, replace the methanol solution of 7mol/L ammonia with dioxane/water (1/1, v /v) solution to synthesize compound 169.

MS(ESI+)m/z=444.1[M+H].

Example 53

By a similar method and procedure in the first to fourth steps in Example 39, the compound 81B in the first step was replaced with the starting material I in the following table, and then in the fifth step, a similar method and procedure in Example 41 was used , using the starting material M in the table below to replace the compound 63A, the corresponding compounds 170-174 in the table can be synthesized.

Example 54

2-Fluoro-N-(5-(5-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H-pyrazole -4-yl)amino)pyrimidin-4-yl)pyridin-3-yl)acrylamide (181)

The first step 5-(2-chloro-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrimidin-4-yl)pyridin-3-amine (181B)

Compound 60B (1.5 g, 4.3 mmol), compound 181A (0.94 g, 4.3 mmol), potassium carbonate (2.2 g, 17 mmol) and (diphenylphosphinoferrocene)palladium dichloride (0.62 g, 0.85 mmol) were combined Combined in 1,4-dioxane (20 mL) and water (2 mL). The resulting mixture was stirred at 100 degrees Celsius for 2 hours under nitrogen atmosphere. Cool to room temperature, add water (50 mL) to the reaction solution, extract with ethyl acetate (100 mL×3), wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product was subjected to preparative high performance liquid chromatography (Waters Xbridge C18, 20-60% acetonitrile aqueous solution (containing 0.01% ammonia water)) to obtain compound 181B (0.67 g, yield: 38%).

MS(ESI+)m/z=409.1[M+H]

The second step 4-(5-aminopyridin-3-yl)-5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-N-(1-methyl) -1H-Pyrazol-4-yl)pyrimidin-2-amine (181C)

Compound 118B (0.52 g, 1.3 mmol), compound 60E (0.24 g, 2.5 mmol), p-toluenesulfonic acid (0.22 g, 1.3 mmol) were dissolved in N-methylpyrrolidone (4 mL). The resulting mixture was placed in a microwave at 140°C and stirred for 1 hour. Cool to room temperature, add water (50 mL) to the reaction solution, extract with ethyl acetate (100 mL×3), wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product. The crude product was subjected to preparative high performance liquid chromatography (Waters Xbridge C18, 20-60% acetonitrile aqueous solution (containing 0.01% ammonia water)) to obtain compound 181C (67 mg, yield 11%).

MS(ESI+)m/z=470.3[M+1].

The third step 2-fluoro-N-(5-(5-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-((1-methyl-1H -Pyrazol-4-yl)amino)pyrimidin-4-yl)pyridin-3-yl)acryloylamide (181)

Compound 181C (10 mg, 0.021 mmol) was dissolved in dichloromethane (2 mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluoro was added Phosphate (16 mg, 0.042 mmol), compound 63A (1.9 mg, 0.021 mmol) and N,N-diisopropylethylamine (8.1 mg, 0.063 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction solution was distilled to remove the solvent under reduced pressure, and the obtained crude product was purified by preparative high performance liquid chromatography (Waters Xbridge C18, 20-60% acetonitrile aqueous solution (containing 0.01% ammonia water)) to obtain compound 181 (2.4 mg, yield: 21%) ).

MS(ESI+)m/z=542.2[M+H].

¹ H NMR (400MHz, DMSO-d ₆ )δ10.70(s,1H), 9.86(s,1H), 8.82(s,1H), 8.80-8.61(m,1H), 8.58(s,1H), 8.46(d, J=5.2Hz, 1H), 8.15(s, 1H), 8.06(s, 1H), 7.54(s, 1H), 7.38-7.26(m, 2H), 7.19(d, J=5.2Hz) ,1H),7.06(d,J＝6.4Hz,1H),5.85-5.68(m,1H),5.51(dd,J＝15.2,3.6Hz,1H),3.84(s,3H),2.42(s, 3H).

Biological evaluation

The following is further described and explained in the present application in conjunction with the test examples, but these examples are not meant to limit the scope of the present application.

Test Example 1. FGFR enzyme inhibition experiment of the compounds of the present invention

The positive control compound BGJ398 used in the experiment was purchased from Selleck as S2183. Test compound samples were dissolved in DMSO, formulated as 10 mM stock solutions, and stored at -30°C.

The enzymatic reaction was carried out using the enzyme reaction kit (FGFR1 Kit No. V2991, FGFR2 kit No. V4060, FGFR3 kit No. VA7459, and the reaction substrate Poly E4Y1) produced by promega company, according to the method recommended by the manufacturer. The reaction product was detected using the ADP detection kit (ADP-Glo ^™ Kinase Assay, product number V9101) produced by promega.

5μL reaction system containing 0.4ng/μL FGFR1 kinase (or 1.4ng/μL FGFR2 (WT (wild type) or V564F mutant) kinase, or 1ng/μL FGFR3 kinase), 0.2μg/μL Poly E4Y1, 5μM ATP and serial dilution of the test compound. The final concentration of DMSO in the reaction system was 1%. Reactions were performed in 384-well plates (Perkinelmer, Cat. 6007290) and all assays were performed in duplicate. In the above system, ATP was added last to initiate the reaction. The above 384-well reaction plate was reacted at 25°C for 60 minutes, then 5 μL of ADP-Glo was added, the reaction was performed at 25°C for 40 minutes, and then 10 μL of detection buffer was added, and the reaction was performed at 25°C for 30 minutes. After the reaction, the Luminescence (fluorescence) value was measured with Perkinelmer Envision. The Luminescence value represents the amount of ADP generated, through high signal (high signal) (Luminescence value with enzyme but no inhibitor), low signal (low signal) (Luminescence value without enzyme), sample signal (sample signal) (additional Luminescence value) The inhibitory rate of kinase activity was calculated using the Luminescence value of enzyme plus inhibitor), and the median inhibitory concentration (IC ₅₀ ) was calculated by XLfit2.0 software (ID Business Solutions Ltd).

Inhibition rate %=(high signal-sample signal)/(high signal-low signal)×100%.

The in vitro activity of the compounds of the examples of the present invention on the wild-type FGFR2 enzyme was determined by the above test, and the measured IC ₅₀ values are shown in Table 1.

Table 1

化合物编号Compound number	IC ₅₀(nM) _IC50 (nM)	化合物编号Compound number	IC ₅₀(nM) _IC50 (nM)	化合物编号Compound number	IC ₅₀(nM) _IC50 (nM)
11	62.662.6	7979	63.963.9	134134	32.332.3
88	69.369.3	8080	5.15.1	135135	8.38.3
1212	85.585.5	8181	9.59.5	136136	59.659.6
1818	92.692.6	8282	124.0124.0	137137	130.6130.6
2020	124.7124.7	8383	164.1164.1	138138	27.427.4
4545	175.4175.4	8484	8.18.1	139139	80.180.1
4747	94.894.8	8989	80.280.2	140140	44.444.4
5050	179.5179.5	9090	40.440.4	141141	154.8154.8
5757	194.8194.8	9393	88.788.7	142142	63.363.3
6060	27.527.5	9696	135.9135.9	143143	47.347.3
6464	9.99.9	9797	137.2137.2	145145	17.717.7
6565	13.213.2	9898	26.126.1	146146	12.612.6
6666	30.230.2	9999	152.0152.0	147147	8.68.6
6767	16.616.6	105105	123.5123.5	148148	42.742.7
6868	18.018.0	109109	8.78.7	149149	48.948.9
6969	23.223.2	114114	69.869.8	150150	179.7179.7
7070	175.2175.2	115115	104.1104.1	156156	72.972.9
7171	37.837.8	118118	140.4140.4	159159	52.552.5
7272	25.825.8	119119	94.694.6	164164	8.78.7
7474	43.143.1	120120	127.1127.1	167167	178.3178.3
7575	189.6189.6	130130	17.217.2	170170	120.7120.7
7676	11.511.5	132132	34.434.4	174174	56.656.6
7777	11.511.5	133133	151.8151.8	181181	149.0149.0

The in vitro activity of the compounds of the examples of the present invention on the V564F mutant FGFR2 enzyme was determined by the above test, and the measured IC ₅₀ values are shown in Table 2.

Table 2

化合物编号Compound number	IC ₅₀(nM) _IC50 (nM)	化合物编号Compound number	IC ₅₀(nM) _IC50 (nM)	化合物编号Compound number	IC ₅₀(nM) _IC50 (nM)
11	104.2104.2	88	105.2105.2	4343	200.4200.4
5050	125.9125.9	6060	11.611.6	6565	13.413.4
6767	15.615.6	6969	22twenty two	7171	55.755.7

7272	12.512.5	7676	14.614.6	7777	14.814.8
7878	22twenty two	7979	105.2105.2	8080	11.911.9
8181	19.819.8	8484	43.843.8	8989	151.6151.6
9090	19.619.6	9393	61.361.3	9696	131.6131.6
9898	23twenty three	9999	35.235.2	105105	21.121.1
109109	11.111.1	114114	41.441.4	115115	43.643.6
118118	142.1142.1	119119	62.262.2	130130	15.815.8
132132	2525	133133	82.482.4	134134	22.822.8
135135	9.19.1	136136	35.935.9	138138	16.616.6
139139	75.475.4	140140	37.437.4	141141	161.5161.5
142142	146.2146.2	143143	101101	144144	136.4136.4
145145	11.911.9	146146	16.716.7	147147	16.316.3
148148	24twenty four	149149	28.128.1	154154	29.429.4
156156	47.547.5	159159	3434	162162	181.2181.2
163163	201.2201.2	163163	56.156.1	164164	16.616.6
170170	125125	174174	20.420.4	BGJ398BGJ398	>1000>1000

Test Example 2. Cell Proliferation Experiment of Compounds of the Invention

Test compound samples were dissolved in DMSO, formulated as 10 mM stock solutions, and stored at -30°C. Compounds were diluted to 10-fold the assay concentration in serum-free medium containing 5% DMSO for the assay.

The cell SNU-16 in the experiment was purchased from ATCC (American Type Culture Collection, USA, item number

CRL-5974), RT-112 were purchased from cobioer (Nanjing Kebai Biotechnology Co., Ltd., item number CBP60316), KG-1 was purchased from ATCC (item number CCL-246), and JMSU-1 was purchased from DSMZ (item number ACC505) . Medium IMDM was purchased from Gibco (Cat. No. 12440-061), Medium 1640 was purchased from Gibco (Cat. No. 12634-010), and serum was purchased from Gibco (Cat. No. 10099-141C). Cell-counting kit-8 (CK04) was purchased from Tongren Chemical Company.

The Luminescent Cell Viability Assay was purchased from Promega (Cat. No. G7570).

Cells in logarithmic growth phase were seeded in 96-well cell culture plates in a volume of 100 μL. Incubate overnight at 37°C in an incubator containing 5% carbon dioxide. The next day, 10 μL/well of the compound to be tested at gradient dilution was added, and 10 μL/well of serum-free medium containing 5% DMSO was added to the control group to replace the drug diluent, and the final concentration of DMSO was 0.5%. Incubate for 72 hours in an incubator. Add 10 μL/well Cell-counting kit-8 reagent (or 50 μL/well CTG). Incubate at 37°C for 40 minutes in a carbon dioxide incubator and read absorbance at 450 nm (CTG reads Luminescence) on a Perkinelmer Envision. The inhibitory rate of the compound on cell growth was calculated according to the following formula, and the half-proliferation inhibitory concentration (GI ₅₀ ) of the drug was calculated by XLFit2.0 software.

Inhibition rate (%)=[1-([ _OD450 ] _compound- [ _OD450 ] _background )/([ _OD450 ] _cell- [ _OD450 ] _background )]×100%

in:

[OD ₄₅₀ ] _compound represents the optical density value of compound-treated wells;

[OD ₄₅₀ ] _cells represent the optical density values on day 3 of cell wells with DMSO instead of compound;

[OD ₄₅₀ ] _Background represents the optical density value on day 0 of cell wells with DMSO instead of compound;

The compounds of the examples of the present invention were determined by the above tests in the cell proliferation test, and the measured GI ₅₀ values are shown in Table 3.

table 3

"-" means not tested

Test Example 3. Blood Stability Test of the Compounds of the Invention

The compounds of the present invention were evaluated in whole blood by liquid chromatography tandem mass spectrometry (LC/MS/MS) to determine the remaining percentages of test compounds in SD rat or human blood (containing EDTA-K2 anticoagulant) at different time points. stability.

Add 398 μL of blood to the wells of the culture plate and pre-treat for 15 minutes at 37 degrees Celsius. Add 2 μL of the tested compound (1 mmol/L DMSO solution) or positive compound (1 mmol/L DMSO solution) to the pretreated 398 μL blood and mix, so that the final concentration of the tested compound (or positive compound) is 5 μM, the organic solvent The final concentration is 0.5%. Each test compound or positive compound is tested twice. The resulting mixture samples were incubated at 37 degrees Celsius. At 0, 15, 30, 60, 120, and 240 minutes of the reaction, 50 μL samples were taken, and 50 μL of ultrapure water and 400 μL of cold acetonitrile containing the internal standard compound (0.5 μM tolbutamide) were added to stop the reaction. All samples were vortexed for 10 minutes and proteins were pelleted by centrifugation at 3220g for 30 minutes. 200 μL of the supernatant was taken for LC-MS/MS analysis.

All calculations were performed using Microsoft Excel. Peak area ratios were determined from the extracted ion chromatograms. The percent compound remaining at each time point was calculated by the following formula:

Remaining percentage _{t min} (%) = peak area ratio _{t min} / peak area ratio _{0 min} x 100%

Wherein the peak area ratio _tmin is the peak area ratio of the tested compound (or positive compound) and the internal standard compound at the time point of t minute;

Peak area ratio _{0 min} is the peak area ratio of the tested compound (or positive compound) and the internal standard compound at the time point of 0 minutes.

The slope value k was determined by natural log linear regression of the remaining percent of test compound versus incubation time curve.

The in vitro half-life (in vitro t _1/2 ) is determined by the slope value k:

in vitro t _1/2 = -(0.693/k)

The measured half-life of the compounds of the present invention in SD rat or human blood is shown in Table 4.

Table 4. Stability of compounds of the invention in SD rat and human blood

"-" means not tested

Test Example 4. CYP enzyme inhibition test of the compounds of the present invention

150-donor pooled human liver microsomes (purchased from Corning, Cat. No. 452117) were used to assess representative substrate metabolism responses of the five major human CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4). Determination of different concentrations of test compounds for phenacetin (CYP1A2), diclofenac sodium (CYP2C9), S-mephentoin (CYP2C19), bufurolol hydrochloride by liquid chromatography tandem mass spectrometry (LC/MS/MS) Effects of salt (CYP2D6) and midazolam (CYP3A4) on metabolic responses.

30 μM phenacetin, 10 μM diclofenac sodium, 35 μM S-mephenytoin, 5 μM bufurolol hydrochloride, 3 μM midazolam, 1 mM nicotinamide adenine dinucleotide phosphate reduced (NADPH), The test compound (concentrations were 0.1, 0.3, 1, 3, 10, 30 μmol/L) or the reaction system of the positive compound or blank control and mixed human liver microsomes (0.2 mg/mL) 200 μL (100 mmol/L phosphate buffer) solution, pH 7.4, containing 0.3% DMSO, 0.6% acetonitrile, 0.1% methanol by volume respectively) and incubated at 37°C for 5 minutes. Then, 200 μL of acetonitrile solution containing 3% formic acid and 40 nM internal standard verapamil was added and centrifuged at 4000 rpm for 50 minutes. Place on ice to cool for 20 minutes, and then centrifuge at 4000 rpm for 20 minutes to separate out proteins. 200 μL of the supernatant was taken for LC-MS/MS analysis.

Peak areas are calculated from chromatograms. The residual activity ratio (%) is calculated by the following formula:

Peak area ratio = metabolite peak area/internal standard peak area

Residual activity ratio (%) = peak area ratio of the test compound group / peak area ratio of the blank group

CYP median inhibitory concentration (IC ₅₀ ) was calculated by Excel XLfit 5.3.1.3.

Table 5 shows the CYP median inhibitory concentration (IC ₅₀ ) values of the compounds of the present invention.

Table 5. The median inhibitory concentration (IC ₅₀ ) of the compounds of the present invention on CYP

Test example 5, Caco-2 permeability test

The apparent permeability coefficient (P _app ) of the analyzed drugs was determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) by the Caco-2 cell model.

In this test example, Caco-2 cells were purchased from the American Type Culture Collection (ATCC), HEPES was purchased from Beijing Soleibo Technology Co., Ltd., Hank's Balanced Salt Solution (HBSS) and non-essential amino acids (NEAA) were purchased from Sai Merchant Technologies, Penicillin, Streptomycin, and Trypsin/EDTA were purchased from Solebold, Fetal Bovine Serum (FBS) and DMEM medium were purchased from Corning, HTS-96-well Transwell plates and other sterile consumables Purchased from Corning Company, Millicell resistance measurement system was purchased from Millipore,

Purchased from Nexcelom Bioscience, Infinite 200 PRO microplate reader was purchased from Tecan, and MTS2/4 orbital shaker was purchased from IKA Labortechnik.

First step cell culture and seeding

Caco-2 was grown in cell culture flasks. The incubator was set at 37°C, 5% CO ₂ , with a guaranteed relative humidity of 95%. Transwells can be seeded when cells are 70-90% confluent. Before cell seeding, 50 μL of cell culture medium was added to each well of the upper chamber of the Transwell, and 25 mL of cell culture medium was added to the lower plate. Plates can be used to seed cells after 1 hour of incubation in a 37°C, 5% CO ₂ incubator. After cell digestion, transfer the cell suspension to a round bottom centrifuge tube and centrifuge at 120g for 5 minutes. Resuspend cells in medium to a final concentration of 6.86 x 10 ⁵ cells/mL (cells/mL). The cell suspension was added to the chamber of a 96-well Transwell plate at 50 μL per well at a final seeding density of 2.4×10 ⁵ cells/cm ² . The medium was changed 24 hours after inoculation, and the medium was changed every other day for 14-18 days. The process of replacing the medium is as follows, separate the Transwell chamber from the receiving plate, discard the medium in the receiving plate first and then discard the medium in the Transwell chamber, and finally add 75 μL of fresh medium to each chamber, and add 25 mL of fresh medium to the receiving plate.

The second step is to evaluate the integrity of the cell monolayer

After approximately 14 days of culture, Caco-2 reaches confluence and completes differentiation. At this time, it can be applied to penetration test. Monolayer membrane resistance was measured with a resistance meter (Millipore, USA) and the resistance per well was recorded. After the assay, return the Transwell plate to the incubator. Calculation of resistance value: measure resistance value (ohms)×film area (cm ² )=TEER value (ohm·cm ² ), if TEER value<230ohms·cm ² , the hole cannot be used for penetration test.

The third step solution preparation

Weigh 2.38g of HEPES and 0.35g of sodium bicarbonate respectively, add 900mL of pure water to dissolve them, then add 100mL of 10×HBSS, stir evenly, adjust the pH to 7.4, and finally filter to obtain 1L of transport buffer (HBSS, 10mM HEPES, pH 7.4 ).

A 1 mM stock solution of the test compound to be tested in DMSO was diluted with transport buffer to give a 5 [mu]M test solution. The control compound digoxin or minoxidil was diluted to 2 mM with DMSO, and the control compound test solution was obtained with the above-mentioned transport buffer to 10 μM. In addition DMSO was also diluted with the above transport buffer to a receiver solution containing 0.5% DMSO.

Step 4 Drug Penetration Test

Remove the Transwell plate from the incubator. Cell monolayers were rinsed twice with transport buffer (10 mM HEPES, pH 7.4) buffer and incubated at 37°C for 30 minutes.

The rate of compound transport from apical to basolateral was determined. Add 125 μL of test solution per well to the upper chamber (apex) and immediately transfer 50 μL of solution from the apex to 200 μL of acetonitrile (0.1 μM tolbutamide) containing internal standard as an initial tip-to-substrate sample. 235 μL of receiver solution was added to each well of the lower chamber (basal side).

The rate of compound transport from basolateral to apical was determined. 285 μL of receiver solution was added to each well of the upper chamber (apex) and 50 μL of solution was immediately transferred from the apex to 200 μL of acetonitrile (0.1 μM tolbutamide) containing internal standard as a base-to-apical initial sample. 75 μL of test solution was added to each well of the lower chamber (basal side).

After combining the upper and lower transport devices, incubate at 37°C for 2 hours.

After incubation, sample 50 μL from each well of the upper and lower chambers of the Transwell plate and add them to new sample tubes. 200 μL of acetonitrile (0.1 μM tolbutamide) containing internal standard was added to the sample tube, vortexed for 10 minutes, and centrifuged at 3220 g for 40 minutes. 150 μL of the supernatant was aspirated and diluted with 150 μL of water for LC-MS/MS analysis. All samples were prepared in triplicate.

The integrity of the cell monolayer after 2 hours of incubation was assessed with the leakage of Lucifer Yellow, and the Lucifer Yellow stock solution was diluted to a final concentration of 100 μM using transport buffer (10 mM HEPES, pH 7.4). Add 100 μL of fluorescent yellow solution to each well of the upper Transwell insert, and add 300 μL of transport buffer solution (10 mM HEPES, pH 7.4) to each well of the lower receiving plate. After incubating at 37°C for 30 minutes, aspirate 80 μL of the solution from the upper and lower layers of each well into a new 96-well plate. Using a microplate reader, fluorescence measurement was performed under the conditions of excitation wavelength 485 nm and emission wavelength 530 nm.

Step 5 Data Analysis All calculations were performed using Microsoft Excel. Peak areas were determined from the extracted ion chromatograms.

The apparent permeability coefficient (P _app , unit: cm/s×10 ^-6 ) is calculated by the following formula:

In the formula: VA is the volume of the receiving end solution ( _Ap →Bl is 0.3mL, Bl→Ap is 0.1mL), Area (membrane area) is the membrane area of Transwell-96 well plate (0.143cm ² ); time (time) is the incubation time (unit: s); [drug] _receiver ([drug] _{receiving end} ) is the drug concentration at the receiving end; [drug] _{initial, donor} ([drug] _{initial, donor} ) is the initial drug concentration at the dosing end.

Efflux ratio is calculated using the following formula:

In the formula: _Papp(BA) is the apparent permeability coefficient from the basal end to the apex;

_Papp(AB) is the apparent permeability coefficient from apical to basal.

The recovery rate ("Percentage recovery"(%)) is calculated using the following formula:

In the formula: VA is the volume of the solution at the receiving end (unit: mL); _{V D} _is the volume of the solution at the giving end (unit: mL), and [drug] _donor ([drug] _donor ) is the drug concentration at the administration end.

The leakage rate (Percentage leakage(%) or LY(%)) is calculated using the following formula:

In the formula: I _receiver (I _{receiving end} ) refers to the fluorescence density of the receiving hole (0.3mL), and I _donor (I _donor ) refers to the fluorescence density of the dosing hole (0.1mL). LY<1.5% indicates that the monolayer cell membrane is intact. For individual cases of LY>1.5%, if the P _app value is close to other parallels, the final data can be adopted based on scientific judgment.

The Caco2 permeability data obtained by testing the compounds of the present invention are shown in Table 6 below.

Table 6. Caco2 permeability data for compounds of the invention

化合物编号Compound number	Papp _(A-B)(10 ^-6,cm/s) Papp _(AB) (10 ^-6 ,cm/s)	Papp _(B-A)(10 ^-6,cm/s) Papp _(BA) (10 ^-6 ,cm/s)	Efflux RatioEfflux Ratio
88	0.900.90	15.415.4	17.217.2
3434	0.500.50	27.127.1	54.754.7
7878	0.710.71	5.05.0	7.07.0
8383	1.451.45	19.519.5	13.513.5
8484	0.590.59	32.032.0	54.454.4
8989	0.530.53	30.630.6	58.358.3
9090	0.850.85	14.614.6	17.317.3
9393	1.201.20	20.220.2	16.916.9
9898	3.103.10	12.412.4	4.04.0
9999	3.753.75	19.919.9	5.45.4
105105	1.471.47	23.723.7	16.116.1
109109	0.890.89	17.817.8	20.220.2
114114	1.271.27	6.56.5	5.15.1
115115	1.761.76	21.221.2	12.112.1
118118	0.550.55	24.124.1	44.244.2
119119	1.621.62	23.923.9	14.914.9
120120	1.751.75	18.818.8	10.810.8
142142	0.390.39	23.623.6	60.260.2
143143	0.400.40	28.728.7	71.271.2
144144	0.700.70	13.013.0	18.818.8
154154	2.082.08	6.26.2	3.03.0
164164	1.991.99	18.018.0	9.29.2

Test Example 6. In vivo pharmacokinetic test of the compound of the present invention in rats

Using SD rats as test animals, LC/MS/MS method was used to determine the drug concentration in the plasma of rats at different times after intravenous injection and intragastric administration of the compounds of the present invention. The pharmacokinetic behavior of the compound of the present invention in rats was studied, and its pharmacokinetic characteristics were evaluated.

There were 3 healthy 6-8 week-old male SD rats in each group.

Intravenous administration: Weigh a certain amount of drug, add 10% volume of N,N-dimethylacetamide, 33% volume of triethylene glycol and 57% volume of normal saline to prepare a colorless clear transparent liquid of 1mg/mL ;

Oral administration: weigh a certain amount of medicine, add 0.5% mass hypromellose, 0.1% volume Tween 80 and 99.6% volume normal saline to prepare a 1 mg/mL white suspension.

SD rats were fasted overnight and administered intravenously or by gavage.

The compounds of the present invention were administered to rats by intravenous injection, and 0.2 mL of blood was collected from the jugular vein at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and placed in a test tube containing EDTA-K2 at 4°C, 4000 Plasma was separated by centrifugation at rpm for 5 minutes and stored at -75°C.

Or rats were administered the compound of the present invention by gavage, and 0.2 mL of blood was collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, and placed in a test tube containing EDTA-K2, 4°C, 3500 rpm Plasma was separated by centrifugation for 10 min/min and stored at -75°C.

Determination of the content of the test compound in rat plasma after intravenous injection or drug gavage administration of different concentrations: take 30 μL of rat plasma at each time after administration, add 200 μL (50ng/mL) of acetonitrile solution of internal standard dexamethasone , vortexed for 30 seconds, centrifuged at 4700 rpm for 15 minutes at 4°C, and the supernatant of the plasma sample was diluted three times with water, and 2.0 μL was taken for LC-MS/MS analysis.

The pharmacokinetic parameters in rats of the compounds of the present invention are as follows in Table 7:

Table 7. In vivo pharmacokinetic results of the compounds of the present invention in SD rats

IV indicates intravenous administration; PO indicates intragastric administration.

Claims

A compound represented by formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof,

X, Z are each independently selected from CR 9 or N;

W is selected from O or C (=O);

Y is selected from C(=O), NHC(=O), C(=O)NH, N( CH3 ) or a bond;

Ring A is selected from 5-10 membered heteroaryl or 5-10 membered heterocyclyl;

Ring B is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl or C 3 -C 10 cyclic hydrocarbon group;

E is selected from C 3 -C 10 cyclic hydrocarbon group, C 6 -C 10 aryl group, 3-12 membered heterocyclic group or 5-12 membered heteroaryl group, said C 3 -C 10 cyclic hydrocarbon group C 6 -C 10 aryl group radical, 3-12 membered heterocyclyl or 5-12 membered heteroaryl optionally substituted with one or more R 1a ;

R 1a is independently selected from halogen, CN, NH 2 , OH, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 alkoxy, -S (=O)-C 1 -C 4 alkyl, -S(=O) 2 -C 1 -C 4 alkyl,
-S(=O)(=NR 8a )R 8b , -N=S(=O)R 8a R 8b , -NR 8a R 8b , -C(=O)NR 8a R 8b or -NR 7 C(= O)R 8b , the C 1 -C 6 alkyl group, C 3 -C 8 cyclic hydrocarbon group, 3-6 membered heterocyclic group, C 1 -C 6 alkoxy group, -S(=O)-C 1 - C4alkyl or -S(=O) 2 - C1 - C4alkyl is optionally substituted with one or more groups independently selected from halogen, OH, C1 - C3alkoxy or CN ;

R 1 is selected from -CN, -(CH 2 ) q CN, -C≡CR 5 , -C(=O)C≡CR 5 , -C(=O)CR 6 =C(R 5 ) 2 , -R 7 C(=O)CH=C(R 5 ) 2 , -NHC(=O)CR 6 =C(R 5 ) 2 , -R 7 NHC(=O)CH=C(R 5 ) 2 , -NHC (=O)C≡CR 5 , -S(=O)CR 6 =C(R 5 ) 2 , -S(=O) 2 CR 6 =C(R 5 ) 2 , -NHS(=O)CR 6 =C(R 5 ) 2 , -NHS(=O) 2 CR 6 =C(R 5 ) 2 , -NR 6 C(=O)CR 6 =C(R 5 ) 2 or NHC(=O)R 5 ;

R 5 is independently selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3-12 membered heterocyclyl or C 6 -C 10 aryl , the C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, C 3 -C 8 cyclic hydrocarbon group, 3-12-membered heterocyclic group or C 6 -C 10 aryl group are optionally replaced by one or more R 5a substitutions;

R 5a is independently selected from halogen, CN, N(R 5b ) 2 , OH, NO 2 , C 3 -C 8 cycloalkyl, or 3-12 membered heterocyclyl;

R 5b is independently selected from H or C 1 -C 6 alkyl;

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

R 7 is selected from C 1 -C 6 alkylene, C 3 -C 8 cycloalkylene or 3-12 membered heterocyclylene;

R 2 is selected from H, NH 2 , C 1 -C 6 alkyl, OH or halogen;

R 3 is independently selected from halogen, CN, NH 2 , OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy or C 3-8 cycloalkyl ;

R 4 is independently selected from halogen, CN, NH 2 , OH, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3-10 membered heterocycle base, -C(=O)R 8a , -C(=O)O R 8a , -NR 8a R 8b , -C(=O)N R 8a R 8b or -NR 7 C(=O)R 8b , the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or 3-10 membered heterocyclyl optionally substituted with one or more R 4a ;

R 4a is independently selected from halogen, CN, NH 2 , OH or C 1 -C 6 alkyl;

R 8a and R 8b are each independently selected from H, halogen, CN, NH 2 , OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkyl;

R 9 is selected from H, CN, OH, NH 2 , -NHR 10 , -NH-C 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or C 3 -C 8 Cycloalkyl, said C1 - C6 alkyl, -NH- C1 - C6 alkyl, C1 - C6 alkoxy, or C3 - C8 cycloalkyl optionally surrounded by one or more R 10 substituted;

R 10 is independently selected from halogen, NH 2 , C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the NH 2 , C 3 - C8 cycloalkyl, 3-10 membered heterocyclyl, C6 - C10 membered aryl or 5-10 membered heteroaryl optionally substituted with one or more R11 ;

R 11 is independently selected from C 1 -C 6 alkyl, halogen, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl or 3-10 membered heterocyclyl, said C 1 -C 6 alkane group, C 3 -C 8 cycloalkyl or 3-10 membered heterocyclyl optionally by C 1 -C 6 alkyl, halogen, OH, -NH-C 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 substituted;

n and m are each independently selected from 0, 1, 2 or 3;

q is selected from 1, 2 or 3.
The compound represented by formula (I) according to claim 1, or its stereoisomer or pharmaceutically acceptable salt, is characterized in that: ring A is selected from 5-6 membered heteroaryl or 5-6 membered heterocycle basis; or

Ring A is selected from 5-6 membered heteroaryl; or

Ring A is selected from pyrimidinyl, pyridyl or tetrahydropyrrolyl.
The compound represented by formula (I) according to any one of claims 1 or 2, or its stereoisomer or pharmaceutically acceptable salt, is characterized in that: ring B is selected from C 6 -C 10 aryl or C 3 -C 10 cyclic hydrocarbon group; or

Ring B is selected from phenyl or cyclohexenyl; or

Ring B is selected from phenyl.
According to the compound represented by formula (I) according to any one of claims 1-3, or its stereoisomer or pharmaceutically acceptable salt, it is characterized in that: E is selected from C 3 -C 6 cyclic hydrocarbon group, C 6 -C 10 -aryl, 3-10-membered heterocyclic group or 5-10-membered heteroaryl group, the C 3 -C 6 cyclic hydrocarbon group, C 6 -C 10 -aryl group, 3-10-membered heterocyclic group or 5-membered heterocyclic group -10-membered heteroaryl is optionally substituted with R 1a .
According to the compound represented by formula (I) according to any one of claims 1-4, or its stereoisomer or pharmaceutically acceptable salt, it is characterized in that: R 1a is independently selected from halogen, CN, NH 2 , OH, -NR 8a R 8b , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 alkoxy, the C 1 -C 6 alkane group, C 3 -C 8 cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 alkoxy optionally by one or more independently selected from halogen, OH or C 1 -C 3 alkoxy group substituted; or

R 1a is independently selected from halogen, CN, NH 2 , OH, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 alkoxy, said C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 3-6 membered heterocyclyl, C 1 -C 6 alkoxy optionally by one or more independently selected from halogen, OH or C 1 -C 3 alkoxy group substitution; or

R 1a is independently selected from halogen, -NR 8a R 8b , C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, optionally by one or more independently Substituted with a group selected from halogen, OH, CN or C1 - C3alkoxy.
The compound represented by formula (I) according to any one of claims 1-5, or its stereoisomer or pharmaceutically acceptable salt, is characterized in that: R 1 is selected from -C≡CR 5 , -C (=O)C≡CR 5 , -C(=O)CR 6 =C(R 5 ) 2 , -R 7 C(=O)CH=C(R 5 ) 2 , -NHC(=O)CR 6 =C(R 5 ) 2 , -R 7 NHC(=O)CH=C(R 5 ) 2 , -NHC(=O)C≡CR 5 , -S(=O)CR 6 =C(R 5 ) 2 , -S(=O) 2 CR 6 =C(R 5 ) 2 , -NHS(=O)CR 6 =C(R 5 ) 2 , -NHS(=O) 2 CR 6 =C(R 5 ) 2 , -NR 6 C(=O)CR 6 =C(R 5 ) 2 or NHC(=O)R 5 ; or

R 1 is selected from -CN, -(CH 2 ) q CN, -C≡CR 5 , -C(=O)C≡CR 5 , -C(=O)CR 6 =C(R 5 ) 2 , -R 7 C(=O)CH=C(R 5 ) 2 , -NHC(=O)CR 6 =C(R 5 ) 2 , -R 7 NHC(=O)CH=C(R 5 ) 2 , -NHC (=O)C≡CR 5 , -NHS(=O) 2 CR 6 =C(R 5 ) 2 , -NR 6 C(=O)CR 6 =C(R 5 ) 2 or NHC(=O)R 5 ; or

R 1 is selected from -C≡CR 5 , -C(=O)C≡CR 5 , -C(=O)CR 6 =C(R 5 ) 2 , -R 7 C(=O)CH=C(R 5 ) 2 , -NHC(=O)CR 6 =C(R 5 ) 2 , -R 7 NHC(=O)CH=C(R 5 ) 2 , -NHC(=O)C≡CR 5 , -NHS (=O) 2 CR 6 =C(R 5 ) 2 , -NR 6 C(=O)CR 6 =C(R 5 ) 2 or NHC(=O)R 5 .
The compound represented by formula (I) according to claim 6, or its stereoisomer or pharmaceutically acceptable salt, is characterized in that: R 1 is selected from the following groups:
The compound represented by formula (I) according to any one of claims 1-7, or its stereoisomer or pharmaceutically acceptable salt, is characterized in that: R 2 is selected from H, NH 2 , CH 3 , OH or halogen; or R 2 is selected from H, NH 2 , CH 3 or halogen.
According to the compound represented by formula (I) according to any one of claims 1-8, or its stereoisomer or pharmaceutically acceptable salt, it is characterized in that: R 3 is independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkyl; or R 3 is independently selected from halogen or C 1 -C 6 alkoxy; or R 3 is selected from halogen.
The compound represented by formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein m is selected from 0 or 1.
According to the compound represented by formula (I) according to any one of claims 1-10, or its stereoisomer or pharmaceutically acceptable salt, it is characterized in that: R 4 is independently selected from halogen, CN, NH 2 , OH, NO 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3-10 membered heterocyclic group, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, 3-10 membered heterocyclyl optionally substituted with one or more R 4a ; or

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

R 4 is independently selected from CN or C 1 -C 6 alkyl.
The compound represented by formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, wherein n is selected from 0 or 1.
The compound represented by formula (I) according to any one of claims 1-12, or its stereoisomer or pharmaceutically acceptable salt, is characterized in that: R 9 is selected from H, CN, OH, NH 2 , -NHR 10 or -NH-C 1 -C 6 alkyl optionally substituted with one or more R 10 ; or

R 9 is selected from H, NH 2 , -NHR 10 , -NH-C 1 -C 6 alkyl or C 1 -C 6 alkyl, said C 1 -C 6 alkyl or -NH-C 1 -C 6 Alkyl is optionally substituted with one or more R 10 .
According to any one of claims 1-2 or 4-13, the compound represented by the formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, is characterized in that: the compound represented by the formula (I) The compound, or its stereoisomer or pharmaceutically acceptable salt is selected from the compound represented by formula (II), or its stereoisomer or pharmaceutically acceptable salt,
According to any one of claims 1 or 3-13, the compound represented by the formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, is characterized in that: the compound represented by the formula (I), Its stereoisomer or pharmaceutically acceptable salt is selected from the compound represented by formula (III), or its stereoisomer or pharmaceutically acceptable salt,
The compound represented by the formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof according to claim 14 or 15, characterized in that: the compound represented by the formula (I), or a stereoisomer thereof Or a pharmaceutically acceptable salt is selected from the compound represented by formula (IV), or its stereoisomer or a pharmaceutically acceptable salt,
The compound represented by formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, according to any one of claims 1-13, characterized in that: the compound represented by formula (I), or its stereoisomer The body or pharmaceutically acceptable salt is selected from the compound represented by formula (V), or its stereoisomer or pharmaceutically acceptable salt,
The compound represented by the formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt, characterized in that: the compound represented by the formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof Acceptable salts are selected from the following compounds, or stereoisomers or pharmaceutically acceptable salts thereof,
A pharmaceutical composition, the pharmaceutical composition comprises the compound shown in the formula (I) described in any one of claims 1-18, or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable of accessories.
Compound shown in formula (I) described in any one of claim 1-18, or its stereoisomer or pharmaceutically acceptable salt, or the described pharmaceutical composition of claim 19 is related to FGFR in preparation, prevention or treatment Use in medicines for diseases.
The use according to claim 20, wherein the FGFR-related disease is selected from cancer.