WO2024208315A1 - Aromatic heterocyclic compound, and preparation method therefor and medical use thereof - Google Patents

Abstract

An aromatic heterocyclic compound, and a preparation method therefor and the medical use thereof. Specifically, the present invention relates to a compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, the use thereof as an FGFR2 inhibitor, and the use thereof for preventing and/or treating diseases related to FGFR2 activity. The definition of each group in the general formula (I) is the same as the definition thereof in the description.

Description

Aromatic heterocyclic compounds and preparation methods and medical uses thereof Technical Field

The present invention belongs to the field of medical technology, and relates to a novel aromatic heterocyclic compound, a preparation method thereof, a pharmaceutical composition containing the same, and its use for inhibiting the activity of FGFR2 protein. The compound of the present invention can be used to treat various tumors such as bile duct cancer, and other diseases related to FGFR2 activity.

Background Art

Cholangiocarcinoma (CCA) is the most common malignant tumor of the biliary tract. According to its location, cholangiocarcinoma can be divided into intrahepatic, perihilar or extrahepatic cholangiocarcinoma. The early symptoms of cholangiocarcinoma are hidden, and more than 70% of patients are in the advanced stage when they seek medical treatment. The treatment options for advanced cholangiocarcinoma are limited. Gemcitabine combined with cis-platinum is the standard first-line regimen, with a median overall survival of only about 1 year. The median overall survival of second-line chemotherapy (FOLFOX) is only 6.2 months, and the 5-year survival rate is only 9% (Juan V et al., N Engl J Med, 2010, 362(14):1273-81; Angela L et al., Lancet Oncol, 2021; 22(5):690-701). About 10-15% of CCA patients have FGFR2 gene fusion and rearrangement (Apinya J et al., Cancer Discov 2017, 7(10):1116-1135). Although a number of pan-FGFR inhibitors have shown significant clinical efficacy in these patients, the emergence of FGFR1-mediated toxicity (hyperphosphatemia, tissue mineralization) and FGFR2 resistance mutations limit the efficacy of pan-FGFR inhibitors (James Y et al., Onco Targets Ther 2021, 14:5145-5160; Ghassan K et al., Lancet Oncol 2020, 21(5):671-684; Chen L et al., J Exp Clin Cancer Res 2021, 40(1):345). Therefore, developing FGFR inhibitors with good selectivity and the ability to overcome off-target FGFR2 resistance can effectively overcome the drawbacks of existing pan-FGFR inhibitors.

RLY-4008 is a highly effective and selective oral small molecule. Preclinical data showed that RLY-4008 showed excellent selectivity for FGFR2. In the clinical data published by ESMO 2022, RLY-4008 achieved tumor shrinkage in 92% of patients with cholangiocarcinoma carrying FGFR2 fusion and rearrangement, and the ORR reached 63.2%. At the RP2D dose, the ORR was as high as 88.2%, significantly better than the non-selective FGFR inhibitors that have been marketed and applied for marketing. In terms of safety, RLY-4008 also showed good tolerability, with no grade 4 or 5 adverse events reported and no hyperphosphatemia (Hollebecque A et al., Annals of Oncology, 2022: S808-S869).

Currently, there are not many highly selective FGFR2 small molecule inhibitors in clinical research. Therefore, the development of FGFR2 inhibitors with high selectivity and overcoming off-target resistance is expected to change the treatment model of CCA and bring significant survival benefits.

Summary of the invention

After intensive research, the inventors designed and synthesized a series of pyridothiophene compounds and screened their FGFR2 activity. The research results showed that the compounds had outstanding FGFR2 inhibitory activity and could be developed as drugs for treating diseases related to FGFR2 activity.

In one aspect, the present invention provides a compound represented by general formula (I) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

in:

X is selected from N or CR ⁷ ;

Y is selected from S, O, CR ⁷ R ⁸ or NR ⁸ ;

R ¹ is selected from hydrogen, -NR ^a R ^b , halogen, hydroxyl, alkyl, which is optionally further substituted with one or more G ¹ ;

^R is selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NR ^a R ^b , -NHC(O)R ^a , -S(O) _nR ^a , -S(O) _nNR ^a R ^b , -NHS(O) _nR ^a , and -P(O)R ^a R ^b , wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally further substituted with one or more G ² ;

^R3 is selected from a bond, alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, wherein said alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene and heteroarylene are each independently optionally further substituted with one or more ^G3 ;

L is selected from a bond, -N( ^Ra )-, -O-, -S-, alkylene, cycloalkylene, heterocyclylene, heteroarylene, -N( ^Ra )C(O)-, -C(O)N( ^Ra )-, -N( ^Ra )S(O) _n- , -S(O) _nN ( ^Ra )-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) _2- ;

^R is selected from hydrogen, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NR ^a R ^b , -NHC(O)R ^a , -S(O) _nR ^a , -S(O) _nNR ^a R ^b and -NHS(O) _nR ^a , wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted with one or more G ⁴ ;

R ⁵ is selected from a bond, alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, wherein said alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene and heteroarylene are each independently optionally further substituted with one or more G ⁵ ;

A is selected from a bond, -N( ^Ra )-, -O-, -S-, alkylene, cycloalkylene, heterocyclylene, heteroarylene, -N( ^Ra )C(O)-, -C(O)N( ^Ra )-, -N( ^Ra )S(O) _n- , -S(O) _nN ( ^Ra )-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) _2- ;

R ⁶ is selected from

^R and ^R are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ^-ORa , -C(O) ^Ra , -OC(O) ^Ra , -C(O) ^ORa , -C( ^O ) ^NRaRb , ^-NRaRb , ^-NHC (O) ^Ra , -S( ^O ) _nRa , _-S (O) ^nNRaRb , and -NHS(O) _nRa , wherein said ^alkyl , alkoxy, cycloalkyl, heterocyclyl, ^aryl , and heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

^R9 , ^R10 , and ^R11 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ^-ORa , -C ⁽ O) ^Ra , -OC(O) ^Ra , -C(O ^{) ORa} , ^{-C (} O ⁾ NRaRb, ^-NRaRb , -NHC( ^O ) ^{Ra ,} -S(O) _nRa , -S(O) _nNRaRb , -NHS(O) _nRa , and -( _CH2 ⁾ _vNRaRb ^. , wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;

Each of ^G1 , ^G2 , ^G3 , ^G4 , and ^G5 is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ^-ORa , -( _CH2 ) _vORa , -C(O) ^Ra , -OC(O) ^Ra , ^-C (O) ^ORa , -C ^{( O} ) ^NRaRb , -NRaRb, -NHC ₍ O) ^Ra , _-S ⁽ O) _nRa , -S ⁽ O) ^nNRaRb , -NHS(O) ^{nRa ,} and -( _CH2 ⁾ _vNRaRb ^. , wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted with one or more groups selected from deuterated, halogen, amino, nitro, cyano, oxo, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

^Ra and ^Rb are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylheterocyclyl, aryl, heteroaryl;

Or ^Ra and ^Rb together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, wherein the nitrogen-containing heterocyclic group is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

Any two of G ¹ , G ² , G ³ , G ⁴ and G ⁵ can be combined to form a saturated or partially saturated cycloalkyl or heterocyclic group;

n is 1 or 2;

v is an integer from 1 to 6.

In a preferred embodiment, according to the compound represented by general formula (I) of the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, X is N.

In another preferred embodiment, according to the compound represented by general formula (I) of the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, Y is S.

In another preferred embodiment, the compound represented by general formula (I) according to the present invention or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (II) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

wherein: R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , L and A are as defined in the general formula (I).

In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R ³ is selected from C _6-10 arylene, 5- to 10-membered heteroarylene, 3- to 10-membered cycloalkylene, 3- to 10-membered heterocyclylene; which is optionally further substituted by one or more G ³ ;

^G3 is selected from halogen, amino, cyano, hydroxyl, mercapto, _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl, ^{-NRaRb ,} wherein the _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl are each independently further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, _C1-6 alkyl, _{C1-6 haloC1-6} alkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, C3-6 cycloalkyl, _4-6 membered heterocyclyl, C6-10 aryl, 5 to 10 membered heteroaryl substituted with one or more groups of _6-10- membered aryl or 5- to 10-membered heteroaryl;

^Ra and ^Rb are each independently selected from a _C1-6 alkyl group.

In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R ³ is selected from 3-10 membered cycloalkylene, 3-10 membered heterocyclylene; which is optionally further substituted by one or more G ³ ;

^G3 is selected from halogen, amino, cyano, hydroxyl, mercapto, _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl, ^{-NRaRb ,} wherein the _C1-6 alkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, 4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl are each independently optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, _C1-6 alkyl, C1-6 _haloC1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-6 cycloalkyl, 4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl _;

^Ra and ^Rb are each independently selected from a _C1-6 alkyl group.

In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R ³ is selected from C _6-10 arylene or 5-10 membered heteroarylene, preferably phenylene or 5-6 membered heteroarylene, more preferably phenylene or 6 membered heteroarylene such as pyridylene; which is optionally further substituted by one or more G ³ ;

^G3 is selected from halogen, amino, cyano, hydroxyl, mercapto, _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl, ^{-NRaRb ,} wherein the _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl are each independently further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, _C1-6 alkyl, _{C1-6 haloC1-6} alkyl, C1-6 alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-6 cycloalkyl, _4-6 membered heterocyclyl, C6-10 aryl, 5 to 10 membered heteroaryl substituted with one or more groups of _6-10- membered aryl or 5- to 10-membered heteroaryl;

^Ra and ^Rb are each independently selected from a _C1-6 alkyl group.

In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R ³ is selected from phenylene, 5- to 6-membered heteroarylene, 3- to 6-membered cycloalkylene, 3- to 6-membered heterocyclylene; which is optionally further substituted by one or more G ³ ;

G ³ is selected from halogen, amino, cyano, C _1-6 alkyl, C _1-6 alkoxy, -NR ^a R ^b , wherein the C _1-6 alkyl and C _1-6 alkoxy are optionally further substituted by halogen;

^Ra and ^Rb are each independently selected from a _C1-6 alkyl group.

In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R ³ is selected from phenylene, 5- to 6-membered heteroarylene; which is optionally further substituted by one or more G ³ ;

^G3 is selected from halogen ^, amino, cyano, _C1-6 alkyl, _C1-6 alkoxy, ^-NRaRb , wherein the _C1-6 alkyl and _C1-6 alkoxy are optionally further substituted by halogen;

^Ra and ^Rb are each independently selected from a _C1-6 alkyl group.

In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R ³ is selected from phenylene, pyridylene, preferably phenylene; which is optionally further substituted by one or more G ³ ;

^G3 is selected from halogen, amino, cyano, _C1-6 ^alkyl , _C1-6 alkoxy, ^-NRaRb , wherein the _C1-6 alkyl, The C _1-6 alkoxy group is optionally further substituted with halogen;

^Ra and ^Rb are each independently selected from a _C1-6 alkyl group.

In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from C _6-10 arylene, 5-10 membered heteroarylene, 3-10 membered cycloalkylene, 3-10 membered heterocyclylene, C _2-6 alkynylene, preferably phenylene, 5-6 membered heteroarylene, 3-10 membered heterocyclylene or C _2-4 alkynylene; which is optionally further substituted by one or more G ⁵ ;

^G5 is selected from halogen, amino, cyano, hydroxyl, mercapto, _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl, -( _CH2 ) _v ^ORa , wherein the _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl are each independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, _C1-6 alkyl, _{C1-6 haloC1-6} alkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, C3-6 cycloalkyl, _4-6 membered heterocyclyl, C6-10 aryl, 5 to 10 membered heteroaryl substituted with one or more groups of _6-10- membered aryl or 5- to 10-membered heteroaryl;

R ^a is selected from C _1-6 alkyl;

v is an integer from 1 to 6.

In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from phenylene, 5- to 6-membered heteroarylene such as pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl; which is optionally further substituted by one or more G ⁵ ;

G ⁵ is selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, -(CH ₂ ) _v OR ^a , wherein the C _1-6 alkyl and C _1-6 alkoxy are optionally further substituted with one or more groups selected from halogen and C _1-6 alkoxy;

R ^a is selected from C _1-6 alkyl;

v is an integer from 1 to 6.

In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from 3 to 10-membered cycloalkylene or 3 to 10-membered heterocyclylene; for example It is optionally further substituted with a C _1-6 alkyl group.

In another preferred embodiment, according to the compound represented by general formula (I) or general formula (II) of the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from C _2-6 alkynylene, preferably C _2-4 alkynylene.

In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (IIIA) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

in,

Ring Z is selected from 3- to 10-membered cycloalkylene or 3- to 10-membered heterocyclylene;

E ₁ , E ₂ , E ₃ , and E ₄ are each independently selected from N or CR ^5a ;

Each R ^3b is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, -NR ^a R ^b , wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl are each independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C _1-6 alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _4-6 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl substituted with one or more groups of _6-10- membered aryl or 5- to 10-membered heteroaryl;

each R ^5a is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, -(CH ₂ ) _v OR ^a , wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl are each independently optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C 1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl substituted with one or more groups of _6-10- membered aryl or 5- to 10-membered heteroaryl;

R ^a and R ^b are each independently selected from C _1-6 alkyl;

v is an integer from 1 to 6;

t is 0, 1, 2, 3, or 4;

R ¹ , R ² , R ⁴ , R ⁶ , L and A are as defined in the general formula (I).

In another preferred embodiment, the compound represented by general formula (I) or general formula (II) according to the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (IIIB) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

in,

Z ₁ , Z ₂ , Z ₃ , and Z ₄ are each independently selected from N or CR ^3a ;

E ₁ , E ₂ , E ₃ , and E ₄ are each independently selected from N or CR ^5a ;

Each R ^3a is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, -NR ^a R ^b , wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl are each independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C _1-6 alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _4-6 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl substituted with one or more groups of _6-10- membered aryl or 5- to 10-membered heteroaryl;

each R ^5a is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, -(CH ₂ ) _v OR ^a , wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl are each independently optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C 1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl substituted with one or more groups of _6-10- membered aryl or 5- to 10-membered heteroaryl;

R ^a and R ^b are each independently selected from C _1-6 alkyl;

v is an integer from 1 to 6;

R ¹ , R ² , R ⁴ , R ⁶ , L and A are as defined in the general formula (I).

In another preferred embodiment, the compound represented by general formula (I), general formula (II), general formula (IIIA) or general formula (IIIB) according to the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from C _6-10 aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic group, preferably phenyl or 5-6 membered heteroaryl, more preferably 6 membered heteroaryl; which is optionally further substituted by one or more G ⁴ ;

^G4 is selected from halogen, amino, cyano, hydroxyl, mercapto, _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl, wherein the _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl are each independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, _C1-6 alkyl, _C1-6 halo The group may be substituted with one or more of a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 haloalkoxy group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-6 cycloalkyl group, a 4-6 membered heterocyclyl group, a C _6-10 aryl group, or a 5- to 10-membered heteroaryl group.

In another preferred embodiment, the compound represented by general formula (I), general formula (II), general formula (IIIA) or general formula (IIIB) according to the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from phenyl, pyridyl, pyrimidinyl, which is optionally further substituted by one or more G ⁴ ;

G ⁴ is selected from halogen, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, and the C _1-6 alkyl is optionally further substituted by one or more groups selected from halogen.

In another preferred embodiment, the compound represented by the general formula (I), general formula (II), general formula (IIIA) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention is the compound represented by the general formula (IVA) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

in,

Ring Z is selected from 3- to 10-membered cycloalkylene or 3- to 10-membered heterocyclylene;

E ₁ , E ₂ , E ₃ , and E ₄ are each independently selected from N or CR ^5a ;

_M1 and _M2 are each independently selected from N or CH;

each R ^3b is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, and the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl;

each R ^5a is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, -(CH ₂ ) _v OR ^a , wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl are each independently optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C 1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl One or more of _6-10- membered aryl, 5- to 10-membered heteroaryl Group substitution;

each R ^4a is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, and the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl;

R ^a and R ^b are each independently selected from C _1-6 alkyl;

v is an integer from 1 to 6;

m is 0, 1 or 2;

t is 0, 1, 2, 3, or 4;

R ¹ , R ² , R ⁶ , L and A are as defined in the general formula (I).

In another preferred embodiment, the compound represented by general formula (I), general formula (II) or general formula (IIIB) according to the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (IVB) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

in,

Z ₁ , Z ₂ , Z ₃ , and Z ₄ are each independently selected from N or CR ^3a ;

E ₁ , E ₂ , E ₃ , and E ₄ are each independently selected from N or CR ^5a ;

_M1 and _M2 are each independently selected from N or CH;

Each R ^3a is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, -NR ^a R ^b , wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl are each independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C _1-6 alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _4-6 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl substituted with one or more groups of _6-10- membered aryl or 5- to 10-membered heteroaryl;

each R ^5a is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, -(CH ₂ ) _v OR ^a , wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl are each independently optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C 1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl substituted with one or more groups of _6-10- membered aryl or 5- to 10-membered heteroaryl;

each R ^4a is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, and the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl;

R ^a and R ^b are each independently selected from C _1-6 alkyl;

v is an integer from 1 to 6;

m is 0, 1 or 2;

R ¹ , R ² , R ⁶ , L and A are as defined in the general formula (I).

In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (III) or general formula (IV) of the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein L is -O-.

In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (III) or general formula (IV) of the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein A is -NH-.

In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (III) or general formula (IV) of the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein L is a bond, -O- or -C(O)-, preferably -O- or -C(O)-, more preferably -O-.

In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (III) or general formula (IV) of the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein A is a bond or -NH-, preferably -NH-.

In another preferred embodiment, the compound represented by general formula (I), general formula (II), general formula (IIIA) or general formula (IVA) according to the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (VA) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

in,

Ring Z, E ₁ to E ₄ , M ₁ to M ₂ , R ^4a , m and t are as defined in the general formula (IVA);

R ¹ , R ² , R ⁹ to R ¹¹ and L are as defined in the general formula (I).

In another preferred embodiment, the compound represented by general formula (I), general formula (II), general formula (IIIA) or general formula (IVA) according to the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (VC) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

in,

Ring Z, E ₁ to E ₄ , M ₁ to M ₂ , R ^4a , m and t are as defined in the general formula (IVA);

R ¹ , R ² , R ¹¹ and L are as defined in the general formula (I).

In another preferred embodiment, the compound represented by general formula (I), general formula (II), general formula (IIIB) or general formula (IVB) according to the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (VB) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

in,

Z ₁ to Z ₄ , E ₁ to E ₄ , M ₁ to M ₂ , R ^4a , and m are as defined in the general formula (IVB);

R ¹ , R ² , R ⁹ to R ¹¹ and L are as defined in the general formula (I).

In another preferred embodiment, the compound represented by general formula (I), general formula (II), general formula (IIIB) or general formula (IVB) according to the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (VD) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

in,

Z ₁ to Z ₄ , E ₁ to E ₄ , M ₁ to M ₂ , R ^4a , and m are as defined in the general formula (IVB);

R ¹ , R ² , R ¹¹ and L are as defined in the general formula (I).

In another preferred embodiment, according to the compound represented by general formula (IIIB), general formula (IVB), general formula (VB), general formula (VD) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein Z ₁ , Z ₂ , Z ₃ , Z ₄ is CR ^3a , or one of Z ₁ , Z ₂ , Z ₃ , Z ₄ is N, and the rest are CR ^3a ; each R ^3a is independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl; preferably hydrogen or halogen.

In another preferred embodiment, the compound represented by general formula (IIIB), general formula (IVB), general formula (VB), general formula (VD) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, wherein Z ₁ , Z ₂ , Z ₃ , Z ₄ is CR ^3a , or one of Z ₁ , Z ₂ , Z ₃ , Z ₄ is N, and the others are CR ^3a ;

Each R ^3a is independently selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -NR ^a R ^b ; ^Ra and R ^b are each independently selected from hydrogen and C _1-6 alkyl.

In another preferred embodiment, according to the compound represented by general formula (IIIA), general formula (IIIB), general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC) or general formula (VD) of the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein _E1 , _E2 , _E3 , and _E4 are each independently selected from ^CR5a ; and each ^R5a is independently selected from hydrogen, halogen, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, and _C1-6 haloalkoxy.

In another preferred embodiment, according to the compound represented by general formula (IIIA), general formula (IIIB), general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC) or general formula (VD) of the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein _E1 , _E2 , _E3 , _E4 are each independently selected from ^CR5a ; or one of _E1 , _E2 , _E3 , _E4 is N, and the others are ^CR5a ; or two of _E1 , _E2 , _E3 , _E4 are N, and the others are ^CR5a ;

Each R ^5a is independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -(CH ₂ ) _v OR ^a ;

R ^a is selected from C _1-6 alkyl;

v is an integer from 1 to 6.

In another preferred embodiment, according to the compound represented by general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC) or general formula (VD) of the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein _M1 and _M2 are N or _M1 is CH and _M2 is N.

In another preferred embodiment, according to the compound represented by general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC) or general formula (VD) of the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein each R ^4a is independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, preferably C _1-6 alkyl; m is 0 or 1, preferably 1.

In another preferred embodiment, according to the compound represented by general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC) or general formula (VD) of the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein each R ^4a is independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-6 cycloalkyl; m is 0 or 1, preferably 1.

In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (IIIA), general formula (IIIB), general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC) or general formula (VD) of the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from hydrogen, C _1-6 alkyl, and 4-6 membered heterocyclic group; preferably, R ⁹ is selected from C _1-6 alkyl, and R ¹⁰ and R ¹¹ are each independently selected from hydrogen.

In another preferred embodiment, according to the general formula (I), general formula (II), general formula (IIIA), (IIIB), (IVA), (IVB), (VA), (VB), (VC) or (VD), or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R ⁹ , R ¹⁰ , R ¹¹ are each independently selected from hydrogen, C _1-6 alkyl, 4-6 membered heterocyclyl and -(CH ₂ ) _v NR ^a R ^b ;

R ^a and R ^b are each independently selected from hydrogen and C _1-6 alkyl;

or ^Ra and ^Rb together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic group;

v is an integer from 1 to 6.

In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (IIIA), general formula (IIIB), general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC) or general formula (VD) of the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ^R9 is selected from _C1-6 alkyl, and ^R10 and ^R11 are each independently selected from hydrogen.

In another preferred embodiment, the compound represented by general formula (I), general formula (II), general formula (IIIA), general formula (IIIB), general formula (IVA), general formula (IVB), general formula (VA), general formula (VB) or its meso form, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof according to the present invention, wherein:

R ⁹ is selected from hydrogen, C _1-6 alkyl and -(CH ₂ ) _v NR ^a R ^b ;

R ¹⁰ is selected from hydrogen and C _1-6 alkyl;

R ¹¹ is selected from hydrogen, C _1-6 alkyl and -(CH ₂ ) _v NR ^a R ^b ;

^Ra and ^Rb are each independently selected from hydrogen and _C1-6 alkyl; or ^Ra and ^Rb together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic group;

v is an integer from 1 to 6.

In another preferred embodiment, according to the compound represented by general formula (VC) or general formula (VD) of the present invention, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, R ¹¹ is selected from hydrogen and C _1-6 alkyl.

In another preferred embodiment, according to the compounds represented by general formula (I), general formula (II), general formula (IIIA), general formula (IIIB), general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC), general formula (VD) or their meso, racemic, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein:

R ¹ is selected from -NR ^a R ^b , hydroxyl, C _1-6 alkyl or C _1-6 haloalkyl; preferably -NR ^a R ^b or hydroxyl;

^Ra and ^Rb are each independently selected from hydrogen and _C1-6 alkyl; preferably hydrogen.

In another preferred embodiment, according to the compounds represented by general formula (I), general formula (II), general formula (IIIA), general formula (IIIB), general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC), general formula (VD) or their racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts ^thereof , wherein ^R2 is selected from -C(O) ^NRaRb , -C(O) ^Ra , -C ⁽ O ^{) ORa} , -S(O) _nRa and -S(O ^)nNRaRb _, ^preferably -C(O) ^NRaRb ;

^Ra and ^Rb are each independently selected from hydrogen and _C1-6 alkyl; n is 1 or 2.

In another preferred embodiment, according to the compounds represented by general formula (I), general formula (II), general formula (IIIA), general formula (IIIB), general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC), general formula (VD) or their racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ¹ is selected from -NH ₂ .

In another preferred embodiment, according to the compounds represented by general formula (I), general formula (II), general formula (IIIA), general formula (IIIB), general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC), general formula (VD) or their racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ^R2 is selected from -C(O) ^NRaRb ; ^Ra and ^{Rb are} each independently selected from hydrogen and _C1-6 alkyl.

In another preferred embodiment, according to the compound represented by general formula (I), general formula (II), general formula (IIIA), general formula (IIIB), general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC), general formula (VD) or its racemate, racemate, enantiomer, diastereomer, or mixture ^thereof , or pharmaceutically acceptable salt thereof, wherein ^R2 is selected from -C(O ^{) NRaRb} , -C(O) ^Ra , -P(O) ^RaRb , -C(O) ^ORa , -S(O) _nRa and -S(O ⁾ _nNRaRb ^, preferably -C(O) ^NRaRb and -P(O) ^{RaRb ,} more preferably -C( ^{O ) NRaRb ;}

^Ra and ^Rb are each independently selected from hydrogen and _C1-6 alkyl; n is 1 or 2.

In another preferred embodiment, according to the compounds represented by formula (I), (II), (IIIA), (IIIB), (IVA), (IVB), (VA), (VB), (VC), (VD) or their meso, racemic, enantiomer, diastereoisomer, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ^R2 is selected ^from halogen, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, -C(O) ^NRaRb , -P(O ^{) RaRb} , wherein the 4-10 membered heterocyclyl and the 5-10 membered heteroaryl are each independently optionally further substituted by one or more ^G2 ;

^G2 is selected from halogen, cyano, _C1-6 alkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, 4-6 ^membered heterocyclyl, -( _CH2 ) _vORa and -( _CH2 ^{)vNRaRb ,} wherein the _C1-6 alkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, 4-6 membered heterocyclyl are each independently optionally further substituted with one or more groups selected _from deuterated, halogen, cyano, hydroxyl, _C1-6 alkyl;

^Ra and ^Rb are each independently selected from hydrogen, _C1-6 alkyl, said _C1-6 alkyl optionally further substituted by 4-6 membered heterocyclyl, _C1-6 alkyl-4-6 membered heterocyclyl, or

^Ra and ^Rb together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic group;

v is an integer from 1 to 6.

In another preferred embodiment, according to the compounds represented by general formula (I), general formula (II), general formula (IIIA), general formula (IIIB), general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC), general formula (VD) or their racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ^R2 is selected from 5-10 membered heteroaryl, preferably 5-6 membered heteroaryl, more preferably pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, Pyrazinyl, which is optionally further substituted with one or more ^G2 ;

G ² is selected from halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl and -(CH ₂ ) _v NR ^a R ^b , wherein the C _1-6 alkyl and 4-6 membered heterocyclyl are each independently optionally further substituted by one or more groups selected from deuterated, halogen, cyano, hydroxyl and C _1-6 alkyl;

R ^a and R ^b are each independently selected from C _1-6 alkyl, or

^Ra and ^Rb together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic group;

v is an integer from 1 to 6.

In another preferred embodiment, according to the compounds represented by general formula (I), general formula (II), general formula (IIIA), general formula (IIIB), general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC), general formula (VD) or their racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ² is selected from halogen.

In another preferred embodiment, according to the compounds represented by general formula (I), general formula (II), general formula (IIIA), general formula (IIIB), general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC), general formula (VD) or their mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ² is selected from -C(O)NR ^a R ^b ;

^Ra and ^Rb are each independently selected from hydrogen, _C1-6 alkyl which is optionally further substituted with a 4-6 membered heterocyclyl, or a _C1-6 alkyl-4-6 membered _heterocyclyl .

In another preferred embodiment, according to the compounds represented by general formula (I), general formula (II), general formula (IIIA), general formula (IIIB), general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC), general formula (VD) or their racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ^{R2 is} selected from -P(O) ^RaRb , and ^Ra and ^Rb are each independently selected from _C1-6 alkyl.

In another preferred embodiment, according to the compounds represented by general formula (I), general formula (II), general formula (IIIA), general formula (IIIB), general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC), general formula (VD) or their meso, racemic, enantiomer, diastereoisomer, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ^R2 is selected from 5-10 membered heteroaryl, preferably It is optionally further substituted with a C _1-6 alkyl group.

In another preferred embodiment, according to the compounds represented by general formula (I), general formula (II), general formula (IIIA), general formula (IIIB), general formula (IVA), general formula (IVB), general formula (VA), general formula (VB), general formula (VC), general formula (VD) or their racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein L is selected from -C(O)- and R ⁴ is selected from a 4-8 membered heterocyclic group.

Typical compounds of the present invention include, but are not limited to:

or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its prodrug or pharmaceutically acceptable salt thereof.

The present invention further provides a method for preparing the compound represented by general formula (I) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which comprises the following steps:

Compound IA is reacted with Im in the presence of a catalyst to obtain a compound represented by the general formula (I) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the catalyst is preferably Pd(dppf)Cl ₂ or tetrakistriphenylphosphine palladium;

X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A and L are as defined in the general formula (I).

The present invention further relates to a method for preparing the compound represented by the general formula (II) or its internal A method for preparing a racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

The compound IIA is reacted with Im in the presence of a catalyst to obtain a compound represented by the general formula (II) or its mesomorph, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the catalyst is preferably Pd(dppf)Cl ₂ or tetrakistriphenylphosphine palladium;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A and L are as defined in the general formula (II).

The present invention further relates to a method for preparing the compound represented by general formula (IIIB) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which comprises the following steps:

The compound IIIa is reacted with IIIm in the presence of a catalyst to obtain a compound represented by the general formula (IIIB) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the catalyst is preferably Pd(dppf)Cl ₂ or tetrakistriphenylphosphine palladium;

Z ₁ to Z ₄ , E ₁ to E ₄ , R ¹ , R ² , R ⁴ , R ⁶ , A and L are as defined in the general formula (IIIB).

The present invention further relates to a method for preparing the compound represented by the general formula (IVB) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which comprises the following steps:

The compound IIIa is reacted with IVm in the presence of a catalyst to obtain a compound represented by the general formula (IVB) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the catalyst is preferably Pd(dppf)Cl ₂ or tetrakistriphenylphosphine palladium;

Z ₁ to Z ₄ , E ₁ to E ₄ , M ₁ to M ₂ , R ¹ , R ² , R ^4a , R ⁶ , m, A and L are as defined in the general formula (IVB).

The present invention further relates to a method for preparing a compound represented by the general formula (VB) according to the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

Compound Va is reacted with Vm in the presence of a catalyst to obtain a compound represented by the general formula (VB) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the catalyst is preferably Pd(dppf)Cl ₂ or tetrakistriphenylphosphine palladium;

Z ₁ to Z ₄ , E ₁ to E ₄ , M ₁ to M ₂ , R ¹ , R ² , R ^4a , R ⁹ , R ¹⁰ , R ¹¹ , and m are as defined in the general formula (VB).

The present invention further provides a pharmaceutical composition comprising the compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

The present invention further relates to the use of the compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same in the preparation of a FGFR2 inhibitor.

The present invention further relates to the use of the compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its prodrug or pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, in the preparation of a medicament for preventing and/or treating a disease associated with FGFR2 activity, such as bile duct cancer, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, rectal cancer, endometrial cancer or urothelial cancer.

The present invention further relates to the compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same, which is used as a FGFR2 inhibitor.

The present invention further relates to the compounds according to the present invention or their meso, racemic, enantiomeric Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, for preventing and/or treating diseases associated with FGFR2 activity, such as bile duct cancer, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, colorectal cancer, endometrial cancer, or urothelial cancer.

The present invention further relates to a method for inhibiting FGFR2, comprising administering to a subject in need thereof an effective amount of a compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

The present invention further relates to a method for preventing and/or treating a disease associated with FGFR2 activity, comprising administering to a subject in need thereof an effective amount of a compound according to the present invention or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, wherein the disease is, for example, bile duct cancer, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, rectal cancer, endometrial cancer, or urothelial cancer.

According to the conventional methods in the field to which the present invention belongs, the compounds of the present invention can form pharmaceutically acceptable basic addition salts with bases. The bases include inorganic bases and organic bases, and acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc., and acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the following: sweeteners, flavoring agents, colorants and preservatives to provide pleasing and palatable pharmaceutical preparations. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as microcrystalline cellulose, crosslinked sodium carboxymethyl cellulose, corn starch or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release action over a longer period of time. For example, water soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time extending materials such as ethylcellulose, cellulose acetate butyrate may be used.

Oral preparations may also be provided in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily vehicle such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing agents or wetting agents, which may be naturally occurring phosphatides such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long chain fatty alcohols, such as heptadecaethyleneoxy cetanol, Or the condensation product of ethylene oxide with partial ester derived from fatty acid and hexitol, for example polyethylene oxide sorbitol monooleate, or the condensation product of ethylene oxide with partial ester derived from fatty acid and hexitol anhydride, for example polyethylene oxide dehydrated sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweeteners, for example sucrose, saccharin or aspartame.

Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.

Dispersible powders and granules suitable for preparing aqueous suspensions can provide the active ingredient and a dispersant or wetting agent, a suspending agent or one or more preservatives for mixing by adding water. Suitable dispersants or wetting agents and suspending agents are as described above. Other excipients such as sweeteners, flavoring agents and coloring agents can also be added. These compositions can be preserved by adding antioxidants such as ascorbic acid.

The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. Emulsions can also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs prepared with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose can be used. Such preparations can also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

The pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution. Acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerol and processed to form a microemulsion. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, the solution and microemulsion may be preferably administered in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain this constant concentration, a continuous intravenous drug delivery device may be used.

The pharmaceutical composition of the present invention can be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared according to known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. The sterile injection preparation can also be a sterile injection solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid can also be used to prepare injections.

The compounds of the invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and which will dissolve in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycol.

It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health condition, the patient's behavior, the patient's diet, the administration time, the administration method, the excretion rate, the combination of drugs, etc. In addition, the best treatment method, such as the mode of treatment, the daily dosage of the general compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment plans.

The present invention can contain the compound shown in the general formula, and its pharmaceutically acceptable salt, hydrate or solvate as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared into a clinically acceptable dosage form. The derivative of the present invention can be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions, etc. The compound of the present invention can be used as the only active ingredient, or it can be used in combination with other drugs. The combination is achieved by administering each component simultaneously, separately or successively.

Terminology

Unless stated otherwise, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, oxo, carboxyl or carboxylate.

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Alkenyl groups typically contain 2 to 20 carbon atoms ( _C2 - _C20 alkenyl), preferably 2 to 12 carbon atoms ( _C2 - _C12 alkenyl), more preferably 2 to 8 carbon atoms ( _C2 - _C8 alkenyl) or 2 to 6 carbon atoms ( _C2 - _C6 alkenyl) or 2 to 4 carbon atoms ( _C2 - _C4 alkenyl). Non-limiting examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio.

The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Alkynyl groups typically contain 2-20 carbon atoms ( _C2 - _C20 alkynyl), preferably 2 to 12 carbon atoms ( _C2 - _C12 alkynyl), more preferably 2 to 8 carbon atoms ( _C2 - _C8 alkynyl) or 2 to 6 carbon atoms ( _C2 - _C6 alkynyl) or 2 to 4 carbon atoms ( _C2 - _C4 alkynyl). Non-limiting examples of alkynyl groups include ethynyl, propynyl, butynyl, etc. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl ring comprises 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. The limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl etc. Polycyclic cycloalkyl includes the cycloalkyl of spiro ring, condensed ring and bridge ring.

The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14, more preferably 7 to 10. According to the number of spiral atoms shared between the rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is a 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of condensed cycloalkyls include:

The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, and more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, oxo, carboxyl or carboxylate.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; it may also contain 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; or it may contain 5 to 8 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms; or it may contain 3 to 6 ring atoms, of which 1 to 2 are heteroatoms; or it may contain 5 to 6 ring atoms, of which 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include oxetanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiral atom) is shared between 5 to 20 monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 4-yuan/4-yuan, 4-yuan/5-yuan, 4-yuan/6-yuan, 5-yuan/5-yuan or 5-yuan/6-yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include: wait.

The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, oxo, carboxyl or carboxylate.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, carboxyl or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms. Non-limiting examples of heteroaryl groups include imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, heterocyclylthio, carboxyl or carboxylate.

The term "alkoxy" refers to -O-(alkyl), wherein the definition of alkyl is as described above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkyloxy, heterocyclic radical oxygen base, cycloalkylthio, heterocyclic radical thio, carboxyl or carboxylate.

The term "sub" means a divalent group obtained by removing two hydrogen atoms from a group. For example, the term "alkylene" refers to a divalent alkyl group obtained by removing two hydrogen atoms from an alkyl group, wherein the alkyl group is as defined above. Similarly, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, and heteroarylene refer to a divalent group obtained by removing two hydrogen atoms from an alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group, wherein the alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

The term "hydroxy" refers to an -OH group.

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

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "oxo" refers to =0.

The term "carboxy" refers to -C(O)OH.

The term "thiol" refers to -SH.

The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

The term "acyl" refers to a compound containing a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl may but need not be present, and the description includes instances where the heterocyclyl is substituted with alkyl and instances where the heterocyclyl is not substituted with alkyl.

"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

"Pharmaceutically acceptable salts" and "pharmaceutically acceptable salts" are used interchangeably and refer to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

Synthesis method of the compound of the present invention

In order to achieve the purpose of the present invention, the present invention adopts the following technical scheme.

When X is N, Y is S, and ^R1 is NR ^a R ^b , the compound of the present invention or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, can be prepared by the following scheme:

Step 1: Compound Ia is reacted with compound Ib in the presence of alkaline conditions and a condensing agent to obtain compound Ic, wherein the reagent providing alkaline conditions is preferably DIEA; and the condensing agent is preferably T ₃ P;

Step 2: Compound Ic is reacted under acidic conditions to obtain compound Id, wherein the reagent under acidic conditions is preferably PPA;

Step 3: reacting compound Id with an iodination reagent to obtain compound Ie, wherein the iodination reagent is preferably NIS;

Step 4: Compound Ie is reacted in the presence of a catalyst to obtain Compound If, wherein the catalyst is preferably Pd(dppf)Cl ₂ ;

Step 5: reacting compound If under acidic conditions to obtain compound Ig, wherein the reagent under acidic conditions is preferably phosphorus oxychloride;

Step 6: Compound Ig is reacted with Ih under alkaline conditions to obtain compound Ii;

Step 7: reacting compound Ii with an iodination reagent under acidic conditions to obtain compound Ij, wherein the acidic reagent is preferably TFA; the iodination reagent is preferably NIS;

Step 8: Compound Ij is reacted with compound Ik in the presence of a catalyst to obtain compound Il, wherein the catalyst is preferably Pd(dppf)Cl ₂ or tetrakistriphenylphosphine palladium;

Step 9: Compound Il is reacted with compound Im in the presence of a catalyst to obtain compound I-1, wherein the catalyst is preferably Pd(dppf)Cl ₂ or tetrakistriphenylphosphine palladium;

R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , Ra , R ^b , ^A and L are as defined in the general formula (I).

DETAILED DESCRIPTION

The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts are given in units of 10 ^-6 (ppm). NMR measurements were made using a Bruker dps 300 NMR spectrometer, with deuterated solvent. Deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was tetramethylsilane (TMS).

Mass spectrometry (MS) was measured using an 1100 Series LC/MSD Trap (ESI) mass spectrometer (manufacturer: Agilent).

Unless otherwise specified in the examples, the preparative liquid chromatography used an LC3000 high performance liquid chromatograph and an LC6000 high performance liquid chromatograph (manufacturer: Chuangxin Tongheng).

High performance liquid chromatography (HPLC) was performed using Shimadzu LC-20AD high pressure liquid chromatograph (Agilent TC-C18 250×4.6mm 5μm column) and Shimadzu LC-2010AHT high pressure liquid chromatograph (Phenomenex C18 250×4.6mm5μm column).

The thin layer chromatography silica gel plate used was Qingdao Ocean Chemical GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15 mm to 0.2 mm, and the specification used for thin layer chromatography separation and purification products was 0.4 mm to 0.5 mm.

Column chromatography generally uses Qingdao Marine Silica Gel 100-200 mesh and 200-300 mesh silica gel as the carrier.

The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Inokai, Nanjing Yaoshi, Anaiji Chemical and other companies.

Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1L.

Microwave reactions were performed using a CEM Discover SP microwave reactor.

Unless otherwise specified in the examples, the solution refers to an aqueous solution.

Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), and the developing solvent systems used in the reaction are: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone, and the volume ratio of the solvent is adjusted according to the polarity of the compound.

The eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying compounds include: A: dichloromethane and methanol system, B: petroleum ether, ethyl acetate and dichloromethane system, C: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Example

Example 1: Preparation of 4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-methylacrylamidephenyl)thieno[3,2-c]pyridine-7-carboxamide (1)

Step 1: Preparation of 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (1c)

At room temperature, cesium carbonate (50.8 g, 0.16 mol) was added to a mixture of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) (30.9 g, 0.13 mol) and 2-chloro-4-methylpyrimidine (1b) (18.7 g, 0.14 mol) in DMF (250 mL), heated to 80°C, and stirred overnight. The reaction solution was cooled, diluted with water (1 L), extracted three times with ethyl acetate, the organic phases were combined, washed with brine, dried, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (mobile phase: PE/EA=PE-4:1) to obtain 26.0 g of the title compound as a brown solid, with a yield of 60.6%.

LC-MS: m/z 331 [M+H] ⁺ .

Step 2: Preparation of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f)

At 0°C, under nitrogen atmosphere, methacryloyl chloride (1e) (5.76 g, 54.8 mmol) was added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d) (10.0 g, 45.7 mmol) and sodium carbonate (9.68 g, 91.3 mmol) in tetrahydrofuran/water (2 mL/1 mL), and stirred at 0°C for 2 hours. The reaction solution was concentrated under reduced pressure and separated and purified by silica gel column chromatography (mobile phase: PE/EA=PE-1:1) to obtain 9.20 g of the title compound as a brown solid, with a yield of 70.1%.

LC-MS: m/z 288 [M+H] ⁺ .

Step 3: Preparation of 4-bromo-N-(2,2-dimethoxyethyl)thiophene-3-carboxamide (1i)

Under ice bath, add dropwise a solution of T ₃ P (73.7 g, 116 mmol) in ethyl acetate to a mixture of 4-bromothiophene-3-carboxylic acid (1 g) (20.0 g, 96.6 mmol), 2,2-dimethoxyethane-1-amine (1h) (11.1 g, 106 mmol) and DIEA (18.7 g, 145 mmol) in ethyl acetate (250 mL), and the reaction solution gradually becomes clear. After reacting at room temperature for 3 hours, the reaction solution is poured into a citric acid aqueous solution, extracted with ethyl acetate for 3 times, the organic phases are combined, dried, concentrated, and separated and purified by silica gel column chromatography (mobile phase: PE/EA=PE-4:1) to obtain 25.0 g of the title compound as a brown solid, yield: 88.0%

LC-MS: m/z 294 [M+H] ⁺ .

Step 4: Preparation of 3-bromothieno[3,2-c]pyridin-4(5H)-one (1j)

At 100°C, 4-bromo-N-(2,2-dimethoxyethyl)thiophene-3-carboxamide (1i) (25.0 g, 85 mmol) was added to PPA (300 g) in batches, stirred at 100°C for 4 hours, cooled to 40-50°C, water (550 mL) was added dropwise, cooled to room temperature and stirred for 30 minutes, filtered, and the filter cake was rinsed with water and acetonitrile in turn to obtain 15.0 g of brown solid compound dried in vacuo, with a yield of 76.7%.

LC-MS: m/z 230 [M+H] ⁺ .

Step 5: Preparation of 3-bromo-7-iodo-thieno[3,2-c]pyridin-4(5H)-one (1k)

NIS (16.4 g, 73.0 mmol) was added in batches to 3-bromothieno[3,2-c]pyridin-4(5H)-one (1j) (14.0 g, 60.9 mmol) in DMF (200 mL) at room temperature. The mixture was stirred overnight at room temperature. The reaction solution was poured into water (500 mL) and filtered. The filter cake was washed with water and acetonitrile in turn and dried in vacuo to give 16.0 g of the title compound as a brown solid in a yield of 74.0%.

LC-MS: m/z 356 [M+H] ⁺ .

Step 6: Preparation of 3-bromo-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carbonitrile (1l)

At room temperature, add Pd(dppf)Cl ₂ (3.28 g, 4.50 mmol) to a solution of 3-bromo-7-iodo-thieno[3,2-c]pyridin-4(5H)-one (1k) (16.0 g, 45.0 mmol), zinc cyanide (3.12 g, 27 mmol) and zinc powder (252 mg, 4.50 mmol) in NMP (200 mL), replace nitrogen three times, raise the temperature to 80°C and stir overnight. Cool the reaction solution to room temperature, filter, add water (400 mL) to the filtrate, solid precipitates, filter, wash the filter cake with water, and dry to obtain 12.4 g of a crude brown solid title compound.

LC-MS: m/z 255 [M+H] ⁺ .

Step 7: Preparation of 3-bromo-4-chlorothieno[3,2-c]pyridine-7-carbonitrile (1m)

Phosphorus oxychloride (10 ml) was added to 3-bromo-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-7-carboxylate (1 l) (8.00 g, 31.4 mmol) at room temperature, and the atmosphere was replaced with nitrogen three times. The reaction was carried out at 110°C for 4 hours. The reaction solution was concentrated under reduced pressure, ice water was added, stirred, filtered, and the filter cake was dried under vacuum to obtain 5.0 g of the title compound as a brown solid, with a yield of 58.1%.

LC-MS: m/z 273 [M+H] ⁺ .

Step 8: Preparation of 4-amino-3-bromothieno[3,2-c]pyridine-7-carbonitrile (1n)

At room temperature, add ammonia water (100 ml) to a mixture of 3-bromo-4-chlorothieno[3,2-c]pyridine-7-carbonitrile (1 m) (5.0 g, 18.2 mmol) in dioxane (100 mL), and stir overnight at 90°C. Cool to room temperature, concentrate under reduced pressure to remove the organic solvent, filter, and dry the filter cake in vacuum to obtain 4.20 g of the title compound as a light yellow solid, with a yield of 90.9%.

LC-MS: m/z 254 [M+H] ⁺ .

Step 9: Preparation of 4-amino-3-bromo-2-iodothieno[3,2-c]pyridine-7-carboxamide (1o)

At room temperature, NIS (8.43 g, 33.1 mmol) was added to a mixture of 4-amino-3-bromothieno[3,2-c]pyridine-7-carbonitrile (1n) (4.20 g, 16.5 mmol) in trifluoroacetic acid/dichloroethane (100 mL, v/v=1/1), and reacted at 70°C for 5 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and the pH was adjusted to 8 with potassium phosphate aqueous solution. The mixture was filtered, and the filter cake was rinsed with water and ethyl acetate in turn, and dried in vacuo to obtain the title compound as a gray solid (4.80 g, yield: 76.4%).

LC-MS: m/z 398 [M+H] ⁺ .

Step 10: Preparation of 4-amino-3-bromo-2-(4-methylacrylamidephenyl)thieno[3,2-c]pyridine-7-carboxamide (1p) Tetrakistriphenylphosphine palladium (208 mg, 0.18 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)phenyl)methacrylamide (1f) (0.51 g, 1.76 mmol) and potassium phosphate (1.12 g, 5.28 mmol) were added to a solution of 4-amino-3-bromo-2-iodothieno[3,2-c]pyridine-7-carboxamide (1o) (0.70 g, 1.76 mmol) in N,N-dimethylformamide/water (15 mL/2 mL) at room temperature, the atmosphere was replaced with nitrogen three times, and the mixture was stirred at 50°C overnight. After the reaction was completed, the temperature was lowered to room temperature, diluted with ethyl acetate (60 mL), washed with water (20 mL × 2), and then washed with saturated brine (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH = 100: 1-20: 1) to obtain 500 mg of the title compound as a brown solid, with a yield of 66.0%.

LC-MS: m/z 431 [M+H] ⁺ .

Step 11: Preparation of 4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-methylacrylamidephenyl)thieno[3,2-c]pyridine-7-carboxamide (1)

At room temperature, tetrakistriphenylphosphine palladium (81 mg, 0.07 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)phenoxy)-4-methylpyrimidine (1c) (276 mg, 0.84 mmol) and potassium phosphate (445 mg, 2.10 mmol) were added to a solution of 4-amino-3-bromo-2-iodothieno[3,2-c]pyridine-7-carboxamide (1p) (300 mg, 0.70 mmol) in N,N-dimethylformamide/water (7 mL/1 mL), replaced with nitrogen three times, and stirred at 50°C overnight. After the reaction was completed, the temperature was cooled to room temperature, diluted with ethyl acetate (60 mL), washed with water (20 mL×2), and then washed with saturated brine (20 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by centrifugation. The residue was concentrated under reduced pressure and separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 10-50%) to obtain 27 mg of the title compound as a white solid. Yield: 6.96%.

LC-MS: m/z 555 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.86 (s, 1H), 8.56 (s, 1H), 8.51 (d, J = 5.0Hz, 1H), 8.01 (s, 1H), 7.64 (d, 2H),7.52-7.43(m,2H),7.34(s,1H),7.30-7.26(m,1H),7.24-7.16(m,3H),5.83-5.70(m,2H),5.52(s, 1H),2.43(s,3H),1.94(s,3H).

Example 2: Preparation of 4-amino-2-(4-methylacrylamidophenyl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (2)

Step 1: Preparation of 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (2b)

At room temperature, cesium carbonate (42.4 g, 0.13 mol) was added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2a) (22.0 g, 0.10 mol) and 2-chloro-4-methylpyrimidine (1b) (12.8 g, 0.10 mol) in DMF (250 mL), heated to 80°C, and stirred overnight. The reaction solution was cooled, diluted with water (1 L), extracted three times with ethyl acetate, the organic phases were combined, washed with brine, dried, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (mobile phase: PE/EA = PE-4:1) to obtain 20.0 g of the title compound as a brown solid, with a yield of 64.1%.

LC-MS: m/z 313 [M+H] ⁺ .

The title compound 2 was prepared in the same manner as in Example 1, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a).

LC-MS: m/z 537 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.83 (s, 1H), 8.54 (s, 1H), 8.50 (d, J = 5.0Hz, 1H), 8.01 (s, 1H), 7.64-7.56 ( m,2H),7.48-7.40(m,2H),7.38-7.25(m,3H),7.24-7.15(m,3H),5.99-5.63(m,3H),5.53-5.48(m,1H), 2.43(s,3H),1.93(s,3H).

Example 3: Preparation of 4-amino-3-(3-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-methylacrylamidephenyl)thieno[3,2-c]pyridine-7-carboxamide (3)

The title compound 3 was prepared in the same manner as in Example 1, except that 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a).

LC-MS: m/z 571 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.87 (s, 1H), 8.57 (s, 1H), 8.50 (d, J = 5.0Hz, 1H), 8.01 (s, 1H), 7.68-7.62 ( m,3H),7.49-7.43(m,2H),7.36(s,1H),7.23-7.17(m,3H),5.91-5.65(m,3H),5.54-5.50(m,1H),2.43( s,3H),1.94(s,3H).

Example 4: Preparation of 4-amino-2-(4-methylacrylamidophenyl)-3-(6-((4-methylpyrimidin-2-yl)oxy)pyridin-3-yl)thieno[3,2-c]pyridine-7-carboxamide (4)

The title compound 4 was prepared in the same manner as in Example 1, except that 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ol was used instead of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a).

LC-MS: m/z 538 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.87 (s, 1H), 8.62-8.51 (m, 2H), 8.22 (d, J = 2.7Hz, 1H), 8.09-7.92 (m, 2H), 7.70-7.59(m,2H),7.42-7.28(m,2H),7.25(d,J＝5.0Hz,1H),7.20-7.13(m,2H),5.88-5.66(m,3H),5.52( s,1H),2.44(s,3H),1.94(s,3H).

Example 5: Preparation of 4-amino-2-(2-fluoro-4-methylacrylamidophenyl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (5)

Step 1: Preparation of N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (5b)

At 0°C, under nitrogen atmosphere, methacryloyl chloride (1e) (5.76 g, 54.8 mmol) was added to a mixture of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (5a) (10.8 g, 45.7 mmol) and sodium carbonate (9.68 g, 91.3 mmol) in tetrahydrofuran/water (2 mL/1 mL), and stirred at 0°C for 2 hours. The reaction solution was concentrated under reduced pressure and separated and purified by silica gel column chromatography (mobile phase: PE/EA=PE-1:1) to obtain 10.2 g of the title compound as a brown solid, with a yield of 73.2%.

LC-MS: m/z 306 [M+H] ⁺ .

The preparation method of Example 1 is the same, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol is used instead of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) and N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (5b) is used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) to obtain the title compound 5.

LC-MS: m/z 555 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 10.03 (s, 1H), 8.58 (s, 1H), 8.48 (d, J = 5.0Hz, 1H), 8.02 (s, 1H), 7.67-7.62 ( m,1H),7.44-7.40(m,1H),7.39-7.30(m,3H),7.28-7.21(m,3H),7.18-7.14(m,1H),6.01-5.67(m,3H), 5.58-5.52(m,1H),2.40(s,3H),1.93(s,3H).

Example 6: Preparation of 4-amino-2-(4-methylacrylamide-2-methylphenyl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (6)

The title compound 6 was prepared by the same preparation method as in Example 1, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d).

LC-MS: m/z 551 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.75 (s, 1H), 8.57 (s, 1H), 8.46 (d, J = 5.1Hz, 1H), 8.16-7.80 (s, 1H), 7.54- 7.46(m,2H),7.38-7.30(m,3H),7.24-7.17(m,3H),7.16-7.11(m,1H),5.97-5.71(m,3H),5.52-5.48(m,1H ),2.40(s,3H),2.07(s,3H),1.93(s,3H).

Example 7: Preparation of 4-amino-2-(3-fluoro-4-methylacrylamidophenyl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (7)

The title compound 7 was prepared by the same preparation method as in Example 1, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d).

LC-MS: m/z 555 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.57 (s, 1H), 8.57 (s, 1H), 8.50 (d, J = 5.0Hz, 1H), 8.02 (s, 1H), 7.57-7.44 ( m,3H),7.43-7.27(m,3H),7.21-7.11(m,2H),7.06-6.98(m,1H),5.90-5.73(m,3H),5.56-5.51(m,1H), 2.42(s,3H),1.93(s,3H).

Example 8: Preparation of 4-amino-2-(4-methylacrylamidophenyl)-N,N-dimethyl-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (8)

Step 1: Preparation of 4-amino-3-bromothieno[3,2-c]pyridine-7-carboxylic acid (8a)

At room temperature, sodium hydroxide (1.98 g, 49.6 mmol) was added to a mixture of 4-amino-3-bromothieno[3,2-c]pyridine-7-carbonitrile (1n) (4.20 g, 16.5 mmol) in ethanol and water (100 mL, v/v = 2/1) in a sealed tube. The mixture was stirred at 80°C overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, the pH was adjusted to about 4 with dilute hydrochloric acid, filtered, and dried in vacuo to obtain 2.70 g of the title compound as a yellow solid, with a yield of 59.9%.

LC-MS: m/z 274 [M+H] ⁺ .

Step 2: Preparation of 4-amino-3-bromo-N,N-dimethylthieno[3,2-c]pyridine-7-carboxamide (8c)

At room temperature, 4-amino-3-bromothieno[3,2-c]pyridine-7-carboxylic acid (8a) (700 mg, 2.57 mmol), dimethylamine hydrochloride (8b) (2.11 g, 25.57 mmol), HATU (1.17 g, 3.08 mmol) and N,N-diisopropylethylamine (995 mg, 7.71 mmol) were added to N,N-dimethylformamide (20 mL) solution in a sealed tube, sealed, and stirred at 60°C overnight. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm*250 mm, C18, 10 um, 100 A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 10-60%) to obtain 250 mg of the title compound as a yellow solid, yield: 32.5%

LC-MS: m/z 300 [M+H] ⁺ .

Step 3-5: The same preparation method as in Example 1, except that 4-amino-3-bromo-N,N-dimethylthieno[3,2-c]pyridine-7-carboxamide (8c) was used instead of 4-amino-3-bromothieno[3,2-c]pyridine-7-carbonitrile (1n) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. -1,3,2-dioxaborolan-2-yl)phenol (1a) to obtain the title compound 8.

LC-MS: m/z 565 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.85 (s, 1H), 8.50 (d, J = 5.0Hz, 1H), 8.06 (s, 1H), 7.65-7.57 (m, 2H), 7.49- 7.41(m,2H),7.34-7.27(m,2H),7.23-7.14(m,3H),5.79-5.76(m,1H),5.68(s,2H),5.53-5.49(m,1H), 3.10(s,6H),2.43(s,3H),1.93(s,3H).

Example 9: Preparation of 4-amino-2-(4-methylacrylamidophenyl)-N-methyl-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (9)

The title compound 9 was prepared in the same manner as in Example 8, except that monomethylamine hydrochloride was used instead of dimethylamine hydrochloride (8b).

LC-MS: m/z 551 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.91-9.85 (m, 1H), 8.71 (d, J = 5.1Hz, 1H), 8.54-8.45 (m, 2H), 7.67-7.60 (m, 2H) ),7.51-7.42(m,2H),7.37-7.31(m,2H),7.24-7.14(m,3H),6.85-6.34(m,2H),5.79-5.75(m,1H),5.53-5.49 (m,1H),2.85(s,3H),2.42(s,3H),1.93(s,3H).

Example 10: Preparation of 4-amino-2-(4-methacrylamido-3-methoxyphenyl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (10)

The title compound 10 was prepared by the same preparation method as in Example 1, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d).

LC-MS: m/z 567 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 8.75 (s, 1H), 8.56 (s, 1H), 8.49 (d, J = 5.0Hz, 1H), 8.00 (s, 1H), 7.88-7.83 ( m,1H),7.51-7.46(m,2H),7.40-7.26(m,3H),7.20-7.17(m,1H),7.07-7.01(m,1H),6.74-6.70(m,1H), 6.03-5.64(m,3H),5.51-5.47(m,1H),3.60(s,3H),2.43(s,3H),1.94(s,3H).

Example 11: Preparation of 4-amino-2-(4-methacrylamido-2-methoxyphenyl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (11)

The title compound 11 was prepared by the same preparation method as in Example 1, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) and 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d).

LC-MS: m/z 567 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.82 (s, 1H), 8.54 (s, 1H), 8.47 (d, J = 5.0Hz, 1H), 7.97 (s, 1H), 7.46-7.41 ( m,1H),7.33-7.28(m,2H),7.27-7.23(m,1H),7.22-7.17(m,2H),7.17-7.13(m,1H),7.12-7.07(m,1H), 5.99-5.67(m,3H),5.54-5.49(m,1H),3.58(s,3H),2.39(s,3H),1.93(s,3H).

Example 12: Preparation of 4-amino-2-(4-methylacrylamidophenyl)-3-(4-((4-methylpyrimidin-2-yl)oxy)-3-(trifluoromethyl)phenyl)thieno[3,2-c]pyridine-7-carboxamide (12)

Step 1: Preparation of 2-(4-bromo-2-(trifluoromethyl)phenoxy)-4-methylpyrimidine (12b)

At room temperature, cesium carbonate (7.03 g, 21.6 mmol) was added to a solution of 2-chloro-4-methylpyrimidine (2.13 g, 16.6 mmol) and 4-bromo-2-(trifluoromethyl)phenol (4.00 g, 16.6 mmol) in N,N-dimethylformamide (100 mL), and the temperature was raised to 100°C and stirred overnight. The reaction solution was cooled, diluted with EA (150 mL), washed with aqueous ammonium chloride solution (400 mL×2), the aqueous phase was extracted with EA (200 mL×2), the organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-4:1) to obtain 4.80 g of the title compound as a yellow oily liquid, with a yield of 86.8%.

LC-MS: m/z 334 [M+H] ⁺ .

Step 2: Preparation of 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)pyrimidine (12c)

At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (525 mg, 0.72 mmol) was added to a mixture of 2-(4-bromo-2-(trifluoromethyl)phenoxy)-4-methylpyrimidine (12b) (4.80 g, 14.46 mmol), 4,4,4',4',5,5',5',2'-octamethyl-2'-bis(1,3,2-dioxaborolane) (4.04 g, 15.9 mmol) and potassium acetate (3.55 g, 36.2 mmol) in dioxane (40 mL), replaced with nitrogen three times, and stirred at 90°C for 3 hours. The reaction solution was cooled and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-4:1) to obtain 4.96 g of the title compound as a white solid, with a yield of 90.2%.

LC-MS: m/z 381 [M+H] ⁺ .

The title compound 12 was prepared by the same preparation method as in Example 1, except that 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)pyrimidine (12c) was used instead of 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (1c).

LC-MS: m/z 605 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.86 (s, 1H), 8.58 (s, 1H), 8.52 (d, J = 4.0Hz, 1H), 8.02 (s, 1H), 7.79 (s, 1H),7.76-7.73(m,1H),7.65(d,J＝8.0Hz,2H),7.53(d,J＝8.0Hz,1H),7.36(s,1H),7.23(d,J＝8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 5.79-5.73 (m, 3H), 5.52 (s, 1H), 2.44 (s, 3H), 1.94 (s, 3H).

Example 13: Preparation of 4-amino-3-(2-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-methylacrylamide-2-methylphenyl)thieno[3,2-c]pyridine-7-carboxamide (13)

The title compound 13 was prepared by the same preparation method as in Example 1, except that 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d).

LC-MS: m/z 569 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.76 (s, 1H), 8.58 (s, 1H), 8.49 (d, J = 8.0Hz, 1H), 8.02 (s, 1H), 7.55-7.54 ( m,1H),7.50-7.47(m,1H),7.44-7.39(m,1H),7.37-7.28(m,1H),7.27-7.24(m,1H),7.19-7.18(m,1H), 7.14-7.12(m,1H),7.09-7.06(m,1H),5.78(s,3H),5.50(s,1H),2.40(s,3H),2.11(s,3H),1.93(s, 3H).

Example 14: Preparation of 4-amino-2-(2-(difluoromethyl)-4-methylacrylamidophenyl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (14)

Step 1: Preparation of 1-bromo-2-(difluoromethyl)-4-nitrobenzene (14b)

In an ice bath, add diethylaminosulfur trifluoride (10.51 g, 65.2 mol) to a solution of 2-bromo-5-nitrobenzaldehyde (10.00 g, 43.48 mol) in dichloromethane (100 mL), slowly warm to room temperature, and stir. Overnight. The reaction solution was quenched by adding saturated sodium bicarbonate aqueous solution. Extraction was performed with dichloromethane (150 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 10 g of the title compound was obtained as a light yellow oily liquid, with a yield of 91.4%.

LC-MS: m/z 252 [M+H] ⁺ .

Step 2: Preparation of 4-bromo-3-(difluoromethyl)aniline (14c)

At room temperature, ammonium chloride (10.614 g, 192.39 mmol) and iron powder (11.071 g, 198.41 mmol) were added to water (200 mL), and then a solution of 1-bromo-2-(difluoromethyl)-4-nitrobenzene (14b) (10 g, 39.68 mmol) in methanol (100 mL) was added, and stirred at 70°C for 3 h. After the reaction was completed, the mixture was filtered, and the filter cake was washed with ethyl acetate (100 mL). The filtrate was combined, extracted with ethyl acetate (150 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 8 g of the title compound as a yellow solid, with a yield of 90.6%.

LC-MS: m/z 222 [M+H] ⁺ .

Step 3: Preparation of N-(4-bromo-3(difluoromethyl)phenyl)methacrylamide (14d)

Methacryloyl chloride (2.071 g, 19.82 mmol) and pyridine (2.138 g, 27.03 mmol) were added to a solution of 4-bromo-3-(difluoromethyl)aniline (14c) (4 g, 18.02 mmol) in tetrahydrofuran (150 mL) at 0°C and stirred at 0°C for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 50:1-4:1) to obtain 4.5 g of the title compound as a light yellow solid, with a yield of 86.1%.

LC-MS: m/z 290 [M+H] ⁺ .

Step 4: Preparation of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e)

At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.500 g, 0.69 mmol) was added to a dioxane (40 mL) solution of N-(4-bromo-3(difluoromethyl)phenyl)methacrylamide (14d) (2 g, 6.89 mmol), bis(pinacolato) (1.750 g, 6.89 mmol) and potassium acetate (2.029 g, 20.68 mmol), replaced with nitrogen three times, and stirred at 90°C overnight. The reaction solution was cooled, diluted with water (100 mL), extracted with EA (100 mL×3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-2:1) to obtain 1.50 g of the title compound as a light yellow solid, with a yield of 64.6%.

LC-MS: m/z 338 [M+H] ⁺ .

The title compound 14 was prepared by the same preparation method as in Example 1, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) and N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f).

LC-MS: m/z 587 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.03 (s, 1H), 8.60 (s, 1H), 8.51-8.39 (m, 1H), 8.08-7.98 (m, 1H), 7.84-7.76 (m, 1H),7.50-7.26(m,3H),7.25-7.10(m,3H),7.02-6.65(m,1H),5.83(s,1H),5.55(s,1H),2.38(s,3H) ,1.94(s,3H).

Example 15: Preparation of 4-amino-2-(4-methacrylamidophenyl)-3-(2-methoxy-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (15)

Step 1: Preparation of 2-(4-bromo-3-methoxyphenoxy)-4-methylpyrimidine (15b)

At room temperature, 4-bromo-3-methoxyphenol (5 g, 24.63 mol), 2-chloro-4-methylpyrimidine (1b) (3.167 g, 24.63 mol), and cesium carbonate (12.022 g, 36.95 mol) were added to N,N-dimethylformamide (30 mL) and stirred at room temperature overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 50:1-1:1) to obtain 6 g of the title compound as a yellow solid, with a yield of 82.7%.

LC-MS: m/z 295 [M+H] ⁺ .

Step 2: Preparation of 2-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (15c)

At room temperature, 2-(4-bromo-3-methoxyphenoxy)-4-methylpyrimidine (15b) (1g, 3.39mmol), bipinacol ester (860mg, 3.39mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (246mg, 0.34mmol) and potassium acetate (997mg, 10.17mmol) were added to N,N-dimethylformamide (10mL) solution, replaced with nitrogen three times, and stirred at 90°C for 3h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-1:1) to obtain 600mg of the title compound as a yellow solid, yield: 51.8%.

LC-MS: m/z 343 [M+H] ⁺ .

Step 3: Preparation of 4-amino-2-(4-methacrylamidophenyl)-3-(2-methoxy-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (15)

At room temperature, 4-amino-3-bromo-2-(4-methylacrylamidophenyl)thieno[3,2-c]pyridine-7-carboxamide (1p) (140 mg, 0.32 mmol), 2-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (15c) (133 mg, 0.39 mmol), tetrakis(triphenylphosphine)palladium (57 mg, 0.05 mmol) and sodium carbonate (103 mg, 0.97 mmol), water (0.8 mL), and ethanol (1.6 mL) were added to a toluene (8 mL) solution, replaced with nitrogen three times, and stirred at 90° C. for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm × 250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% ammonia solution, gradient: 30-33%) to obtain 23 mg of the title compound as a white solid, yield: 12.5%.

LC-MS: m/z 567 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.83 (s, 1H), 8.57-8.43 (m, 2H), 7.97 (s, 1H), 7.69-7.54 (m, 2H), 7.45-7.00 (m, 5H),6.89-6.76(m,1H),5.77(s,1H),5.51(s,1H),3.68(s,3H),2.43(s,3H),1.93(s,3H).

Example 16: Preparation of 4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-methylacrylamide-2-methylphenyl)-N-methylthieno[3,2-c]pyridine-7-carboxamide (16)

The title compound 16 was prepared in the same manner as in Example 8, except that 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, and methylamine hydrochloride was used instead of dimethylamine hydrochloride (8b).

LC-MS: m/z 583 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.76 (s, 1H), 8.68-8.32 (m, 3H), 7.60-7.45 (m, 2H), 7.42-7.30 (m, 2H), 7.26-7.12 ( m,3H),5.78(s,1H),5.51(s,1H),2.90-2.74(m,3H),2.38(s,3H),2.08(s,3H),1.94(s,3H).

Example 17: Preparation of 4-amino-3-(3-cyano-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-methylacrylamidophenyl)thieno[3,2-c]pyridine-7-carboxamide (17)

Step 1: Preparation of 2-(4-methylpyrimidin-2-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (17b)

At room temperature, cesium carbonate (50.8 g, 0.16 mol) was added to a mixture of 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (17a) (31.8 g, 0.13 mol) and 2-chloro-4-methylpyrimidine (1b) (18.7 g, 0.14 mol) in DMF (250 mL), heated to 80°C, and stirred overnight. The reaction solution was cooled, diluted with water (1 L), extracted three times with ethyl acetate, the organic phases were combined, washed with brine, dried, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (mobile phase: PE/EA=PE-4:1) to obtain 27.0 g of the title compound as a brown solid, with a yield of 61.5%.

LC-MS: m/z 337 [M+H] ⁺ .

The title compound 17 was prepared by the same preparation method as in Example 1, except that 2-(4-methylpyrimidin-2-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (17b) was used instead of 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (1c).

LC-MS: m/z 562 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.87 (s, 1H), 8.60-8.54 (m, 2H), 8.11-7.96 (m, 2H), 7.77-7.72 (m, 1H), 7.68-7.63 ( m,2H),7.57-7.52(m,1H),7.44-7.31(m,1H),7.30-7.26(m,1H),7.21-7.15(m,2H),5.85-5.68(m,3H), 5.54-5.50(m,1H),2.46(s,3H),1.94(s,3H).

Example 18: Preparation of 4-amino-2-(4-methylacrylamidophenyl)-3-(3-methyl-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (18)

Step 1: Preparation of 4-methyl-2-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (18b)

At room temperature, cesium carbonate (42.4 g, 0.13 mol) was added to a mixture of 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) (18a) (23.4 g, 0.10 mol) and 2-chloro-4-methylpyrimidine (1b) (12.8 g, 0.10 mol) in DMF (250 mL), heated to 80°C, and stirred overnight. The reaction solution was cooled, diluted with water (1 L), extracted three times with ethyl acetate, the organic phases were combined, washed with brine, dried, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (mobile phase: PE/EA=PE-4:1) to obtain 21.1 g of the title compound as a brown solid, with a yield of 64.7%.

LC-MS: m/z 337 [M+H] ⁺ .

The title compound 18 was prepared by the same preparation method as in Example 1, except that 4-methyl-2-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (18b) was used instead of 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (1c).

LC-MS: m/z 551 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.84 (s, 1H), 8.54 (s, 1H), 8.48 (d, J = 5.0Hz, 1H), 7.99 (s, 1H), 7.65-7.59 (m ,2H),7.38-7.35(m,1H),7.29-7.26(m,1H),7.25-7.20(m,3H),7.17-7.14(m,1H),5.96-5.61(m,3H),5.53 -5.49(m,1H),2.42(s,3H),2.09(s,3H),1.93(s,3H).

Example 19: Preparation of 4-amino-3-(3-(dimethylamino)-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-methylacrylamidophenyl)thieno[3,2-c]pyridine-7-carboxamide (19)

Step 1: Preparation of 4-bromo-2-(dimethylamino)phenol (19b)

At room temperature, add 2-amino-4-bromophenol (3.9 g, 20.74 mmol) to acetic acid (120 mL). Heat to 40 ° C, add paraformaldehyde (1.9 g, 62.23 mmol) to the reaction solution, and then slowly add sodium cyanoborohydride (3.9 g, 62.23 mmol) in batches. Stir at 40 ° C for 1 hour. Then add another portion of paraformaldehyde (1.9 g, 62.23 mmol) and sodium cyanoborohydride (3.9 g, 62.23 mmol) to the reaction solution. Stir overnight at 40 ° C. Cool to room temperature, concentrate under reduced pressure, dilute with water, extract with ethyl acetate 3 times, combine the organic phases, dry, concentrate, and separate and purify by silica gel column chromatography (mobile phase: PE/EA=4:1-2:1) to obtain 2.76 g of the title compound as an orange-yellow oil, yield: 61.5%.

LC-MS: m/z 216 [M+H] ⁺ .

Step 2: Preparation of 5-bromo-N,N-dimethyl-2-((4-methylpyrimidin-2-yl)oxy)aniline (19c)

At room temperature, 4-bromo-2-(dimethylamino)phenol (19b) (2.2 g, 10.23 mmol), 2-chloro-4-methylpyrimidine (1.4 g, 11.26 mmol) and cesium carbonate (5.0 g, 15.35 mmol) were added to DMF (50 mL). The mixture was stirred at 100°C for 3 hours. The mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate three times, the organic phases were combined, dried, concentrated, and separated and purified by silica gel column chromatography (mobile phase: PE/EA=PE-4:1) to obtain 2.8 g of the title compound as a black solid, with a yield of 89.1%.

LC-MS: m/z 308 [M+H] ⁺ .

Step 3: Preparation of N,N-dimethyl-2-((4-methylpyrimidin-2-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (19d)

At room temperature, Pd(dppf)Cl ₂ (622 mg, 0.85 mmol), biboronic acid pinacol ester (2.2 g, 8.47 mmol) and potassium acetate (2.5 g, 25.41 mmol) were added to a solution of 5-bromo-N,N-dimethyl-2-((4-methylpyrimidin-2-yl)oxy)aniline (19c) (2.6 g, 8.47 mmol) in 1,4-dioxane (400 mL), replaced with nitrogen three times, and stirred at 90°C overnight. The mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate three times, the organic phases were combined, dried, concentrated, and separated and purified by silica gel column chromatography (mobile phase: PE/EA=PE-4:1) to obtain 2.8 g of the title compound as a yellow solid, with a yield of 93.1%.

LC-MS: m/z 356 [M+H] ⁺ .

Step 4: 4-amino-3-(3-(dimethylamino)-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-methylpropane Preparation of (19)-(4-(4-(4-(4-(4-nitrophenyl)thieno[3,2-c]pyridine-7-carboxamide)

Pd(dppf) _Cl2 (34 mg, 0.0465 mmol), N,N-dimethyl-2-((4-methylpyrimidin-2-yl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (19d) (198 mg, 0.56 mmol) and potassium carbonate (193 mg, 1.40 mmol) were added to a solution of 4-amino-3-bromo-2-(4-methylacrylamidophenyl)thieno[3,2-c]pyridine-7-carboxamide (1p) (200 mg, 0.465 mmol) in DMF/water (5 mL/0.5 mL) at room temperature, the atmosphere was replaced with nitrogen three times and the mixture was stirred at 80°C overnight. The mixture was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, the organic phases were combined, dried, concentrated, separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=DCM-5:1), and then separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm×250mm, C18, 10um, 100A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 10-50%) to obtain 34 mg of the title compound as a white solid. Yield: 12.6%.

LC-MS: m/z 580 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.85 (s, 1H), 8.56-8.53 (m, 1H), 8.49-8.42 (m, 1H), 8.00 (s, 1H), 7.66-7.61 (m, 2H),7.36-7.30(m,1H),7.27-7.22(m,2H),7.17-7.11(m,2H),6.99-6.90(m,2H),6.17-5.89(m,2H),5.80- 5.76(m,1H),5.54-5.49(m,1H),2.71-2.57(m,6H),2.41(s,3H),1.94(s,3H).

Example 20: Preparation of 4-amino-2-(2-cyano-4-methylacrylamidophenyl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (20)

Step 1: Preparation of N-(3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (20b)

At 0°C, under nitrogen atmosphere, methacryloyl chloride (1e) (5.76 g, 54.8 mmol) was added to a mixture of 5-amino-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (20a) (11.2 g, 45.7 mmol) and sodium carbonate (9.68 g, 91.3 mmol) in tetrahydrofuran/water (2 mL/1 mL), and stirred at 0°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=PE-1:1) to obtain 10.8 g of the title compound as a brown solid, with a yield of 75.7%.

LC-MS: m/z 313 [M+H] ⁺ .

The title compound 20 was prepared in the same manner as in Example 1, except that N-(3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (20b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f).

LC-MS: m/z 562 [M+H] ⁺ .

1H NMR (400MHz, DMSO-d6) δppm 10.15(s,1H),8.63(s,1H),8.48-8.44(m,1H),8.16-8.14(m,1H),8.06(s,1H),7.94 -7.87(m,1H),7.50-7.48(m,1H),7.40-7.30(m,3H),7.29-7.20(m,2H),7.17-7.14(m,1H),6.07-5.70(m, 3H),5.61-5.55(m,1H),2.39(s,3H),1.94(s,3H).

Example 21: Preparation of 4-amino-2-(4-methylacrylamide-2-(trifluoromethyl)phenyl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (21)

Step 1: Preparation of N-(3-trifluoromethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacryloyl (23b)

At 0°C, under nitrogen atmosphere, methacryloyl chloride (1e) (5.76 g, 54.8 mmol) was added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)aniline (23a) (13.1 g, 45.7 mmol) and sodium carbonate (9.68 g, 91.3 mmol) in tetrahydrofuran/water (2 mL/1 mL), and stirred at 0°C for 2 hours. The reaction solution was concentrated under reduced pressure and separated and purified by silica gel column chromatography (mobile phase: PE/EA=PE-1:1) to obtain 10.1 g of the title compound as a brown solid, with a yield of 62.3%.

LC-MS: m/z 356 [M+H] ⁺ .

The title compound 21 was prepared in the same manner as in Example 1, except that N-(3-trifluoromethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (23b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f).

LC-MS: m/z=605 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.14 (s, 1H), 8.59 (s, 1H), 8.46 (d, J = 5.0 Hz,1H),8.19-8.15(m,1H),8.02(s,1H),7.93-7.88(m,1H),7.54-7.40(m,2H),7.34(s,1H),7.27-7.07( m,4H),6.02-5.64(m,3H),5.59-5.55(m,1H),2.37(s,3H),1.94(s,3H).

Example 22: Preparation of 4-amino-2-(4-methylacrylamide-2-(methoxymethyl)phenyl)-3-(4-(((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (22)

Step 1: Preparation of (2-bromo-5-nitrophenyl)methanol (22b)

Under ice bath, add sodium borohydride (4.98 g, 0.13 mol) to a solution of 2-bromo-5-nitrobenzaldehyde (10.00 g, 0.044 mmol) in methanol (200 mL), slowly warm to room temperature, and stir for 1 h. Add the reaction solution into saturated aqueous ammonium chloride solution to quench, and a light yellow solid precipitates. Filter, wash the filter cake with water, and dry under reduced pressure. 10.44 g of the title compound is obtained as a light yellow solid.

Step 2: Preparation of 1-bromo-2-(methoxymethyl)-4-nitrobenzene (22c)

Under ice bath, sodium hydrogen hydride (2.71 g, 67.78 mmol) was added to tetrahydrofuran (200 mL) of (2-bromo-5-nitrophenyl)methanol (22b) (10.44 g, 45.19 mmol), and stirred at 0°C for 0.5 h. Iodomethane (7.70 g, 54.23 mmol) was slowly added dropwise to the reaction solution, warmed to room temperature, and stirred for 2 h. The reaction solution was poured into ice water (200 mL), and solid precipitated. Stirring was continued for 10 minutes, filtered, and the filter cake was washed with water and dried under reduced pressure to obtain 10.70 g of the title compound as a yellow solid.

Step 3: Preparation of 4-bromo-3-(methoxymethyl)aniline (22d)

Iron powder (12.23 g, 218.37 mmol) and ammonium chloride (11.79 g, 218.37 mmol) were added to a mixture of 1-bromo-2-(methoxymethyl)-4-nitrobenzene (22c) (10.70 g, 43.67 mmol) in ethanol/water (v=2:1, 300 mL) at room temperature and stirred at 75°C overnight. The reaction solution was filtered and the filter cake was washed with methanol. The filtrate was decompressed Concentrate, extract three times with ethyl acetate, combine the organic phases, wash with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, and filter to obtain 9.00 g of the title compound as a brown solid.

LC-MS: m/z 216 [M+H] ⁺ .

Step 4: Preparation of 3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (22e)

At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.50 g, 4.20 mmol) was added to a solution of 4-bromo-3-(methoxymethyl)aniline (22d) (9.00 mg, 41.86 mmol), bis(pinacolato) (10.60 g, 41.86 mmol) and potassium acetate (8.20 g, 83.72 mmol) in dioxane (200 mL), replaced with nitrogen three times, and stirred at 90°C overnight. The reaction solution was cooled, diluted with water (300 mL), extracted with EA (10 mL×3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-2:1) to obtain 7.30 g of the title compound as a light yellow solid, with a yield of 66.3%.

LC-MS: m/z 264 [M+H] ⁺ .

Step 5: Preparation of N-(3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (22f)

Methacryloyl chloride (3.20 g, 31.48 mmol) was added to a solution of 3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (22e) (6.90 g, 26.23 mmol) in tetrahydrofuran (150 mL) at 0°C, and stirred at 0°C for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 50:1-4:1) to obtain 2.10 g of the title compound as a light yellow solid, with a yield of 24.18%.

LC-MS: m/z 332 [M+H] ⁺ .

The title compound 22 was prepared in the same manner as in Example 1, except that N-(3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (22f) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f).

LC-MS: m/z 581 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.84 (s, 1H), 8.58 (s, 1H), 8.46 (d, J = 5.0Hz, 1H), 8.00 (s, 1H), 7.74-7.70 (m ,1H),7.64-7.60(m,1H),7.41-7.26(m,3H),7.23-7.12(m,4H),6.03-5.64(m,3H),5.53-5.49(m,1H),4.19 (s,2H),3.19(s,3H),2.38(s,3H),1.93(s,3H).

Example 23: Preparation of 4-amino-2-(4-methylacrylamide-2-methylphenyl)-3-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)thieno[3,2-c]pyridine-7-carboxamide (23)

Step 1: Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylic acid (23b)

At room temperature, add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester (3.0 g, 10.71 mmol) to a solution of lithium hydroxide (2.6 g, 107.14 mmol) in ethanol/water (V=1:2, 30 mL), and stir at 40°C overnight. Cool to room temperature, concentrate the reaction solution under reduced pressure, adjust the pH to 5-6 with dilute hydrochloric acid (2N), and a white solid precipitates. Filter, wash the filter cake with water, and dry the filter cake to obtain 1.4 g of the title compound as a white solid, with a yield of 51.9%.

Step 2: Preparation of pyrrolidin-1-yl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methanone (23c)

At room temperature, T3P (50% in EA, 3.4 g, 10.70 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylic acid (23b) (1.35 g, 5.35 mmol), pyrrolidine (1.90 g, 26.75 mmol) and triethylamine (1.62 g, 16.05 mmol) in acetonitrile (30 mL), and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-2:1) to obtain 1.3 g of the title compound as a light yellow solid, yield: 79.6%.

LC-MS: m/z 306 [M+H] ⁺ .

Step 3: Preparation of 4-amino-2-(4-methylacrylamide-2-methylphenyl)-3-(4-(pyrrolidine-1-carbonyl)cyclohex-1-en-1-yl)thieno[3,2-c]pyridine-7-carboxamide (23)

Pd(dppf) _Cl2 (33 mg, 0.045 mmol) was added to a solution of 4-amino-3-bromo-2-(4-methylacrylamidophenyl)thieno[3,2-c]pyridine-7-carboxamide (1p) (200 mg, 0.45 mmol), pyrrolidin-1-yl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methanone (23c) (165 mg, 0.54 mmol) and cesium fluoride (205 mg, 1.35 mmol) in N,N-dimethylformamide/water (V=10:1, 10 mL) at room temperature, the atmosphere was replaced with nitrogen three times and the mixture was stirred at 70°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=100:1-10:1), and then separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm×250mm, C18, 10um, 100A, mobile phase: acetonitrile/water (0.05% formic acid), gradient: 10-50%) to obtain 47 mg of the title compound as a white solid. Yield: 19.2%.

LC-MS: m/z 544 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.81 (s, 1H), 8.52-8.46 (m, 1H), 7.91 (s, 1H), 7.65-7.60 (m, 1H), 7.59-7.53 (m, 1H),7.29-7.08(m,2H),6.71(s,1H),6.47(s,1H),5.84-5.81(m,1H),5.80-5.71(m,1H),5.55-5.50(m, 1H),3.54- 3.44(m,1H),3.42-3.35(m,2H),3.28-3.22(m,2H),2.68-2.58(m,1H),2.30-2.22(m,1H),2.17(s,3H), 2.11-2.06(m,1H),1.96(s,3H),1.89-1.79(m,3H),1.78-1.69(m,3H),1.53-1.39(m,1H).

Example 24: Preparation of 4-amino-2-(4-methylacrylamide-2-methylphenyl)-3-(4-(pyrrolidine-1-carbonyl)phenyl)thieno[3,2-c]pyridine-7-carboxamide (24)

Step 1: Preparation of (4-bromophenyl)(pyrrolidin-1-yl)methanone (24b)

Under ice bath, add T ₃ P (87.0 g, 0.137 mol) to a solution of 4-bromobenzoic acid (25.0 g, 0.124 mmol), pyridine (9.73 g, 0.137 mol) and triethylamine (18.8 g, 0.186 mol) in ethyl acetate (250 mL), slowly warm to room temperature, and stir for 3 h. Add the reaction solution to water (250 mL), extract with ethyl acetate three times, dry, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-1:1). 26.1 g of the title compound was obtained as a brown solid, with a yield of 82.5%.

LC-MS: m/z 254 [M+H] ⁺ .

Step 2: Preparation of pyrrolidin-1-yl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (24c)

At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (2.20 g, 3.00 mmol) was added to a solution of (4-bromophenyl)(pyrrolidin-1-yl)methanone (24b) (15.0 g, 59.1 mmol), bis(pinacolato) ester (16.5 g, 65.0 mmol) and potassium acetate (17.4 g, 177.3 mmol) in dioxane (250 mL), replaced with nitrogen three times, and stirred at 90°C overnight. The reaction solution was cooled, diluted with water (300 mL), extracted with ethyl acetate (100 mL×3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-4:1) to obtain 11.0 g of the title compound as a light yellow solid, with a yield of 61.6%.

LC-MS: m/z 302 [M+H] ⁺ .

The title compound 24 was prepared in the same manner as in Example 23, except that pyrrolidin-1-yl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (24c) was used instead of pyrrolidin-1-yl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)methanone (23c).

LC-MS: m/z 540 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δppm 9.72(s,1H),8.57(s,1H),8.00(s,1H),7.51-7.43(m,4H),7.39-7.23(m,3H) ,7.15(d,J＝8.3Hz,1H),5.92-5.57(m,3H),5.52-5.48(m,1H),3.47-3.42(m,2H),3.34-3.31(m,2H),2.04 (s,3H),1.92(s,3H),1.87-1.76(m,4H).

Example 25: Preparation of 4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-methylacrylamido-2-methylphenyl)thieno[3,2-c]pyridine-7-carboxamide (25)

The title compound 25 was prepared in the same manner as in Example 1, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d) was replaced with 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.

LC-MS: m/z=569 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.76 (s, 1H), 8.58 (s, 1H), 8.47 (d, J = 5.0Hz, 1H), 8.01 (s, 1H), 7.55-7.48 (m ,2H),7.40-7.26(m,3H),7.22-7.16(m,3H),5.94-5.71(m,3H),5.52-5.48(m,1H),2.38(s,3H),2.08(s ,3H),1.94(s,3H).

Example 26: Preparation of 4-amino-3-(3-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-methylacrylamido-2-methylphenyl)thieno[3,2-c]pyridine-7-carboxamide (26)

The title compound 26 was prepared by the same preparation method as in Example 1, except that 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was replaced with 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d) was replaced with 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.

LC-MS: m/z=585 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.76 (s, 1H), 8.59 (s, 1H), 8.46 (d, J = 5.0Hz, 1H), 8.01 (s, 1H), 7.56-7.49 (m ,3H),7.41-7.25(m,3H),7.23-7.16(m,2H),5.94-5.70(m,3H),5.52-5.48(m,1H),2.39(s,3H),2.08(s ,3H),1.94(s,3H).

Example 27: Preparation of 4-amino-3-(3-cyano-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-methacrylamido-2-methylphenyl)thieno[3,2-c]pyridine-7-carboxamide (27).

The title compound 27 was prepared by the same preparation method as in Example 1, except that 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile was used instead of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d).

LC-MS: m/z=576 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6) δppm 9.77 (s, 1H), 8.60 (s, 1H), 8.52 (d, J＝5.0Hz, 1H), 8.06 (s, 1H), 7.87 (d, J＝ 2.2Hz,1H),7.67-7.64(m,1H),7.56-7.50(m,2H),7.47-7.43(m,1H),7.34(s,1H),7.26-7.19(m,2H),5.86 -5.70(m,3H),5.52-5.49(m,1H),2.41(s,3H),2.05(s,3H),1.94(s,3H).

Example 28: Preparation of 4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(2-fluoro-4-methylacrylamidophenyl)-N-isopropylthieno[3,2-c]pyridine-7-carboxamide (28)

The title compound 28 was prepared in the same manner as in Example 8, except that 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d), and isopropylamine hydrochloride was used instead of dimethylamine hydrochloride (8b).

LC-MS: m/z 615 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.05 (s, 1H), 8.61 (s, 1H), 8.51-8.46 (m, 1H), 8.28-8.22 (m, 1H), 7.69-7.64 (m, 1H),7.47-7.34(m,3H),7.28-7.23(m,1H),7.22-7.17(m,2H),5.97-5.74(m,3H),5.58-5.54(m,1H),4.20- 4.12(m,1H),2.40(s,3H),1.94(s,3H),1.20(d,J=6.6Hz,6H).

Example 29: Preparation of 4-amino-2-(2-(fluoromethyl)-4-methylacrylamidophenyl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (29)

Step 1: Preparation of (2-bromo-5-nitrophenyl)methanol (29a)

Under ice bath, sodium borohydride (1.16 g, 31.0 mmol) was added to a solution of 2-bromo-5-nitrobenzaldehyde (10.00 g, 44.0 mol) in ethanol (200 mL), and stirred at 0°C for 2 h. Saturated aqueous ammonium chloride solution was added to the reaction solution to quench. The mixture was concentrated under reduced pressure, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 8.7 g of the title compound was obtained as a light yellow oily liquid, with a yield of 86.2%.

Step 2: Preparation of 1-bromo-2-(difluoromethyl)-4-nitrobenzene (29b)

In an ice bath, add diethylaminosulfur trifluoride (9.07 g, 56.3 mol) to a solution of (2-bromo-5-nitrophenyl)methanol (8.70 g, 37.5 mol) in dichloromethane (100 mL), slowly warm to room temperature, and stir overnight. The reaction solution is quenched by adding saturated sodium bicarbonate aqueous solution. Extract with dichloromethane (150 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. 6.20 g of the title compound is obtained as a light yellow oily liquid, with a yield of 70.7%.

The title compound 29 was prepared in the same manner as in Example 14, except that 1-bromo-2-(difluoromethyl)-4-nitrobenzene (29b) was used instead of dioxaborolane.

LC-MS: m/z 569 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.92 (s, 1H), 8.60-8.56 (m, 1H), 8.48-8.43 (m, 1H), 8.00 (s, 1H), 7.84-7.79 (m, 1H),7.70-7.65(m,1H),7.39-7.25(m,4H),7.22-7.13(m,3H),6.02-5.67(m,3H),5.54-5.50(m,1H),5.26( s,1H),5.14(s,1H),2.38(s,3H),1.94(s,3H).

Example 30: Preparation of 4-amino-2-(4-methacrylamidophenyl)-3-(3-methoxy-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (30)

The title compound 30 was prepared in the same manner as in Example 1, except that 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a).

LC-MS: m/z 567 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.85 (s, 1H), 8.58-8.53 (m, 1H), 8.48-8.41 (m, 1H), 8.06-7.93 (m, 1H), 7.68-7.59 ( m,2H),7.38-7.28(m,1H)7.29-7.22(m,3H),7.19-7.10(m,2H),7.00-6.94(m,1H),6.15-5.82(m,2H),5.79 -5.75(m,1H),5.54-5.49(m,1H),3.62(s,3H),2.40(s,3H),1.94(s,3H).

Example 31: Preparation of 4-amino-2-(4-methacrylamidophenyl)-3-(3-methoxy-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (31).

The title compound 31 was prepared in the same manner as in Example 1, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)phenol was used instead of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a).

LC-MS: m/z 567 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.85 (s, 1H), 8.58-8.53 (m, 1H), 8.48-8.41 (m, 1H), 8.06-7.93 (m, 1H), 7.68-7.59 ( m,2H),7.38-7.28(m,1H)7.29-7.22(m,3H),7.19-7.10(m,2H),7.00-6.94(m,1H),6.15-5.82(m,2H),5.79 -5.75(m,1H),5.54-5.49(m,1H),3.62(s,3H),2.40(s,3H),1.94(s,3H).

Example 32: Preparation of 4-amino-2-(2-chloro-4-methylacrylamidophenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carboxamide (32).

The title compound 32 was prepared in the same manner as in Example 1, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d) was replaced with 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.

LC-MS: m/z 589 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6) δppm 10.01 (s, 1H), 8.60 (s, 1H), 8.47 (d, J = 5.0Hz, 1H), 8.03 (s, 1H), 7.95-7.88 (m, 1H),7.64-7.58(m,1H),7.44-7.29(m,4H),7.22-7.14(m,2H),5.97-5.73(m,3H),5.56(s,1H),2.38(s, 3H),1.94(s,3H).

Example 33: Preparation of 4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-methylacrylamido-2-methylphenyl)-N-((1-methylpiperidin-4-yl)methyl)thieno[3,2-c]pyridine-7-carboxamide (33)

The title compound 33 was prepared in the same manner as in Example 8, except that 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d), and (1-methylpiperidin-4-yl)methanamine hydrochloride was used instead of dimethylamine hydrochloride (8b).

LC-MS: m/z 680 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.76(s,1H),8.59(s,1H),8.56–8.44(m,2H),7.58-7.46(m,2H),7.41-7.30(m,2H),7.25-7.11(m,3H), 5.97-5.66(m,3H),5.54-5.48(m,1H),3.23-3.17(m,2H),2.95-2.88(m,2H),2.38(s,3H),2.29(s,3H), 2.16-2.01(m,5H),1.96-1.88(m,3H),1.76-1.67(m,2H),1.66-1.55(m,1H),1.31-1.20(m,2H).

Example 34: Preparation of N-(4-(4-amino-7-(dimethylphosphoryl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)phenyl)methacrylamide (34)

Step 1: Preparation of 4-bromo-5-iodothiophene-3-carboxylic acid (34a)

A mixture of 4-bromothiophene-3-carboxylic acid (15.0 g, 72.5 mmol) and acetic acid (360 mL) was heated to 90°C and stirred for 30 minutes. A solution of iodic acid (3.20 g, 18.1 mmol) and sulfuric acid (1.5 mL) in water (14 mL) was added dropwise to the mixture, stirred at 90°C for 5 minutes, iodine (7.40 g, 29.0 mmol) was added in batches, stirred at 90°C for 3 hours, cooled to room temperature and stirred overnight. The reaction solution was cooled to 0°C, filtered, the filter cake was rinsed with petroleum ether, and the filter cake was dried to obtain 19.2 g of the title compound as a white solid, with a yield of 79.3%.

LC-MS: m/z 335 [M+H] ⁺ .

Step 2: Preparation of 4-bromo-N-(2,2-dimethoxyethyl)-5-iodothiophene-3-carboxamide (34b)

At 0°C, 1-propylphosphoric anhydride (43.5 g, 68.5 mmol, 50% EA solution) was added to a solution of 4-bromo-5-iodothiophene-3-carboxylic acid (34a) (19.0 g, 57.1 mmol), 2,2-dimethoxyethane-1-amine (7.19 g, 68.5 mmol) and N,N-diisopropylethylamine (18.4 g, 142.6 mmol) in ethyl acetate (600 mL), and the mixture was naturally warmed to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-20:1) to obtain 21.8 g of the title compound as a yellow oily liquid, with a yield of 90.7%.

LC-MS: m/z 422 [M+H] ⁺ .

Step 3: Preparation of 4-bromo-N-(2,2-dimethoxyethyl)-5-(4-nitrophenyl)thiophene-3-carboxamide (34c)

Tetrakis(triphenylphosphine)palladium (1.39 g, 1.19 mmol) was added to a mixture of 4-bromo-N-(2,2-dimethoxyethyl)-5-iodothiophene-3-carboxamide (34b) (10.0 g, 23.8 mmol), (4-nitrophenyl)boric acid (3.97 g, 23.8 mmol) and potassium phosphate (15.1 g, 71.8 mmol) in N,N-dimethylformamide/water (150 mL, v/v=10:1) at room temperature, replaced with nitrogen three times, heated to 70°C and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-1:1) to obtain 8.67 g of the title compound as a yellow oily liquid, yield: 87.7%

LC-MS: m/z 417 [M+H] ⁺ .

Step 4: Preparation of 3-bromo-2-(4-nitrophenyl)thieno[3,2-c]pyridin-4(5H)-one (34d) 4-bromo-N-(2,2-dimethoxyethyl)-5-(4-nitrophenyl)thiophene-3-carboxamide (34c) (8.50 g, 20.48 mmol) was added to polyphosphoric acid (90 g) in batches at 100°C and stirred overnight under nitrogen atmosphere at 100°C. The reaction solution was poured into water (400 mL) while hot, and solid precipitated. The mixture was stirred for 10 minutes, filtered, and the filter cake was dried to obtain 6.24 g of the title compound as a brown solid, with a yield of 86.7%.

LC-MS: m/z 353 [M+H] ⁺ .

Step 5: Preparation of 3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-nitrophenyl)thieno[3,2-c]pyridin-4-ol (34e)

To a mixture of 3-bromo-2-(4-nitrophenyl)thieno[3,2-c]pyridin-4(5H)-one (34d) (6.00 g, 17.08 mmol), (4-((4-methylpyrimidin-2-yl)oxy)phenyl)boronic acid (4.32 g, 18.79 mmol) and potassium phosphate (7.25 g, 34.16 mmol) in N,N-dimethylformamide/water (40 mL, v/v=10:1) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (875 mg, 1.19 mmol) at room temperature, the atmosphere was replaced with nitrogen three times, the temperature was raised to 90°C and stirred overnight. The reaction solution was cooled, diluted with EA (200 mL), washed with water (200 mL×2), the aqueous phase was extracted with EA (150 mL×2), the organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-10:1) to obtain 4.62 g of the title compound as a brown-yellow solid. Yield: 59.2%.

LC-MS: m/z 457 [M+H] ⁺ .

Step 6: Preparation of 7-iodo-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-nitrophenyl)thieno[3,2-c]pyridin-4-ol (34f)

At room temperature, N-iodosuccinimide (2.44 g, 10.84 mmol) was added to 3-(4-((4-methylpyrimidine The reaction mixture was added with 1,4-dimethylformamide (100 mL) of 4-nitrophenylthieno[3,2-c]pyridin-4-ol (34e) (4.50 g, 9.86 mmol) and stirred at room temperature overnight. The reaction mixture was poured into ice water (200 mL) and solid precipitated. The mixture was stirred for 10 minutes and filtered. The filter cake was slurried with ethanol (70 mL), filtered again, rinsed with ethanol, and dried to obtain 5.25 g of the title compound as a brown solid with a yield of 91.4%.

LC-MS: m/z 583 [M+H] ⁺ .

Step 7: Preparation of (4-hydroxy-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-nitrophenyl)thieno[3,2-c]pyridin-7-yl)dimethylphosphine oxide (34 g)

Palladium acetate (193 mg, 0.86 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (497 mg, 0.86 mmol) were added to a mixture of 7-iodo-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-nitrophenyl)thieno[3,2-c]pyridin-4-ol (34f) (5.00 g, 8.58 mmol), dimethylphosphine oxide (737 mg, 9.44 mmol) and potassium phosphate (2.00 g, 9.44 mmol) in N,N-dimethylformamide (50 mL) at room temperature, the atmosphere was replaced with nitrogen three times, the temperature was raised to 150° C. and stirred for 4 hours. The reaction solution was cooled and poured into ice water (100 mL). Solid precipitated. The solution was stirred for 10 minutes and filtered. The filter cake was slurried with ethanol (70 mL), filtered again, rinsed with ethanol, and dried to obtain 2.06 g of the title compound as a brown solid. Yield: 90.2%.

LC-MS: m/z 533 [M+H] ⁺ .

Step 8: Preparation of (4-chloro-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-nitrophenyl)thieno[3,2-c]pyridin-7-yl)dimethylphosphine oxide (34h)

At room temperature, (4-hydroxy-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-nitrophenyl)thieno[3,2-c]pyridin-7-yl)dimethylphosphine oxide (34 g) (2.00 g, 3.75 mmol) was added to phosphorus oxychloride (40 mL), and the temperature was raised to 100°C and stirred for 3 hours. The reaction solution was cooled, concentrated under reduced pressure, slowly poured into ice water (100 mL), extracted with EA (100 mL×3), and the organic phase was washed with sodium bicarbonate aqueous solution and brine in sequence, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure to obtain 1.80 g of the title compound as an orange solid, with a yield of 87.1%.

LC-MS: m/z 552 [M+H] ⁺ .

Step 9: Preparation of (4-amino-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-nitrophenyl)thieno[3,2-c]pyridin-7-yl)dimethylphosphine oxide (34i)

At room temperature, ammonia water (20 mL) was added to a solution of (4-chloro-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-nitrophenyl)thieno[3,2-c]pyridin-7-yl)dimethylphosphine oxide (34h) (1.80 g, 3.27 mmol) in dioxane (20 mL), and the mixture was heated to 100° C. and stirred overnight. The reaction solution was cooled and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-10:1) to obtain 355 mg of the title compound as a yellow solid, with a yield of 20.4%.

LC-MS: m/z 532 [M+H] ⁺ .

Step 10: Preparation of (4-amino-2-(4-aminophenyl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-7-yl)dimethylphosphine oxide (34j)

At room temperature, under nitrogen atmosphere, palladium carbon (20 mg, 10%) was added to a solution of (4-amino-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-nitrophenyl)thieno[3,2-c]pyridin-7-yl)dimethylphosphine oxide (34i) (200 mg, 0.376 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL), and the atmosphere was replaced with hydrogen three times. The mixture was stirred at room temperature for 1 h. The mixture was stirred overnight at room temperature. The reaction solution was filtered through a pad of celite, and washed with a mixture of DCM and MeOH. The filtrate was concentrated under reduced pressure to obtain 155 mg of the title compound as a yellow solid. The yield was 82.2%.

LC-MS: m/z 502 [M+H] ⁺ .

Step 11: Preparation of N-(4-(4-amino-7-(dimethylphosphoryl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)phenyl]methacrylamide (34)

Methacryloyl chloride (26 mg, 0.249 mmol) was added to a mixture of (4-amino-2-(4-aminophenyl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-7-yl)dimethylphosphine oxide (34j) (125 mg, 0.249 mmol) and pyridine (30 mg, 0.373 mmol) in dichloromethane (5 mL) at 0°C and stirred at 0°C for 30 minutes. The reaction solution was concentrated under reduced pressure and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm×250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% ammonia solution, gradient: 20-42%) to obtain 50 mg of the title compound as an off-white solid, yield: 35.2%.

LC-MS: m/z 570 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.85 (s, 1H), 8.50 (d, J = 4.0Hz, 1H), 8.10 (d, J = 8.0Hz, 1H), 7.62 (d, J = 8.0Hz,2H),7.45(d,J＝8.0Hz,2H),7.31(d,J＝8.0Hz,2H),7.21-7.17(m,3H),5.91-5.62(m,3H),5.51( s,1H),2.42(s,3H),1.93(s,3H),1.79(s,3H),1.76(s,3H).

Example 35: Preparation of N-(4-(4-amino-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)phenyl)methacrylamide (35)

Step 1: Preparation of 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (35b)

At room temperature, cesium carbonate (50.8 g, 0.16 mol) was added to a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a) (28.6 g, 0.13 mol) and 2-chloro-4-methylpyrimidine (1b) (18.7 g, 0.14 mol) in DMF (250 mL), heated to 80°C, and stirred overnight. The reaction solution was cooled, diluted with water (1 L), extracted three times with ethyl acetate, the organic phases were combined, washed with brine, dried, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=PE-4:1) to obtain 30.0 g of the title compound as a brown solid, with a yield of 74.0%.

LC-MS: m/z 313 [M+H] ⁺ .

Step 2: Preparation of 3-bromo-4-chlorothienyl[3,2-c]pyridine (35c)

At room temperature, 3-bromothieno[3,2-c]pyridine-4-ol (20.0 g, 86.9 mmol) was added to phosphorus oxychloride (200 mL), and the mixture was heated to 75°C and stirred for 1 hour. The reaction solution was cooled and concentrated under reduced pressure, and the residue was slowly poured into ice water (200 mL). Solids precipitated, stirred for 10 minutes, filtered, and the filter cake was added to sodium bicarbonate aqueous solution (200 mL). Sodium carbonate was added to adjust the pH to about 8, filtered again, and the filter cake was dried to obtain 13.2 g of the title compound as a brown solid, with a yield of 61.1%.

LC-MS: m/z 250 [M+H] ⁺ .

Step 3: Preparation of 3-bromo-N-(2,4-dimethoxybenzyl)thieno[3,2-c]pyridin-4-amine (35d)

At room temperature, triethylamine (10.6 g, 104.6 mmol) was added to 3-bromo-4-chlorothienyl[3,2-c]pyridine (35c) (13.0 g, 52.3 mmol) and (2,4-dimethoxyphenyl)methylamine (11.4 g, 68.0 mmol) in N-methylpyrrolidone (200 mL), and the temperature was raised to 120°C and stirred overnight. The reaction solution was cooled, diluted with EA (400 mL), washed with water (800 mL×2), the aqueous phase was extracted with EA (400 mL×2), the organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain 18.8 g of the title compound as a brown oily liquid, with a yield of 94.8%.

LC-MS: m/z 380 [M+H] ⁺ .

Step 4: Preparation of 3-bromothienyl[3,2-c]pyridin-4-amine (35e)

Trifluoroacetic acid (70 mL) was added to a solution of 3-bromo-N-(2,4-dimethoxybenzyl)thieno[3,2-c]pyridin-4-amine (35d) (18.3 g, 48.25 mmol) in dichloromethane (140 mL) at room temperature and stirred overnight at room temperature. The reaction solution was concentrated, and sodium bicarbonate aqueous solution (300 mL) was added. Sodium carbonate was added to adjust the pH to about 8, and solids precipitated. The mixture was stirred for 10 minutes, filtered, and the filter cake was dried to obtain 10.7 g of the title compound as a brown solid, with a yield of 96.8%.

LC-MS: m/z 230 [M+H] ⁺ .

Step 5: Preparation of 3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-4-amine (35f)

To a mixture of 3-bromothienyl[3,2-c]pyridin-4-amine (35e) (2.35 g, 10.25 mmol), 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (35b) (3.20 g, 10.25 mmol) and potassium carbonate (4.24 g, 30.75 mmol) in N,N-dimethylformamide/water (50 mL, v/v=10:1) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (750 mg, 1.02 mmol) at room temperature, the atmosphere was replaced with nitrogen three times, the temperature was raised to 80°C and stirred overnight. The reaction solution was cooled, diluted with EA (150 mL), washed with water (200 mL × 2), the aqueous phase was extracted with EA (150 mL × 2), the organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-20:1) to obtain 1.41 g of the title compound as a brown-yellow solid, yield: 41.1%

LC-MS: m/z 335 [M+H] ⁺ .

Step 6: Preparation of 7-bromo-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-4-amine (35 g)

N-bromosuccinimide (745 mg, 4.19 mmol) was added to a solution of 3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-4-amine (35f) (1.40 g, 4.19 mmol) in dichloromethane (30 mL) at room temperature and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-1:50) to obtain 1.10 g of the title compound as a brown-green solid, yield: 63.5%.

LC-MS: m/z 414 [M+H] ⁺ .

Step 7: Preparation of 7-bromo-2-iodo-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-4-amine (35h)

N-iodosuccinimide (653 mg, 2.90 mmol) was added to a solution of 7-bromo-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-4-amine (35 g) (1.00 g, 2.42 mmol) in trifluoroethane at room temperature. Acid (5mL) and dichloroethane (15mL) solution, stirred at 45°C overnight. The reaction solution was cooled, sodium bicarbonate aqueous solution (40mL) was added, sodium carbonate was added to adjust the pH to about 8, extracted with EA (60mL×2), the organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA＝50:1-1:50) to obtain 890mg of the title compound as a brown solid, yield: 68.2%.

LC-MS: m/z 540 [M+H] ⁺ .

Step 8: Preparation of N-(4-(4-amino-7-bromo-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)phenyl)methacrylamide (35i)

To a mixture of 7-bromo-2-iodo-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-4-amine (35h) (790 mg, 1.46 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) (379 mg, 1.32 mmol) and cesium fluoride (668 mg, 4.40 mmol) in N,N-dimethylformamide/water (15 mL, v/v=10:1) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (107 mg, 0.15 mmol) at room temperature, the atmosphere was replaced with nitrogen three times, the temperature was raised to 60°C and stirred overnight. The reaction solution was cooled and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-20:1) to obtain 500 mg of the title compound as a brown-yellow solid. Yield: 59.6%

LC-MS: m/z 573 [M+H] ⁺ .

Step 9: Preparation of N-(4-(4-amino-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)phenyl)methacrylamide (35)

[1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (13 mg, 0.018 mmol) was added to a mixture of N-(4-(4-amino-7-bromo-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)phenyl)methacrylamide (35i) (100 mg, 0.175 mmol), (1H-pyrazol-4-yl)boronic acid (59 mg, 0.524 mmol) and cesium fluoride (80 mg, 0.524 mmol) in N,N-dimethylformamide/water (2 mL, v/v=8:1) at room temperature, purged with nitrogen for 1 min, and reacted in a microwave at 90 °C for 2 h. The reaction solution was filtered through a sodium sulfate pad, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm × 250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% ammonia solution, gradient: 10-50%) to obtain 21 mg of the title compound as an off-white solid. Yield: 21.4%.

LC-MS: m/z 560 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 13.10 (s, 1H), 9.86 (s, 1H), 8.50 (d, J = 4.0Hz, 1H), 8.09-8.07 (m, 3H), 7.63- 7.61(m,2H),7.48-7.46(m,2H),7.33-7.31(m,2H),7.23-7.18(m,3H),5.78(s,1H),5.52(s,1H),5.29( s,2H),2.43(s,3H),1.93(s,3H).

Example 36: Preparation of N-(4-(4-amino-7-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)3-methylphenyl)methacrylamide (36)

Step 1: Preparation of N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b)

At 0°C, under nitrogen atmosphere, methacryloyl chloride (1e) (5.76 g, 54.8 mmol) was added to a mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (36a) (10.6 g, 45.7 mmol) and sodium carbonate (9.68 g, 91.3 mmol) in tetrahydrofuran/water (2 mL/1 mL), and stirred at 0°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and separated and purified by silica gel column chromatography (mobile phase: PE/EA=PE-1:1) to obtain 9.50 g of the title compound as a brown solid, with a yield of 69.1%.

LC-MS: m/z 302 [M+H] ⁺ .

Step 2: Preparation of 4-amino-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carbaldehyde (36c)

7-Bromo-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-4-amine was added at room temperature. (35g)(2g, 4.84mmol) was dissolved in tetrahydrofuran (100mL), cooled to -78°C, n-butyl lithium (16mL, 15.49mmol) was added and stirred for 30min, then N,N-dimethylformamide (3.537g, 48.39mmol) was added to the reaction solution and stirred for 2h. After the reaction was completed, the reaction solution was added dropwise into ice-cold saturated ammonium chloride (100mL) to quench. Ethyl acetate was extracted (150mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH＝50:1-10:1) to obtain 900mg of the title compound as a yellow solid, with a yield of 51.5%.

LC-MS: m/z 363 [M+H] ⁺ .

Step 3: Preparation of 7-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-4-amine (36d)

At room temperature, 4-amino-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridine-7-carbaldehyde (36c) (620 mg, 1.71 mmol), ethylenediamine hydrochloride (334 mg, 4.28 mmol), potassium carbonate (1.300 g, 9.41 mmol) were added to a tert-butyl alcohol (10 mL) solution, stirred at 50°C for 3 h, iodine (1.302 g, 5.13 mmol) was added, and stirred at 90°C overnight. After the reaction was completed, the reaction solution was added dropwise to saturated sodium chloride (100 mL) to quench, extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-5:1) to obtain 400 mg of the title compound as a yellow solid, yield: 58.1%.

LC-MS: m/z 403 [M+H] ⁺ .

Step 4: Preparation of 7-(4,5-dihydro-1H-imidazol-2-yl)-2-iodo-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-4-amine (36e)

7-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-4-amine (36d) (350 mg, 0.87 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (10 mL) at room temperature, and N-iodosuccinimide (782 mg, 3.48 mmol) was added, and stirred at 45°C for 24 h. After the reaction was completed, the reaction solution was added dropwise to saturated sodium bicarbonate (100 mL), the pH was adjusted to neutral, and extracted with ethyl acetate (100 mL×3, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-10:1) to obtain 80 mg of the title compound as a yellow solid, yield: 17.4%.

LC-MS: m/z 529 [M+H] ⁺ .

Step 5: Preparation of N-(4-(4-amino-7-(4,5-dihydro-1H-imidazol-2-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (36)

At room temperature, 7-(4,5-dihydro-1H-imidazol-2-yl)-2-iodo-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-4-amine (36e) (70 mg, 0.13 mmol), N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) (48 mg, 0.16 mmol), Pd(dppf)Cl ₂ (10 mg, 0.01 mmol), cesium fluoride (60 mg, 0.40 mmol) and water (0.5 mL) were added to N,N-dimethylformamide (5 mL), replaced with nitrogen three times, and stirred at 80°C overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/0.1% trifluoroacetic acid solution, gradient: 5-35%) to obtain a white solid standard The title compound was 22 mg, with a yield of 28.9%.

LC-MS: m/z 576 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δppm 9.74(s,1H),8.51-8.42(m,1H),8.30(s,1H),8.16(s,1H),7.56-7.42(m,2H) ,7.38-7.26(m,2H),7.24-7.09(m,4H),5.77(s,1H),5.71(s,2H),5.53-5.46(m,1H),3.66(s,4H),2.39 (s,3H),2.07(s,3H),1.93(s,3H).

Example 37: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1H-pyrrol-3-yl)thieno[3,2-c]pyridin-2-yl)phenyl)methacrylamide (37)

The same preparation method as Example 35 was used, except that 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (1c) was used instead of 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (35b) to prepare compound 37a.

Step 1: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1H-pyrrol-3-yl)thieno[3,2-c]pyridin-2-yl)phenyl]methacrylamide (37)

Tetrakis(triphenylphosphine)palladium (40 mg, 0.034 mmol) was added to N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)phenyl]methacrylamide (37a) (200 mg, 0.339 mmol), 1-methyl-4-(tributyltinyl)-1H-imidazole (176 mg, 0.4 74mmol) in N,N-dimethylformamide (5mL). Under nitrogen atmosphere, react at 90°C overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm×250mm, C18, 10um, 100A, mobile phase: acetonitrile/0.1% formic acid aqueous solution, gradient: 5-30%) to obtain 43mg of the title compound as a white solid, yield: 21.4%.

LC-MS: m/z 592 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.86 (s, 1H), 8.60-8.43 (m, 1H), 8.30 (s, 1H), 7.82-7.73 (m, 1H), 7.69-7.58 (m, 3H),7.55-7.42(m,2H),7.34-7.27(m,1H),7.26-7.15(m,3H),5.79(s,1H),5.52(s,1H),5.26(s,2H) ,3.75(s,3H),2.43(s,3H),2.01-1.83(m,3H).

Example 38: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-imidazol-5-yl)thieno[3,2-c]pyridin-2-yl)phenyl)methacrylamide (38)

Step 1: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-imidazol-5-yl)thieno[3,2-c]pyridin-2-yl)phenyl (38)

To a mixture of N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)phenyl)methacrylamide (37a) (103 mg, 0.175 mmol), 1-methyl-1-H-imidazole-5-boronic acid pinacol ester (109 mg, 0.524 mmol) and cesium fluoride (80 mg, 0.524 mmol) in N,N-dimethylformamide/water (2 mL, v/v=8:1) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13 mg, 0.018 mmol) at room temperature, the mixture was purged with nitrogen for 1 min, and microwaved at 90 °C for 2 h. The reaction solution was filtered through a sodium sulfate pad, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisugei 30 mm × 250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% ammonia solution, gradient: 10-50%) to obtain 25 mg of the title compound as an off-white solid. Yield: 24.1%.

LC-MS: m/z 592 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.87 (s, 1H), 8.52 (d, J = 8.0Hz, 1H), 7.90 (s, 1H), 7.80 (s, 1H), 7.65-7.61 ( m,2H),7.45-7.49(m,2H),7.34-7.32(m,1H),7.32-7.22(m,1H),7.20-7.18(m,3H),5.77(s,1H),5.52( s,3H),3.63(s,3H),2.44(s,3H),1.93(s,3H).

Example 39: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)phenyl)methacrylamide (39)

The title compound 39 was prepared in the same manner as Example 38, except that (1-methyl-1H-pyrazol-4-yl)boronic acid was used instead of 1-methyl-1-H-imidazole-5-boronic acid pinacol ester (38a).

LC-MS: m/z 592 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.88 (s, 1H), 8.52 (d, J = 4.0Hz, 1H), 8.19 (s, 1H), 8.07 (s, 1H), 7.91 (d, J＝4.0Hz,1H),7.67-7.64(m,2H),7.52-7.48(m,2H),7.33-7.30(m,1H),7.25-7.21(m,3H),5.78(s,1H) ,5.52(s,1H),5.31(s,2H),3.94(s,3H),2.43(s,3H),1.93(s,3H).

Example 40: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-imidazol-2-yl)thieno[3,2-c]pyridin-2-yl)phenyl)methacrylamide (40)

The title compound 40 was prepared in the same manner as Example 37, except that (1-methyl-2-(tributyltinyl)-1H-imidazole was used instead of 1-methyl-4-(tributyltinyl)-1H-imidazole.

LC-MS: m/z 592 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.86 (s, 1H), 8.65-8.39 (m, 1H), 7.89 (s, 1H), 7.83-7.78 (m, 1H), 7.67-7.60 (m, 2H),7.55-7.46(m,2H),7.36-7.28(m,1H),7.26-7.13(m,4H),5.77(s,1H),5.52(s,3H),3.63(s,3H) ,2.44(s,3H),2.01-1.83(m,3H).

Example 41: N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H- Preparation of 2-(4-pyrazol-3-yl)thieno[3,2-c]pyridin-2-yl)phenyl)methacrylamide (41)

The title compound 41 was prepared in the same manner as Example 38, except that 1-methylpyrazole-3-boronic acid pinacol ester was used instead of 1-methyl-1-H-imidazole-5-boronic acid pinacol ester (38a).

LC-MS: m/z 592 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.87 (s, 1H), 8.52 (d, J = 4.0Hz, 1H), 8.36 (s, 1H), 7.81-7.80 (m, 1H), 7.68- 7.64(m,2H),7.51-7.46(m,2H),7.32-7.29(m,1H),7.26-7.21(m,3H),6.83-6.82(m,1H),5.79(s,1H), 5.52(s,1H),5.41(s,2H),3.95(s,3H),2.43(s,3H),1.94(s,3H).

Example 42: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1H-pyrazol-3-yl)thieno[3,2-c]pyridin-2-yl)phenyl)methacrylamide (42)

The title compound 42 was prepared in the same manner as Example 38, except that 1H-pyrazole-3-boronic acid was used instead of 1-methyl-1-H-imidazole-5-boronic acid pinacol ester (38a).

LC-MS: m/z 578 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 13.00 (s, 1H), 9.87 (s, 1H), 8.52 (d, J = 8.0Hz, 1H), 8.38 (s, 1H), 7.86-7.85 ( m,1H),7.67-7.64(m,2H),7.51-7.47(m,2H),7.32-7.30(m,1H),7.25-7.21(m,3H),6.87-6.86(m,1H), 5.78(s,1H),5.52(s,1H),5.40(s,2H),2.44(s,3H),1.94(s,3H).

Example 43: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1H-imidazol-4-yl)thieno[3,2-c]pyridin-2-yl)phenyl)methacrylamide (43)

The title compound 43 was prepared in the same manner as Example 38, except that imidazol-5-ylboronic acid was used instead of 1-methyl-1-H-imidazole-5-boronic acid pinacol ester (38a).

LC-MS: m/z 578 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 12.31 (s, 1H), 9.86 (s, 1H), 8.52 (d, J = 8.0Hz, 1H), 8.34 (s, 1H), 7.83 (s, 1H),7.68-7.64(m,3H),7.50-7.46(m,2H),7.31-7.29(m,1H),7.25-7.21(m,3H),5.79(s,1H),5.52(s, 1H),5.25(s,2H),2.44(s,3H),1.94(s,3H).

Example 44: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1H-pyrrol-3-yl)thieno[3,2-c]pyridin-2-yl)phenyl)methacrylamide (44)

The title compound 44 was prepared in the same manner as Example 38, except that pyrrole-3-boronic acid pinacol ester was used instead of 1-methyl-1-H-imidazole-5-boronic acid pinacol ester (38a).

LC-MS: m/z 577 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 11.07 (s, 1H), 9.87 (s, 1H), 8.52 (d, J = 8.0Hz, 1H), 8.01 (s, 1H), 7.66-7.64 ( m,2H),7.51-7.47(m,2H),7.32-7.29(m,1H),7.24-7.21(m,4H),6.92-6.90(m,1H),6.54-6.52(m,1H), 5.78(s,1H),5.52(s,1H),5.18(s,2H),2.44(s,3H),1.94(s,3H).

Example 45: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1H-pyrrol-2-yl)thieno[3,2-c]pyridin-2-yl)phenyl)methacrylamide (45)

Step 1: Preparation of tert-butyl 2-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-methylacrylamidophenyl)thieno[3,2-c]pyridin-7-yl)-1H-pyrrole-1-carboxylate (45b)

At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (50 mg, 0.068 mmol) was added to N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)phenyl]methacrylamide (37a) (400 mg, 0.677 mmol), (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid (45a) (428 mg, 2.032 mmol) and cesium fluoride (309 mg, 2.032 mmol) in a mixture of N,N-dimethylformamide/water (4.0 mL, v/v = 10:1), purged with nitrogen for 1 minute, and microwaved at 90°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH = 50:1-15:1) to obtain 393 mg of the title compound as a brown oily liquid, with a yield of 85.8%.

LC-MS: m/z 677 [M+H] ⁺ .

Step 2: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1H-pyrrol-2-yl)thieno[3,2-c]pyridin-2-yl)phenyl]methacrylamide (45)

At room temperature, hydrochloric acid/dioxane (3 mL, 4 M) was added to a solution of tert-butyl 2-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(4-methylacrylamidophenyl)thieno[3,2-c]pyridin-7-yl)-1H-pyrrole-1-carboxylate (45b) (200 mg, 0.295 mmol) in dichloromethane (3 mL), and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm×250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% formic acid aqueous solution, gradient: 10-35%) to obtain 39 mg of the title compound as a gray solid, yield: 22.9%.

LC-MS: m/z 577 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 11.32 (s, 1H), 9.88 (s, 1H), 8.52 (d, J = 8.0Hz, 1H), 8.16 (s, 1H), 7.67-7.64 ( m,2H),7.52-7.48(m,2H),7.33-7.30(m,1H),7.25-7.22(m,3H),6.90-6.88(m,1H),6.55-6.54(m,1H), 6.23-6.21(m,1H),5.78(s, 1H),5.52(s,1H),5.32(s,2H),2.44(s,3H),1.94(s,3H).

Example 46: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (46)

The title compound 46 was prepared in the same manner as in Example 39, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f).

LC-MS: m/z 606 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.77 (s, 1H), 8.47 (d, J = 4.0Hz, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.89 (s, 1H),7.56-7.55(m,1H),7.52-7.50(m,1H),7.41-7.36(m,2H),7.26-7.18(m,3H),5.78(s,1H),5.51(s, 1H),5.33(s,2H),3.92(s,3H),2.39(s,3H),2.12(s,3H),1.93(s,3H).

Example 47: Preparation of N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)phenyl]methacrylamide (47)

Step 1: Preparation of 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-4-amine (47a)

To a mixture of 3-bromothienyl[3,2-c]pyridin-4-amine (35e) (14.00 g, 61.10 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (1c) (18.20 g, 55.00 mmol) and potassium carbonate (25.3 g, 183.3 mmol) in N,N-dimethylformamide/water (300 mL, v/v=10:1) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (4.46 g, 6.10 mmol) at room temperature, the atmosphere was replaced with nitrogen three times, the temperature was raised to 75°C and stirred overnight. The reaction solution was cooled and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-20:1) to obtain 18.3 g of the title compound as a brown solid. Yield: 85.0%.

LC-MS: m/z 353 [M+H] ⁺ .

Step 2: Preparation of 7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-4-amine (47b)

At room temperature, N-bromosuccinimide (NBS) (9.09 g, 51.08 mmol) was added to a solution of 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-4-amine (47a) (18.0 g, 51.08 mmol) in dichloromethane (300 mL), and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-1:50) to obtain 8.30 g of the title compound as a brown solid, with a yield of 37.7%.

LC-MS: m/z 431 [M+H] ⁺ .

Step 3: Preparation of 7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-iodothieno[3,2-c]pyridin-4-amine (47c)

At room temperature, N-iodosuccinimide (5.19 g, 23.09 mmol) was added to a solution of 7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-4-amine (47b) (8.30 g, 19.24 mmol) in trifluoroacetic acid (100 mL) and dichloroethane (100 mL), and stirred at 45°C overnight. The reaction mixture was cooled. The residue was concentrated under reduced pressure, poured into an ice-water solution of sodium bicarbonate (70 mL), and sodium carbonate was added to adjust the pH to about 8, extracted with EA (100 mL×3), the organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-1:50) to obtain 7.58 g of the title compound as a brown solid, yield: 70.7%

LC-MS: m/z 557 [M+H] ⁺ .

Step 4: Preparation of N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)phenyl]methacrylamide (47)

To a mixture of 7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-iodothieno[3,2-c]pyridin-4-amine (47c) (100 mg, 0.18 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) (52 mg, 0.18 mmol) and cesium fluoride (82 mg, 0.54 mmol) in N,N-dimethylformamide/water (5 mL, v/v=10:1) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13 mg, 0.02 mmol) at room temperature, the atmosphere was replaced with nitrogen three times, the temperature was raised to 60°C and stirred overnight. The reaction solution was cooled and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-20:1). The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm×250mm, C18, 10um, 100A, mobile phase: acetonitrile/0.1% formic acid aqueous solution, gradient: 25-65%) to obtain 20 mg of the title compound as a white solid. Yield: 18.9%.

LC-MS: m/z 590 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.89 (s, 1H), 8.58-8.43 (m, 1H), 7.97 (s, 1H), 7.77-7.58 (m, 2H), 7.57-7.43 (m, 2H),7.37-7.28(m,1H),7.27-7.16(m,3H),5.78(s,1H),5.61-5.36(m,3H),2.43(s,3H),1.94(s,3H) .

Example 48: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-(difluoromethyl)phenyl)methacrylamide (48)

Step 1: Preparation of N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-(difluoromethyl)phenyl)methacrylamide (48a)

To a mixture of 7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-iodothieno[3,2-c]pyridin-4-amine (47c) (1.00 g, 1.80 mmol), N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) (726 mg, 2.15 mmol) and cesium fluoride (817 mg, 5.38 mmol) in N,N-dimethylformamide/water (20 mL, v/v=10:1) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (132 mg, 0.18 mmol) at room temperature, the atmosphere was replaced with nitrogen three times, the temperature was raised to 70°C and stirred overnight. The reaction solution was cooled and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-20:1) to obtain 947 mg of the title compound as a brown solid. Yield: 82.3%.

LC-MS: m/z 640 [M+H] ⁺ .

Step 2: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-(difluoromethyl)phenyl)methacrylamide (48)

At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (45 mg, 0.033 mmol) was added to a mixture of N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-(difluoromethyl)phenyl)methacrylamide (48a) (400 mg, 0.624 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (236 mg, 1.873 mmol) and cesium fluoride (284 mg, 1.873 mmol) in N,N-dimethylformamide/water (4.0 mL, v/v=10:1), purged with nitrogen for 1 min, and reacted in a microwave at 90 °C for 30 min. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm×250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% formic acid aqueous solution, gradient: 5-35%) to obtain 25 mg of the title compound as a white solid, yield: 6.2%.

LC-MS: m/z 642 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 10.06 (s, 1H), 8.47 (d, J = 4.0Hz, 1H), 8.17 (s, 1H), 8.12 (s, 1H), 8.06-8.05 ( m,1H),7.89(s,1H),7.86-7.83(m,1H),7.49-7.37(m,3H),7.28-7.25(m,1H),7.18(d,J＝8.0Hz,1H) ,6.92(t,J＝52.0Hz,1H),5.84(s,1H),5.56(s,1H),5.35(s,2H),3.94(s,3H),2.37(s,3H),1.95( s,3H).

Example 49: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-fluorophenyl)methacrylamide (49)

The same preparation method as Example 48 was used, except that N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (5b) was used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) to prepare Compound 49.

LC-MS: m/z 610 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 10.06 (s, 1H), 8.49 (d, J = 8.0Hz, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.90 (s, 1H),7.70-7.67(m,1H),7.47-7.40(m,3H),7.31-7.27(m,1H),7.24-7.22(m,1H),7.20-7.19(m,1H),5.81( s,1H),5.56(s,1H),5.38(s,2H),3.93(s,3H),2.40(s,3H),1.94(s,3H).

Example 50: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-cyanophenyl)methacrylamide (50)

The same preparation method as Example 48 was used, except that N-(3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (20b) was used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) to prepare Compound 50.

LC-MS: m/z 617 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 10.18 (s, 1H), 8.48 (d, J = 8.0Hz, 1H), 8.19-8.18 (m, 2H), 8.15 (s, 1H), 7.96- 7.93(m,1H),7.90(s,1H),7.56(d,J＝8.0Hz,1H),7.46-7.38(m,2H),7.24-7.19(m,2H),5.84(s,1H) ,5.60(s,1H),5.43(s,2H),3.93(s,3H),2.38(s,3H),1.95(s,3H).

Example 51: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(isoxazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (51)

The preparation method is the same as that of Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) is used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and isoxazol-4-ylboronic acid is used instead of (1-methyl-1H-pyrazol-4-yl)boronic acid to prepare Compound 51.

LC-MS: m/z 593 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.77 (s, 1H), 8.47 (d, J = 8.0Hz, 1H), 8.08-8.05 (m, 1H), 7.91-7.78 (m, 1H), 7.56-7.55(m,1H),7.52-7.49(m,1H),7.40-7.34(m,2H),7.25-7.17(m,3H),5.78(s,1H),5.51(s,1H), 5.37-5.33(m,2H),2.38(s,3H),2.10(s,3H),1.93(s,3H).

Example 52: Preparation of N-(4-(4-amino-3-(3-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (52)

Compound 52 was prepared in the same manner as in Example 46, except that 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a).

LC-MS: m/z 622 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.78 (s, 1H), 8.49-8.44 (m, 1H), 8.19-8.14 (m, 1H), 8.10 (s, 1H), 7.92-7.87 (m, 1H),7.59-7.49(m,3H),7.40-7.34(m,2H),7.28-7.24(m,1H),7.19-7.15(m,1H),5.80-5.76(m,1H),5.53- 5.49(m,1H),5.32(s,2H),3.92(s,3H),2.39(s,3H),2.11(s,3H),1.93(s,3H).

Example 53: Preparation of N-(4-(4-amino-3-(3-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-(difluoromethyl)phenyl)methacrylamide (53).

The same preparation method as Example 52 was used, except that N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) was used instead of N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) to prepare Compound 53.

LC-MS: m/z 658 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.07 (s, 1H), 8.47-8.44 (m, 1H), 8.18-8.11 (m, 2H), 8.08-8.04 (m, 1H), 7.91-7.88 ( m,1H),7.87-7.82(m,1H),7.67-7.64(m,1H),7.45-7.36(m,3H),7.19-7.15(m,1H),7.07-6.75(m,1H), 5.84(s,1H),5.56(s,1H),5.33(s,2H),3.92(s,3H),2.38(s,3H),1.95(s,3H).

Example 54: Preparation of N-(4-(4-amino-7-(1-methyl-1H-pyrazol-4-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (54)

The same preparation method as Example 35 was used, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) and (1-methyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid to prepare Compound 54.

LC-MS: m/z 588 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.75 (s, 1H), 8.52-8.39 (m, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.59 -7.44(m,2H),7.43-7.33(m,2H),7.26-7.18(m,3H), 7.17-7.13(m,1H),5.78(s,1H),5.50(s,1H),5.31(s,2H),3.92(s,3H),2.39(s,3H),2.11(s,3H) ,1.93(s,3H).

Example 55: Preparation of N-(4-(4-amino-7-(1-ethyl-1H-pyrazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)phenyl]methacrylamide (55)

The title compound 55 was prepared by the same preparation method as Example 35, except that 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (1c) was used instead of 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (35b) and (1-ethyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 606 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.87 (s, 1H), 8.52 (d, J = 5.0Hz, 1H), 8.22 (s, 1H), 8.08 (s, 1H), 7.93 (s, 1H) ),7.76-7.60(m,2H),7.58-7.46(m,2H),7.38-7.16(m,4H),5.78(s,1H),5.52(s,1H),5.31(s,2H), 4.26-4.21(m,2.43(s,3H),1.94(s,3H),1.45(t,J=7.3Hz,3H).

Example 56: Preparation of N-(4-(4-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)phenyl]methacrylamide (56)

The preparation method was the same as that of Example 35, except that 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (1c) was used instead of 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (35b) and (1-cyclopropyl-1H-pyrazol-4-yl)boronic acid was used instead of (1H- The title compound 56 was prepared by adding 2-(4-pyrazol-4-yl)boronic acid.

LC-MS: m/z 618 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.87 (s, 1H), 8.52 (d, J = 5.0Hz, 1H), 8.25 (s, 1H), 8.07 (s, 1H), 7.91 (s, 1H) ),7.66(d,J＝8.7Hz,2H),7.55-7.46(m,2H),7.36-7.17(m,4H),5.79(s,1H),5.52(s,1H),5.32(s, 2H),3.86-3.81(m,1H),2.43(s,3H),1.94(s,3H),1.29-1.12(m,2H),1.07-0.98(m,2H).

Example 57: Preparation of N-(4-(4-amino-3-(3-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-fluorophenyl)methacrylamide (57)

The title compound 57 was prepared by the same preparation method as in Example 35, except that 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a), N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) and (1-methyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 626 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δppm 10.06(s,1H),8.48(s,1H),8.30-8.01(m,2H),7.90(s,1H),7.77-7.65(m,1H) ,7.59(s,1H),7.52-7.35(m,3H),7.35-7.27(m,1H),7.19(s,1H),5.81(s,1H),5.57(s,1H),5.37(s ,2H),3.93(s,3H),2.40(s,3H),1.94(s,3H).

Example 58: Preparation of N-(4-(4-amino-3-(3-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-cyanophenyl)methacrylamide (58).

The title compound 58 was prepared in the same manner as in Example 35, except that 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a), N-(3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) and (1-methyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 633 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.19 (s, 1H), 8.49-8.45 (m, 1H), 8.21-8.12 (m, 3H), 7.98-7.88 (m, 2H), 7.61-7.55 ( m,2H),7.45-7.35(m,2H),7.20-7.16(m,1H),5.85(s,1H),5.60(s,1H),5.42(s,2H),3.93(s,3H) ,2.38(s,3H),1.95(s,3H).

Example 59: Preparation of N-(4-(4-amino-3-(3-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-(fluoromethyl)phenyl)methacrylamide (59).

The title compound 59 was prepared by the same preparation method as in Example 35, except that 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a), N-(3-(fluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (29e) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f), and (1-methyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 640 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.95 (s, 1H), 8.46 (d, J = 5.0Hz, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.92-7.83 (m ,2H),7.73-7.68(m,1H),7.63-7.58(m,1H),7.42-7.31(m,3H),7.17(d,J＝5.0Hz,1H),5.82(s,1H), 5.54(s,1H),5.33(s,3H),5.21(s,1H),3.92(s,3H),2.38(s,3H),1.95(s,3H).

Example 60: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-(fluoromethyl)phenyl)methacrylamide (60)

The same preparation method as Example 48 was used, except that N-(3-(fluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (29e) was used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) to prepare Compound 60.

LC-MS: m/z 624 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.95 (s, 1H), 8.48 (d, J = 4.0Hz, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.89 (s, 1H),7.86-7.85(m,1H),7.72-7.69(m,1H),7.45-7.37(m,2H),7.35-7.33(m,1H),7.26-7.23(m,1H),7.19- 7.18(m,1H),5.82(s,1H),5.54(s,1H),5.35-5.33(m,3H),5.22(s,1H),3.92(s,3H),2.38(s,3H) ,1.95(s,3H).

Example 61: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-imidazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (61)

The same preparation method as Example 37 was used, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) to prepare Compound 61.

LC-MS: m/z 606 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.76 (s, 1H), 8.47 (d, J = 5.0Hz, 1H), 8.31 (s, 1H), 7.74-7.70 (m, 1H), 7.67-7.63 (m,1H),7.57-7.54(m,1H),7.53-7.48(m,1H),7.40-7.34(m,2H),7.26-7.16(m,3H),5.78(s,1H),5.53 -5.49(m,1H),5.28(s,2H),3.73(s,3H),2.39(s,3H),2.11(s,3H),1.94(s,3H).

Example 62: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-isopropyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (62)

The preparation method is the same as that of Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) is used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and (1-isopropyl-1H-pyrazol-4-yl)boric acid is used instead of (1-methyl-1H-pyrazol-4-yl)boric acid, to prepare Compound 62.

LC-MS: m/z 634 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77 (s, 1H), 8.48 (d, J = 5.0Hz, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 7.90 (s, 1H) ),7.59-7.48(m,2H),7.44-7.35(m,2H),7.29-7.16(m,3H),5.79(s,1H),5.51(s,1H),5.32(s,2H), 4.64-4.52(m,1H),2.39(s,3H),2.11(s,3H),1.94(t,J＝1.3Hz,3H),1.47(d,J＝6.7Hz,6H).

Example 63: Preparation of N-(4-(4-amino-7-(1-cyclobutyl-1H-pyrazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (63)

The preparation method is the same as that of Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) is used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and (1-cyclobutyl-1H-pyrazol-4-yl)boric acid is used instead of (1-methyl-1H-pyrazol-4-yl)boric acid, to prepare Compound 63.

LC-MS: m/z 646 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77 (s, 1H), 8.48 (d, J = 5.1Hz, 1H), 8.25 (s, 1H), 8.11 (s, 1H), 7.94 (s, 1H) ),7.60-7.48(m,2H),7.43-7.35(m,2H),7.29-7.15(m,3H),5.79(s,1H),5.51(s,1H),5.33(s,2H), 4.99-4.86(m,1H),2.61-2.52(m,2H),2.46-2.35(m,5H),2.11(s,3H),1.94(s,3H),1.86-1.75(m,2H).

Example 64: Preparation of N-(4-(4-amino-7-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (64)

The preparation method is the same as that of Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) is used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and (1-(difluoromethyl)-1H-pyrazol-4-yl)boric acid is used instead of (1-methyl-1H-pyrazol-4-yl)boric acid, to prepare Compound 64.

LC-MS: m/z 642 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.78 (s, 1H), 8.67 (s, 1H), 8.48 (d, J = 5.0Hz, 1H), 8.33 (s, 1H), 8.22 (s, 1H) ),8.04-7.73(m,1H),7.58-7.55(m,1H),7.54-7.49(m,1H),7.44-7.36(m,2H),7.29-7.17(m,3H),5.78(s ,1H),5.54-5.41(m,3H),2.39(s,3H),2.12(s,3H),1.93(s,3H).

Example 65: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-(trifluoromethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (65)

The preparation method is the same as that of Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) is used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and (1-(trifluoromethyl)-1H-pyrazol-4-yl)boric acid is used instead of (1-methyl-1H-pyrazol-4-yl)boric acid, to prepare Compound 65.

LC-MS: m/z 660 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δppm 9.78(s,1H),8.87(s,1H),8.55-8.44(m,2H),8.24(s,1H),7.59-7.55(m,1H) ,7.55-7.50(m,1H),7.45-7.36(m,2H),7.29-7.16(m,3H),5.79(s,1H),5.68-5.48(m,3H),2.39(s,3H) ,2.12(s,3H),1.94(s,3H).

Example 66: Preparation of N-(4-(4-amino-7-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (66)

The preparation method is the same as that of Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) is used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethane-1-amine is used instead of (1-methyl-1H-pyrazol-4-yl)boric acid to prepare Compound 66.

LC-MS: m/z 663 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.77 (s, 1H), 8.47 (d, J = 4.0Hz, 1H), 8.22 (s,1H),8.11(s,1H),7.90(s,1H),7.57-7.56(m,1H),7.52-7.50(m,1H),7.41-7.36(m,2H),7.27-7.25 (m,1H),7.23-7.21(m,1H),7.19-7.18(m,1H),5.78(s,1H),5.51(s,1H),5.33(s,2H),4.26(t,J =4.0Hz,2H),2.71(t,J=4.0Hz,2H),2.39(s,3H),2.19(s,6H),2.11(s,3H),1.94(s,3H).

Example 67: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (67)

The preparation method is the same as that of Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) is used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and (1-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrazol-4-yl)boric acid is used instead of (1-methyl-1H-pyrazol-4-yl)boric acid, to prepare Compound 67.

LC-MS: m/z 689 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77(s,1H),8.48(d,J＝5.0Hz,1H),8.23(s,1H),8.11(s,1H),7.90(s,1H),7.58-7.54(m,1H),7.54 -7.48(m,1H),7.42-7.35(m,2H),7.28-7.15(m,3H),5.78(s,1H),5.51(s,1H),5.33(s,2H),4.28(t ,J＝6.6Hz,2H),2.88(t,J＝6.6Hz,2H),2.49-2.45(m,4H),2.39(s,3H),2.12(s,3H),1.94(s,3H) ,1.71-1.60(m,4H).

Example 68: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (68)

The preparation method is the same as that of Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) is used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and (1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)boric acid is used instead of (1-methyl-1H-pyrazol-4-yl)boric acid, to prepare Compound 68.

LC-MS: m/z 676 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77(s,1H),8.48(d,J＝5.0Hz,1H),8.26(s,1H),8.11(s,1H),7.93(s,1H),7.58-7.54(m,1H),7.53 -7.49(m,1H),7.42-7.34(m,2H),7.28-7.16(m,3H),5.78(s,1H),5.51(d,J＝1.5Hz,1H),5.33(s,2H ),4.55-4.43(m,1H),4.03-3.93(m,2H),3.53-3.44(m,2H),2.39(s,3H),2.11(s,3H),2.06-1.98(m,4H ),1.94(s,3H).

Example 69: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-(2-morpholinylethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (69)

The preparation method is the same as that of Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) is used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and (1-(2-morpholinoethyl)-1H-pyrazol-4-yl)boric acid is used instead of (1-methyl-1H-pyrazol-4-yl)boric acid, to prepare Compound 69.

LC-MS: m/z 705 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77 (s, 1H), 8.48 (d, J = 5.0Hz, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 7.91 (s, 1H) ),7.56(d,J＝2.3Hz,1H),7.51(dd,J＝8.3,2.3Hz,1H),7.44-7.35(m,2H),7.30-7.15(m,3H), 5.78(s,1H),5.51(s,1H),5.33(s,2H),4.30(t,J＝6.5Hz,2H),3.63-3.50(m,4H),2.75(t,J＝6.5Hz ,2H),2.43(t,J＝4.7Hz,4H),2.39(s,3H),2.12(s,3H),1.94(s,3H).

Example 70: Preparation of N-(4-(4-amino-7-(1-(3-(dimethylamino)propyl)-1H-pyrazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (70)

Compound 70 was prepared by the same preparation method as Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and N,N-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-amine was used instead of (1-methyl-1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 677 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.78 (s, 1H), 8.47 (d, J = 4.0Hz, 1H), 8.19 (s, 2H), 7.92 (s, 1H), 7.57-7.56 ( m,1H),7.52-7.50(m,1H),7.41-7.37(m,2H),7.26-7.24(m,1H),7.23-7.21(m,1H),7.19-7. 18(m,1H),5.78(s,1H),5.51(s,1H),5.33(s,2H),4.20(t,J＝8.0Hz,2H),2.39(s,3H),2.28(t ,J=4.0Hz,2H),2.18(s,6H),2.11(s,3H),1.99-1.95(m,2H),1.94(s,3H).

Example 71: Preparation of N-(4-(4-amino-7-(1-(cyanomethyl)-1H-pyrazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide amine (71)

The preparation method is the same as that of Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) is used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and (1-(cyanomethyl)-1H-pyrazol-4-yl)boric acid is used instead of (1-methyl-1H-pyrazol-4-yl)boric acid, to prepare Compound 71.

LC-MS: m/z 631 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.78 (s, 1H), 8.48 (d, J = 5.0Hz, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H) ),7.59-7.55(m,1H),7.54-7.49(m,1H),7.44-7.35(m,2H),7.29-7.16(m,3H),5.78(s,1H),5.57(s,2H ),5.51(s,1H),5.40(s,2H),2.39(s,3H),2.12(s,3H),1.94(s,3H).

Example 72: Preparation of N-(4-(4-amino-7-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (72)

The preparation method is the same as that of Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) is used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and (1-(2-cyanoethyl)-1H-pyrazol-4-yl)boric acid is used instead of (1-methyl-1H-pyrazol-4-yl)boric acid, to prepare Compound 72.

LC-MS: m/z 645 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.78 (s, 1H), 8.48 (d, J = 5.0Hz, 1H), 8.31 (s, 1H), 8.14 (s, 1H), 8.01 (s, 1H) ),7.58-7.55(m,1H),7.54-7.49(m,1H),7.43-7.36(m, 2H),7.29-7.17(m,3H),5.78(s,1H),5.51(s,1H),5.36(s,2H),4.52-4.44(m,2H),3.17-3.08(m,2H) ,2.39(s,3H),2.12(s,3H),1.93(s,3H).

Example 73: Preparation of N-(4-(4-amino-7-(1-methyl-1H-pyrazol-4-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-fluoromethylphenyl)methacrylamide (73)

The title compound 73 was prepared by the same preparation method as Example 35, except that N-(3-(fluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (29e) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f), and (1-methyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 606 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.93 (s, 1H), 8.60-8.37 (m, 1H), 8.20-8.05 (m, 2H), 7.93-7.79 (m, 2H), 7.72-7.65 ( m,1H),7.45-7.36(m,2H),7.35-7.29(m,1H),7.26-7.18(m,2H),7.17-7.10(m,1H),5.81(s,1H),5.53( s,1H),5.32(s,2H),5.31(s,1H),5.19(s,1H),3.92(s,3H),2.39(s,3H),1.94(s,3H).

Example 74: Preparation of N-(4-(4-amino-7-(1-methyl-1H-pyrazol-4-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-difluoromethylphenyl)methacrylamide (74)

The title compound 74 was prepared in the same manner as in Example 35, except that N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f), and (1-methyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 624 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.04 (s, 1H), 8.51-8.35 (m, 1H), 8.23-7.97 (m, 3H), 7.95-7.76 (m, 2H), 7.50-7.36 ( m,3H),7.27-7.11(m,3H),7.08-6.73(m,1H),5.83(s,1H),5.55(s,1H),5.32(s,2H),3.92(s,3H) ,2.38(s,3H),1.94(s,3H).

Example 75: Preparation of N-(4-(4-amino-3-(3-chloro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)phenyl]methacrylamide (75).

The title compound 75 was prepared by the same preparation method as Example 35, except that 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a), and (1-methyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 608 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δppm 9.88(s,1H),8.53-8.48(m,1H),8.19(s,1H),8.07(s,1H),7.91(s,1H),7.70 -7.62(m,3H),7.53-7.45(m,2H),7.27-7.18(m,3H),5.79(s,1H),5.53(s,1H),5.30(s,2H),3.94(s ,3H),2.43(s,3H),1.94(s,3H).

Example 76: Preparation of N-(4-(4-amino-7-(1,2-dimethyl-1H-imidazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (76)

Step 1: Preparation of 1,2-dimethyl-4-(tributyltinyl)-1H-imidazole (76b)

At room temperature, hexabutylditin (795 mg, 1.371 mmol) and tris(dibenzylideneacetone)dipalladium (104 mg, 0.114 mmol) were added to a mixture of 4-bromo-1,2-dimethyl-1H-imidazole (76a) (200 mg, 1.143 mmol), tricyclohexylphosphine (32 mg, 0.114 mmol) and lithium chloride (291 mg, 6.858 mmol) in 1,4-dioxane (10 mL), the atmosphere was replaced with nitrogen three times, and the temperature was raised to 100° C. and stirred overnight. The reaction solution was cooled, concentrated under reduced pressure, and used in the next step.

LC-MS: m/z 387 [M+H] ⁺ .

The preparation method is the same as that of Example 47, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) is used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) to prepare compound 76c.

Step 2: Preparation of N-(4-(4-amino-7-(1,2-dimethyl-1H-imidazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (76)

Tetrakis(triphenylphosphine)palladium (38 mg, 0.033 mmol) was added to a mixture of N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (76c) (200 mg, 0.331 mmol) and 1,2-dimethyl-4-(tributyltinyl)-1H-imidazole (76b) (crude) in N,N-dimethylformamide (4.0 mL) at room temperature, the atmosphere was replaced with nitrogen three times, the temperature was raised to 100°C and stirred overnight. The reaction solution was concentrated under reduced pressure and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm×250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% formic acid aqueous solution, gradient: 10-35%) to obtain 51 mg of the title compound as a white solid, yield: 24.9%.

LC-MS: m/z 620 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.80 (s, 1H), 8.47 (d, J = 4.0Hz, 1H), 8.30 (s, 1H), 7.74 (s, 1H), 7.58-7.57 ( m,1H),7.55-7.52(m,1H),7.43-7.37(m,2H),7.27-7.25(m,1H),7.24-7.21(m,1H),7.19-7.18(m,1H), 5.83-5.79(m,3H),5.52-5.51(m,1H),3.69(s,3H),2.45(s,3H),2.39(s,3H),2.09(s,3H),1.94(s, 3H).

Example 77: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (77)

The preparation method was the same as that of Example 35, except that 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (1c) was used instead of 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (35b), and N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (35c) was used instead of 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (35b). The title compound 77 was prepared by replacing N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) with (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid instead of (1H-pyrazol-4-yl)boronic acid.

LC-MS: m/z 607 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.78 (s, 1H), 8.52-8.46 (m, 2H), 8.36 (s, 1H), 7.58-7.55 (m, 1H), 7.55-7.50 (m, 1H),7.43-7.36(m,2H),7.29-7.17(m,3H),5.79(s,1H),5.58(s,2H),5.51(s,1H),4.23(s,3H),2.39 (s,3H),2.10(s,3H),1.94(s,3H).

Example 78: Preparation of N-(4-(4-amino-7-(1-methyl-1H-pyrazol-4-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-fluorophenyl)methacrylamide (78)

Compound 78 was prepared by the same preparation method as Example 35, except that N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) and (1-methyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 592 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 10.04 (s, 1H), 8.48 (d, J = 4.0Hz, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.89 (s, 1H),7.68-7.65(m,1H),7.44-7.39(m,3H),7.29-7.24 (m,3H),7.17-7.16(m,1H),5.80(s,1H),5.56(s,1H),5.36(s,2H),3.93(s,3H),2.40(s,3H), 1.93(s,3H).

Example 79: Preparation of N-(4-(4-amino-7-(1-methyl-1H-imidazol-4-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-fluorophenyl)methacrylamide (79)

The same preparation method as Example 37 was used, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) and N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f), to prepare Compound 79.

LC-MS: m/z 592 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 10.02 (s, 1H), 8.48 (d, J = 8.0Hz, 1H), 8.31 (s, 1H), 7.74 (s, 1H), 7.67-7.63 ( m,2H),7.43-7.41(m,1H),7.40-7.36(m,2H),7.28-7.22(m,3H),7.17-7.16(m,1H),5.80(s,1H),5.55( s,1H),5.31(s,2H),3.74(s,3H),2.40(s,3H),1.94(s,3H).

Example 80: Preparation of N-(4-(4-amino-7-(1-methyl-1H-pyrazol-4-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-cyanophenyl)methacrylamide (80)

The preparation method was the same as that of Example 35, except that N-(3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f), and (1-methyl-1H-pyrazol-4-yl)boronic acid was used instead of (1H-pyrazol-4-yl)boronic acid. The title compound 80 was prepared by adding 1-(2-(4-(2-aminobutyric acid))boronic acid.

LC-MS: m/z 599 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.16 (s, 1H), 8.57-8.34 (m, 1H), 8.30-8.08 (m, 3H), 8.02-7.80 (m, 2H), 7.59-7.49 ( m,1H),7.47-7.36(m,2H),7.28-7.22(m,2H),7.19-7.12(m,1H),5.84(s,1H),5.59(s,1H),5.40(s, 2H),3.93(s,3H),2.39(s,3H),1.94(s,3H).

Example 81: Preparation of N-(4-(4-amino-7-(1-methyl-1H-pyrazol-4-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-2-(trifluoromethyl)phenyl)methacrylamide (81)

Step 1: Preparation of N-(4-bromo-2-(trifluoromethyl)phenyl)methacrylamide (81b)

At room temperature, 4-bromo-2-(trifluoromethyl)aniline (81a) (5 g, 20.83 mmol) and sodium bicarbonate (3.499 g, 41.66 mmol) were added to dichloromethane (100 mL), stirred in an ice bath for 30 min, methacryloyl chloride (2.395 g, 22.92 mmol) was added, and the mixture was slowly returned to room temperature and stirred overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 50:1-1:1) to obtain 3.2 g of the title compound as a white solid, with a yield of 49.9%.

LC-MS: m/z 308 [M+H] ⁺ .

Step 2: Preparation of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)methacrylamide (81c)

At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.713 g, 0.97 mmol) was added to N-(4-bromo-2-(trifluoromethyl)phenyl)methacrylamide (81b) (3 g, 9.74 mmol), bipinacol ester (2.472g, 9.74mmol) and potassium acetate (2.866g, 29.21mmol) in dioxane (40mL), replaced with nitrogen three times, stirred at 90°C overnight. The reaction solution was cooled, diluted with water (100mL), extracted with EA (100mL×3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA＝50:1-2:1) to obtain 600mg of the title compound as a light yellow solid, with a yield of 17.4%.

LC-MS: m/z 356 [M+H] ⁺ .

Step 3: Preparation of N-(4-(4-amino-7-bromo-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-2-(trifluoromethyl)phenyl)methacrylamide (81d)

7-Bromo-2-iodo-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-4-amine (35h) (350 mg, 0.65 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)methacrylamide (81c) (151 mg, 0.55 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (48 mg, 0.07 mmol), cesium fluoride (296 mg, 1.95 mmol) and H ₂ O (0.5 mL) were added to a solution of N,N-dimethylformamide (5 mL) at room temperature, replaced with nitrogen three times, and stirred at 75°C overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-10:1) to obtain 390 mg of the title compound as a yellow oily liquid. Yield: 93.8%.

LC-MS: m/z 640 [M+H] ⁺ .

Step 4: Preparation of N-(4-(4-amino-7-(1-methyl-1H-pyrazol-4-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-2-(trifluoromethyl)phenyl)methacrylamide (81)

To a mixture of N-(4-(4-amino-7-bromo-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-2-(trifluoromethyl)phenyl)methacrylamide (81d) (350 mg, 0.546 mmol), (1H-pyrazol-3-yl)boronic acid (206 mg, 1.639 mmol) and cesium fluoride (249 mg, 1.639 mmol) in N,N-dimethylformamide/water (4.4 mL, v/v=10:1) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (40 mg, 0.055 mmol) at room temperature, the mixture was purged with nitrogen for 1 min and microwaved at 90 °C for 2 h. The reaction solution was concentrated under reduced pressure and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm × 250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% formic acid aqueous solution, gradient: 10-50%) to obtain 66 mg of the title compound as a yellow solid. Yield: 18.8%.

LC-MS: m/z 642 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δppm 9.51(s,1H),8.51-8.45(m,1H),8.21(s,1H),8.10(s,1H),7.95-7.91(m,1H) ,7.69-7.63(m,1H),7.56-7.50(m,3H),7.50-7.45(m,1H),7.39-7.31(m,2H),7.21-7.14(m,1H),5.82(s, 1H),5.53(s,1H),5.38(s,2H),3.95(s,3H),2.42(s,3H),1.92(s,3H).

Example 82: Preparation of N-(4-(4-amino-7-(1-methyl-1H-pyrazol-4-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-2-cyanophenyl)methacrylamide (82)

The title compound 82 was prepared in the same manner as Example 81, except that 2-amino-5-bromobenzonitrile was used instead of 4-bromo-2-(trifluoromethyl)aniline (81a).

LC-MS: m/z 599 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.07 (s, 1H), 8.50 (d, J = 5.0Hz, 1H), 8.22-8.19 (m, 1H), 8.10 (s, 1H), 7.94-7.91 (m,1H),7.67-7.63(m,1H),7.59-7.47(m,4H),7.37-7.33(m,2H),7.18(d,J＝5.0Hz,1H),5.93-5.89(m ,1H),5.63-5.59(m,1H),5.41-5.31(m,2H),3.94(s,3H),2.43(s,3H),1.95(s,3H).

Example 83: Preparation of N-(4-(4-amino-7-(1-methyl-1H-pyrazol-4-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-2-(trifluoromethoxy)phenyl)methyl acrylamide (83).

The title compound 83 was prepared in the same manner as Example 81, except that 4-bromo-2-trifluoromethoxyaniline was used instead of 4-bromo-2-(trifluoromethyl)aniline (81a).

LC-MS: m/z 658 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δppm 9.61(s,1H),8.52-8.46(m,1H),8.20(s,1H),8.08(s,1H),7.95-7.89(m,1H) ,7.69-7.63(m,1H),7.54-7.32(m,5H),7.20-7.15(m,1H),7.15-7.10(m,1H),5.85-5.78(m,1H),5.57-5.51( m,1H),5.42-5.25(m,2H),3.95(s,3H),2.42(s,3H),1.93(s,3H).

Example 84: Preparation of N-(4-(4-amino-7-(1-methyl-1H-pyrazol-4-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-2-chlorophenyl)methacrylamide (84)

The title compound 84 was prepared in the same manner as Example 81, except that 4-bromo-2-chloroaniline was used instead of 4-bromo-2-(trifluoromethyl)aniline (181a).

LC-MS: m/z 608 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.40 (s, 1H), 8.50 (d, J = 5.0Hz, 1H), 8.22-8.18 (m, 1H), 8.08 (s, 1H), 7.94-7.91 (m,1H),7.58-7.49(m,3H),7.37-7.26(m,4H),7.18(d,J＝5.0Hz,1H),5.91-5.87(m,1H),5.57-5.53(m ,1H),5.39-5.29(m,2H),3.94(s,3H),2.43(s,3H),1.95(s,3H).

Example 85: Preparation of N-(4-(4-amino-7-(1-methyl-1H-pyrazol-4-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-2-methylphenyl)methacrylamide (85)

The title compound 85 was prepared in the same manner as Example 81, except that 4-bromo-2-methylaniline was used instead of 4-bromo-2-(trifluoromethyl)aniline (81a).

LC-MS: m/z 588 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.29 (s, 1H), 8.52-8.46 (m, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.52 -7.45(m,2H),7.37-7.29(m,2H),7.28-7.22(m,1H),7.21-7.16(m,1H),7.16-7.12(m,1H),7.12-7.06(m, 1H),5.83(s,1H),5.49(s,1H),5.31(s,2H),3.94(s,3H),2.43(s,3H),2.11(s,3H),1.94(s,3H ).

Example 86: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)thieno[3,2]pyridin-2-yl)-3-methylphenyl)methacrylamide (86) preparation

The preparation method is the same as that of Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) is used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine is used instead of (1-methyl-1H-pyrazol-4-yl)boric acid to prepare Compound 86.

LC-MS: m/z 689 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.77 (s, 1H), 8.48 (d, J = 4.0Hz, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.91 (s, 1H),7.57-7.56(m,1H),7.52-7.50(m,1H),7.41-7.36(m,2H),7.26-7.24(m,1H),7.23-7.21(m,1H) ,7.19-7.18(m,1H),5.78(s,1H),5.51(s,1H),5.32(s,2H),4.24-4.18(m,1H),2.90-2.87(m,2H),2.39 (s,3H),2.23(s,3H),2.11(s,3H),2.08-2.00(m,6H),1.94(s,3H).

Example 87: Preparation of N-(4-(4-amino-7-(1-ethyl-1H-pyrazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (87)

The preparation method is the same as that of Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) is used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and (1-ethyl-1H-pyrazol-4-yl)boric acid is used instead of (1-methyl-1H-pyrazol-4-yl)boric acid, to prepare Compound 87.

LC-MS: m/z 620 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77 (s, 1H), 8.48 (d, J = 5.0Hz, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.90 (s, 1H) ),7.57-7.54(m,1H),7.54-7.49(m,1H),7.43-7.35(m,2H),7.27-7.17(m,3H),5.78(s,1H),5.51(s,1H ),5.32(s,2H),4.25-4.17(m,2H),2.39(s,3H),2.11(s,3H),1.94(s,3H),1.43(t,J＝7.3Hz,3H) .

Example 88: Preparation of N-(4-(4-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (88)

The preparation method is the same as that of Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) is used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and (1-cyclopropyl-1H-pyrazol-4-yl)boric acid is used instead of (1-methyl-1H-pyrazol-4-yl)boric acid, to prepare Compound 88.

LC-MS: m/z 632 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77(s,1H),8.47(d,J＝5.0Hz,1H),8.22(s,1H),8.10(s,1H),7.88(s,1H),7.58-7.54(m,1H),7.54 -7.48(m,1H),7.43-7.35(m,2H),7.27-7.17(m,3H),5.79(s,1H),5.51(s,1H),5.33(s,2H),3.86-3.76 (m,1H),2.39(s,3H),2.11(s,3H),1.93(d,J=1.2Hz,3H),1.17-1.09(m,2H),1.04-0.96(m,2H).

Example 89: Preparation of N-(4-(4-amino-3-(3-cyano-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (89)

The title compound 89 was prepared by the same preparation method as in Example 35, except that 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a), N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f), and (1-methyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 613 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δppm 9.79(s,1H),8.57-8.47(m,1H),8.21(s,1H),8.12(s,1H),7.97-7.93(m,1H) ,7.92-7.89(m,1H),7.75-7.66(m,1H),7.60-7.56(m,1H),7.55-7.51(m,1H),7.50-7.46(m,1H),7.30-7.19( m,2H),5.79(s,1H),5.55(s,2H),5.52(s,1H),3.92(s,3H),2.41(s,3H),2.08(s,3H),1.93(s ,3H).

Example 90: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (90).

Compound 90 was prepared by the same preparation method as Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethane-1-ol was used instead of (1-methyl-1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 636 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77(s,1H),8.50-8.44(m,1H),8.20-8.16(m,1H),8.13-8.08(m,1H),7.95-7.89(m,1H),7.57-7.49(m,2H ),7.43-7.35(m,2H),7.27-7.17(m,3H),5.81-5.76(m,1H),5.53-5.48(m,1H),5.40-5.28(m,2H),4.96-4.90 (m,1H),4.26-4.19(m,2H),3.83-3.76(m,2H),2.39(s,3H),2.11(s,3H),1.93(s,3H).

Example 91: Preparation of 1-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-2-methylprop-2-en-1-one (91)

Step 1: Preparation of tert-butyl 4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (91b)

7-Bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-iodothieno[3,2-c]pyridin-4-amine (47c) (500 mg, 0.90 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (91a) (236 mg, 0.76 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (66 mg, 0.09 mmol), and cesium fluoride (409 mg, 2.69 mmol) were added to a mixture of N,N-dimethylformamide/water (6 mL, v/v=10:1) at room temperature and stirred at 75°C overnight under nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-10:1) to obtain 480 mg of the title compound as a white solid. Yield: 87.8%.

LC-MS: m/z 612 [M+H] ⁺ .

Step 2: Preparation of 7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-c]pyridin-4-amine (91c)

At room temperature, tert-butyl 4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (91b) (430 mg, 0.70 mmol) was dissolved in 10 mL of hydrochloric acid in dioxane and stirred at room temperature for 1 h. After the reaction was completed, the mixture was filtered and the filter cake was washed with dichloromethane (3×10 mL) to obtain 400 mg of the title compound as a yellow solid, with a yield of 97.5%.

LC-MS: m/z 512 [M+H] ⁺ .

Step 3: Preparation of 1-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-2-methylprop-2-en-1-one (91d)

At room temperature, 7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)thieno[3,2-c]pyridin-4-amine (91c) (380 mg, 0.74 mmol) and sodium bicarbonate (125 mg, 1.48 mmol) were added to dichloromethane (10 mL), stirred in an ice bath for 30 min, methacryloyl chloride (93 mg, 0.89 mmol) was added, and the mixture was slowly returned to room temperature and stirred overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-10:1) to obtain 400 mg of the title compound as a yellow oily liquid, with a yield of 93.2%.

LC-MS: m/z 580 [M+H] ⁺ .

Step 4: Preparation of 1-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3,6-dihydropyridin-1(2H)-yl)-2-methylprop-2-en-1-one (91)

To a mixture of N-(4-(4-amino-7-bromo-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-2-methylphenyl)methacrylamide (91d) (300 mg, 0.52 mmol), (1H-pyrazol-3-yl)boronic acid (195 mg, 1.55 mmol) and cesium fluoride (235 mg, 1.55 mmol) in N,N-dimethylformamide/water (4.4 mL, v/v=10:1) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (38 mg, 0.052 mmol) at room temperature, the mixture was purged with nitrogen for 1 min and microwaved at 90 °C for 2 h. The reaction solution was concentrated under reduced pressure and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm × 250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% formic acid aqueous solution, gradient: 5-35%) to obtain 21 mg of the title compound as a yellow solid. Yield: 6.9%.

LC-MS: m/z 582 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.52-8.46(m,1H),8.20-8.13(m,1H),8.04(s,1H),7.91-7.83(m,1H),7.58-7.46( m,2H),7.37-7.29(m,1H),7.27-7.17(m,1H),5.96(s,1H),5.28(s,2H),5.16(s,1H),4.92(s,1H) ,4.04(s,2H),3.93(s,3H),3.50(s,2H),2.43(s,3H),2.07(s,2H),1.80(s,3H).

Example 92: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-(trifluoromethyl)phenyl)methacrylamide (92)

The same preparation method as in Example 48 was used except that N-(3-trifluoromethyl-4-(4,4,5,5-tetramethyl-1,3,2-difluoromethyl)- Compound 92 was prepared by replacing N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) with 1,4-dioxaborolan-2-yl)phenyl)methacrylamide (23b).

LC-MS: m/z 660 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.17(s,1H),8.50-8.44(m,1H),8.24-8.19(m,1H),8.17-8.14(m,1H),8.12(s, 1H),7.98-7.90(m,1H),7.91-7.84(m,1H),7.61-7.55(m,1H),7.43-7.36(m,1H),7.20-7.15(m,1H),5.85( s,1H),5.59(s,1H),5.34(s,2H),3.92(s,3H),2.37(s,3H),1.95(s,3H).

Example 93: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(5-methylthiazol-2-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (93)

Step 1: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(5-methylthiazol-2-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (93)

5-Methyl-2-(tributyltinyl)thiazole (93a) (578 mg, 1.489 mmol) was added to a mixture of N-(4-(4-amino-7-bromo-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-fluorophenyl)methacrylamide (73c) (150 mg, 0.248 mmol) and 1,1-bis(diphenylphosphino)diphenylferric palladium dichloride (18 mg, 0.025 mmol) in N-methylpyrrolidone (3 mL) at room temperature, the atmosphere was replaced with nitrogen three times, the temperature was raised to 130°C and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-10:1), then recrystallized from dimethyl sulfoxide (5 mL), rinsed with acetonitrile and dried to obtain 77 mg of the title compound as a light brown solid. Yield: 49.9%.

LC-MS: m/z 623 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.77 (s, 1H), 8.47 (d, J = 4.0Hz, 1H), 8.44 (s,1H),7.63-7.61(m,1H),7.57-7.55(m,1H),7.53-7.50(m,1H),7.42-7.37(m,2H),7.25-7.21(m,2H) ,7.19-7.18(m,1H),5.87-5.75(m,3H),5.51(s,1H),2.54(s,3H),2.39(s,3H),2.10(s,3H),1.94(s ,3H).

Example 94: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-chlorophenyl)methacrylamide (94)

The same preparation method as Example 48 was used, except that N-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide was used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) to prepare compound 94.

LC-MS: m/z 626 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δppm 10.02(s,1H),8.52-8.44(m,1H),8.22-8.15(m,1H),8.12(s,1H),7.95-7.93(m, 1H),7.90-7.87(m,1H),7.68-7.58(m,1H),7.48-7.35(m,3H),7.25-7.14(m,2H),5.81(s,1H),5.57(s, 1H),5.36(s,2H),3.92(s,3H),2.38(s,3H),1.94(s,3H).

Example 95: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (95)

Step 1: Preparation of 2-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (95b)

At room temperature, tert-butyl 2-bromo-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (95a) (1 g, 3.3 mmol) was dissolved in 20 mL of hydrochloric acid/dioxane and stirred overnight at room temperature. After the reaction was completed, the mixture was filtered and the filter cake was washed with dioxane (10 mL × 3) and dried to obtain 900 mg of the crude title compound as a white solid.

LC-MS: m/z 202 [M+H] ⁺ .

Step 2: Preparation of 2-bromo-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (95c)

At room temperature, 2-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (95b) (900 mg, 4.4 mmol), sodium triacetoxyborohydride (4.012 mg, 44.5 mmol), and paraformaldehyde (9.436 mg, 44.5 mmol) were added to 20 mL of 1,2-dichloroethane and stirred overnight at room temperature. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-10:1) to obtain 500 mg of an off-white solid with a yield of 52.6%.

LC-MS: m/z 216 [M+H] ⁺ .

Step 3: Preparation of 7-methyl-2-(tributyltin)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (95d)

At room temperature, 2-bromo-7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (95c) (200 mg, 0.9 mmol), hexabutylditin (537 mg, 0.9 mmol), lithium chloride (233 mg, 5.5 mmol), tris(dibenzylideneacetone)dipalladium (85 mg, 0.09 mmol), tri(cyclohexyl)phosphine (26 mg, 0.09 mmol) were dissolved in 10 mL of dioxane solution and stirred at 100°C overnight under nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 1 g of a black oily crude product, which was directly used in the next step.

LC-MS: m/z 428 [M+H] ⁺ .

Step 4: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(7-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (95)

At room temperature, N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (76c) (280 mg, 0.46 mmol), crude 7-methyl-2-(tributyltinyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (95d) (1 g, 0.9 mmol), and tetrakis(triphenylphosphine)palladium (53 mg, 0.046 mmol) were dissolved in 5 mL of N,N-dimethylformamide. The reaction was carried out at 90°C overnight under a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm×250mm, C18, 10um, 100A, mobile phase: acetonitrile/0.1% ammonia aqueous solution, gradient: 10-50%) to obtain 30 mg of the title compound as a yellow solid, yield: 9.9%.

LC-MS: m/z 661 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.76 (s, 1H), 8.53-8.42 (m, 1H), 8.32 (s, 1H), 7.66-7.45 (m, 3H), 7.41-7.32 (m, 2H),7.29-7.12(m,3H),5.79(s,1H),5.51(s,1H),5.28(s,2H),4.04(t,J＝5.4Hz,2H),3.60(s,2H ), 2.81 (t, J = 5.4Hz, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 2.09 (s, 3H), 1.94 (s, 3H).

Example 96: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(thiazol-2-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (96)

Compound 96 was prepared in the same manner as Example 93, except that 2-(tributyltinyl)thiazole was used instead of 5-methyl-2-(tributyltinyl)thiazole (93a).

LC-MS: m/z 609 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.78 (s, 1H), 8.55 (s, 1H), 8.47 (d, J = 4.0Hz, 1H), 7.95 (d, J = 4.0Hz, 1H) ,7.71(d,J＝4.0Hz,1H),7.57-7.58(m,1H),7.53-7.51(m,1H),7.43-7.37(m,2H),7.26-7.22(m,2H),7.19 -7.18(m,1H),5.90-5.76(m,3H),5.51(s,1H),2.39(s,3H),2.11(s,3H),1.94(s,3H).

Example 97: Preparation of N-(4-(4-amino-7-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (97)

Compound 97 was prepared in the same manner as Example 76, except that 2-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole was used instead of 4-bromo-1,2-dimethyl-1H-imidazole (76a).

LC-MS: m/z 632 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.76 (s, 1H), 8.47 (d, J = 4.0Hz, 1H), 8.31 (s, 1H), 7.62 (s, 1H), 7.56-7.55 ( m,1H),7.52-7.50(m,1H),7.39-7.35(m,2H),7.24-7.18(m,3H),5.79(s,1H),5.51(s,1H),5.33(s, 2H),4.02(t,J＝8.0Hz,2H),2.81(t,J＝8.0Hz,2H),2.58-2.53(m,2H),2.39(s,3H),2.10(s,3H), 1.94(s,3H).

Example 98: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(pyridin-2-yl)thieno[3,2-c]pyridin-2-yl]-3-methylphenyl)methacrylamide (98)

The title compound 98 was prepared in the same manner as in Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and pyridin-2-ylboronic acid was used instead of (1H-pyrazol-4-yl)boronic acid.

LC-MS: m/z 603 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.76 (s, 1H), 8.74 (s, 1H), 8.70-8.65 (m, 1H), 8.50-8.45 (m, 1H), 8.22-8.17 (m, 1H),7.92-7.86(m,1H),7.56-7.50(m,2H),7.41-7.35(m,2H),7.31-7.18(m,4H),5.79(s,1H),5.66(s, 2H),5.51(s,1H),2.39(s,3H),2.09(s,3H),1.94(s,3H).

Example 99: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(pyrimidin-2-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (99)

Compound 99 was prepared in the same manner as Example 93, except that 2-(tributyltinyl)pyrimidine was used instead of 5-methyl-2-(tributyltinyl)thiazole (93a).

LC-MS: m/z 604 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δppm 9.23 (s, 1H), 8.83 (d, J = 4.0Hz, 2H), 8.35 (d, J = 4.0Hz, 1H), 7.47-7.44 (m, 2H) ,7.37-7.35(m,1H),7.24-7.20(m,2H),7.17-7.10(m,3H),6.93-6.92(m,1H),5.78(s,1H),5.47(s,1H) ,5.18(s,2H),2.45(s,3H),2.16(s,3H),2.06(s,3H).

Example 100: Preparation of N-(4-(4-amino-7-(2-(difluoromethyl)-1-methyl-1H-imidazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (100)

Step 1: Preparation of 4-bromo-1-methyl-1H-imidazole-2-carbaldehyde (100b)

At room temperature, active manganese dioxide (18.3 g, 210.53 mmol) was added to (4-bromo-1-methyl-1H-imidazol-2-yl)methanol (100a) (8.0 g, 42.10 mmol) in acetonitrile (160 mL), a drying tube was added, and the temperature was raised to 50°C and stirred for 3 hours. The reaction solution was cooled, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 50:1-2:1) to obtain 7.5 g of the title compound as a white solid, with a yield of 94.7%.

LC-MS: m/z 189 [M+H] ⁺ .

Step 2: Preparation of 4-bromo-2-(difluoromethyl)-1-methyl-1H-imidazole (100c)

At 0°C, add diethylaminosulfur trifluoride (18.0 g, 111.70 mmol) to a solution of 4-bromo-1-methyl-1H-imidazole-2-carboxaldehyde (100b) (7.0 g, 37.23 mmol) in dichloromethane (200 mL). Stir at 0°C for 0.5 hours under a nitrogen atmosphere, slowly warm to room temperature and stir for 3 hours. Add saturated sodium bicarbonate aqueous solution dropwise to the reaction solution under an ice bath to quench. Then extract with dichloromethane. The organic phase is dried, filtered, and concentrated under reduced pressure. The residue is separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-4:1) to obtain 6.0 g of the title compound as a yellow-brown solid, yield: 76.7%

LC-MS: m/z 211 [M+H] ⁺ .

Step 3: Preparation of 2-(difluoromethyl)-1-methyl-4-(tributyltinyl)-1H-imidazole (100d) At room temperature, tetrakistriphenylphosphine palladium (277 mg, 0.24 mmol) was added to a dioxane (10 mL) solution of 4-bromo-2-(difluoromethyl)-1-methyl-1H-imidazole (100c) (500 mg, 2.38 mmol) and hexa-n-butylditin (1.45 g, 2.50 mmol), the atmosphere was replaced with nitrogen three times, and the mixture was stirred at 120°C overnight. The reaction solution was cooled to room temperature, filtered, the filtrate was dried under reduced pressure, and the residue was directly used for the next reaction.

LC-MS: m/z 423 [M+H] ⁺ .

Step 4: Preparation of N-(4-(4-amino-7-(2-(difluoromethyl)-1-methyl-1H-imidazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (100)

Tetrakistriphenylphosphine palladium (58 mg, 0.05 mmol) was added to a mixture of N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (76c) (300 mg, 0.498 mmol) and 2-(difluoromethyl)-1-methyl-4-(tributyltinyl)-1H-imidazole (100d) (crude) in N-methylpyrrolidone (6 mL) at room temperature, the atmosphere was replaced with nitrogen three times, the temperature was raised to 120° C. and stirred overnight. The reaction solution was concentrated under reduced pressure and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm × 250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% formic acid solution, gradient: 10-40%) to obtain 14 mg of the title compound as a white solid. Yield: 4.30%.

LC-MS: m/z 656 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77 (s, 1H), 8.50-8.45 (m, 1H), 8.34 (s, 1H), 7.92-7.88 (m, 1H), 7.56-7.50 (m, 2H),7.41-7.34(m,2H),7.30-7.13(m,4H),5.81-5.77(m,1H),5.53-5.49(m,1H),5.42-5.32(m,2H),3.85( s,3H),2.39(s,3H),2.09(s,3H),1.94(s,3H).

Example 101: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (101)

Step 1: Preparation of 1-methyl-2-(trifluoromethyl)-1H-imidazole (101b)

At room temperature, 2-(trifluoromethyl)-1H-imidazole (101a) (10.0 g, 73.47 mmol) was dissolved in tetrahydrofuran (400 mL), and the atmosphere was replaced with nitrogen three times. The temperature was lowered to 0°C, and sodium hydride (4.41 g, 110.2 mmol, 60%) was added in batches, and the mixture was stirred at 0°C for 30 minutes. Iodomethane (12.5 g, 88.17 mmol) was added, and the mixture was stirred at 0°C for 1 hour. The reaction solution was poured into ice water (800 mL), extracted with EA (300 mL×3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase (mobile phase: acetonitrile/0.1% formic acid aqueous solution, gradient: 10-30%) to obtain 3.67 g of the title compound as a colorless oily liquid, yield: 33.3%

LC-MS: m/z 151 [M+H] ⁺ .

Step 2: Preparation of 4,5-dibromo-1-methyl-2-(trifluoromethyl)-1H-imidazole (101c)

At room temperature, N-bromosuccinimide (NBS) (8.61 g, 48.37 mmol) was added to a solution of 1-methyl-2-(trifluoromethyl)-1H-imidazole (101b) (3.30 g, 21.98 mmol) in N,N-dimethylformamide (130 mL), and stirred at room temperature overnight. The reaction solution was diluted with EA (400 mL), washed with brine (700 × 2 mL), the aqueous phase was extracted with EA (300 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 50:1-10:1) to obtain 5.28 g of the title compound as a white solid, yield: 78.0%

LC-MS: m/z 307 [M+H] ⁺ .

Step 3: Preparation of 4-bromo-1-methyl-2-(trifluoromethyl)-1H-imidazole (101d)

At room temperature, 4,5-dibromo-1-methyl-2-(trifluoromethyl)-1H-imidazole (101c) (4.70 g, 15.26 mmol) was dissolved in tetrahydrofuran (100 mL), replaced with nitrogen three times, and the temperature was lowered to -25°C. Isopropylmagnesium chloride (7.90 mL, 15.87 mmol, 2 mol/L THF solution) was added, and the mixture was stirred at -25°C for 10 minutes. Isopropylmagnesium chloride (5.80 mL, 11.60 mmol, 2 mol/L THF solution) was then added, and stirring was continued at -25°C for 1 hour. The reaction solution was poured into ice water (100 mL), extracted with EA (70 mL×3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-10:1) to give 3.36 g of the title compound as a colorless oily liquid. Yield: 96.1%.

LC-MS: m/z 229 [M+H] ⁺ .

Step 4: Preparation of 1-methyl-4-(tributyltinyl)-2-(trifluoromethyl)-1H-imidazole (101e)

At room temperature, hexabutylditin (1.33 g, 2.29 mmol) and tris(dibenzylideneacetone)dipalladium (199 mg, 0.218 mmol) were added to a mixture of 4-bromo-1-methyl-2-(trifluoromethyl)-1H-imidazole (101d) (500 mg, 2.18 mmol), tricyclohexylphosphine (83 mg, 0.218 mmol) and lithium chloride (555 mg, 13.10 mmol) in 1,4-dioxane (20 mL), and the atmosphere was replaced with nitrogen three times, and the mixture was heated to 100° C. and stirred overnight. The reaction solution was cooled, concentrated under reduced pressure, and used directly in the next step.

LC-MS: m/z 441 [M+H] ⁺ .

Step 5: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-2-(trifluoromethyl)-1H-imidazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (101)

To a mixture of N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (76c) (150 mg, 0.248 mmol) and 1-methyl-4-(tributyltinyl)-2-(trifluoromethyl)-1H-imidazole (101e) (crude) in N,N-dimethylformamide (3.0 mL) was added bistriphenylphosphine palladium dichloride (18 mg, 0.025 mmol) at room temperature, the atmosphere was replaced with nitrogen three times, the temperature was raised to 100°C and stirred overnight. The reaction solution was concentrated under reduced pressure and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm × 250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% ammonia solution, gradient: 35-70%) to obtain 27 mg of the title compound as a white solid. Yield: 16.2%.

LC-MS: m/z 674 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.77 (s, 1H), 8.47 (d, J = 4.0Hz, 1H), 8.36 (s, 1H), 8.04 (s, 1H), 7.57-7.55 ( m,1H),7.54-7.51(m,1H),7.40-7.36(m,2H),7.27-7.25(m,1H),7.23-7.20(m,1H),7.19-7.18(m,1H), 5.79(s,1H),5.51(s,1H),5.44(s,2H),3.89(s,3H),2.39(s,3H),2.09(s,3H),1.94(s,3H).

Example 102: Preparation of N-(4-(4-amino-7-(2-cyano-1-methyl-1H-imidazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (102)

Step 1: Preparation of 4-bromo-1-methyl-1H-imidazole-2-carbonitrile (102a)

At room temperature, iodine (2.62 g, 10.32 mmol) was added to a mixture of 4-bromo-1-methyl-1H-imidazole-2-carboxaldehyde (100b) (1.50 g, 7.94 mmol) in aqueous ammonia (22.5 mL) and tetrahydrofuran (7.5 mL), and stirred at room temperature for 1 hour. Water (100 mL) was added to the reaction solution, and sodium sulfite was added until the reaction solution became colorless, and extracted with EA (50 mL×3). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-4:1) to obtain 1.38 g of the title compound as a white solid, with a yield of 93.5%.

LC-MS: m/z 186 [M+H] ⁺ .

Step 2: Preparation of 1-methyl-4-(tributyltinyl)-1H-imidazole-2-carbonitrile (102b)

At room temperature, hexabutylditin (3.60 g, 6.21 mmol) and tris(dibenzylideneacetone)dipalladium (541 mg, 0.591 mmol) were added to a mixture of 4-bromo-1-methyl-1H-imidazole-2-carbonitrile (1.10 g, 5.91 mmol), tricyclohexylphosphine (225 mg, 0.591 mmol) and lithium chloride (1.50 g, 35.48 mmol) in anhydrous 1,4-dioxane (55 mL), the atmosphere was replaced with nitrogen three times, the temperature was raised to 100°C and stirred overnight. The reaction solution was cooled and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-10:1) to obtain 660 mg of the title compound as a light yellow oily liquid, with a yield of 28.2%.

LC-MS: m/z 398 [M+H] ⁺ .

Step 3: N-(4-(4-amino-7-(2-cyano-1-methyl-1H-imidazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidine-2- Preparation of 2-(4-(2-(4-(2-(4-(2-(4-(2-thiophene-[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (102)

1,1-Bis(diphenylphosphino)diphenylferric palladium chloride (24 mg, 0.033 mmol) was added to a mixture of N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (76c) (200 mg, 0.331 mmol) and 1-methyl-4-(tributyltinyl)-1H-imidazole-2-carbonitrile (102b) (655 mg, 1.654 mmol) in N-methylpyrrolidone (4.0 mL) at room temperature, purged with nitrogen for 1 minute, and reacted in a microwave at 100°C for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm × 250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% formic acid aqueous solution, gradient: 5-35%) to obtain 66 mg of the title compound as a white solid. Yield: 31.6%.

LC-MS: m/z 631 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.77 (s, 1H), 8.47 (d, J = 4.0Hz, 1H), 8.39 (s, 1H), 8.18 (s, 1H), 7.58-7.55 ( m,1H),7.53-7.51(m,1H),7.41-7.36(m,2H),7.26-7.24(m,1H),7.23-7.20(m,1H),7.19-7.18(m,1H), 5.79(s,1H),5.51-5.49(m,3H),3.92(s,3H),2.39(s,3H),2.10(s,3H),1.94(s,3H).

Example 103: Preparation of N-(4-(4-amino-7-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (103)

Compound 103 was prepared in the same manner as Example 76, except that 2-bromo-5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine was used instead of 4-bromo-1,2-dimethyl-1H-imidazole (76a).

LC-MS: m/z 648 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.36-8.34(m,2H),7.47(s,1H),7.43-7.42(m,1H),7.35-7.32(m,1H),7.28(s,1H) ),7.23-7.18(m,2H),7.11-7.08(m,2H),6.91(d,J＝4.0Hz,1H),5.77(s,1H),5.46(s,1H),4.94(s, 2H),4.84(s,2H),4.12(s,4H),2.46(s,3H),2.13(s,3H),2.05(s,3H).

Example 104: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)-2-(morpholinomethyl)acrylamide (104)

Step 1: Preparation of N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(morpholinomethyl)acrylamide (104a)

At room temperature, 1-propylphosphonic anhydride (12.9 g, 20.32 mmol) was added to a solution of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (36a) (2.37 g, 10.16 mmol), 2-(morpholinemethyl)acrylic acid (1.74 g, 10.16 mmol) and triethylamine (4.10 g, 40.64 mmol) in tetrahydrofuran (100 mL), and the mixture was heated to 50° C. and stirred overnight. The reaction solution was cooled and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-4:1) to obtain 780 mg of the title compound as a white solid, with a yield of 19.9%.

LC-MS: m/z 387 [M+H] ⁺ .

Step 2: Preparation of N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)-2-(morpholinomethyl)acrylamide (104b)

To a mixture of 7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-iodothieno[3,2-c]pyridin-4-amine (47c) (173 mg, 0.311 mmol), N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-(morpholinomethyl)acrylamide (104a) (120 mg, 0.311 mmol) and cesium fluoride (143 mg, 0.933 mmol) in N,N-dimethylformamide/water (5 mL, v/v=10:1) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (23 mg, 0.031 mmol) at room temperature, the atmosphere was replaced with nitrogen three times, the temperature was raised to 75°C and stirred overnight. The reaction solution was cooled and concentrated under reduced pressure, and the residue was separated by silica gel column chromatography. The title compound was obtained as a pale yellow solid (160 mg). Yield: 74.6%.

LC-MS: m/z 689 [M+H] ⁺ .

Step 3: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)-2-(morpholinomethyl)acrylamide (104)

To a mixture of N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)-2-(morpholinomethyl)acrylamide (104b) (130 mg, 0.188 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (71 mg, 0.565 mmol) and cesium fluoride (86 mg, 0.565 mmol) in N,N-dimethylformamide/water (3.0 mL, v/v=10:1) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (14 mg, 0.019 mmol) at room temperature, the mixture was purged with nitrogen for 1 min, and microwave reaction was performed at 90 °C for 45 min. The reaction solution was concentrated under reduced pressure and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm×250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% formic acid aqueous solution, gradient: 5-50%) to obtain 79 mg of the title compound as a white solid, yield: 60.8%.

LC-MS: m/z 691 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 10.98 (s, 1H), 8.47 (d, J = 4.0Hz, 1H), 8.16 (s, 1H), 8.09 (s, 1H), 7.89 (s, 1H),7.51-7.50(m,1H),7.48-7.46(m,1H),7.43-7.37(m,2H),7.29(d,J＝8.0Hz,1H),7.25-7.22 (m,1H),7.18(d,J＝4.0Hz,1H),6.05(s,1H),5.61(s,1H),5.32(s,2H),3.92(s,3H),3.65-3.63( m,4H),3.34-3.31(m,2H),2.48-2.45(m,4H),2.39(s,3H),2.14(s,3H).

Example 105: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-ethylphenyl)methacrylamide (105)

Step 1: Preparation of N-(4-bromo-3-ethylphenyl)methacrylamide (105b)

Under ice water bath, methacryloyl chloride (1e) (2.87 g, 27.5 mmol) was slowly added dropwise to 4-bromo-3-ethylaniline (105a) (5 g, 25.0 mmol) and sodium bicarbonate (3.15 g, 37.5 mmol) in dichloromethane (50 mL). After the addition was complete, the mixture was transferred to room temperature for 2 h. Water (100 mL) was added to the reaction solution, and the mixture was extracted with DCM (50 mL × 2). The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 50:1-1:50) to obtain 6.63 g of the title compound as a brown oil, with a yield of 99.4%.

LC-MS: m/z 268 [M+H] ⁺ .

Step 2: Preparation of N-(3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (105c)

At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.69 g, 0.94 mmol) was added to a dioxane (25 mL) solution of N-(4-bromo-3-ethylphenyl)methacrylamide (105b) (2.5 g, 9.35 mmol), bis(pinacolato) ester (2.38 g, 18.7 mmol) and potassium acetate (2.8 g, 28.1 mmol), the atmosphere was replaced with nitrogen three times, and the temperature was raised to 90°C for 7 h. After the reaction, the reaction solution was cooled to room temperature, diluted with water (100 mL), extracted with EA (100 mL×3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-1:50) to obtain 1.10 g of the title compound as an off-white solid, with a yield of 37.4%.

LC-MS: m/z 316 [M+H] ⁺ .

The title compound 105 was prepared in the same manner as in Example 48, except that N-(3-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (105c) was used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e).

LC-MS: m/z 620 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.79 (s, 1H), 8.47 (d, J = 5.0Hz, 1H), 8.18-8.14 (m, 1H), 8.10 (s, 1H), 7.91-7.86 (m,1H),7.62-7.59(m,1H),7.57-7.52(m,1H),7.42-7.35(m,2H),7.28-7.24(m,1H ),7.23-7.19(m,1H),7.19-7.17(m,1H),5.79(s,1H),5.51(s,1H),5.32(s,2H),3.92(s,3H),2.48- 2.44(m,2H),2.38(s,3H),1.94(s,3H),1.04(t,J=7.5Hz,3H).

Example 106: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl))oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-fluoro-5-methylphenyl)methacrylamide (106)

The title compound 106 was prepared in the same manner as Example 105, except that 4-bromo-3-fluoro-5-methylaniline was used instead of 4-bromo-3-ethylaniline (105a).

LC-MS: m/z 624 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.95 (s, 1H), 8.48 (d, J = 5.0Hz, 1H), 8.18 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H) ),7.57-7.49(m,1H),7.44-7.15(m,5H),5.80(s,1H),5.55(s,1H),5.37(s,2H),3.92(s,3H),2.37( s,3H),2.13(s,3H),1.93(s,3H).

Example 107: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3,5-dimethylphenyl)methacrylamide (107)

The title compound 107 was prepared in the same manner as Example 105, except that 4-bromo-3,5-dimethylaniline was used instead of 4-bromo-3-ethylaniline (105a).

LC-MS: m/z 620 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δppm 8.35 (d, J = 5.0Hz, 1H), 8.04-8.00 (m, 1H), 7.90-7.86 (m, 1H), 7.78-7.74 (m, 1H), 7.44 -7.37(m,1H),7.34-7.29(m,1H),7.25-7.19(m,2H),7.10-7.03(m,2H),6.92(d,J＝5.0Hz,1H),5.76(s ,1H),5.46(s,1H),4.91(s,2H),4.00(s,3H),2.46(s,3H),2.18-2.09(m,6H),2.05(s,3H).

Example 108: Preparation of N-(4-(4-amino-7-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (108)

The title compound 108 was prepared by the same preparation method as Example 35, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 624 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.76 (s, 1H), 8.67 (s, 1H), 8.51-8.43 (m, 1H), 8.33 (s, 1H), 8.20 (s, 1H), 8.07 -7.68(m,1H),7.61-7.46(m,2H),7.43-7.33(m,2H),7.28-7.18(m,3H),7.17-7.12(m,1H),5.78(s,1H) ,5.50(s,1H),5.45(s,2H),2.39(s,3H),2.11(s,3H),1.93(s,3H).

Example 109: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(4-(trifluoromethyl)pyridin-2-yl)thieno[3,2-c]pyridin-2-yl]-3-methylphenyl)methacrylamide (109)

Step 1: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(4-(trifluoromethyl)pyridin-2-yl)thieno[3,2-c]pyridin-2-yl]-3-methylphenyl)methacrylamide (109)

Tetrakis(triphenylphosphine)palladium (38 mg, 0.033 mmol) was added to a mixture of N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (76c) (200 mg, 0.331 mmol), (4-(trifluoromethyl)pyridin-2-yl)boric acid (316 mg, 1.654 mmol) and sodium carbonate (105 mg, 0.993 mmol) in N-methylpyrrolidone/water (3.5 mL, v/v=10:1) at room temperature, and the mixture was purged with nitrogen for 1 min and subjected to microwave reaction at 90 °C for 6 h. The reaction solution was concentrated under reduced pressure and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm×250mm, C18, 10um, 100A, mobile phase: acetonitrile/0.1% aqueous ammonia solution, gradient: 40-80%) to obtain 46 mg of the title compound as a yellow solid, yield: 20.7%.

LC-MS: m/z 671 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77(s,1H),8.97(s,1H),8.96-8.91(m,1H),8.57(s,1H),8.52-8.45(m,1H) ,7.66-7.60(m,1H),7.58-7.49(m,2H),7.43-7.36(m,2H),7.28-7.21(m,2H),7.20-7.17(m,1H),5.83(s, 2H),5.79(s,1H),5.51(s,1H),2.39(s,3H),2.09(s,3H),1.94(s,3H).

Example 110: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(6-(trifluoromethyl)pyridin-2-yl)thieno[3,2-c]pyridin-2-yl]-3-methylphenyl)methacrylamide (110).

The title compound 110 was prepared in the same manner as Example 109, except that (6-(trifluoromethyl)pyridin-2-yl)boronic acid was used instead of (4-(trifluoromethyl)pyridin-2-yl)boronic acid.

LC-MS: m/z 671 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.79 (s, 1H), 8.88 (s, 1H), 8.56-8.51 (m, 1H), 8.50-8.47 (m, 1H), 8.22-8.09 (m, 1H),7.79-7.73(m,1H),7.59-7.55(m,1H),7.55-7.51(m,1H),7.43-7.36(m,2H),7.28-7.17(m,3H),5.82( s,2H),5.79(s,1H),5.52(s,1H),2.39(s,3H),2.10(s,3H),1.94(s,3H).

Example 111: Preparation of N-(4-(4-amino-7-(1,2-dimethyl-1H-imidazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (111)

The title compound 111 was prepared in the same manner as Example 109, except that (5-(trifluoromethyl)pyridin-2-yl)boronic acid was used instead of (4-(trifluoromethyl)pyridin-2-yl)boronic acid.

LC-MS: m/z 671 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ): δppm 8.99-8.98 (m, 1H), 8.65 (s, 1H), 8.35 (d, J = 4.0Hz, 1H), 8.04-7.97 (m, 2H), 7.47- 7.44(m,2H),7.37-7.34(m,1H),7.23-7.18(m,2H),7.12-7.09(m,2H),6.92(d,J＝4.0Hz,1H),5.78(s, 1H),5.47(s,1H),4.97(s,2H),2.46(s,3H),2.15(s,3H),2.06(s,3H).

Example 112: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(6-methoxypyridin-2-yl)thieno[3,2-c]pyridin-2-yl]-3-methylphenyl)methacrylamide (112)

The title compound 112 was prepared in the same manner as Example 109, except that 2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was used instead of (4-(trifluoromethyl)pyridin-2-yl)boronic acid.

LC-MS: m/z 633 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.76 (s, 1H), 8.68 (s, 1H), 8.54-8.39 (m, 1H), 7.83-7.70 (m, 2H), 7.57-7.53 (m, 1H),7.52-7.47(m,1H),7.43-7.35(m,2H),7.27-7.20(m,2H),7.20-7.16(m,1H),6.75-6.70(m,1H),5.78( s,1H),5.65(s,2H),5.51(s,1H),4.02(s,3H),2.39(s,3H),2.12(s,3H),1.94(s,3H).

Example 113: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (113)

Step 1: Preparation of 2-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (113b)

At room temperature, 2,3-dibromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (113a) (9.4 g, 33.6 mmol) was dissolved in 150 mL of tetrahydrofuran. The temperature was lowered to -40°C under nitrogen atmosphere. 34.9 mL of a tetrahydrofuran solution of isopropylmagnesium chloride (2M) was added dropwise to the reaction system. The temperature was slowly restored to room temperature and stirred overnight. After the reaction was completed, the reaction solution was added dropwise to 300 mL of ice water to quench, extracted with ethyl acetate (250 mL × 3), the organic phases were combined, dried, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH = 50:1-10:1) to obtain 4.2 g of the title compound as a white solid, with a yield of 62.2%.

LC-MS: m/z 201 [M+H] ⁺ .

Step 2: Preparation of 2-(tributyltinyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (113c)

At room temperature, 2-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (113b) (600 mg, 2.98 mmol), hexabutylditin (1728 mg, 2.98 mmol), lithium chloride (759 mg, 17.9 mmol), tris(dibenzylideneacetone)dipalladium (273 mg, 0.30 mmol), tri(cyclohexyl)phosphine (84 mg, 0.30 mmol) were dissolved in 10 mL of dioxane solution and stirred at 100°C overnight under nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 2 g of a black oily liquid crude product, which was directly used in the next step.

LC-MS: m/z 413 [M+H] ⁺ .

Step 3: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (113)

At room temperature, N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (76c) (200 mg, 0.33 mmol), crude 2-(tributyltinyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (113c) (2 g, 2.98 mmol), tetrakis(triphenylphosphine)palladium (38 mg, 0.033 mmol) were dissolved in 5 mL of N,N-dimethylformamide. The mixture was reacted at 90°C overnight under a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm × 250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% ammonia aqueous solution, gradient: 20-70%), 58 mg of the title compound was obtained as a yellow solid. Yield: 27.1%.

LC-MS: m/z 646 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.76 (s, 1H), 8.51-8.42 (m, 1H), 8.31 (s, 1H), 7.60-7.46 (m, 3H), 7.42-7.32 (m, 2H),7.28-7.14(m,3H),5.79(s,1H),5.51(s,1H),5.26(s,2H),4.06-3.93(m,2H),2.85-2.75(m,2H) ,2.39(s,3H),2.09(s,3H),1.94(s,3H),1.92-1.81(m,4H).

Example 114: Preparation of N-(4-(4-amino-7-(1-methyl-1H-pyrazol-4-yl)-3-(5-(((4-methylpyrimidin-2-yl)oxy)pyridin-2-yl)thieno[3,2-c]pyridin-2-yl]-3-methylphenyl)methacrylamide (114)

Step 1: Preparation of 2-((6-bromopyridin-3-yl)oxy)-4-methylpyrimidine (114b)

At room temperature, cesium carbonate (22.5 g, 69.0 mmol) was added to a mixture of 6-bromo-3-hydroxypyridine (114a) (10.0 g, 57.5 mmol) and 2-chloro-4-methylpyrimidine (1b) (7.4 g, 57.5 mmol) in DMF (150 mL), heated to 100°C, and stirred overnight. The reaction solution was cooled, diluted with water (1 L), extracted three times with ethyl acetate, the organic phases were combined, washed with brine, dried, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = PE-4:1) to obtain 13.8 g of the title compound as a brown solid, with a yield of 91.2%.

LC-MS: m/z 266 [M+H] ⁺ .

Step 2: Preparation of 4-methyl-2-((6-(tributylstannyl)pyridin-3-yl)oxy)pyrimidine (114c)

At room temperature, under nitrogen atmosphere, 2-((6-bromopyridin-3-yl)oxy)-4-methylpyrimidine (114a) (2.00 g, 7.50 mmol) was dissolved in toluene (40 mL), and n-hexabutylditin (8.75 g, 11.3 mmol), Pd(dppf)Cl ₂ (548 mg, 0.75 mmol), and potassium acetate (2.22 g, 22.6 mmol) were added, and the reaction solution was stirred at 110°C overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by neutral alumina column chromatography (mobile phase: PE:EA=5:1) to obtain 973 mg of a yellow oil.

LC-MS: m/z=478 [M+H] ⁺ .

Step 3: Preparation of tert-butyl (3-bromothieno[3,2-c]pyridin-4-yl)carbamate (114d)

At room temperature, di-tert-butyl dicarbonate (33.4 g, 125.8 mmol) was added to a solution of 3-bromothienyl[3,2-c]pyridin-4-amine (35e) (10 g, 43.6 mmol) and DIEA (33.8 g, 261.6 mmol) in N,N-dimethylformamide (150 mL), and the mixture was reacted at 50°C overnight. The reaction solution was quenched by adding ice water (250 mL), extracted with ethyl acetate (250 mL×3), the organic phases were combined, dried, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA＝50:1-1:1) to obtain 5 g of the title compound as a yellow solid, with a yield of 35.0%.

LC-MS: m/z 329 [M+H] ⁺ .

Step 4: Preparation of tert-butyl (3-bromo-2-iodothieno[3,2-c]pyridin-4-yl)carbamate (114e)

At room temperature, tert-butyl (3-bromothieno[3,2-c]pyridin-4-yl)carbamate (114d) (1 g, 3.04 mmol) was dissolved in THF (20 mL). The temperature was lowered to -78°C under nitrogen atmosphere, and LDA (4.6 mL, 9.11 mmol) was added dropwise. The mixture was stirred for 1.5 h. A THF solution (4 mL) of iodine (1.2 g, 4.56 mmol) was slowly added dropwise. The mixture was stirred for 2 h. The reaction mixture was quenched by adding 250 mL of ice water, extracted with ethyl acetate (250 mL × 3), the organic phases were combined, dried, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/EA = 50:1-1:1) to obtain 1 g of the title compound as a yellow solid. The yield was 72.4%.

LC-MS: m/z 455 [M+H] ⁺ .

Step 5: Preparation of N-(4-(4-amino-3-bromothieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (114f)

At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (80 mg, 0.11 mmol) was added to a mixture of tert-butyl (3-bromo-2-iodothieno[3,2-c]pyridin-4-yl)carbamate (114e) (500 mg, 1.10 mmol), N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) (298 mg, 0.99 mmol) and cesium fluoride (501 mg, 3.30 mmol) in N,N-dimethylformamide/water (5 mL, v/v=10:1), the atmosphere was replaced with nitrogen three times, the temperature was raised to 80°C and stirred overnight. The reaction solution was cooled and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-20:1) to obtain 400 mg of the title compound as a brown solid. Yield: 90.5%.

LC-MS: m/z 402 [M+H] ⁺ .

Step 6: Preparation of N-(4-(4-amino-3-(5-((4-methylpyrimidin-2-yl)oxy)pyridin-2-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (114 g)

At room temperature, under nitrogen atmosphere, N-(4-(4-amino-3-bromothieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (114f) (693 mg, 1.73 mmol) was dissolved in DMF (40 mL), and 4-methyl -2-((6-(tributylstannyl)pyridin-3-yl)oxy)pyrimidine (114c) (823 mg, 1.73 mmol), tetrakistriphenylphosphine palladium (200 mg, 0.17 mmol), triphenylphosphine (453 mg, 1.73 mmol), cuprous iodide (329 mg, 1.73 mmol), lithium chloride (145 mg, 3.46 mmol), sodium carbonate (367 mg, 3.46 mmol), the reaction solution was stirred at 100°C overnight. After the reaction was completed, it was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane: methanol = 20:1) to obtain 403 mg of a yellow oil.

LC-MS: m/z=509 [M+H] ⁺ .

Step 7: Preparation of N-(4-(4-amino-7-bromo-3-(5-((4-methylpyrimidin-2-yl)oxy)pyridin-2-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (114h)

At room temperature, N-bromosuccinimide (132 mg, 0.74 mmol) was added to a solution of N-(4-(4-amino-3-(5-((4-methylpyrimidin-2-yl)oxy)pyridin-2-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (114 g) (350 mg, 0.69 mmol) in dichloromethane (10 mL), and stirred at room temperature overnight. The reaction solution was cooled and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-20:1) to obtain 350 mg of the title compound as a brown solid, with a yield of 86.3%.

LC-MS: m/z 587 [M+H] ⁺ .

Step 8: Preparation of N-(4-(4-amino-7-(1-methyl-1H-pyrazol-4-yl)-3-(5-(((4-methylpyrimidin-2-yl)oxy)pyridin-2-yl)thieno[3,2-c]pyridin-2-yl]-3-methylphenyl)methacrylamide (114)

At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (44 mg, 0.08 mmol) was added to a mixture of N-(4-(4-amino-7-bromo-3-(5-((4-methylpyrimidin-2-yl)oxy)pyridin-2-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (114h) (350 mg, 0.60 mmol), (1-methyl-1H-pyrazol-4-yl)boric acid (227 mg, 1.80 mmol) and cesium fluoride (274 mg, 1.80 mmol) in N,N-dimethylformamide/water (2.5 mL, v/v=10:1), purged with nitrogen for 1 min, and reacted in a microwave at 90 °C for 2 h. The reaction solution was concentrated under reduced pressure and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm × 250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% formic acid aqueous solution, gradient: 5-35%) to obtain 25 mg of the title compound as a white solid. Yield: 7.1%.

LC-MS: m/z 589 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d6) δppm 9.81 (s, 1H), 8.69 (d, J = 2.8Hz, 1H), 8.50 (d, J = 5.0Hz, 1H), 8.19 (s, 1H), 8.12 (d,J＝14.0Hz,1H),7.91(s,1H),7.65-7.53(m,3H),7.32-7.15(m,3H),6.24(s,2H),5.79(s,1H), 5.52(d,J＝1.9Hz,1H),3.93(s,3H),2.41(s,3H),1.97-1.91(m,6H).

Example 115: Preparation of N-(4-(4-amino-3-(3-fluoro-4-(pyrimidin-2-yloxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (115)

The title compound 115 was prepared in the same manner as in Example 35, except that 2-chloropyrimidine was used instead of 2-chloro-4-methylpyrimidine (1b), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (36a) was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d), and (1-methyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 592 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δppm 9.78(s,1H),8.70-8.64(m,2H),8.17(s,1H),8.11-8.08(m,1H),7.89(s,1H) ,7.59-7.55(m,1H),7.53-7.49(m,1H),7.45-7.40(m,2H),7.34-7.31(m,1H),7.28-7.22(m,2H),5.79(s, 1H),5.52(s,1H),5.30(s,2H),3.92(s,3H),2.13(s,3H),1.94(s,3H).

Example 116: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((5-fluoropyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (116)

The preparation method was the same as that of Example 35, except that 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a), 2-chloro-5-fluoropyrimidine was used instead of 2-chloro-4-methylpyrimidine (1b), and N-(3-methyl-4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) and (1-methyl-1H-pyrazol-4-yl)boronic acid was used instead of (1H-pyrazol-4-yl)boronic acid to prepare the title compound 116.

LC-MS: m/z 610 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.78(s,1H),8.77(s,2H),8.17(s,1H),8.10(s,1H),7.89(s,1H),7.57- 7.56(m,1H),7.52-7.49(m,1H),7.46-7.41(m,2H),7.27-7.24(m,2H),5.79(s,1H),5.52(s,1H),5.29( s,2H),3.92(s,3H),2.12(s,3H),1.94(s,3H).

Example 117: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-(trifluoromethyl)pyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (117)

The preparation method was the same as that of Example 35, except that 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a), 2-chloro-4-(trifluoromethyl)pyrimidine was used instead of 2-chloro-4-methylpyrimidine (1b), and N-(3-methyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) and (1-methyl-1H-pyrazol-4-yl)boronic acid was used instead of (1H-pyrazol-4-yl)boronic acid to prepare the title compound 117.

LC-MS: m/z 660 [M+H] ⁺ .

1H NMR (400MHz, DMSO-d ₆ ) δppm 9.77 (s, 1H), 9.04 (d, J = 4.9Hz, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.89 (s, 1H) ,7.84(d,J＝5.0Hz,1H),7.58–7.43(m,4H),7.30–7.20(m,2H),5.78(s,1H),5.53–5.49(m,1H),5.33(s ,2H),3.92(s,3H),2.10(s,3H),1.93(s,3H).

Example 118: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl]-3-methylphenyl)methacrylamide (118)

The preparation method was the same as that of Example 35, except that 2-fluoro-6-methylpyridine was used instead of 2-chloro-4-methylpyrimidine (1b), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a), and N-(3-methyl-4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) and (1-methyl-1H-pyrazol-4-yl)boronic acid was used instead of (1H-pyrazol-4-yl)boronic acid to prepare the title compound 118.

LC-MS: m/z 605 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77(s,1H),8.18-8.16(m,1H),8.10(s,1H),7.91-7.88(m,1H),7.77-7.70(m,1H),7.57-7.54(m,1H), 7.53-7.49(m,1H),7.38-7.33(m,1H),7.32-7.21(m,2H),7.20-7.14(m,1H),7.03-6.97(m,1H),6.88-6.82(m ,1H),5.78(s,1H),5.51(s,1H),5.37(s,2H),3.92(s,3H),2.25(s,3H),2.10(s,3H),1.94(s, 3H).

Example 119: Preparation of N-(6-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)pyridin-3-yl)methacrylamide (119)

Step 1: Preparation of (5-aminopyridin-2-yl)boronic acid (119b)

Trisdibenzylideneacetone dipalladium (531 mg, 0.58 mmol) and Sphos (238 mg, 0.58 mmol) were added to a mixture of 6-bromopyridin-3-amine (119a) (1.00 g, 5.81 mmol), bis(pinacolato) (1.77 g, 6.98 mmol) and potassium acetate (1.71 g, 17.43 mmol) in 1,4-dioxane (20 mL) at room temperature, replaced with nitrogen three times, and stirred at 90°C for 15 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by reverse phase silica gel column chromatography (mobile phase: 5% ammonia water/acetonitrile = 100:1-10:1) to obtain 500 mg of the title compound as a white solid, with a yield of 62.3%.

LC-MS: m/z 139 [M+H] ⁺ .

Step 2: Preparation of (5-methacrylamidopyridin-2-yl)boronic acid (119c)

At 0°C, under nitrogen atmosphere, methacryloyl chloride (1e) (570 mg, 5.43 mmol) was added to a mixture of (5-aminopyridin-2-yl)boric acid (119b) (500 mg, 3.62 mmol) and sodium carbonate (1.20 g, 10.9 mmol) in tetrahydrofuran/water (2 mL/1 mL), and stirred at 0°C for 2 hours. The reaction solution was concentrated under reduced pressure and purified by reverse phase preparative chromatography to obtain 300 g of the title compound as a brown solid, with a yield of 40.2%.

LC-MS: m/z 207 [M+H] ⁺ .

The title compound 119 was prepared by the same preparation method as in Example 35, except that (5-methylacrylamidopyridin-2-yl)boric acid (119c) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41a) and (1-methyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 593 [M+H] ⁺ .

¹ H NMR (400MHz, CHCl ₃ -d) δppm 8.65-8.58(m,1H),8.46-8.40(m,1H),8.02-7.96(m,1H),7.93-7.80(m,3H),7.58( s,1H),7.53-7.46(m,1H),7.36-7.28(m,2H),7.02-6.96(m,1H),6.82-6.75(m,1H),5.86-5.80(m,1H), 5.61-5.39(m,3H),4.02(s,3H),2.53(s,3H),2.07(s,3H).

Example 120: Preparation of (E)-N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy))-7-(1-methyl-1H-pyrazol-4-yl)thieno(3,2-c)pyridin-2-yl)-3-methylphenyl)but-2-enamide (120)

Step 1: Preparation of (E)-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamide (120a)

At room temperature, 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (36a) (1.0 g, 4.29 mmol) and potassium carbonate (592 mg, 4.29 mmol) were dissolved in dichloromethane (10 mL). At 0°C, (E)-but-2-enoyl chloride (535 mg, 5.15 mmol) was slowly added. Stir for another hour, and the reaction mixture was quenched with water. Extract with dichloromethane (3×10 ml). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1.0 g of the crude title compound as a white solid, which was used directly in the next step.

LC-MS: m/z 302 [M+H] ⁺ .

The title compound 120 was prepared by the same preparation method as Example 48, except that (E)-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamide (120b) was used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e).

LC-MS: m/z 606 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.95 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.17 (s, 1H), 8.10 (s, 1H), 7.89 (d, J ＝0.9Hz,1H),7.54-7.34(m,4H),7.28-7.15(m,3H),6.86-6.72(m,1H),6.15-6.05(m,1H),5.37(s,2H), 3.92(s,3H),2.38(s,3H),2.11(s,3H),1.86(s,3H).

Example 121: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-(methyl-d ₃ )-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (121)

The preparation method was the same as that of Example 35, except that 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (35b) was replaced by 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (1c), N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was replaced by N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) and 1-(methyl- _4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36c). )-1H-pyrazol-4-yl)boronic acid was used instead of (1H-pyrazol-4-yl)boronic acid to give the title compound 121.

LC-MS: m/z 609 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77(s,1H),8.47(s,1H),8.17(s,1H),8.10(s,1H),7.89(s,1H),7.59-7.54 (m,1H),7.54-7.49(m,1H),7.43-7.34(m,2H),7.27-7.24(m,1H),7.24-7.20(m,1H),7.20-7.16(m,1H) ,5.78(s,1H),5.51(s,1H),5.32(s,2H),2.39(s,3H),2.12(s,3H),1.93(s,3H).

Example 122: Preparation of N-(4-(3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-hydroxy-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (122)

Step 1: Preparation of 4-bromo-N-(2,2-dimethoxyethyl)-5-(2-methyl-4-nitrophenyl)thiophene-3-carboxamide (122a)

Tetrakistriphenylphosphine palladium (6.88 g, 5.95 mmol) was added to a mixture of 4-bromo-N-(2,2-dimethoxyethyl)-5-iodothiophene-3-carboxamide (34b) (25.0 g, 59.52 mmol), 4,4,5,5-tetramethyl-2-(2-methyl-4-nitrophenyl)-1,3,2-dioxaborolane (17.2 g, 65.48 mmol) and potassium phosphate (37.9 g, 178.56 mmol) in N,N-dimethylformamide/water (300 mL, v/v=10:1) at room temperature, replaced with nitrogen three times, heated to 70°C and stirred overnight. The reaction solution was cooled, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-4:1) to obtain 17.6 g of the title compound as a light yellow solid. Yield: 68.9%.

LC-MS: m/z 430 [M+H] ⁺ .

Step 2: Preparation of 3-bromo-2-(2-methyl-4-nitrophenyl)thieno[3,2-c]pyridin-4-ol (122b)

At 100°C, 4-bromo-N-(2,2-dimethoxyethyl)-5-(2-methyl-4-nitrophenyl)thiophene-3-carboxamide (122a) (15 g, 35.05 mmol) was added to polyphosphoric acid (700 g) and stirred for 8 hours. The reaction solution was poured into ice water while hot and stirred for 20 minutes. The mixture was extracted with ethyl acetate three times, insoluble impurities were filtered out, and the organic phase was combined. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-1:100) to obtain 5.94 g of the title compound as a brown-yellow solid. The yield was 46.6%.

LC-MS: m/z 365 [M+H] ⁺ .

Step 3: Preparation of 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(2-methyl-4-nitrophenyl)thieno[3,2-c]pyridin-4-ol (122c)

To a mixture of 3-bromo-2-(2-methyl-4-nitrophenyl)thieno[3,2-c]pyridin-4-ol (122b) (2.0 g, 5.50 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (1c) (2.2 g, 6.60 mmol) and potassium carbonate (2.3 g, 16.5 mmol) in N,N-dimethylformamide/water (33 mL, v/v=10:1) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (201 mg, 0.28 mmol) at room temperature, the atmosphere was replaced with nitrogen three times and the mixture was stirred at 80°C for 15 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-1:100) to obtain 1.0 g of the title compound as a light yellow solid. Yield: 37.3%.

LC-MS: m/z 489 [M+H] ⁺ .

Step 4: Preparation of 7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(2-methyl-4-nitrophenyl)thieno[3,2-c]pyridin-4-ol (122d)

N-bromosuccinimide (348 mg, 1.96 mmol) was added to a solution of 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(2-methyl-4-nitrophenyl)thieno[3,2-c]pyridin-4-ol (122c) (868 mg, 1.78 mmol) in dichloromethane (20 mL) at room temperature, and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-1:1) to obtain 1.0 g of the title compound as a light yellow solid, yield: 95.8%.

LC-MS: m/z 567 [M+H] ⁺ .

Step 5: Preparation of 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)-2-(2-methyl-4-nitrophenyl)thieno[3,2-c]pyridin-4-ol (122e)

To a mixture of 7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-(2-methyl-4-nitrophenyl)thieno[3,2-c]pyridin-4-ol (122d) (410 mg, 0.72 mmol), (1H-pyrazol-3-yl)boronic acid (278 mg, 2.17 mmol) and cesium fluoride (330 mg, 2.17 mmol) in N,N-dimethylformamide/water (11 mL, v/v=10:1) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (53 mg, 0.072 mmol) at room temperature, the mixture was purged with nitrogen for 30 seconds and microwaved at 90°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=100:1-15:1) to obtain 297 mg of the title compound as a white solid. Yield: 72.2%.

LC-MS: m/z 569 [M+H] ⁺ .

Step 6: Preparation of 2-(4-amino-2-methylphenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-4-ol (122f)

Palladium on carbon (100 mg, 10%) was added to 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)-2-(2-methyl-4-nitrophenyl)thieno[3,2-c]pyridin-4-ol (122e) at room temperature. The mixture of 1,4-dihydro-1-nitropropene (544 mg, 0.96 mmol) and methanol/tetrahydrofuran (20 mL, v/v = 4:1) was replaced with hydrogen three times, and the mixture was heated to 40°C and stirred overnight in a hydrogen atmosphere. The reaction solution was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH = 100:1-10:1) to obtain 200 mg of the title compound as a light yellow solid, with a yield of 38.8%.

LC-MS: m/z 539 [M+H] ⁺ .

Step 7: Preparation of N-(4-(3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-hydroxy-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (122)

Methacryloyl chloride (42 mg, 0.41 mmol) was added to a solution of 2-(4-amino-2-methylphenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-4-ol (122f) (182 mg, 0.34 mmol) in tetrahydrofuran (5 mL) at 0°C, and stirred at 0°C for 0.5 hours and at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm×250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% ammonia solution, gradient: 10-60%) to obtain 28 mg of the title compound as a white solid, yield: 13.7%.

LC-MS: m/z 607 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 11.57(s,1H),9.78(s,1H),8.50-8.46(m,1H),8.14(s,1H),7.83(s,1H),7.56 -7.51(m,2H),7.46-7.40(m,1H),7.27-7.23(m,1H),7.20-7.12(m,3H),6.98-6.93(m,1H),5.79(s,1H) ,5.51(s,1H),3.90(s,3H),2.41(s,3H),1.97(s,3H),1.94(s,3H).

Example 123: Preparation of N-(5-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl))oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-1-methyl-1H-pyrazol-3-yl)methacrylamide (123)

The title compound 123 was prepared in the same manner as Example 105, except that 5-bromo-1-methyl-1H-pyrazol-3-amine was used instead of 4-bromo-3-ethylaniline (105a).

LC-MS: m/z 596 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.36 (s, 1H), 8.49 (d, J = 5.0Hz, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H) ),7.60-7.48(m,2H),7.36-7.30(m,1H),7.21(d,J＝5.0Hz,1H),6.69(s,1H),6.27(s,2H),5.85(s, 1H),5.48(s,1H),3.95(s,3H),3.47(s,3H),2.40(s,3H),1.90(s,3H).

Example 124: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(pyrimidin-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (124)

Step 1: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(pyrimidin-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (124)

At room temperature, bis(triphenylphosphine)palladium dichloride (23 mg, 0.033 mmol) was added to a solution of N-(4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (76c) (200 mg, 0.331 mmol) and 4-(tributyltinyl)pyrimidine (366 mg, 0.993 mmol) in N,N-dimethylformamide (5 mL), and the mixture was reacted at 90° C. under a nitrogen atmosphere overnight. The reaction solution was concentrated under reduced pressure and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm × 250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% aqueous ammonia solution, gradient: 20-60%) to obtain 35 mg of the title compound as a white solid. Yield: 17.5%.

LC-MS: m/z 604 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δppm 9.77(s,1H),9.23(s,1H),8.94(s,1H),8.85-8.72(m,1H),8.54-8.42(m,1H) ,8.34-8.23(m,1H),7.63-7.49(m,2H),7.45-7.35(m,2H),7.30-7.20(m,2H),7.20-7.16(m,1H),5.98(s, 2H),5.79(s,1H),5.51(s,1H),2.39(s,3H),2.10(s,3H),1.94(s,3H).

Example 125: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(pyrazin-2-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (125)

The title compound 125 was prepared in the same manner as Example 124, except that 2-(tributyltinyl)pyrazine was used instead of 4-(tributyltinyl)pyrimidine.

LC-MS: m/z 604 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δppm 9.77(s,1H),9.60-9.47(m,1H),8.93(s,1H),8.74-8.68(m,1H),8.53-8.50(m, 1H),8.50-8.45(m,1H),7.59-7.55(m,1H),7.55-7.49(m,1H),7.44-7.35(m,2H),7.29-7.15(m,3H),5.83( s,2H),5.79(s,1H),5.51(s,1H),2.39(s,3H),2.09(s,3H),1.94(s,3H).

Example 126: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(5-fluoropyridin-2-yl)thieno[3,2-c]pyridin-2-yl]-3-methylphenyl)methacrylamide (126)

The title compound 126 was prepared in the same manner as Example 109, except that (5-fluoropyridin-2-yl)boronic acid was used instead of (4-(trifluoromethyl)pyridin-2-yl)boronic acid.

LC-MS: m/z 621 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77 (s, 1H), 8.79-8.64 (m, 2H), 8.54-8.40 (m, 1H), 8.33-8.21 (m, 1H), 7.91-7.80 ( m,1H),7.60-7.49(m,2H),7.44-7.33(m,2H),7.28-7.13(m,3H),5.79(s,1H),5.66(s,2H),5.51(s, 1H),2.39(s,3H),2.09(s,3H),1.94(s,3H).

Example 127: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(5-methoxypyridin-2-yl)thieno[3,2-c]pyridin-2-yl]-3-methylphenyl)methacrylamide (127)

The title compound 127 was prepared in the same manner as Example 109, except that (5-methoxypyridin-2-yl)boronic acid was used instead of (4-(trifluoromethyl)pyridin-2-yl)boronic acid.

LC-MS: m/z 633 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.76 (s, 1H), 8.63 (s, 1H), 8.49-8.46 (m, 1H), 8.43-8.39 (m, 1H), 8.17-8.08 (m, 1H),7.60-7.48(m,3H),7.42-7.34(m,2H),7.27-7.16(m,3H),5.79(s,1H),5.54(s,2H),5.51(s,1H) ,3.89(s,3H),2.39(s,3H),2.09(s,3H),1.94(s,3H).

Example 128: Preparation of N-(4-(4-amino-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy)phenyl)-7-(4-methoxypyridin-2-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (128)

Step 1: Preparation of 4-methoxy-2-(tributyltinyl)pyridine (128b)

2-Bromo-4-methoxypyridine (128a) (200 mg, 1.064 mmol), hexabutylditin (648 mg, 1.117 mmol), tri(cyclohexyl)phosphine (30 mg, 1.106 mmol), tri(dibenzylideneacetone)dipalladium (97 mg, 1.106 mmol) and lithium chloride (268 mg, 6.384 mmol) were added to dioxane (7 mL) at room temperature, replaced with nitrogen three times, and heated to 100° C. for overnight reaction. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was directly used for the next reaction.

LC-MS: m/z 400 [M+H] ⁺ .

The title compound 128 was prepared in the same manner as Example 124, except that 4-methoxy-2-(tributyltinyl)pyridine (128b) was used instead of 4-(tributyltinyl)pyrimidine.

LC-MS: m/z 633 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.76 (s, 1H), 8.77 (s, 1H), 8.51-8.45 (m, 2H), 7.72-7.68 (m, 1H), 7.55-7.49 (m, 2H),7.41-7.35(m,2H),7.26-7.17(m,3H),6.92-6.85(m,1H),5.79(s,1H),5.64(s,2H),5.51(s,1H) ,3.94(s,3H),2.39(s,3H),2.09(s,3H),1.94(s,3H).

Example 129: Preparation of N-(4-(4-amino-7-(5-chloropyridin-2-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl]-3-methylphenyl)methacrylamide (129).

The title compound 129 was prepared in the same manner as Example 109, except that (5-chloropyridin-2-yl)boronic acid was used instead of (4-(trifluoromethyl)pyridin-2-yl)boronic acid.

LC-MS: m/z 637 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77 (s, 1H), 8.81-8.68 (m, 2H), 8.54-8.42 (m, 1H), 8.30-8.13 (m, 1H), 8.06-7.96 ( m,1H),7.62-7.47(m,2H),7.44-7.33(m,2H),7.29-7.14(m,3H),5.79(s,1H),5.73(s,2H),5.51(s, 1H),2.39(s,3H),2.09(s,3H),1.94(s,3H).

Example 130: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-(methyl-d ₃ )-1H-imidazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (130)

Step 1: Preparation of 2,4,5-tribromo-1-(methyl-d ₃ )-1H-imidazole (130b).

At room temperature, 2,4,5-tribromo-1H-imidazole (130a) (15 g, 49.2 mmol), deuterated iodomethane (8.56 g, 59.1 mmol), potassium carbonate (10.2 g, 73.8 mmol) were added to ethanol (200 mL), and the temperature was raised to reflux for reaction for 2 h. After the reaction was completed, the mixture was filtered, washed with a small amount of ethanol, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 50:1-1:50) to obtain 15.64 g of the title compound as a white solid, with a yield of 98.8%.

LC-MS: m/z 321[M+H] ⁺

Step 2: Preparation of 4-bromo-1-(methyl- _d3 )-1H-imidazole (130c).

At room temperature, 2,4,5-tribromo-1-(methyl-d ₃ )-1H-imidazole (130b) (14.64 g, 45.49 mmol) was added to tetrahydrofuran (50 mL), and the atmosphere was replaced with nitrogen three times. The mixture was transferred to -20°C, and a tetrahydrofuran solution of ethylmagnesium bromide (1M, 182 mL, 182 mmol) was slowly added. After the addition was completed, the mixture was heated to room temperature for overnight reaction. After the reaction was completed, a saturated aqueous solution of ammonium chloride (7 mL) was slowly added under an ice-water bath, the mixture was filtered, and the mixture was concentrated under reduced pressure. Methanol (50 mL) was added to the residue, and a dioxane solution of hydrochloric acid was slowly added to adjust the pH value to 8. The mixture was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Welflash, C18, 20-40 μm, 100A, mobile phase: methanol/water, gradient: 35-65%) to obtain 6.0 g of the title compound as a yellow oil, with a yield of 80.4%.

LC-MS: m/z 164[M+H] ⁺

Step 3: Preparation of 1-(methyl-d ₃ )-4-(tributyltinyl)-1H-imidazole (130d).

At room temperature, 4-bromo-1-(methyl-d ₃ )-1H-imidazole (130c) (150 mg, 0.915 mmol), hexabutylditin (557 mg, 0.960 mmol), tricyclohexylphosphine (26 mg, 0.092 mmol), trisdibenzylideneacetone dipalladium (84 mg, 0.092 mmol) and lithium chloride (230 mg, 5.488 mmol) were added to dioxane (7 mL), nitrogen was replaced three times, and the temperature was raised to 100° C. for overnight reaction. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was directly used for the next reaction.

LC-MS: m/z 376[M+H] ⁺

The preparation method is the same as that of Example 124, except that 1-(methyl-d ₃ )-4-(tributyltinyl)-1H-imidazole is used. (130d) Substituting 4-(tributyltinyl)pyrimidine, the title compound 130 was prepared.

LC-MS: m/z 609[M+H] ⁺

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.76ppm (s, 1H), 8.47 (d, J = 5.0Hz, 1H), 8.31 (s, 1H), 7.75-7.70 (m, 1H), 7.67- 7.63(m,1H),7.57-7.53(m,1H),7.52-7.48(m,1H),7.40-7.33(m,2H),7.25-7.16(m,3H),5.78(s,1H), 5.51(s,1H),5.28(s,2H),2.39(s,3H),2.11(s,3H),1.94(s,3H).

Example 131: Preparation of N-(4-(4-amino-7-(2-cyano-1-(methyl-d ₃ )-1H-imidazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (131)

Step 1: Preparation of 4-bromo-1-(methyl-d ₃ )-1H-imidazole-2-carbaldehyde (131a)

4-Bromo-1-(methyl-d ₃ )-1H-imidazole (130c) (4.3 g, 26.220 mmol) was added to tetrahydrofuran (50 mL) at room temperature. After nitrogen replacement for 3 times, the temperature was transferred to -10°C, and a tetrahydrofuran/n-hexane/ethylbenzene solution of lithium diisopropylamide (2M, 15.7 mL, 31.4 mmol) was slowly added dropwise. After the addition was completed, the temperature was raised to -5°C and stirred for 1 h. N,N-dimethylformamide (3.0 mL, 39.329 mmol) was slowly added dropwise, and the temperature was raised to 5°C for reaction for 1 h. After the reaction, saturated aqueous ammonium chloride solution (10 mL) was slowly added in an ice-water bath, water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-5:1) to obtain 2.23 g of a white solid crude product, which was then separated by preparative liquid chromatography (chromatographic column model: Welflash, C18, 20-40 μm, 100A, mobile phase: methanol/water, gradient: 30-45%) to obtain 1.97 g of the title compound as a white solid, with a yield of 39.3%.

LC-MS: m/z 192 [M+H] ⁺ .

Step 2: Preparation of 4-bromo-1-(methyl-d ₃ )-1H-imidazole-2-carbonitrile (131b)

Iodine (1.55 g, 6.094 mmol) was added to a mixed solution of 4-bromo-1-(methyl-d ₃ )-1H-imidazole-2-carbaldehyde (131a) (0.9 g, 4.688 mmol) in aqueous ammonia (13.5 mL) and tetrahydrofuran (4.5 mL) at room temperature. After the reaction, water (50 mL) was added to the reaction solution, and the mixture was transferred to an ice-water bath, and sodium bisulfite was slowly added until colorless, and extracted with ethyl acetate (50 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 50:1-4:1) to obtain 0.82 g of the title compound as a white solid, with a yield of 93.0%.

LC-MS: m/z 189 [M+H] ⁺ .

Step 3: Preparation of 1-(methyl-d ₃ )-4-(tributyltinyl)-1H-imidazole-2-carbonitrile (131c)

At room temperature, 4-bromo-1-(methyl-d ₃ )-1H-imidazole-2-carbonitrile (131b) (300 mg, 1.587 mmol), hexabutylditin (967 mg, 1.667 mmol), tricyclohexylphosphine (45 mg, 0.159 mmol), trisdibenzylideneacetone dipalladium (146 mg, 0.159 mmol) and lithium chloride (400 mg, 9.522 mmol) were added to dioxane (7 mL), replaced with nitrogen three times, heated to 100° C., and reacted overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-5:1) to obtain 0.97 g of the crude product of the title compound as a yellow oil, which was directly used in the next step.

LC-MS: m/z 401 [M+H] ⁺ .

The title compound 131 was prepared in the same manner as Example 124, except that 1-(methyl-d ₃ )-4-(tributyltinyl)-1H-imidazole-2-carbonitrile (131c) was used instead of 4-(tributyltinyl)pyrimidine.

LC-MS: m/z 634 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77 (s, 1H), 8.47 (d, J = 5.0Hz, 1H), 8.39 (s, 1H), 8.18 (s, 1H), 7.57-7.49 (m ,2H),7.42-7.34(m,2H),7.28-7.24(m,1H),7.23-7.20(m,1H),7.20-7.16(m,1H),5.79(s,1H),5.51(s ,1H),5.48(s,2H),2.39(s,3H),2.10(s,3H),1.94(s,3H).

Example 132: Preparation of N-(4-(4-amino-7-(6-(difluoromethyl)pyridin-2-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl]-3-methylphenyl)methacrylamide (132)

Step 1: Preparation of (6-(difluoromethyl)pyridin-2-yl)boronic acid (132b)

At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (528 mg, 0.72 mmol) was added to a dioxane (10 mL) solution of 2-bromo-6-(difluoromethyl)pyridine (132a) (1.5 g, 7.21 mmol), bipinacol borate (1.8 g, 7.21 mmol) and potassium acetate (2.1 g, 21.6 mmol), replaced with nitrogen three times, and stirred at 90°C overnight. The reaction solution was cooled, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 50:1-2:1) to obtain 420 mg of the title compound as a black oil, with a yield of 33.7%.

LC-MS: m/z 174 [M+H] ⁺ .

The title compound 132 was prepared in the same manner as Example 109, except that (6-(difluoromethyl)pyridin-2-yl)boronic acid (132b) was used instead of (4-(trifluoromethyl)pyridin-2-yl)boronic acid.

LC-MS: m/z 653 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δppm 9.77(s,1H),8.83(s,1H),8.51-8.45(m,1H),8.43-8.35(m,1H),8.12-8.03(m, 1H),7.61-7.54(m,2H),7.54-7.49(m,1H),7.42-7.34(m,2H),7.28-7.16(m,3H),7.10-6.92(m,1H),5.79( s,1H),5.76(s,2H),5.51(s,1H),2.39(s,3H),2.10(s,3H),1.94(s,3H).

Example 133: Preparation of N-(4-(4-amino-7-(1-methyl-1H-pyrazol-4-yl)-3-(3-methyl-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (133)

The title compound 133 was prepared in the same manner as in Example 35, except that 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (18a) was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a), N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) and (1-methyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 602 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.76(s,1H),8.47-8.39(m,1H),8.17(s,1H),8.08(s,1H),7.91-7.87(m,1H),7.58-7.53(m,1H),7.52- 7.47(m,1H),7.34-7.30(m,1H),7.28-7.23(m,1H),7.22-7.18(m,1H),7.15-7.08(m,2H),5.78(s,1H), 5.51(s,1H),5.41(s,2H),3.92(s,3H),2.39(s,3H),2.12(s,3H),2.04(s,3H),1.93(s,3H).

Example 134: Preparation of N-(4-(4-amino-3-(3,5-difluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (134)

The title compound 134 was prepared by the same preparation method as in Example 35, except that 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a), N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f), and (1-methyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 624 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.73 (s, 1H), 8.47-8.41 (m, 1H), 8.14-8.10 (m, 1H), 8.07-8.02 (m, 1H), 7.86-7.80 ( m,1H),7.54-7.44(m,2H),7.28-7.15(m,4H),5.75-5.69(m,1H),5.54-5.35(m,3H),3.85(s,3H),2.33( s,3H),2.06(s,3H),1.87(s,3H).

Example 135: Preparation of N-(4-(4-amino-3-(3,5-dimethyl-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (135)

The title compound was prepared in the same manner as in Example 35, except that 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a), N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f), and (1-methyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid. 135.

LC-MS: m/z 616 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.76 (s, 1H), 8.44-8.39 (m, 1H), 8.16-8.13 (m, 1H), 8.07 (s, 1H), 7.91-7.86 (m, 1H),7.56-7.48(m,2H),7.28-7.24(m,1H),7.15-7.08(m,3H),5.81-5.77(m,1H),5.53-5.49(m,1H),5.36- 5.24(m,2H),3.91(s,3H),2.39(s,3H),2.14(s,3H),2.01-1.91(m,9H).

Example 136: Preparation of N-(4-(4-amino-3-(2,3-difluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (136)

The title compound 136 was prepared by the same preparation method as in Example 35, except that 2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a), N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) and (1-methyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 624 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.73 (s, 1H), 8.43 (d, J = 4.0Hz, 1H), 8.15 (s, 1H), 8.04 (s, 1H), 7.85 (s, 1H),7.53-7.52(m,1H),7.48-7.45(m,1H),7.26-7.19(m,2H),7.16-7.15(m,1H),7.11-7.09(m,1H),5.75- 5.53(m,3H),5.45(s,1H),3.86(s,3H),2.32(s,3H),2.07(s,3H),1.87(s,3H).

Example 137: Preparation of N-(4-(4-amino-7-(2-(difluoromethyl)-1-(methyl-d ₃ )-1H-imidazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (137)

Step 1: Preparation of 4-bromo-2-(difluoromethyl)-1-(methyl-d ₃ )-1H-imidazole (137a)

Under an ice-water bath, diethylaminosulfur trifluoride (4.60 g, 28.536 mmol) was slowly added to a dichloromethane (30 mL) solution of 4-bromo-1-(methyl-d ₃ )-1H-imidazole-2-carboxaldehyde (131a) (0.99 g, 5.156 mmol). After the addition was completed, the temperature was raised to room temperature and the reaction was allowed to proceed overnight. After the reaction was completed, the reaction solution was slowly dropped into a saturated sodium bicarbonate aqueous solution (60 mL) under an ice-water bath, the pH was maintained at 8, and the mixture was extracted with dichloromethane (50 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-4:1) to obtain 0.75 g of the title compound as a white solid, with a yield of 68.3%.

LC-MS: m/z 214 [M+H] ⁺ .

Step 2: Preparation of 2-(difluoromethyl)-1-(methyl-d ₃ )-4-(tributyltinyl)-1H-imidazole (137b)

At room temperature, 4-bromo-2-(difluoromethyl)-1-(methyl-d ₃ )-1H-imidazole (137a) (200 mg, 0.935 mmol), hexabutylditin (542 mg, 0.935 mmol), tri(cyclohexyl)phosphine (26 mg, 0.093 mmol), tri(dibenzylideneacetone)dipalladium (85 mg, 0.093 mmol) and lithium chloride (236 mg, 5.610 mmol) were added to dioxane (7 mL), nitrogen was replaced three times, and the temperature was raised to 100° C. for overnight reaction. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was directly used for the next reaction.

LC-MS: m/z 426 [M+H] ⁺ .

The title compound 137 was prepared in the same manner as Example 124, except that 2-(difluoromethyl)-1-(methyl-d ₃ )-4-(tributyltinyl)-1H-imidazole (137b) was used instead of 4-(tributyltinyl)pyrimidine.

LC-MS: m/z 659 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77 (s, 1H), 8.48 (d, J = 5.0Hz, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.57-7.49 (m ,2H),7.40-7.35(m,2H),7.30-7.25(m,1H),7.25-7.14(m,3H),5.79(s,1H),5.51(s,1H),5.38(s,2H ),2.39(s,3H),2.09(s,3H),1.94(s,3H).

Example 138: N-(4-(4-amino-3-(3-fluoro-5-methyl-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1- Preparation of methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (138)

Step 1: Preparation of 4-bromo-2-fluoro-6-methylphenol (138b)

At room temperature, NBS (14.52 g, 81.602 mmol) was added in batches to a solution of 2-fluoro-6-methylphenol (138a) (9.8 g, 77.716 mmol) in acetic acid (200 mL). After the addition was complete, the reaction was continued at room temperature overnight. Water (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL×3). The mixture was washed with a saturated sodium bicarbonate aqueous solution until the pH of the aqueous phase was 5-6, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-20:1) to obtain 11.74 g of the title compound as an orange oil, with a yield of 74.0%.

LC-MS: m/z 203 [M+H] ^- .

Step 2: Preparation of 2-(4-bromo-2-fluoro-6-methylphenoxy)-4-methylpyrimidine (138c)

At room temperature, 4-bromo-2-fluoro-6-methylphenol (138b) (11.74 g, 57.268 mmol), 2-chloro-4-methylpyrimidine (1b) (8.10 g, 62.995 mmol) and cesium carbonate (22.403 g, 68.722 mmol) were added to N,N-dimethylformamide (150 mL), and the temperature was raised to 100°C for overnight reaction. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 50:1-20:1) to obtain 14.52 g of the title compound as a yellow oil, with a yield of 85.7%.

LC-MS: m/z 297 [M+H] ⁺ .

Step 3: Preparation of 2-(2-fluoro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (138d)

At room temperature, Pd(dppf)Cl ₂ (3.58 g, 4.887 mmol), biboronic acid pinacol ester (13.65 g, 53.760 mmol) and potassium acetate (14.38 g, 146.617 mmol) were added to a solution of 2-(4-bromo-2-fluoro-6-methylphenoxy)-4-methylpyrimidine (138c) (14.52 g, 48.872 mmol) in 1,4-dioxane (150 mL), the atmosphere was replaced with nitrogen three times, and the temperature was raised to 100°C for overnight reaction. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-20:1) to obtain 18.01 g of the title compound as an orange-yellow oil, with a yield of 107.1%.

LC-MS: m/z 345 [M+H] ⁺ .

The title compound 138 was prepared in the same manner as in Example 35, except that 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (35b) was replaced with 2-(2-fluoro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (138d), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d) was replaced with 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (36a) and (1-methyl-1H-pyrazol-4-yl)boric acid was replaced with (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 620 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.78 (s, 1H), 8.46 (d, J = 5.0Hz, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.91-7.87 (m ,1H),7.58-7.50(m,2H),7.29-7.25(m,1H),7.23-7.15(m,3H),5.79(s,1H),5.51(s,1H),5.36(s,2H ),3.92(s,3H),2.39(s,3H),2.14(s,3H),2.11(s,3H),1.94(s,3H).

Example 139: Preparation of N-(4-(4-amino-3-(2,5-difluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (139)

Step 1: Preparation of 2-(4-bromo-2,5-difluorophenoxy)-4-methylpyrimidine (139b)

At room temperature, 4-bromo-2,5-difluorophenol (139a) (10 g, 47.847 mmol), 2-chloro-4-methylpyrimidine (1b) (6.77 g, 52.632 mmol) and cesium carbonate (18.72 g, 57.416 mmol) were added to N,N-dimethylformamide (150 mL), and the temperature was raised to 100°C for overnight reaction. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 50:1-20:1) to obtain 13.11 g of the title compound as a yellow oil, with a yield of 90.9%.

LC-MS: m/z 301 [M+H] ⁺ .

Step 2: Preparation of 2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (139c)

At room temperature, Pd(dppf)Cl ₂ (3.06 g, 4.185 mmol), bipyrimidine (11.69 g, 46.031 mmol) and potassium acetate (12.32 g, 125.541 mmol) were added to a solution of 2-(4-bromo-2,5-difluorophenoxy)-4-methylpyrimidine (139b) (12.6 g, 41.847 mmol) in 1,4-dioxane (150 mL), the atmosphere was replaced with nitrogen three times, and the temperature was raised to 100°C for overnight reaction. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-20:1) to obtain 17.0 g of the title compound as a reddish brown oil, with a yield of 116.7%.

LC-MS: m/z 349 [M+H] ⁺ .

The title compound 139 was prepared by the same preparation method as in Example 35, except that 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (35b) was replaced by 2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (139c), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d) was replaced by 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (36a) and (1-methyl-1H-pyrazol-4-yl)boric acid was replaced by (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 624 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.80 (s, 1H), 8.50 (d, J = 5.0Hz, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.95-7.87 (m ,1H),7.64-7.58(m,1H),7.57-7.45(m,3H),7.26-7.16(m,2H),5.79(s,1H),5.54(s,2H),5.52(s,1H ),3.92(s,3H),2.39(s,3H),2.15(s,3H),1.94(s,3H).

Example 140: Preparation of N-(4-(4-amino-3-(4-cyanophenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (140)

Step 1: Preparation of N-(4-(4-amino-3-(4-cyanophenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (140a)

Tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol) was added to N-(4-(4-amino-3-bromothieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (114f) (400 mg, 0.99 mmol), (4-cyanophenyl The mixture of 1,4-dimethyl-1-boric acid (146 mg, 0.99 mmol) and sodium carbonate (316 mg, 2.98 mmol) in toluene/ethanol/water (5 mL, v/v/v = 10:2:1) was replaced with nitrogen three times, and the mixture was heated to 80°C and stirred overnight. The reaction solution was cooled and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH = 50:1-20:1) to obtain 350 mg of the title compound as a brown solid, with a yield of 83.1%.

LC-MS: m/z 425 [M+H] ⁺ .

Step 2: Preparation of N-(4-(4-amino-7-bromo-3-(4-cyanophenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (140b)

At room temperature, N-bromosuccinimide (132 mg, 0.74 mmol) was added to a solution of N-(4-(4-amino-3-(4-cyanophenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (140a) (350 mg, 0.82 mmol) in dichloromethane (10 mL), and stirred at room temperature overnight. The reaction solution was cooled and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: DCM/MeOH=50:1-20:1) to obtain 400 mg of the title compound as a brown solid, yield: 97.0%

LC-MS: m/z 503 [M+H] ⁺ .

Step 3: Preparation of N-(4-(4-amino-3-(4-cyanophenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (140)

At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (59 mg, 0.08 mmol) was added to a mixture of N-(4-(4-amino-7-bromo-3-(4-cyanophenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (140b) (400 mg, 0.80 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (300 mg, 2.38 mmol) and cesium fluoride (362 mg, 2.38 mmol) in N,N-dimethylformamide/water (2.5 mL, v/v=10:1), purged with nitrogen for 1 min, and reacted in a microwave at 90 °C for 2 h. The reaction solution was concentrated under reduced pressure and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm × 250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% formic acid aqueous solution, gradient: 5-35%) to obtain 20 mg of the title compound as a white solid. Yield: 5.0%.

LC-MS: m/z 505 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.76 (s, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 7.91 (s, 1H), 7.89-7.81 (m, 2H), 7.58 -7.50(m,3H),7.50-7.41(m,1H),7.23-7.16(m,1H),5.78(s,1H),5.51(s,1H),5.48(s,2H),3.92(s ,3H),2.04(s,3H),1.93(s,3H).

Example 141: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-3-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (141)

The title compound 141 was prepared in the same manner as Example 109, except that (1-methyl-1H-pyrazol-3-yl)boronic acid was used instead of (4-(trifluoromethyl)pyridin-2-yl)boronic acid.

LC-MS: m/z 606 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.77 (s, 1H), 8.48 (d, J = 5.0Hz, 1H), 8.37 (s, 1H), 7.78 (d, J = 2.2Hz, 1H), 7.59-7.49(m,2H),7.42-7.33(m,2H),7.29-7.15(m,3H),6.81(d,J＝2.3Hz,1H),5.79(s,1H),5.51(s, 1H),5.42(s,2H),3.91(s,3H),2.39(s,3H),2.09(s,3H),1.94(s,3H).

Example 142: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)-2-fluoroacrylamide (142)

Step 1: Preparation of 2-fluoro-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (142a)

At room temperature, 2-fluoroacrylic acid (2.0 g, 21.450 mmol) and triethylamine (8.7 g, 85.800 mmol) were added to DMF (50 mL), and a solution of T ₃ P in EA (30.0 g, 47.190 mmol) was slowly added dropwise. After the addition was completed, the mixture was stirred for 0.5 h, and then 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (36a) (5.0 g, 21.450 mmol) was added. The reaction mixture was continued to react overnight at room temperature. Water (200 mL) was added to the reaction solution, and the mixture was extracted with EA (50 mL×3). The organic phase was washed with brine, dried over anhydrous Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-1:50) to obtain 1.61 g of the title compound as a white solid, with a yield of 24.6%.

LC-MS: m/z 306 [M+H] ⁺ .

The title compound 142 was prepared by the same preparation method as Example 48, except that 2-fluoro-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (142a) was used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e).

LC-MS: m/z 610 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.21 (s, 1H), 8.40 (d, J = 5.0Hz, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.83 (s, 1H) ),7.57-7.53(m,1H),7.51-7.46(m,1H),7.37-7.29(m, 2H),7.26-7.21(m,1H),7.19-7.14(m,1H),7.13-7.09(m,1H),5.71-5.56(m,1H),5.46-5.36(m,2H),5.37- 5.28(m,1H),3.85(s,3H),2.32(s,3H),2.06(s,3H).

Example 143: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)acrylamide (143)

Step 1: Preparation of N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (143a)

At room temperature, 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (36a) (3 g, 12.9 mmol), acrylic anhydride (2.4 g, 19.3 mmol), potassium carbonate (5.3 g, 38.7 mmol), and H ₂ O (6 mL) were added to tetrahydrofuran (30 mL) and stirred at 30°C overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 50:1-1:1) to obtain 2 g of the title compound as a yellow solid, with a yield of 54.1%.

LC-MS: m/z 288 [M+H] ⁺ .

The title compound 143 was prepared by the same preparation method as Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (143a) was used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e).

LC-MS: m/z 592 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δppm 10.09(s,1H),8.44-8.37(m,1H),8.15(s,1H),8.03(s,1H),7.85(s,1H),7.51 -7.39(m,2H),7.38-7.29(m,2H),7.22-7.18(m,1H),7.18-7.14(m,1H),7.13-7.09(m,1H),6.41-6.29(m, 1H),6.23-6.13(m,1H),5.73-5.60(m,3H),3.85(s,3H),2.31(s,3H),2.05(s,3H).

Example 144: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)but-2-ynamide (144).

Step 1: Preparation of N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-ynamide (144b)

At room temperature, 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (36a) (1.864 g, 8.00 mmol) and but-2-ynoic acid (144a) (2.957 g, 35.2 mmol) were dissolved in ethyl acetate (40 mL), and propylphosphonic acid cyclic anhydride (25.44 g, 40.0 mmol) (50% ethyl acetate solution) and N,N-diisopropylethylamine (10.32 g, 80.0 mmol) were added in sequence, and the temperature was raised to 30°C for 16 hours. Under ice bath, the reaction system was poured into water (100 mL), extracted twice with ethyl acetate (200 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EA, 0-50%, 20 min) to obtain 2.2 g of the title compound as a white solid.

LC-MS: m/z 300 [M+H] ⁺ .

The title compound 144 was prepared in the same manner as in Example 48, except that N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-ynamide (144b) was used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e).

LC-MS: m/z 604 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.62 (s, 1H), 8.48 (d, J = 5.0Hz, 1H), 8.21-8.16 (m, 1H), 8.10 (s, 1H), 7.90 (d ,J＝0.9Hz,1H),7.48(d,J＝2.1Hz,1H),7.42-7.34(m,3H),7.29-7.16(m,3H),5.52(s,2H),3.92(s, 3H),2.39(s,3H),2.10(s,3H),2.04(s,3H).

Example 145: Preparation of N-(4-(4-amino-3-(4-((4-cyclopropylpyrimidin-2-yl)oxy)-3-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (145)

The preparation method was the same as that of Example 35, except that 2-chloro-4-methylpyrimidine (1b) was replaced by 2-chloro-4-cyclopropylpyrimidine, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a) was replaced by 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a), and N-(3-methyl-4- The title compound 145 was prepared by replacing N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) with (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) and replacing (1H-pyrazol-4-yl)boronic acid with (1-methyl-1H-pyrazol-4-yl)boronic acid.

LC-MS: m/z 632 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.78(s,1H),8.40(d,J＝4.0Hz,1H),8.21(s,1H),8.10(s,1H),7.91(s,1H),7.60-7.59(m,1H),7.55 -7.52(m,1H),7.41-7.34(m,2H),7.27-7.25(m,1H),7.22-7.20(m,2H),5.77(s,1H),5.69-5.57(m,2H) ,5.51(s,1H),3.92(s,3H),2.09(s,3H),2.06-2.02(m,1H),1.93(s,3H),1.03-0.98(m,2H),0.76-0.72 (m,2H).

Example 146: Preparation of N-(4-(4-amino-3-(3-fluoro-4-(4-(fluoromethyl)pyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (146)

Step 1: Preparation of methyl 2-(4-bromo-2-fluorophenoxy)pyrimidine-4-carboxylate (146b)

At room temperature, 4-bromo-2-fluorophenol (146a) (5.00 g, 26.3 mmol) and methyl 2-chloropyridine-4-carboxylate (4.98 g, 29.0 mmol) were dissolved in DMF (80 mL), potassium carbonate (10.3 g, 31.6 mmol) was added, and the reaction solution was stirred at 100°C for 2 h. Water and ethyl acetate were added to the reaction solution for extraction, and the organic phase was dried and concentrated to obtain 8.22 g of a light yellow solid.

LC-MS: m/z=328 [M+H] ⁺ .

Step 2: Preparation of (2-(4-bromo-2-fluorophenoxy)pyrimidin-4-yl)methanol (146c)

At 0°C, methyl 2-(4-bromo-2-fluorophenoxy)pyrimidine-4-carboxylate (146b) (8.22 g, 27.6 mmol) was dissolved in a THF/ethanol (1/1) mixed solution (150 mL), and lithium borohydride (913 mg, 41.4 mmol) was added in batches, and the reaction solution was stirred at 0°C for 1 h. Water was added to quench the reaction, and the white solid was removed by filtration. The filtrate was extracted with water and ethyl acetate, and the organic phase was dried and concentrated to obtain 5.95 g of a white solid.

LC-MS: m/z=300 [M+H] ⁺ .

Step 3: Preparation of 2-(4-bromo-2-fluorooxy)-4-(fluoromethyl)pyrimidine (146d)

At 0°C, (2-(4-bromo-2-fluorophenoxy)pyrimidin-4-yl)methanol (146c) (2.50 g, 8.39 mmol) was dissolved in dichloromethane (40 mL), and DAST solution (2.70 g, 16.8 mmol) dissolved in dichloromethane (20 mL) was added. The reaction solution was slowly warmed to room temperature and stirred overnight. Saturated NaHCO ₃ aqueous solution was added to quench the reaction, and water and dichloromethane were added for extraction. The organic phase was dried and concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE:EA=5:1) to obtain 915 mg of a yellow oily liquid.

LC-MS: m/z=301 [M+H] ⁺ .

Step 4: Preparation of 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-(fluoromethyl)pyrimidine (146e)

At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (219 mg, 0.30 mmol) was added to a dioxane (25 mL) solution of 2-(4-bromo-2-fluorooxy)-4-(fluoromethyl)pyrimidine (146d) (910 mg, 3.02 mmol), bis(pinacolato) (767 mg, 3.02 mmol) and potassium acetate (888 mg, 9.06 mmol), the atmosphere was replaced with nitrogen three times, and the temperature was raised to 90°C for 7 h. After the reaction, the reaction solution was cooled to room temperature, diluted with water (100 mL), extracted with EA (100 mL×3), the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-1:50) to obtain 700 mg of the title compound as an off-white solid, with a yield of 66.6%.

LC-MS: m/z 316 [M+H] ⁺ .

The preparation method was the same as that of Example 35, except that 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-(fluoromethyl)pyrimidine (146e) was used instead of 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (35b), and N-(3-methyl-4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrimidine (35b) was used. (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) and (1-methyl-1H-pyrazol-4-yl)boronic acid was used instead of (1H-pyrazol-4-yl)boronic acid to prepare the title compound 146.

LC-MS: m/z 624 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.80 (s, 1H), 8.72 (d, J = 5.0Hz, 1H), 8.22 (s, 1H), 8.12 (d, J = 11.9Hz, 1H), 7.92(s,1H),7.68–7.49(m,3H),7.48-7.39(m,2H),7.36(d,J＝4.9Hz,1H),7.32-7.21(m,2H),5.79(s, 1H),5.73(s,1H),5.54-5.47(m,2H),5.38(s,1H),3.93(s,3H),2.11(s,3H),1.94(s,3H).

Example 147: Preparation of N-(4-(4-amino-3-((4-(difluoromethyl)pyrimidin-2-yl)oxy)-3-fluorophenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (147)

Step 1: Preparation of 2-(4-bromo-2-fluorophenyl)pyrimidine-4-carbaldehyde (147a)

At room temperature, (2-(4-bromo-2-fluorophenoxy)pyrimidin-4-yl)methanol (146c) (3.10 g, 10.4 mmol) was dissolved in dichloromethane (40 mL), and Dess-Martin periodinane (4.85 g, 11.4 mmol) was added, and stirred at room temperature for 2 h. The reaction solution was extracted with water and ethyl acetate, and the organic phase was dried and concentrated to obtain 3.05 g of a yellow oil.

Step 2: Preparation of 2-(4-bromo-2-fluorophenoxy)-4-(difluoromethyl)pyrimidine (147b)

At 0°C, 2-(4-bromo-2-fluorophenoxy)pyrimidine-4-carbaldehyde (147a) (3.05 g, 10.3 mmol) was dissolved in DAST solution (5.81 g, 36.1 mmol) dissolved in dichloromethane (20 mL) was added to dichloromethane (40 mL), the reaction solution was slowly warmed to room temperature and stirred overnight. Saturated NaHCO ₃ aqueous solution was added to quench the reaction, water and dichloromethane were added for extraction, the organic phase was dried and concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE:EA=5:1) to obtain 2.04 g of yellow oily liquid.

LC-MS: m/z=319 [M+H] ⁺ .

The title compound 147 was prepared in the same manner as Example 146, except that 2-(4-bromo-2-fluorophenoxy)-4-(difluoromethyl)pyrimidine (147b) was used instead of 2-(4-bromo-2-fluorooxy)-4-(fluoromethyl)pyrimidine (146d).

LC-MS: m/z 642 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.79 (s, 1H), 8.90 (d, J = 4.9Hz, 1H), 8.22 (s, 1H), 8.15-8.09 (m, 1H), 7.92 (s ,1H),7.63-7.43(m,6H),7.31-7.23(m,2H),6.89(t,J＝54.0Hz,1H),5.79(s,1H),5.63(s,1H),5.52( s,1H),3.93(s,3H),2.12(s,3H),1.94(s,3H).

Example 148: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)-7-(1-methyl-1H-imidazol-4-yl)thieno[3,2-c]pyridin-2-yl]-3-methylphenyl)methacrylamide (148)

The title compound 148 was prepared by the same preparation method as Example 37, except that 2-fluoro-6-methylpyridine was used instead of 2-chloro-4-methylpyrimidine (1b), and N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f).

LC-MS: m/z 605 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.75(s,1H),8.31(s,1H),7.76-7.71(m,2H),7.67-7.64(m,1H),7.57-7.53(m,1H),7.53-7.48(m,1H), 7.35-7.30(m,1H),7.30-7.24(m,1H),7.24-7.20(m,1H),7.18-7.13(m,1H),7.02-6.96(m,1H),6.87-6.82(m ,1H),5.78(s,1H),5.51(s,1H),5.32(s,2H),3.73(s,3H),2.26(s,3H),2.10(s,3H),1.94(s, 3H).

Example 149: Preparation of N-(6-(4-amino-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-5-methylpyridin-3-yl)methacrylamide (149)

Step 1: Preparation of N-(6-bromo-5-methylpyridin-3-yl)methacrylamide (149b)

At room temperature, 6-bromo-5-methylpyridin-3-amine (149a) (1.50 g, 8.02 mmol) was dissolved in dichloromethane (40 mL), and methacryloyl chloride (0.92 g, 8.82 mmol) and sodium bicarbonate (2.02 g, 24.1 mmol) were added, and the reaction solution was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE:EA=5:1) to obtain 1.82 g of yellow solid.

LC-MS: m/z=255 [M+H] ⁺ .

Step 2: Preparation of N-(5-methyl-6-(tributylmethyltinyl)pyridin-3-yl)methacrylamide (149c)

At room temperature and under nitrogen atmosphere, N-(6-bromo-5-methylpyridin-3-yl)methacrylamide (149b) (1.80 g, 7.09 mmol) was dissolved in dioxane (40 mL), and hexabutylditin (12.3 g, 21.3 mmol), Pd ₂ (dba) ₃ (649 mg, 0.71 mmol), tri(cyclohexyl)phosphine (198 mg, 0.71 mmol), and lithium chloride (595 mg, 14.2 mmol) were added, and the reaction solution was stirred at 100° C. overnight. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by neutral alumina column chromatography (mobile phase: PE:EA=5:1) to obtain 4.2 g of a yellow oil.

LC-MS: m/z=467 [M+H] ⁺ .

Step 3: Preparation of N-(6-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-5-methylpyridin-3-yl)methacrylamide (149d)

At room temperature under nitrogen atmosphere, 7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-iodothieno[3,2-c]pyridin-4-amine (47c) (1.49 g, 2.68 mmol) was dissolved in DMF (40 mL), and N-(5-methyl-6-(tributylmethyltinyl)pyridin-3-yl)methacrylamide (149c) (1.50 g, 3.22 mmol), tetrakis(triphenylphosphine)palladium (310 mg, 0.27 mmol), triphenylphosphine (702 mg, 2.68 mmol), cuprous iodide (509 g, 4.0 mmol) were added. mg, 2.68mmol), lithium chloride (225mg, 5.36mmol), sodium carbonate (568mg, 5.36mmol), the reaction solution was stirred at 100°C overnight. It was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane: methanol = 20:1) to obtain 240mg of yellow oil.

LC-MS: m/z=605 [M+H] ⁺ .

Step 4: Preparation of N-(6-(4-amino-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-5-methylpyridin-3-yl)methacrylamide (149)

To a mixture of N-(6-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-5-methylpyridin-3-yl)methacrylamide (149d) (240 mg, 0.40 mmol), (1H-pyrazol-4-yl)boronic acid (150 mg, 1.19 mmol) and cesium fluoride (181 mg, 1.19 mmol) in N,N-dimethylformamide/water (2 mL, v/v=8:1) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13 mg, 0.018 mmol) at room temperature, the mixture was purged with nitrogen for 1 min and microwaved at 90 °C for 2 h. The reaction solution was filtered through a sodium sulfate pad, and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisugei 30 mm × 250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% ammonia solution, gradient: 10-50%) to obtain 230 mg of the title compound as an off-white solid. Yield: 4.94%.

LC-MS: m/z 607 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.03 (s, 1H), 8.74 (d, J = 2.3Hz, 1H), 8.49 (d, J = 5.0Hz, 1H), 8.19 (s, 1H), 8.13(s,1H),8.00-7.88(m,2H),7.43-7.29(m,2H),7.22-7.14(m,2H),5.86(s,1H),5.58(s,1H),5.45( s,2H),3.92(s,3H),2.39(s,3H),2.00-1.94(m,6H).

Example 150: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyridin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl]-3-methylphenyl)methacrylamide (150)

The preparation method was the same as that of Example 35, except that 2-fluoro-4-methylpyridine was used instead of 2-chloro-4-methylpyrimidine (1b), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a), and N-(3-methyl-4- The title compound 150 was prepared by replacing N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) with (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) and replacing (1H-pyrazol-4-yl)boronic acid with (1-methyl-1H-pyrazol-4-yl)boronic acid.

LC-MS: m/z 605 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δppm 9.79(s,1H),8.22(s,1H),8.10(s,1H),7.98(d,J＝4.0Hz,1H),7.92(s,1H),7.58-7.56(m,1H),7.53 -7.51(m,1H),7.41-7.37(m,1H),7.34-7.30(m,1H),7.26-7.24(m,1H),7.22-7.20(m,1H),7.00-6.99(m, 1H),6.92(s,1H),5.79-5.75(m,3H),5.52(s,1H),3.92(s,3H),2.34(s,3H),2.11(s,3H),1.94(s ,3H).

Example 151: Preparation of N-(5-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-4-methylpyridin-2-yl)methacrylamide (151)

Step 1: Preparation of N-(5-bromo-6-methylpyridin-2-yl)methacrylamide (151b)

Under ice bath, methacryloyl chloride (1e) (2.8 g, 26.88 mmol) was added to 5-bromo-6-methylpyridin-2-amine (151a) (5.0 g, 26.88 mmol) and triethylamine (4.1 g, 40.32 mmol) in dichloromethane (100 mL), and the temperature was slowly raised to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 100:1-4:1) to obtain 4.5 g of the title compound as a yellow solid, with a yield of 65.9%.

LC-MS: m/z 255 [M+H] ⁺ .

Step 2: Preparation of N-(6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methacrylamide (151c)

At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.3 g, 1.77 mmol) was added to a mixture of N-(5-bromo-6-methylpyridin-2-yl)methacrylamide (151b) (4.5 g, 17.72 mmol), bis(pinacolato) (5.4 g, 21.26 mmol) and potassium acetate (5.2 g, 53.16 mmol) in 1,4-dioxane (90 mL), replaced with nitrogen three times, and stirred at 90°C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 100:1-2:1) to obtain 5.0 g of the title compound as a yellow solid, with a yield of 93.5%.

LC-MS: m/z 303 [M+H] ⁺ .

Step 3: Preparation of N-(5-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-6-methylpyridin-2-yl)methacrylamide (151d)

To a mixture of 7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-iodothieno[3,2-c]pyridin-4-amine (47c) (350 mg, 0.63 mmol), N-(6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methacrylamide (151c) (171 mg, 0.57 mmol) and cesium fluoride (287 mg, 1.89 mmol) in N,N-dimethylformamide/water (5.5 mL, v/v=10:1) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (46 mg, 0.063 mmol) at room temperature, the atmosphere was replaced with nitrogen three times and the mixture was stirred at 70°C for 15 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=100:1-1:100) to obtain 247 mg of the title compound as a light yellow solid. Yield: 65.0%.

LC-MS: m/z 605 [M+H] ⁺ .

Step 4: Preparation of N-(6-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)pyridin-3-yl)methacrylamide (151)

To a mixture of N-(5-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-6-methylpyridin-2-yl)methacrylamide (151d) (200 mg, 0.33 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (125 mg, 0.99 mmol) and cesium fluoride (150 mg, 0.99 mmol) in N,N-dimethylformamide/water (4.4 mL, v/v=10:1) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (25 mg, 0.033 mmol) at room temperature, the mixture was purged with nitrogen for 30 s and microwaved at 90 °C for 120 min. The temperature was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30 mm × 250 mm, C18, 10 um, 100A, mobile phase: acetonitrile/0.1% formic acid aqueous solution, gradient: 15-65%) to obtain 90 mg of the title compound as a white solid. Yield: 44.9%.

LC-MS: m/z 607 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.28 (s, 1H), 8.50-8.44 (m, 1H), 8.21 (s, 1H), 8.14-8.10 (m, 1H), 7.97-7.88 (m, 2H),7.76-7.71(m,1H),7.48-7.38(m,2H),7.27-7.17(m,2H),5.92(s,1H),5.61(s,2H),5.55-5.52(m, 1H),3.93(s,3H),2.37(s,3H),2.27(s,3H),1.94(s,3H).

Example 152: Preparation of N-(5-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-6-methylpyridin-2-yl)methacrylamide (152) Preparation

The title compound 152 was prepared in the same manner as Example 151, except that 5-bromo-4-methylpyridin-2-amine was used instead of 5-bromo-6-methylpyridin-2-amine (151a).

LC-MS: m/z 607 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δppm 10.25(s,1H),8.50-8.46(m,1H),8.23(s,2H),8.13-8.09(m,1H),7.99(s,1H) ,7.93(s,1H),7.52-7.39(m,2H),7.30-7.25(m,1H),7.21-7.17(m,1H),5.92(s,1H),5.81-5.63(m,2H) ,5.56(s,1H),3.93(s,3H),2.38(s,3H),2.20(s,3H),1.94(s,3H).

Example 153: Preparation of N-(4-(4-amino-3-(2-fluoro-5-methyl-4-(4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (153)

The title compound 153 was prepared in the same manner as Example 138, except that 5-fluoro-2-methylphenol was used instead of 2-fluoro-6-methylphenol (138a).

LC-MS: m/z 620 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.79 (s, 1H), 8.46 (d, J = 5.0Hz, 1H), 8.22 (d, J = 0.8Hz, 1H), 8.09 (s, 1H), 7.92(d,J＝0.9Hz,1H),7.58(d,J＝2.1Hz,1H),7.56-7.49(m,1H),7.40(d,J＝8.3Hz,1H),7.26-7.10(m ,3H),5.79(s,1H),5.66(s,2H),5.52(s,1H),3.93(s,3H),2.39(s,3H),2.15(s,3H),2.02(s, 3H),1.94(s,3H).

Example 154: Preparation of N-(4-(4-amino-3-(2,5-difluoro-4-((4-methylpyrimidin-2-yl)oxy))-7-(2-methyl-2H-1,2,3-triazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (154) Preparation

Step 1: Preparation of N-(4-(4-amino-3-(2(5-difluoro-4-(4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (154a)

N-(4-(4-amino-3-bromothieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (114f) (1.0 g, 2.486 mmol), 2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (139c) (0.87 g, 2.486 mmol), tetrakistriphenylphosphine palladium (0.43 g, 0.373 mmol) and sodium carbonate (0.79 g, 7.457 mmol) were added to a mixed solvent of toluene, ethanol and water (10:2:1, 19.5 mL) at room temperature, replaced with nitrogen three times, and heated to 90°C for overnight reaction. LCMs showed that the SM reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA=50:1-1:50) to obtain 599 mg of the title compound as a brown solid. Yield: 44.4%.

LC-MS: m/z 544 [M+H] ⁺ .

Step 2: Preparation of N-(4-(4-amino-7-bromo-3-(2,5-difluoro-4-(4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (154b)

NBS (196 mg, 1.102 mmol) was added to a dichloromethane solution (10 mL) of N-(4-(4-amino-7-bromo-3-(2,5-difluoro-4-(4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (154a) (599 mg, 1.102 mmol) at room temperature. The reaction was allowed to proceed overnight. lcms showed that the SM reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE/EA = 50:1-1:50) to obtain 371 mg of the title compound as a red-brown solid, with a yield of 54.2%.

LC-MS: m/z 622 [M+H] ⁺ .

Step 3: Preparation of N-(4-(4-amino-3-(2,5-difluoro-4-((4-methylpyrimidin-2-yl)oxy))-7-(2-methyl-2H-1,2,3-triazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (154)

At room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (18 mg, 0.024 mmol) was added to a mixed solution of N-(4-(4-amino-7-bromo-3-(2,5-difluoro-4-(4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (154b) (150 mg, 0.241 mmol), (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid (92 mg, 0.723 mmol) and cesium carbonate (110 mg, 0.723 mmol) in DMF and water (10:1, 4 mL), and the mixture was purged with nitrogen for 1 min, and then heated to 90°C for 45 min in a microwave oven. LCMs showed that the SM reaction was complete. The reaction solution was concentrated under reduced pressure and the residue was separated by preparative liquid chromatography (chromatographic column model: Daisogei 30mm*250mm, C18, 10um, 100A, mobile phase: acetonitrile/0.1% formic acid aqueous solution, gradient: 5-45%) to obtain 64 mg of the title compound as a white solid. Yield: 42.6%.

LC-MS: m/z 625 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.80 (s, 1H), 8.56-8.46 (m, 2H), 8.38 (s, 1H), 7.63-7.45 (m, 4H), 7.27-7.17 (m, 2H),5.80(s,1H),5.69(s,2H),5.52(s,1H),4.23(s,3H),2.39(s,3H),2.13(s,3H),1.94(s,3H ).

Example 155: Preparation of N-(4-(4-amino-3-(3-fluoro-4-(5-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (155)

The title compound 155 was prepared in the same manner as in Example 35, except that 2-chloro-5-methylpyrimidine was used instead of 2-chloro-4-methylpyrimidine (1b), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (36a) was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1d), and (1-methyl-1H-pyrazol-4-yl)boric acid was used instead of (1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 606[M+H] ⁺

¹ H NMR(400MHz, DMSO-d ₆ )δppm 9.79(s,1H),8.50(s,2H),8.22(s,1H),8.10(s,1H),7.92(s,1H),7.61-7.55 (m,1H),7.55-7.48(m,1H),7.46-7.36(m,2H),7.31-7.21(m,2H),5.80(s,1H),5.69(s,2H),5.52(s ,1H),3.92(s,3H),2.22(s,3H),2.12(s,3H),1.94(s,3H).

Example 156: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methoxypyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)methacrylamide (156)

The preparation method was the same as that of Example 35, except that 2-chloro-4-methoxypyrimidine was used instead of 2-chloro-4-methylpyrimidine (1b), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1a) was used instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (35a), and N-(3-methyl-4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (36b) was used instead of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (1f) and (1-methyl-1H-pyrazol-4-yl)boronic acid was used instead of (1H-pyrazol-4-yl)boronic acid to prepare the title compound 156.

LC-MS: m/z 622 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.79 (s, 1H), 8.40-8.29 (m, 1H), 8.21 (s, 1H), 8.10 (s, 1H), 7.91 (s, 1H), 7.61 -7.54(m,1H),7.53-7.48(m,1H),7.47-7.38(m,2H),7.33-7.17(m,2H),6.77-6.64(m,1H),5.79(s,1H) ,5.65(s,2H),5.52(s,1H),3.92(s,3H),3.67(s,3H),2.10(s,3H),1.94(s,3H).

Example 157: Preparation of (E)-N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)-2-methylbut-2-enamide (157)

The title compound 157 was prepared in the same manner as Example 104, except that trans-2-methyl-2-butenoic acid was used instead of 2-(morpholinemethyl)acrylic acid.

LC-MS: m/z 620 [M+H] ⁺ .

¹ H NMR(400MHz, DMSO-d ₆ )δppm 9.65(s,1H),8.55-8.44(m,1H),8.21(s,1H),8.10(s,1H),7.96-7.85(m,1H) ,7.59-7.55(m,1H),7.53-7.47(m,1H),7.45-7.35(m,2H),7.27-7.21(m,2H),7.20-7.16(m,1H),6.47-6.38( m,1H),5.66(s,2H),3.92(s,3H),2.39(s,3H),2.10(s,3H),1.82(s,3H),1.80-1.71(m,3H).

Example 158: Preparation of N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylbut-2-enamide (158)

The title compound 158 was prepared in the same manner as Example 104, except that 3-methyl-2-butenoic acid was used instead of 2-(morpholinemethyl)acrylic acid.

LC-MS: m/z 620 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.85 (s, 1H), 8.48 (d, J = 5.0Hz, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.95-7.88 (m ,1H),7.56-7.50(m,1H),7.45-7.34(m,3H),7.26-7.15(m,3H),5.85(s,1H),5.71(s,2H),3.92(s,3H ),2.39(s,3H),2.14(s,3H),2.10(s,3H),1.86(s,3H).

Example 159: Preparation of N-(5-(4-amino-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)pyrazin-2-yl)methacrylamide (159)

The same preparation method as in Example 149, using 5-bromopyrazine-2-amine instead of 6-bromo-5-methylpyridin-3-amine (149a) to obtain the title compound 159.

LC-MS: m/z 594 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.66 (s, 1H), 9.35-9.27 (m, 1H), 8.53 (d, J = 5.0Hz, 1H), 8.22 (s, 1H), 8.10 (s ,1H),7.92(s,1H),7.76-7.61(m,3H),7.53-7.44(m,1H),7.25(d,J＝5.1Hz,1H),5.98(s,1H),5.64( d,J＝1.8Hz,1H),5.38(s,2H),3.96(s,3H),2.47(s,3H),1.96(s,3H).

Example 160: Preparation of N-(5-(4-amino-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-6-methylpyrazin-2-yl)methacrylamide (160)

The title compound 160 was prepared in the same manner as in Example 149, except that 5-bromo-6-methylpyrazin-2-amine was used instead of 6-bromo-5-methylpyridin-3-amine (149a).

LC-MS: m/z 608 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.72 (s, 1H), 9.22 (s, 1H), 8.48 (d, J = 5.0Hz, 1H), 8.24 (s, 1H), 8.14 (s, 1H) ),7.93(s,1H),7.49-7.38(m,2H),7.24-7.13(m,2H),6.00(s,1H),5.88(s,2H),5.63(s,1H),3.94( s,3H),2.39(s,3H),2.13(s,3H),1.96(s,3H).

Example 161: Preparation of 1-(7-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-2-azaspiro[3.5]non-6-en-2-yl)-2-methylprop-2-en-1-one (161)

Step 1: Preparation of tert-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.5]non-6-ene-2-carboxylate (161b)

At room temperature, under nitrogen atmosphere, tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (161a) (3.00 g, 12.6 mmol) was dissolved in tetrahydrofuran (60 mL), the reaction solution was cooled to -78 °C, 2M lithium diisopropylamide solution (7.5 mL, 15.1 mmol) was added, the reaction solution was stirred at -78 °C for 1 h, N-phenylbis(trifluoromethylsulfonimide) (4.49 g, 13.8 mmol) was added, the reaction solution was slowly warmed to room temperature and stirred overnight. 50 mL of water was added to the reaction solution, extracted with 30 mL of ethyl acetate, and the aqueous phase was extracted twice with 20 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4.60 g of a yellow oil.

LC-MS: m/z=372 [M+H] ⁺ .

Step 2: Preparation of tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.5]non-6-ene-2-carboxylate (161c)

At room temperature and under nitrogen atmosphere, tert-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[3.5]non-6-ene-2-carboxylate (161b) (4.60 g, 12.4 mmol) was dissolved in dioxane (40 mL), and diboric acid pinacol (7.19 g, 12.4 mmol), potassium acetate (3.65 g, 37.2 mmol), and Pd(dppf)Cl ₂ (900 mg, 1.24 mmol) were added. The reaction solution was stirred at 90° C. for 4 h. The mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: PE:EA=4:1) to obtain 2.03 g of a yellow solid.

The title compound 161 was prepared by the same preparation method as in Example 91, except that tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[3.5]non-6-ene-2-carboxylate (161c) was used instead of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (91a).

LC-MS: m/z 622.20 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.52 (d, J = 5.0 Hz, 1H), 8.22 (s, 1H), 8.04 (s, 1H), 7.91 (s, 1H), 7.56-7.45 (m ,2H),7.36-7.28(m,1H),7.22(d,1H),5.92(s,1H),5.81(s,1H),5.33-5.28(m,1H),5.21 (s,1H),3.94(s,3H),3.86(d,J＝8.8Hz,1H),3.77(d,J＝8.6Hz,1H),3.64-3.56(m,1H),3.55-3.48( m,1H),2.57-2.51(m,3H),2.41(s,3H),2.31(s,2H),1.74(s,5H).

Example 162: Preparation of 1-(5-(4-amino-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-6-methylindolin-1-yl)-2-methylprop-2-en-1-one (162)

Step 1: Preparation of tert-butyl 6-methylindoline-1-carboxylate (162b)

At room temperature, add Boc anhydride (12.3 g, 56.3 mmol) dropwise to a solution of 6-methylindoline (5.00 g, 37.5 mmol) and triethylamine (7.60 g, 75.1 mmol) in dichloromethane (100 mL), and stir the reaction solution at room temperature for 16 h. Add water and dichloromethane for extraction, dry and concentrate the organic phase, and separate and purify the residue by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1) to obtain 8.76 g of a white solid.

LC-MS: m/z=234 [M+H] ⁺ .

Step 2: Preparation of tert-butyl 5-bromo-6-methylindoline-1-carboxylate (162c)

At 0°C, tert-butyl 6-methylindoline-1-carboxylate (162b) (8.50 g, 36.5 mmol) was dissolved in dichloromethane (150 mL), and NBS (6.50 g, 36.5 mmol) was added in batches. The reaction solution was stirred at room temperature for 16 h. Water and dichloromethane were added for extraction, the organic phase was dried and concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1) to obtain 11.0 g of a white solid.

LC-MS: m/z=312 [M+H] ⁺ .

Step 3: Preparation of 5-bromo-6-methylindoline (162d)

At room temperature, tert-butyl 5-bromo-6-methylindoline-1-carboxylate (162c) (11.0 g, 35.3 mmol) was dissolved in dichloromethane (80 mL), and hydrochloric acid/1,4-dioxane (60 ml) was added. The reaction solution was stirred at room temperature for 16 h. After the reaction was completed, concentrated acid was added and used directly in the next step.

LC-MS: m/z=212 [M+H] ⁺ .

Step 4: Preparation of 1-(5-bromo-6-methylindolin-1-yl)-2-methylprop-2-en-1-one (162e)

At room temperature, 5-bromo-6-methylindoline (162d) (1.00 g, 4.74 mmol) was dissolved in dichloromethane (20 mL), triethylamine (2.40 g, 23.7 mmol) was added, and methacryloyl chloride (743 mg, 7.11 mmol) was added dropwise, and the reaction solution was stirred at room temperature for 2 h. Water and dichloromethane were added for extraction, the organic phase was dried and concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 50:1) to obtain 1.02 g of white solid.

LC-MS: m/z=280 [M+H] ⁺ .

Step 5: Preparation of 2-methyl-1-(6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)prop-2-en-1-one (162f)

1-(5-Bromo-6-methylindolin-1-yl)-2-methylprop-2-en-1-one (162e) (1.02 mg, 3.64 mmol) and biboronic acid pinacol ester (1.02 g, 4.01 mmol) were dissolved in 1,4-dioxane (20 mL) at room temperature. Under atmosphere, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (267 mg, 0.36 mmol) and potassium acetate (1.07 g, 10.9 mmol) were added and reacted at 80°C for 16 hours. Water and ethyl acetate were added for extraction, the organic phase was dried and concentrated, and the residue was separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 30:1) to obtain 1.08 g of oily liquid.

The title compound 162 was prepared by the same preparation method as Example 48, except that 2-methyl-1-(6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)prop-2-en-1-one (162f) was used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e).

LC-MS: m/z 632 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.48 (d, J = 5.0 Hz, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 7.91 (s, 1H), 7.80 (s, 1H) ),7.49-7.37(m,2H),7.29-7.16(m,3H),5.61(s,2H),5.37-5.31(m,1H),5.24(s,1H),4.08(t,J＝8.3 Hz, 2H), 3.92 (s, 3H), 3.02 (t, J = 8.3Hz, 2H), 2.40 (s, 3H), 2.10 (s, 3H), 1.93 (s, 3H).

Example 163: Preparation of 1-(5-(4-amino-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)isoindolin-2-yl)-2-methylprop-2-en-1-one (163)

The title compound 163 was prepared in the same manner as Example 162, except that tert-butyl 4-bromoisoindoline-2-carbonate was used instead of tert-butyl 5-bromo-6-methylindoline-1-carboxylate (162c).

LC-MS: m/z 618.20 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.57–8.46 (m, 1H), 8.24 (d, J = 5.2Hz, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.58-7.47 (m,2H),7.39-7.20(m,6H),5.84(s,1H),5.33(s,1H),5.27(s,1H),4.82(d,J＝20.0Hz,2H),4.68( d,J＝15.0Hz,2H),3.95(s,3H),2.44(s,3H),1.90(s,3H).

Example 164: Preparation of N-(3-(4-amino-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)prop-2-yn-1-yl)methacrylamide (164)

Step 1: Preparation of tert-butyl (3-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)prop-2-yn-1-yl)carbamate (164a)

At room temperature, under nitrogen atmosphere, 7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-2-iodothieno[3,2-c]pyridin-4-amine (47c) (500 mg, 0.90 mmol) was dissolved in tetrahydrofuran (40 mL), and tert-butyl prop-2-en-1-ylcarbamate (139 mg, 0.90 mmol), bistriphenylphosphine palladium dichloride (63 mg, 0.09 mmol), and cuprous iodide (17 mg, 0.09 mmol) were added. The reaction solution was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (mobile phase: dichloromethane:methanol=20:1) to obtain 670 mg of a yellow oil.

The title compound 164 was prepared by the same preparation method as Example 91, except that tert-butyl (3-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)prop-2-yn-1-yl)carbamate (164a) was used instead of tert-butyl 4-(4-amino-7-bromo-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (91b).

LC-MS: m/z 554.10 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.51 (d, J = 5.0Hz, 1H), 8.42 (t, J = 5.6Hz, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 7.88(d,J＝0.9Hz,1H),7.59-7.49(m,2H),7.41-7.33 (m,1H),7.23(d,J＝5.0Hz,1H),5.70-5.64(m,1H),5.50(s,2H),5.36(p,J＝1.5Hz,1H),4.12(d, J＝5.6Hz,2H),3.93(s,3H),2.45(s,3H),1.83(s,3H).

Example 165: Preparation of (E)-N-(4-(4-amino-7-(1-(difluoromethyl)-1H-pyrazol-4-yl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)but-2-enamide (165)

The title compound 165 was prepared by the same preparation method as Example 48, except that (E)-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamide (120b) was used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of (1-methyl-1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 642 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 12.73 (s, 1H), 9.96 (s, 1H), 8.68 (d, J = 0.7Hz, 1H), 8.47 (d, J = 5.0Hz, 1H), 8.33(s,1H),8.22(s,1H),7.88(t,1H),7.55-7.35(m,4H),7.29-7.15(m,3H),6.78-6.80(m,1H),6.09- 6.11(m,1H),5.55(s,1H),2.39(s,3H),2.11(s,3H),1.86(s,3H).

Example 166: Preparation of N-(4-(4-amino-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)but-2-ynamide (166)

The same preparation method as Example 144 was used, except that (2-methyl-2H-1,2,3-triazol-4-yl)boronic acid was used instead of (1- The title compound 166 was prepared by adding 1H-pyrazol-4-yl)boronic acid.

LC-MS: m/z 605.10 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.63 (s, 1H), 8.53-8.45 (m, 2H), 8.37 (s, 1H), 7.48 (d, J = 2.1Hz, 1H), 7.44-7.35 (m,3H),7.29-7.17(m,3H),5.75(s,2H),4.23(s,3H),2.39(s,3H),2.08(s,3H),2.05(s,3H).

Example 167: Preparation of (E)-N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)-4-(dimethylamino)but-2-enamide (167)

The title compound 167 was prepared in the same manner as Example 104, except that (E)-4-(dimethylamino)but-2-enoic acid was used instead of 2-(morpholinemethyl)acrylic acid.

LC-MS: m/z 649 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 10.06 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.16 (s, 1H), 8.10 (s, 1H), 7.89 (d, J ＝0.8Hz,1H),7.57-7.51(m,1H),7.49-7.35(m,3H),7.27-7.16(m,3H),6.71-6.73(m,1H),6.24-6.26(m,1H ),5.32(s,2H),3.91(s,3H),3.05(dd,J＝5.8,1.6Hz,2H),2.38(s,3H),2.17(s,6H),2.11(s,3H) .

Example 168: Preparation of N-(4-(4-amino-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy)phenyl)-7-(1-methyl-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-2-yl]-3-methylphenyl)-2-((dimethylamino)methyl)acrylamide (168)

The same preparation method as in Example 104 was used except that 3-((dimethylamino)methyl)-2-oxobut-3-enoic acid was used instead of Substituting 2-(morpholinemethyl)acrylic acid for 2-(morpholinemethyl)acrylic acid, the title compound 168 was prepared.

LC-MS: m/z 649 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 11.10 (s, 1H), 8.47 (d, J = 5.0Hz, 1H), 8.17 (d, J = 0.8Hz, 1H), 8.09 (s, 1H), 7.89(d,J＝0.9Hz,1H),7.50-7.34(m,4H),7.30-7.15(m,3H),6.01(d,J＝1.8Hz,1H),5.56(d,J＝1.7Hz ,1H),5.32(s,2H),3.92(s,3H),3.21(s,2H),2.68(s,1H),2.38(s,3H),2.24(s,5H),2.13(s, 3H).

Example 169: Preparation of (E)-N-(4-(4-amino-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-7-(2-methyl-2H-1,2,3-triazol-4-yl)thieno[3,2-c]pyridin-2-yl)-3-methylphenyl)but-2-enamide (169)

The title compound 169 was prepared by the same preparation method as Example 48, except that (E)-N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-2-enamide (120b) was used instead of N-(3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methacrylamide (14e) and (2-methyl-2H-1,2,3-triazol-4-yl)boric acid was used instead of (1-methyl-1H-pyrazol-4-yl)boric acid.

LC-MS: m/z 607 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 9.97 (s, 1H), 8.53-8.44 (m, 2H), 8.38 (s, 1H), 7.55-7.35 (m, 4H), 7.29-7.15 (m, 3H),6.78-6.80(m,1H),6.16-6.07(m,1H),5.85(s,2H),4.23(s,3H),2.38(s,3H),2.09(s,3H),1.87 (s,3H).

Biological tests

Test Example 1: In vitro biological evaluation

FGFR2 kinase assay: The HTRF assay was used to detect the inhibitory activity of the test compound on FGFR2 kinase.

Main reagents and consumables: FGFR2: Invitrogen, PV3368; HTRF KinEASE-TK kit 20000 assay kit (Cisbio, 62TKOPEC); ATP solution-100 mM (Promega, V910B), DTT (Sigma, D43816), MgCl ₂ (Sigma, M1028), DMSO (Sigma, D8418), 384 White Low Volume Plates (Greiner, 784075), MICROPLATE 96 WELL (Greiner, 651201), 384-LDV plate (Labcyte, P-05525-BC), Plate shaker (Thermo 4625-1 CECN/THZ Q), Envision 2104 multi-label Reader (PerkinElmer, 74785).

Experimental steps:

1) Prepare 1× kinase assay buffer: 1 volume of 5× kinase reaction buffer and 4 volumes of double distilled water; 5 mM MgCl ₂ ; 1 mM DTT.

2) Compound preparation: Prepare the compound concentration in the compound dilution plate MICROPLATE 96 WELL at 100 times the final concentration, dilute from the highest concentration point using the 27-fold dilution method, for a total of 4 concentration points, and transfer to the 384-LDV plate pulse plate, adding 8 μL of compound solution to each well.

3) Use the Echo (Labcyte, 550) instrument to pulse the compound from the pulse plate to the 384-LDV plate (LABCYTE, LP-0200) experimental plate, so that the compound becomes a 3-fold dilution matrix with 11 concentration points;

4) Prepare 2× kinase (FGFR2) working solution using 1× enzyme reaction buffer;

5) Add 5 μL of kinase to each well of the experimental plate, add 5 μL of buffer to the blank control group (Low and High), seal the plate with a sealing film, centrifuge at 1000 rpm/min for 30 seconds, and incubate at 25°C for 15 minutes;

6) Prepare 2×TK-substrate-biotin and ATP substrate working solution with 1× enzyme reaction buffer, add 5 μL substrate working solution to the experimental plate, seal the plate with a sealing film, centrifuge at 1000 rpm/min, centrifuge for 30 seconds, and incubate at 25°C for 45 minutes;

7) Add HTRF detection buffer, prepare 2×Streptavidin-XL 665 and TK-antibody-Cryptate detection working solution, add 10 μL of detection working solution to each well, centrifuge at 1000 rpm/min for 30 seconds, then incubate at 25°C for 1 hour and 4°C overnight;

8) The fluorescence intensity ratio of 615 nm and 665 nm (665/615) was read using Envision (PerkinElmer, 74785); the inhibition rate of the compound at each concentration was calculated by comparing the fluorescence intensity ratio of the compound group with that of the blank control group; GraphPad 8.0 was used for nonlinear fitting to calculate the IC ₅₀ value of the compound. The inhibition rate formula is as follows:
Y(IC ₅₀ )＝Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope))

X represents the log value of compound concentration; Y represents the inhibition level of kinase; Top and Bottom are the Y values of the highest and lowest plateaus of the curve; Hillslope is the Hill constant.

FGFR1 kinase assay: The HTRF assay was used to detect the inhibitory activity of the test compound on FGFR1 kinase.

Main reagents and consumables: FGFR1: Invitrogen, PV3146; HTRF KinEASE-TK kit 20000 assay kit (Cisbio, 62TKOPEC), ATP solution-100mM (Promega, V910B), DTT (Sigma, D43816), MgCl ₂ (Sigma, M1028), DMSO (Sigma, D8418), 384 White Low Volume Plates (Greiner, 784075), MICROPLATE 96 WELL (Greiner, 651201), 384-LDV plate (Labcyte, P-05525-BC), Plate shaker (Thermo 4625-1 CECN/THZ Q), Envision 2104 multi-label Reader (PerkinElmer, 74785).

1) Prepare 1× kinase assay buffer: 1 volume of 5× kinase reaction buffer and 4 volumes of double distilled water; 5 mM MgCl ₂ ; 1 mM DTT;

2) Compound preparation: Prepare a compound concentration 100 times the final concentration in the compound dilution plate MICROPLATE 96WELL (Greiner, 651201), dilute from the highest concentration point according to the 27-fold dilution method, a total of 4 concentration points, and transfer to the 384-LDV plate (LABCYTE, LP-0200) pulse plate, and add 8 μL of compound solution to each well;

3) Use the Echo (Labcyte, 550) instrument to pulse the compound from the pulse plate to the 384-LDV plate (LABCYTE, LP-0200) experimental plate, so that the compound becomes a 3-fold dilution matrix with 11 concentration points;

4) Prepare 2× kinase (FGFR1) working solution using 1× enzyme reaction buffer;

5) Add 5 μL of kinase to each well of the experimental plate, add 5 μL of buffer to the blank control group (Low and High), seal the plate with a sealing film, centrifuge at 1000 rpm/min for 30 seconds, and incubate at 25°C for 15 minutes;

6) Prepare 2×TK-substrate-biotin and ATP substrate working solution with 1× enzyme reaction buffer, add 5 μL substrate working solution to the experimental plate, seal the plate with a sealing film, centrifuge at 1000 rpm/min, centrifuge for 30 seconds, and incubate at 25°C for 45 minutes;

7) Add HTRF detection buffer, prepare 2×Streptavidin-XL 665 and TK-antibody-Cryptate detection working solution, add 10 μL of detection working solution to each well, centrifuge at 1000 rpm/min for 30 seconds, then incubate at 25°C for 1 hour and 4°C overnight;

8) The fluorescence intensity ratio of 615 nm and 665 nm (665/615) was read using Envision (PerkinElmer, 74785); the inhibition rate of the compound at each concentration was calculated by comparing the fluorescence intensity ratio of the compound group with that of the blank control group; GraphPad 8.0 was used for nonlinear fitting to calculate the IC ₅₀ value of the compound. The inhibition rate formula is as follows:
Y(IC ₅₀ )＝Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope))

X represents the log value of compound concentration; Y represents the inhibition level of kinase; Top and Bottom are the Y values of the highest and lowest plateaus of the curve; Hillslope is the Hill constant.

SNU16 cell proliferation assay: The CTG method was used to detect the inhibitory effects of the test compounds on the proliferation of FGFR2 amplified SNU16 (ATCC, CRL-5974) cells.

SNU16 was purchased from ATCC and cultured in RPMI-1640 (Invitrogen, A10491-01) + 10% FBS (Gbico, 10099141) + double antibody (1% penicillin and streptomycin, Gibco, 15140122). First, the compound was dissolved in DMSO and diluted, with a starting concentration of 10 mM, 3-fold dilution, 10 concentration gradients, and 2 replicates for each gradient. Then, the cells were seeded in a white transparent bottom 384-well plate (Corning, 3570), 450 cells/well, and the compound to be tested was added. The incubator was 37°C, 5% CO ₂ , and the incubation time was 96h. The cells in the 384-well plate were removed and equilibrated at room temperature for 20 minutes; 20 μL CellTiter Glo (Promega, catalog number G7572) was added to each well, oscillated and mixed, and incubated at room temperature for 10 minutes; the luminescence value was read by a multifunctional microplate reader (Biotek, model Cytation 3). The experimental data were plotted with the Log value of the compound concentration as the X-axis and the percentage inhibition level as the Y-axis. GraphPad prism 8.0 software was used for nonlinear fitting to obtain the dose-effect relationship, and the IC ₅₀ value of the compound's inhibition of cell proliferation was calculated using the following formula:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope))

X is the log value of compound concentration; Y is the inhibition level of cells; Top and Bottom are the Y values of the highest and lowest plateaus of the curve; Hillslope is the Hill constant.

BaF3 FGFR2-BICC1-N550K cell proliferation experiment: The CTG method was used to detect the inhibitory effect of the test compounds on the proliferation of FGFR2 resistant mutant cells BaF3 FGFR2-BICC1-N550K.

The stable cell line BaF3 FGFR2-BICC1-N550K was purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd. After functional identification by sequencing and protein experiments, it was cultured in RPMI1640 (Invitrogen, A10491-01) + 10% FBS (Gbico, 10099141) + puromycin (0.8μg/mL, Invitrogen, QLL-41-02). The compound was dissolved in DMSO and diluted, with a starting concentration of 10mM, 3-fold dilution, 10 concentration gradients, and 2 replicates for each gradient. Then, the cells were inoculated in a white transparent bottom 384-well plate (Corning, 3570), 450 cells/well, and the compound to be tested was added. The incubator was 37°C, 5% CO ₂ , and the incubation time was 72h. The cells in the 384-well plate were removed and equilibrated at room temperature for 20 minutes; 20 μL CellTiter Glo (Promega, catalog number G7572) was added to each well, oscillated and mixed, and incubated at room temperature for 10 minutes; the luminescence value was read by a multifunctional microplate reader (Biotek, model Cytation 3). The experimental data were plotted with the Log value of the compound concentration as the X-axis and the percentage inhibition level as the Y-axis. GraphPad prism 8.0 software was used for nonlinear fitting to obtain the dose-effect relationship, and the IC ₅₀ value of the compound's inhibition of cell proliferation was calculated using the following formula:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope))

X is the log value of compound concentration; Y is the inhibition level of cells; Top and Bottom are the Y values of the highest and lowest plateaus of the curve; Hillslope is the Hill constant.

BaF3 FGFR2-BICC1-V565F cell proliferation experiment: The CTG method was used to detect the inhibitory effect of the test compounds on the proliferation of FGFR2 resistant mutant cells BaF3 FGFR2-BICC1-V565F.

The stable cell line BaF3 FGFR2-BICC1-V565F was purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd. After functional identification by sequencing and protein experiments, it was cultured in RPMI1640 (Invitrogen, A10491-01) + 10% FBS (Gbico, 10099141) + puromycin (0.8 μg/mL, Invitrogen, QLL-41-02). The compound was dissolved in DMSO and diluted, with a starting concentration of 10 mM, 3-fold dilution, 10 concentration gradients, and 2 replicates for each gradient. Then, the cells were inoculated in a white transparent bottom 384-well plate (Corning, 3570), 450 cells/well, and the compound to be tested was added. The incubator was 37°C, 5% CO ₂ , and the incubation time was 72h. The cells in the 384-well plate were removed and equilibrated at room temperature for 20 minutes; 20 μL CellTiter Glo (Promega, catalog number G7572) was added to each well, oscillated and mixed, and incubated at room temperature for 10 minutes; the luminescence value was read by a multifunctional microplate reader (Biotek, model Cytation 3). The experimental data were plotted with the Log value of the compound concentration as the X-axis and the percentage inhibition level as the Y-axis. GraphPad prism 8.0 software was used for nonlinear fitting to obtain the dose-effect relationship, and the IC ₅₀ value of the compound's inhibition of cell proliferation was calculated using the following formula:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope))

X is the log value of compound concentration; Y is the inhibition level of cells; Top and Bottom are the Y values of the highest and lowest plateaus of the curve; Hillslope is the Hill constant.

In the following table, the kinase and cell _IC50 values are as follows: "+" indicates less than or equal to 100 nM; "++" indicates less than or equal to 500 nM; "+++" indicates less than or equal to 1 μM; and "++++" indicates greater than 1 μM.

Table 1 In vitro kinase and cell proliferation inhibitory activity results of the compounds of the present invention

The above results indicate that the compounds of the present invention can significantly inhibit the activity of FGFR2 at the kinase and cell levels, and also have a certain selectivity for FGFR1.

Claims (27)

A compound represented by general formula (I) or its meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
in: X is selected from N or CR ⁷ ; Y is selected from S, O, CR ⁷ R ⁸ or NR ⁸ ; R ¹ is selected from hydrogen, -NR ^a R ^b , halogen, hydroxyl, alkyl, which is optionally further substituted with one or more G ¹ ; ^R is selected from hydrogen, halogen, amino, nitro, cyano, hydroxy, thiol, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NR ^a R ^b , -NHC(O)R ^a , -S(O) _nR ^a , -S(O) _nNR ^a R ^b , -NHS(O) _nR ^a , and -P(O)R ^a R ^b , wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally further substituted with one or more ^G ; ^R3 is selected from a bond, alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, wherein said alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene and heteroarylene are each independently optionally further substituted with one or more ^G3 ; L is selected from a bond, -N( ^Ra )-, -O-, -S-, alkylene, cycloalkylene, heterocyclylene, heteroarylene, -N( ^Ra )C(O)-, -C(O)N( ^Ra )-, -N( ^Ra )S(O) _n- , -S(O) _nN ( ^Ra )-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) _2- ; ^R is selected from hydrogen, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R ^a , -O(O)CR ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -NR ^a R ^b , -NHC(O)R ^a , -S(O) _nR ^a , -S(O) _nNR ^a R ^b and -NHS(O) _nR ^a , wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted with one or more G ⁴ ; R ⁵ is selected from a bond, alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, wherein said alkylene, alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene and heteroarylene are each independently optionally further substituted with one or more G ⁵ ; A is selected from a bond, -N( ^Ra )-, -O-, -S-, alkylene, cycloalkylene, heterocyclylene, heteroarylene, -N( ^Ra )C(O)-, -C(O)N( ^Ra )-, -N( ^Ra )S(O) _n- , -S(O) _nN ( ^Ra )-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O) _2- ; R ⁶ is selected from ^R and ^R are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ^-ORa , -C(O) ^Ra , -OC(O) ^Ra , -C(O) ^ORa , -C( ^O ) ^NRaRb , ^-NRaRb , ^-NHC (O) ^Ra , -S( ^O ) _nRa , _-S (O) ^nNRaRb , and -NHS(O) _nRa , wherein said ^alkyl , alkoxy, cycloalkyl, heterocyclyl, ^aryl , and heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; ^R9 , ^R10 , and ^R11 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ^-ORa , -C ⁽ O) ^Ra , -OC(O) ^Ra , -C(O ^{) ORa} , ^{-C (} O ⁾ NRaRb, ^-NRaRb , -NHC( ^O ) ^{Ra ,} -S(O) _nRa , -S(O) _nNRaRb , -NHS(O) _nRa , and -( _CH2 ⁾ _vNRaRb ^. , wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; Each of ^G1 , ^G2 , ^G3 , ^G4 , and ^G5 is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ^-ORa , -( _CH2 ) _vORa , -C(O) ^Ra , -OC(O) ^Ra , ^-C (O) ^ORa , -C ^{( O} ) ^NRaRb , -NRaRb, -NHC ₍ O) ^Ra , _-S ⁽ O) _nRa , -S ⁽ O) ^nNRaRb , -NHS(O) ^{nRa ,} and -( _CH2 ⁾ _vNRaRb ^. , wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted with one or more groups selected from deuterated, halogen, amino, nitro, cyano, oxo, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; ^Ra and ^Rb are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, alkylheterocyclyl, aryl, heteroaryl; Or ^Ra and ^Rb together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, wherein the nitrogen-containing heterocyclic group is optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, sulfhydryl, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl; Any two of G ¹ , G ² , G ³ , G ⁴ and G ⁵ can be combined to form a saturated or partially saturated cycloalkyl or heterocyclic group; n is 1 or 2; v is an integer from 1 to 6. The compound represented by the general formula (I) according to claim 1, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein X is N. The compound represented by the general formula (I) according to claim 1 or 2, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is S. A compound represented by the general formula (I) according to any one of claims 1 to 3, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein: R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , L and A are as defined in claim 1. The compound represented by the general formula (I) according to any one of claims 1 to 4, or its meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: ^R3 is selected from _C6-10 arylene, 5- to 10-membered heteroarylene, 3- to 10-membered cycloalkylene, 3- to 10-membered heterocyclylene; which is optionally further substituted by one or more ^G3 ; ^G3 is selected from halogen, amino, cyano, hydroxyl, mercapto, _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl, ^{-NRaRb ,} wherein the _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl are each independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, _C1-6 alkyl, _{C1-6 haloC1-6} alkyl, C1-6 alkoxy, C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-6 cycloalkyl, _4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl substituted with one or more groups of _6-10- membered aryl or 5- to 10-membered heteroaryl; ^Ra and ^Rb are each independently selected from a _C1-6 alkyl group. The compound represented by the general formula (I) according to any one of claims 1 to 5, or its meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: ^R5 is selected from _C6-10 arylene, 5- to 10-membered heteroarylene, 3- to 10-membered cycloalkylene, 3- to 10-membered Heterocyclyl, C _2-6 alkynylene, preferably phenylene, 5- to 6-membered heteroarylene, 3- to 10-membered heterocyclylene or C _2-4 alkynylene; which is optionally further substituted by one or more G ⁵ ; ^G5 is selected from halogen, amino, cyano, hydroxyl, mercapto, _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 ^membered heteroaryl, -( _CH2 ) _vORa , wherein the _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl are each independently optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, _C1-6 alkyl, _{C1-6 haloC1-6} alkyl, _C1-6 alkoxy, C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-6 cycloalkyl, _4-6 membered heterocyclyl, C6-10 aryl, 5 to 10 membered heteroaryl substituted with one or more groups of _6-10- membered aryl or 5- to 10-membered heteroaryl; R ^a is selected from C _1-6 alkyl; v is an integer from 1 to 6. A compound represented by the general formula (I) according to any one of claims 1 to 6, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIIA) or the general formula (IIIB) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
in, Ring Z is selected from 3- to 10-membered cycloalkylene or 3- to 10-membered heterocyclylene; Z ₁ , Z ₂ , Z ₃ , and Z ₄ are each independently selected from N or CR ^3a ; E ₁ , E ₂ , E ₃ , and E ₄ are each independently selected from N or CR ^5a ; Each R ^3a is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, -NR ^a R ^b , wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl are each independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C _1-6 alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _4-6 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl substituted with one or more groups of _6-10- membered aryl or 5- to 10-membered heteroaryl; Each R ^3b is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, mercapto, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, wherein the C _1-6 alkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, 4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-6 cycloalkyl, 4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl; each R ^5a is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, -(CH ₂ ) _v OR ^a , wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl are each independently optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C 1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl substituted with one or more groups of _6-10- membered aryl or 5- to 10-membered heteroaryl; R ^a and R ^b are each independently selected from C _1-6 alkyl; v is an integer from 1 to 6; t is 0, 1, 2, 3, or 4; R ¹ , R ² , R ⁴ , R ⁶ , L and A are as defined in claim 1. The compound represented by the general formula (I) according to any one of claims 1 to 7, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from C _6-10 aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic group, preferably phenyl or 5-6 membered heteroaryl, more preferably 6 membered heteroaryl; which is optionally further substituted by one or more G ⁴ ; ^G4 is selected from halogen, amino, cyano, hydroxyl, mercapto, _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl, and the _C1-6 alkyl, _C1-6 alkoxy, C3-6 cycloalkyl, _4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl are each independently optionally further substituted by one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, _C1-6 alkyl, _{C1-6 haloC1-6} alkyl, _{C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl , C2-6} alkynyl, _C3-6 cycloalkyl, 4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl. A compound represented by the general formula (I) according to any one of claims 1 to 8, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IVA) or the general formula (IVB) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
in, Ring Z is selected from 3- to 10-membered cycloalkylene or 3- to 10-membered heterocyclylene; Z ₁ , Z ₂ , Z ₃ , and Z ₄ are each independently selected from N or CR ^3a ; E ₁ , E ₂ , E ₃ , and E ₄ are each independently selected from N or CR ^5a ; _M1 and _M2 are each independently selected from N or CH; each R ^3a is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, -NR ^a R ^b , wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl are each independently optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C _1-6 alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, _4-6 membered heterocyclyl, C 6-10 aryl, 5 to 10 membered heteroaryl substituted with one or more groups of _6-10- membered aryl or 5- to 10-membered heteroaryl; each R ^3b is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, and the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl; each R ^5a is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, thiol, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, -(CH ₂ ) _v OR ^a , wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl are each independently optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C 1-6 haloalkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl substituted with one or more groups of _6-10- membered aryl or 5- to 10-membered heteroaryl; Each R ^4a is independently selected from hydrogen, halogen, amino, cyano, hydroxyl, mercapto, C _1-6 alkyl, C _{1-6 alkoxy, C 3-6 cycloalkyl} , 4-6 membered heterocyclyl, C _6-10 aryl, 5 to 10 membered heteroaryl, wherein the C _1-6 alkyl, _C1-6 alkoxy, _C3-6 cycloalkyl, 4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl are each independently optionally further substituted with one or more groups selected from halogen, amino, nitro, cyano, oxo, hydroxyl, thiol, carboxyl, ester, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C3-6 cycloalkyl, 4-6 membered heterocyclyl, _C6-10 aryl, 5 to 10 membered heteroaryl; R ^a and R ^b are each independently selected from C _1-6 alkyl; v is an integer from 1 to 6; m is 0, 1 or 2; t is 0, 1, 2, 3, or 4; R ¹ , R ² , R ⁶ , L and A are as defined in claim 1. A compound represented by the general formula (I) according to any one of claims 1 to 9, or its mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein A is selected from a bond or -NH-, preferably -NH-. A compound represented by the general formula (I) according to any one of claims 1 to 10, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (VA) or (VB) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
in, Z ₁ to Z ₄ , E ₁ to E ₄ , M ₁ to M ₂ , R ^4a , R ^3b , t, and m are as defined in claim 9; R ¹ , R ² , R ⁹ to R ¹¹ and L are as defined in claim 1. A compound represented by the general formula (I) according to any one of claims 1 to 10, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (VC) or (VD) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
in, Z ₁ to Z ₄ , E ₁ to E ₄ , M ₁ to M ₂ , R ^4a , R ^3b , t, and m are as defined in claim 9; R ¹ , R ² , R ¹¹ , and L are as defined in claim 1. A compound represented by the general formula (I) according to any one of claims 1 to 12, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, -O- or -C(O)-, preferably -O- or -C(O)-, more preferably -O-. The compound represented by the general formula (I) according to any one of claims 7 to 13, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z ₁ , Z ₂ , Z ₃ , and Z ₄ are CR ^3a , or one of Z ₁ , Z ₂ , Z ₃ , and Z ₄ is N, and the others are CR ^3a ; Each R ^3a is independently selected from hydrogen, halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -NR ^a R ^b ; ^Ra and R ^b are each independently selected from hydrogen and C _1-6 alkyl. A compound represented by the general formula (I) according to any one of claims 7 to 14, or its meso form, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein E ₁ , E ₂ , E ₃ , and E ₄ are each independently selected from CR ^5a ; or one of E ₁ , E ₂ , E ₃ , and E ₄ is N, and the others are CR ^5a ; or two of E ₁ , E ₂ , E ₃ , and E ₄ are N, and the others are CR ^5a ; Each R ^5a is independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -(CH ₂ ) _v OR ^a ; R ^a is selected from C _1-6 alkyl; v is an integer from 1 to 6. A compound represented by the general formula (I) according to any one of claims 11 to 15, or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein _M1 and _M2 are N or _M1 is CH and _M2 is N. The compound represented by the general formula (I) according to any one of claims 11 to 16 or its endogenous A racemate, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R ^4a is independently selected from hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-6 cycloalkyl; m is 0 or 1, preferably 1. The compound represented by the general formula (I) according to any one of claims 1 to 17, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁹ , R ¹⁰ , and R ¹¹ are each independently selected from hydrogen, C _1-6 alkyl, 4-6 membered heterocyclic group and -(CH ₂ ) _v NR ^a R ^b ; R ^a and R ^b are each independently selected from hydrogen and C _1-6 alkyl; or ^Ra and ^Rb together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic group; v is an integer from 1 to 6. The compound represented by the general formula (I) according to any one of claims 1 to 18, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is selected from -NR ^a R ^b , hydroxyl, C _1-6 alkyl or C _1-6 haloalkyl; preferably -NR ^a R ^b or hydroxyl; ^Ra and ^Rb are each independently selected from hydrogen and _C1-6 alkyl; preferably hydrogen. A compound represented by the general formula (I) according to any one of claims 1 to 19, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ^R2 is selected from -C(O) ^NRaRb , -C(O) ^Ra , -P(O ^{) RaRb} , ^-C (O) ^ORa , -S(O) _nRa and -S(O ^{) nNRaRb} , preferably -C(O ⁾ _NRaRb ^and -P(O) ^RaRb , more ^{preferably -C} (O) ^{NRaRb ; Ra} and ^Rb are each independently selected from hydrogen and _C1-6 alkyl; n is 1 or 2. A compound represented by the general formula (I) according to any one of claims 1 to 19, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is selected from halogen, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, -C(O)NR ^a R ^b , -P(O)R ^a R ^b , wherein the 4-10 membered heterocyclyl and the 5-10 membered heteroaryl are each independently optionally further substituted by one or more G ² ; G ² is selected from halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl, -(CH ₂ ) _v OR ^a and -(CH ₂ ) _v NR ^a R ^b , wherein the C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl are each independently optionally further substituted with one or more groups selected from deuterated, halogen, cyano, hydroxyl, C _1-6 alkyl; ^Ra and ^Rb are each independently selected from hydrogen, _C1-6 alkyl, said _C1-6 alkyl optionally further substituted by 4-6 membered heterocyclyl, _C1-6 alkyl-4-6 membered heterocyclyl, or ^Ra and ^Rb together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic group; v is an integer from 1 to 6. The compound represented by the general formula (I) according to any one of claims 1 to 19, or its mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: R ² is selected from 5-10 membered heteroaryl, preferably 5-6 membered heteroaryl, more preferably pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, which is optionally further substituted with one or more G ² ; G ² is selected from halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 4-6 membered heterocyclyl and -(CH ₂ ) _v NR ^a R ^b , wherein the C _1-6 alkyl and 4-6 membered heterocyclyl are each independently optionally further substituted by one or more groups selected from deuterated, halogen, cyano, hydroxyl and C _1-6 alkyl; R ^a and R ^b are each independently selected from C _1-6 alkyl, or ^Ra and ^Rb together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic group; v is an integer from 1 to 6. The compound represented by the general formula (I) according to any one of claims 1 to 22, or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:







A method for preparing a compound represented by the general formula (I) according to any one of claims 1 to 23 or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:
Compound IA is reacted with Im in the presence of a catalyst to obtain a compound represented by the general formula (I) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the catalyst is preferably Pd(dppf)Cl ₂ or tetrakistriphenylphosphine palladium; X, Y, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A and L are as defined in claim 1. A pharmaceutical composition comprising a compound represented by the general formula (I) according to any one of claims 1 to 23 or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Use of a compound represented by the general formula (I) according to any one of claims 1 to 23 or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 25 in the preparation of a FGFR2 inhibitor. Use of a compound represented by general formula (I) according to any one of claims 1 to 23 or its mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 25 in the preparation of a medicament for preventing and/or treating a disease associated with FGFR2 activity, wherein the disease is preferably bile duct cancer, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, rectal cancer, endometrial cancer and urothelial cancer.