WO2023011581A1

WO2023011581A1 - Nitrogen-containing heterocyclic compound, preparation method therefor, and pharmaceutical application thereof

Info

Publication number: WO2023011581A1
Application number: PCT/CN2022/110232
Authority: WO
Inventors: 李心; 张志高; 陆标; 沈晓冬; 贺峰; 陶维康
Original assignee: 江苏恒瑞医药股份有限公司; 上海恒瑞医药有限公司
Priority date: 2021-08-04
Filing date: 2022-08-04
Publication date: 2023-02-09
Also published as: CN117677621A; TW202321253A

Abstract

Disclosed are a nitrogen-containing heterocyclic compound, a preparation method therefor, and a pharmaceutical application thereof. Specifically, disclosed are a nitrogen-containing heterocyclic compound as shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and a use of the nitrogen-containing heterocyclic compound as a therapeutic agent, especially a use as an FGFR2 inhibitor and a use in preparation of drugs for treating and/or preventing tumors.

Description

Nitrogen-containing heterocyclic compound, its preparation method and its application in medicine

technical field

The disclosure belongs to the field of medicine, and relates to a nitrogen-containing heterocyclic compound, its preparation method and its application in medicine. Specifically, the present disclosure relates to a nitrogen-containing heterocyclic compound represented by general formula (I), its preparation method, a pharmaceutical composition containing the compound, and its use as a therapeutic agent, especially as an FGFR2 inhibitor And use in the preparation of medicines for treating and/or preventing tumors.

Background technique

Fibroblast growth factor receptors (Fibroblast growth factors receptors, FGFRs) is a member of the receptor tyrosine kinase family (RTKs), is a class of classic RTKs, including four members FGFR1, FGFR2, FGFR3 and FGFR4, all Contains three parts: extracellular region, transmembrane region and intracellular tyrosine kinase region. Fibroblast growth factors (FGFs) bind to FGFRs and cause receptor dimerization, leading to autophosphorylation and activation of multiple tyrosine residues in the intracellular tyrosine kinase domain; activated FGFRs activate substrates through phosphorylation PLCγ and the signal adapter protein FRS2 further activate downstream RAS-RAF-MAPK, PI3K/AKT, PKC, STAT and other signaling pathways, thereby affecting cell proliferation, differentiation, migration, angiogenesis, tissue repair and other physiological functions (Signal Transduct Targeted Ther , 2020, 2;5(1):181).

FGFs in the human body are divided into 6 subfamilies, which are divided into two categories: classical FGFs and hormone FGFs. Classical FGFs include FGF1-10, 16-18, 20, and 22, which can bind to FGFR1-4 and have a strong affinity with heparin, and mainly affect cell proliferation, differentiation, angiogenesis, wound repair, and cancer development (Nat Rev Cancer , 2010; 10(2):116-129); hormonal FGFs include FGF19, 21, and 23, which mainly bind to FGFR1 and FGFR4, and use α/β-Klotho as co-receptors to regulate metabolic processes in vivo. Among them, FGF19-FGFR4 regulates bile acid metabolism, and FGF23-FGFR1 regulates blood calcium, phosphorus and vitamin D levels (Nat Rev Drug Discov.2016; 15(1):51-69), which makes the inhibition of FGFR1 and FGFR4 cause target Point-related toxicity, causing severe adverse reactions such as hyperphosphatemia and diarrhea.

When FGFR is abnormal, it will cause excessive activation of FGFR signaling pathway, and further induce normal cells to become cancerous. FGFR gene abnormalities are common in many cancers. A NGS study of 4853 solid tumors of various types showed that 7% of cancers had FGFR abnormalities, including FGFR1 (49%), FGFR2 (19%), FGFR3 (26%) and FGFR4 (7%). Among them, endometrial cancer, cholangiocarcinoma and gastric cancer have a high incidence of FGFR2 abnormality (Clin Cancer Res. 2016 1; 22(1):259-267).

At present, there are two pan-FGFR inhibitor drugs approved for marketing for FGFR, Jassen’s erdatinib (Erdatinib), which is approved for locally advanced or metastatic urothelial carcinoma with abnormal FGFR2 or FGFR3 (N Engl J Med.2019,381(4):338-348) and Incyte's Pemigatinib, approved for locally advanced or metastatic cholangiocarcinoma with FGFR2 fusion or rearrangement (The Lancet Oncology.2020, 21(5):671-684). However, due to adverse reactions such as severe hyperphosphatemia and diarrhea caused by the inhibition of FGFR1 and FGFR4, most pan-FGFR inhibitors are administered at intervals to reduce adverse reactions, which greatly reduces the efficacy of the drug. In addition to target-related toxicities, resistance to pan-FGFR inhibitors can develop during treatment. For example, in patients with cholangiocarcinoma with FGFR2 fusion or mutation, after receiving pan-FGFR inhibitor therapy, acquired drug resistance mutations at V564, N549, E565, L617, K641 and other sites will occur (Cancer Discov.2017, 7( 3): 252-263). These adverse effects, interval dosing and acquired drug resistance have greatly limited the application of pan-FGFR inhibitors.

Currently, RELAY has published the only patent application (WO2020231990A1) on FGFR2 selective inhibitors. In 2020, RELAY's small-molecule FGFR2 inhibitor RLY4008 entered the first phase of clinical trials. There are currently no FGFR2 selective inhibitors approved for marketing, so there is still a significant unmet medical need in the relevant patient population.

Contents of the invention

The purpose of this disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

in:

X is selected from -O-, -S-, -NR ⁵ - and -C(R ^a R ^b )-;

Y ¹ , Y ² and Y ³ are the same or different, and each independently is a nitrogen atom or CR ⁴ ;

Z ¹ , Z ² , Z ³ and Z ⁴ are the same or different, and each independently selected from a carbon atom, a nitrogen atom, NR ⁰ and CR ^c ;

Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

^R is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein each of the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group is independently any is selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, -NR ⁸ R ⁹ , hydroxyl, hydroxyalkyl, cycloalkyl, hetero One or more substituents in ring group, aryl group and heteroaryl group are substituted;

R ^c is selected from hydrogen atom, alkyl, halogen, cyano, oxo, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ¹⁰ , -C(O)OR ¹⁰ , -OC(O)R ¹⁰ , -OR ¹⁰ , -S(O) _p R ¹⁰ , -S(O) _p NR ⁶ R ⁷ , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein all The alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, - NR ⁸ R ⁹ , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;

Each ^R is the same or different, and each independently selected from halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, oxo, -(CR ^d R ^e ) _r -NR ⁶ R ⁷ and -L ² -R ² ;

L ¹ is selected from chemical bond, -(CR ^f R ^g ) _r -, -NR ^5a -, -O-, -OC(R ^f R ^g )-, -C(R ^f R ^g )-O-, -C( R ^f R ^g )-NR ^5a -, -NR ^5a -C(R ^f R ^g )-, -C(O)-, -OC(O)-, -C(O)-O-, -S(O ) _p -, -NR ^5a -C(O)-, -C(O)-NR ^5a -, -C(O)-NR ^5a -C(R ^f R ^g )-, -C(R ^f R ^g ) -NR ^5a -C(O)-, -NR ^5a -C(O)-C(R ^f R ^g )-, -NR ^5a -S(O) ₂ -, -S(O) ₂ -NR ^5a -, Cycloalkylene, heterocyclylene, arylene and heteroarylene, wherein said cycloalkylene, heterocyclylene, arylene and heteroarylene are each independently selected from halogen , oxo, alkyl, haloalkyl, methylene, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, -NR ⁸ R ⁹ , hydroxyl and hydroxyalkyl base replaced;

L ² is selected from chemical bond, -(CR ^f R ^g ) _r -, -NR ^5a -, -O-, -OC(R ^f R ^g )-, -C(R ^f R ^g )-O-, -C( R ^f R ^g )-NR ^5a -, -NR ^5a -C(R ^f R ^g )-, -C(O)-, -OC(O)-, -C(O)-O-, -S(O ) _p -, -NR ^5a -C(O)-, -C(O)-NR ^5a -, -C(O)-NR ^5a -C(R ^f R ^g )-, -C(R ^f R ^g ) -NR ^5a -C(O)-, -NR ^5a -C(O)-C(R ^f R ^g )-, -NR ^5a -S(O) ₂ -, -S(O) ₂ -NR ^5a -, Cycloalkylene, heterocyclylene, arylene and heteroarylene, wherein said cycloalkylene, heterocyclylene, arylene and heteroarylene are each independently selected from halogen , oxo, alkyl, haloalkyl, methylene, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, -NR ⁸ R ⁹ , hydroxyl and hydroxyalkyl base replaced;

R ² is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -C(O)R ¹⁰ , -C(O)OR ¹⁰ ,

Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, One or more substituents in haloalkyl, methylene, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, -NR ⁸ R ⁹ , hydroxyl and hydroxyalkyl;

R ¹¹ , R ¹² and R ¹³ are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, -C(O)NR ⁶ R ⁷ , -C(O)R ¹⁰ , -C(O)OR ^10. -C(O)-N(R ^5b )-OR ¹⁰ , cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, Aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -NR ⁸ R ⁹ , hydroxyl, hydroxyalkyl, ring One or more substituents in alkyl, heterocyclyl, aryl and heteroaryl;

Or R ¹¹ and R ¹² form a cycloalkyl or heterocyclic group together with the connected carbon atoms, wherein each of the cycloalkyl or heterocyclic groups is independently optionally selected from halogen, oxo, alkyl, alkane Oxygen, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;

Or R ¹² and R ¹³ form a cycloalkyl or heterocyclic group together with the connected carbon atoms, wherein each of the cycloalkyl or heterocyclic groups is independently selected from halogen, oxo, alkyl, alkane Oxygen, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;

R ^a , R ^b , R ^d , R ^e , R ^f and R ^g are the same or different, and each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group and Haloalkoxy;

Each R ³ is the same or different, and each independently selected from alkyl, halogen, cyano, oxo, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ¹⁰ , - C(O)OR ¹⁰ , -OC(O)R ¹⁰ , -OR ¹⁰ , -S(O) _p R ¹⁰ , -S(O) _p NR ⁶ R ⁷ , cycloalkyl, heterocyclyl, aryl and Heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkane Oxygen, cyano, -NR ⁸ R ⁹ , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;

R ⁴ is the same or different at each occurrence, and is each independently selected from a hydrogen atom, an alkyl group, a halogen, a cyano group, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O)R ¹⁰ , -C(O)OR ¹⁰ , -OC(O)R ¹⁰ , -OR ¹⁰ , -S(O) _p R ¹⁰ , -S(O) _p NR ⁶ R ⁷ , cycloalkyl, heterocyclyl, Aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, haloalkyl, alkoxy One or more substituents in radical, haloalkoxy, cyano, -NR ⁸ R ⁹ , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁵ , R ^5a and R ^5b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group;

R ⁶ , R ⁷ , R ⁸ and R ⁹ are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy ;

Or R ⁶ and R ⁷ form a heterocyclic group together with the connected nitrogen atom, wherein the heterocyclic group is optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano One or more substituents in radical, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Or R ⁸ and R ⁹ form a heterocyclic group together with the connected nitrogen atom, wherein the heterocyclic group is optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano One or more substituents in radical, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ¹⁰ are the same or different at each occurrence, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein said alkyl group, ring Alkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

p is 0, 1 or 2;

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

r is 0, 1, 2, 3, 4, 5 or 6;

s is 0, 1, 2, 3, 4 or 5; and

t is 0, 1, 2, 3, 4 or 5.

In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein Z ¹ is a nitrogen atom, Z ² is a carbon atom, Z ³ is NR ⁰ , and Z ⁴ is a carbon atom, wherein R ⁰ is as defined in the general formula (I); or Z ¹ is a nitrogen atom, Z ² is a nitrogen atom, Z ³ is CR ^c , and Z ⁴ is a carbon atom, wherein R ^c is as in the general formula ( as defined in I); or Z ¹ is CR ^c , Z ² is a nitrogen atom, Z ³ is a nitrogen atom, and Z ⁴ is a carbon atom, wherein R ^c is as defined in general formula (I); or Z ¹ is CR ^c , Z ² is a carbon atom, Z ³ is NR ⁰ , and Z ⁴ is a carbon atom, wherein R ⁰ and R ^c are as defined in the general formula (I); preferably, Z ¹ is a nitrogen atom, Z ² is carbon atom, Z ³ is NR ⁰ , and Z ⁴ is a carbon atom, wherein R ⁰ is as defined in general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein

selected from

wherein R ⁰ , R ^c , R ⁵ , Y ¹ to Y ³ and m are as defined in general formula (I); preferably,

for

wherein R ⁰ , R ⁵ , Y ¹ to Y ³ and m are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein X is -NR ⁵ -, wherein R ⁵ is as defined in general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein s is 0, 1, 2 or 3; preferably, s is 1, 2 or 3; More preferably, s is 1 or 2; most preferably, s is 1.

In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein at least one R ¹ is -L ² -R ² , wherein L ² and R ² are as in the general formula as defined in (I).

In some embodiments of the present disclosure, in the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, one R ¹ is -L ² -R ² , and the remaining R ^1s are the same or different, and Each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkoxy , C _1-6 hydroxyalkyl, cyano, oxo and -(CR ^d R ^e ) _r -NR ⁶ R ⁷ , where L ² , R ² , R ^d , R ^e , R ⁶ , R ⁷ and r As defined in general formula (I); preferably, one R ¹ is -L ² -R ² , and the remaining R ^1s are the same or different, and each independently selected from halogen, C _1-6 alkyl, C _{1 -6} haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl and -(CR ^d R ^e ) _r -NR ⁶ R ⁷ , where L ² , R ² , R ^d , ^Re , R ⁶ , R ⁷ and r are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

in:

Each R ^1a is the same or different, and each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy , C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, cyano, oxo and -(CR ^d R ^e ) _r -NR ⁶ R ⁷ ;

s1 is 0, 1, 2, 3 or 4;

Ring A, ring B, L ¹ , L ² , Y ¹ to Y ³ , R ⁰ , R ^d , R ^e , R ² , R ³ , R ⁵ to R ⁷ , r, m and t are as in general formula (I) defined in .

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof, wherein Y ¹ , Y ² and Y ³ are the same or different, and each independently is a nitrogen atom or CR ⁴ , wherein R ⁴ is the same or different, and each independently is a hydrogen atom or a halogen; preferably, Y ¹ , Y ² and Y ³ are all CR ⁴ , wherein R ⁴ is the same or different, and each are independently a hydrogen atom or a halogen; more preferably, Y ¹ is CR ⁴ , and R ⁴ is a hydrogen atom or a halogen, Y ² and Y ³ are CR ⁴ , and R ⁴ is a hydrogen atom; most preferably, Y ¹ is CR ⁴ , and R ⁴ is a hydrogen atom or a fluorine atom, Y ² and Y ³ are CR ⁴ , and R ⁴ is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a hydrogen atom.

In some embodiments of the present disclosure, in the compound represented by general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2; preferably, m is 2.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II) or a pharmaceutically acceptable salt thereof, wherein m is 1.

In some embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof the salt:

in:

R ^4a and R ^4b are the same or different, and each independently selected from hydrogen atom, C _1-6 alkyl, halogen, cyano, -NR ⁶ R ⁷ , -C(O)NR ⁶ R ⁷ , -C(O )R ¹⁰ , -C(O)OR ¹⁰ and -OR ¹⁰ , wherein the C _1-6 alkyl is optionally selected from halogen, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano Substituted by one or more substituents in group, -NR ⁸ R ⁹ , hydroxyl and C _1-6 hydroxyalkyl;

s1 is 0, 1, 2, 3 or 4;

Ring A, Ring B, L ¹ , L ² , Y ¹ , R ⁰ , R ^d , ^Re , R ² , R ³ , R ⁶ to R ¹⁰ , r and t are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein L ² is a chemical bond or -NR ^5a - C(O)-, wherein R ^5a is as defined in general formula (I); preferably, L ² is -NR ^5a -C(O)-, wherein R ^5a is as defined in general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein L ² is a chemical bond.

In some embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IIIN) or a pharmaceutically acceptable salt thereof the salt:

in:

s1 is 0, 1, 2, 3 or 4;

m is 1 or 2;

Ring A, Ring B, L ¹ , Y ¹ , R ⁰ , R ^d , ^Re , R ² , R ³ , R ^5a , R ⁶ to R ¹⁰ , r and t are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN) or a pharmaceutically acceptable salt thereof, wherein ring A is 6 to 10 membered aryl or 5 to 10 membered heteroaryl; Preferably, Ring A is selected from phenyl, pyridyl and pyrimidinyl; More preferably, Ring A is phenyl or pyridyl; Most preferably, Ring A For phenyl.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN) or a pharmaceutically acceptable salt thereof, wherein ring B is selected from From 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group, 6 to 10 membered aryl group and 5 to 10 membered heteroaryl group; preferably, ring B is selected from 3 to 6 membered heterocyclic group, phenyl and 5 or 6 membered heteroaryl; more preferably, ring B is selected from pyridyl, pyrimidinyl and tetrahydropyrrolyl; most preferably, ring B is pyridyl or pyrimidinyl.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN) or a pharmaceutically acceptable salt thereof, wherein ring B is selected from From phenyl, pyridyl, pyrimidinyl and tetrahydropyrrolyl.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein ring B is a 6- to 10-membered aryl group or 5 to 10 membered heteroaryl; preferably, ring B is selected from phenyl, pyridyl and pyrimidinyl.

In some embodiments of the present disclosure, the compound represented by general formula (II), general formula (III) or a pharmaceutically acceptable salt thereof, wherein

selected from

wherein L ² , R ^1a , R ² and s1 are as defined in general formula (II); preferably,

selected from

wherein L ² , R ^1a , R ² and s1 are as defined in general formula (II); more preferably,

for

wherein L ² , R ^1a , R ² and s1 are as defined in general formula (II); most preferably,

for

wherein L ² , R ^1a , R ² and s1 are as defined in the general formula (II).

In some embodiments of the present disclosure, the compound represented by the general formula (IIIN) or a pharmaceutically acceptable salt thereof, wherein

selected from

wherein R ^1a , R ² , R ^5a and s1 are as defined in general formula (IIIN); preferably,

for

wherein R ^1a , R ² , R ^5a and s1 are as defined in general formula (IIIN).

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN) or a pharmaceutically acceptable salt thereof, wherein R ² is selected from From halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano, -C(O)R ¹⁰ , -C(O)OR ¹⁰ ,

wherein R ¹⁰ to R ¹³ are as defined in general formula (I); preferably, R ² is

wherein R ¹¹ to R ¹³ are as defined in general formula (I); more preferably, R ² is

wherein R ¹¹ to R ¹³ are as defined in the general formula (I).

for

L ² is a chemical bond or -NR ^5a -C(O)-, R ² is

R ¹¹ to R ¹³ , R ^1a , R ^5a and s1 are as defined in general formula (II); preferably,

for

L ² is a chemical bond or -NR ^5a -C(O)-, R ² is

R ¹¹ to R ¹³ , R ^1a , R ^5a and s1 are as defined in general formula (II); more preferably,

for

^R2 is

R ¹¹ to R ¹³ , R ^1a , R ^5a and s1 are as defined in the general formula (II).

for

L ² , R ^1a , R ² and s1 are as defined in general formula (II); preferably,

for

L ² , R ^1a , R ² and s1 are as defined in general formula (II); preferably,

for

L ² is a chemical bond or -NR ^5a -C(O)-, R ² is

for

wherein R ^1a , R ¹² and s1 are as defined in general formula (II).

for

L ² is a chemical bond or -NR ^5a -C(O)-, R ² is

for

wherein R ^1a , R ¹² and s1 are as defined in general formula (II).

In some embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof the salt:

in:

s1 is 0, 1, 2 or 3;

m is 1 or 2;

Ring B, L ¹ , Y ¹ , R ⁰ , R ^d , ^Re , R ³ , R ⁶ to R ¹⁰ , R ¹² , r and t are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein ring B is selected from 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; preferably, ring B is selected from 3- to 6-membered heterocyclyl, phenyl and 5 or 6-membered heteroaryl; more preferably, ring B is pyridyl or pyrimidinyl.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) or its pharmaceutically acceptable Salt, wherein each R ³ is the same or different, and each independently selected from C _1-6 alkyl, C _1-6 haloalkyl, halogen, cyano, oxo, -NR ⁶ R ⁷ , C _1-6 alkane Oxygen, C _1-6 haloalkoxy and C _1-6 hydroxyalkyl, wherein R ⁶ and R ⁷ are as defined in general formula (I); preferably, R ³ is C _1-6 alkyl; more preferably Ground, R ³ is methyl.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) or its pharmaceutically acceptable A salt wherein t is 0, 1 or 2; preferably, t is 0 or 1.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) or its pharmaceutically acceptable Salt, wherein each R ³ is the same or different, and each independently selected from C _1-6 alkyl, C _1-6 haloalkyl, halogen, cyano, oxo, -NR ⁶ R ⁷ , C _1-6 alkane Oxygen, C _1-6 haloalkoxy and C _1-6 hydroxyalkyl, and t is 0, 1 or 2, wherein R ⁶ and R ⁷ are as defined in general formula (I); preferably, R ³ is C _1-6 alkyl, and t is 0, 1 or 2; more preferably, R ³ is C _1-6 alkyl, and t is 0 or 1; most preferably, R ³ is methyl, and t is 0 or 1.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) or its pharmaceutically acceptable Salt, wherein R ^O is selected from hydrogen atom, C _1-6 alkyl, 3 to 8 membered cycloalkyl and 3 to 12 membered heterocyclic group, wherein said C _1-6 alkyl, 3 to 8 membered cycloalkane The radical and the 3- to 12-membered heterocyclyl are each independently optionally selected from halogen, oxo, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _1-6 alkoxy, C _1-6 haloalkoxy, cyano, -NR ⁸ R ⁹ , hydroxyl and C _1-6 hydroxyalkyl are substituted by one or more substituents, wherein R ⁸ and R ⁹ is as defined in claim 1; preferably, R ⁰ is a hydrogen atom or a C _1-6 alkyl group; more preferably, R ⁰ is a C _1-6 alkyl group; most preferably, R ⁰ is a methyl group.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) or its pharmaceutically acceptable salt, wherein Y ¹ is a nitrogen atom or CR ⁴ , and R ⁴ is a hydrogen atom or a halogen; preferably, Y ¹ is CR ⁴ , and R ⁴ is a hydrogen atom or a halogen; more preferably, Y ¹ is CR ⁴ , and R ⁴ is a hydrogen atom or a fluorine atom.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) or its pharmaceutically acceptable Salt, wherein Y ¹ is a nitrogen atom or CH.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) or its pharmaceutically acceptable salt, wherein L ¹ is -O- or -C(O)-.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) or its pharmaceutically acceptable Salt, wherein L ¹ is -O-.

In some embodiments of the present disclosure, the compound represented by general formula (II), general formula (III), general formula (IIIN), general formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R ^1a The same or different, and each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl and -(CR ^d R ^e ) _r -NR ⁶ R ⁷ , wherein R ^d , R ^e , R ⁶ , R ⁷ and r are as defined in general formula (I); preferably, each R ^1a is the same or different, and each independently selected from halogen, C _1-6 alkyl and C _1-6 alkoxy; more preferably, each R ^1a is the same or different, and each independently is halogen or C _1-6 alkyl.

In some embodiments of the present disclosure, the compound represented by general formula (II), general formula (III), general formula (IIIN), general formula (IV) or a pharmaceutically acceptable salt thereof, wherein s1 is 0 , 1 or 2; preferably, s1 is 0 or 1; more preferably, s1 is 0.

In some embodiments of the present disclosure, the compound represented by general formula (II), general formula (III), general formula (IIIN), general formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R ^1a The same or different, and each independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl and -(CR ^d R ^e ) _r -NR ⁶ R ⁷ , and s1 is 0, 1 or 2, wherein R ^d , R ^e , R ⁶ , R ⁷ and r are as defined in general formula (I).

In some embodiments of the present disclosure, the compound represented by general formula (II), general formula (III), general formula (IIIN), general formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R ^1a The same or different, and each independently selected from halogen, C _1-6 alkyl and C _1-6 alkoxy, and s1 is 0, 1 or 2; preferably, each R ^1a is the same or different, and each independently selected from halogen, C _1-6 alkyl and C _1-6 alkoxy, and s1 is 0 or 1.

In some embodiments of the present disclosure, the compound represented by general formula (II), general formula (III), general formula (IIIN), general formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R ^1a are the same or different, and are independently halogen or C _1-6 alkyl, and s1 is 0, 1 or 2; preferably, R ^1a is halogen or C _1-6 alkyl, and s1 is 0 or 1.

In some embodiments of the present disclosure, the compound represented by general formula (III), general formula (IIIN), general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R ^4a and R ^4b are the same or different, And each independently selected from hydrogen atom, C _1-6 alkyl, C _1-6 haloalkyl, halogen, cyano, -NR ⁶ R ⁷ , C _1-6 alkoxy, C _1-6 haloalkoxy and C _1-6 hydroxyalkyl, wherein R ⁶ and R ⁷ are as defined in the general formula (I); preferably, R ^4a and R ^4b are the same or different, and each independently is a hydrogen atom or a halogen; more preferably, Both R ^4a and R ^4b are hydrogen atoms.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN) or a pharmaceutically acceptable salt thereof, wherein R ^5a is A hydrogen atom or a C _1-6 alkyl group; preferably, R ^5a is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN) or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is selected from from hydrogen atom, halogen, C _1-6 alkyl, -C(O)NR ⁶ R ⁷ and -C(O)R ¹⁰ , wherein said C _1-6 alkyl is optionally selected from halogen, C _{1 -6} alkoxy, C _1-6 haloalkoxy, cyano, -NR ⁸ R ⁹ , hydroxyl and C _1-6 hydroxyalkyl are substituted by one or more substituents, wherein R ⁶ to R ¹⁰ are as Defined in general formula (I); Preferably, R ¹¹ is selected from hydrogen atom, halogen and C _1-6 alkyl; More preferably, R ¹¹ is selected from hydrogen atom, fluorine atom and methyl group; Most preferably, R ¹¹ is a hydrogen atom or a fluorine atom.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN) or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is a hydrogen atom or a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) or its pharmaceutically acceptable salt, wherein R ¹² is selected from hydrogen atom, halogen, C _1-6 alkyl, -C(O)NR ⁶ R ⁷ and -C(O)R ¹⁰ , wherein said C _1-6 alkyl is optionally Substituted by one or more substituents selected from halogen, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano, -NR ⁸ R ⁹ , hydroxyl and C _1-6 hydroxyalkyl, wherein R ⁶ to R ¹⁰ are as defined in the general formula (I); preferably, R ¹² is a hydrogen atom or a C _1-6 alkyl group; more preferably, R ¹² is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN) or a pharmaceutically acceptable salt thereof, wherein R ¹³ is selected from from a hydrogen atom, a halogen and a C _1-6 alkyl group; preferably, R ¹³ is a hydrogen atom or a C _1-6 alkyl group; more preferably, R ¹³ is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) or its pharmaceutically acceptable Salt, wherein R ⁶ and R ⁷ are the same or different, and are each independently selected from a hydrogen atom, C _1-6 alkyl, C _1-6 hydroxyalkyl, 3 to 8-membered cycloalkyl and 3 to 12-membered heterocycle group, wherein said C _1-6 alkyl, 3 to 8 membered cycloalkyl and 3 to 12 membered heterocyclic group are each independently selected from halogen, C _1-6 alkyl, C _1-6 alkane Oxygen, C _1-6 haloalkyl and C _1-6 haloalkoxy are substituted by one or more substituents.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) or its pharmaceutically acceptable Salt, wherein R ⁸ and R ⁹ are the same or different, and are each independently selected from a hydrogen atom, C _1-6 alkyl, C _1-6 hydroxyalkyl, 3 to 8-membered cycloalkyl and 3 to 12-membered heterocycle group, wherein said C _1-6 alkyl, 3 to 8 membered cycloalkyl and 3 to 12 membered heterocyclic group are each independently selected from halogen, C _1-6 alkyl, C _1-6 alkane Oxygen, C _1-6 haloalkyl and C _1-6 haloalkoxy are substituted by one or more substituents.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) or its pharmaceutically acceptable Salt, wherein R ¹⁰ is the same or different at each occurrence, and each independently selected from a hydrogen atom, C _1-6 alkyl and C _1-6 hydroxyalkyl.

In some embodiments of the present disclosure, the compound represented by general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) or its pharmaceutically acceptable Salt, wherein R ^d and R ^e are the same or different, and are each independently a hydrogen atom or a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, pyridyl and pyrimidinyl; ring B is selected from 3-6 membered Heterocyclyl, phenyl and 5- or 6-membered heteroaryl; L ¹ is -O- or -C(O)-; L ² is a chemical bond or -NR ^5a -C(O)-; R ^5a is a hydrogen atom or C _1-6 alkyl; Y ¹ , Y ² and Y ³ are the same or different, and are each independently a nitrogen atom or CR ⁴ , wherein R ⁴ are the same or different, and are each independently a hydrogen atom or a halogen; R ⁰ is Hydrogen atom or C _1-6 alkyl; R ² is

R ¹¹ is selected from hydrogen atom, halogen and C _1-6 alkyl; R ¹² is hydrogen atom or C _1-6 alkyl; R ¹³ is hydrogen atom or C _1-6 alkyl; R ³ is C _1-6 alkane and t is 0, 1 or 2; R ⁵ is a hydrogen atom; m is 1 or 2; each R ^1a is the same or different, and each independently selected from halogen, C _1-6 alkyl and C _1-6 alkane Oxygen, and s1 is 0, 1 or 2.

R ¹¹ is selected from hydrogen atom, halogen and C _1-6 alkyl; R ¹² is hydrogen atom or C _1-6 alkyl; R ¹³ is hydrogen atom or C _1-6 alkyl; R ³ is C _1-6 alkane and t is 0, 1 or 2; R ⁵ is a hydrogen atom; m is 1 or 2; R ^1a is halogen or C _1-6 alkyl, and s1 is 0 or 1.

In some embodiments of the present disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, pyridyl and pyrimidinyl; ring B is selected from phenyl, pyridine and pyrimidinyl; L ¹ is -O-; L ² is a chemical bond or -NR ^5a -C(O)-; R ^5a is a hydrogen atom or a C _1-6 alkyl group; Y ¹ is a nitrogen atom or CH; R ⁰ is a hydrogen atom or a C _1-6 alkyl group; R ^4a and R ^4b are the same or different, and each independently is a hydrogen atom or a halogen; R ² is

R ¹¹ is a hydrogen atom or a C _1-6 alkyl group; R ¹² is a hydrogen atom or a C _1-6 alkyl group; R ¹³ is a hydrogen atom or a C _1-6 alkyl group; R ³ is a C _1-6 alkyl group, and t is 0, 1 or 2; s1 is 0.

In some embodiments of the present disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein

for

Ring B is selected from phenyl, pyridyl and pyrimidinyl; L ¹ is -O-; L ² is a chemical bond or -NR ^5a -C(O)-; R ^5a is a hydrogen atom or C _1-6 alkyl; Y ¹ is a nitrogen atom or CH; R ⁰ is a hydrogen atom or a C _1-6 alkyl group; R ^4a and R ^4b are the same or different, and each independently is a hydrogen atom or a halogen; R ² is

In some embodiments of the present disclosure, the compound represented by the general formula (IIIN) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, pyridyl and pyrimidyl; ring B is selected from pyridyl, pyrimidine and tetrahydropyrrolyl; L ¹ is -O- or -C(O)-; R ^5a is hydrogen atom; Y ¹ is nitrogen atom or CR ⁴ , R ⁴ is hydrogen atom or halogen; R ⁰ is C _{1- 6} alkyl; R ^4a and R ^4b are hydrogen atoms; R ² is

R ¹¹ is selected from hydrogen atom, halogen and C _1-6 alkyl; R ¹² is hydrogen atom or C _1-6 alkyl; R ¹³ is hydrogen atom; R ³ is C _1-6 alkyl; t is 0 or 1 m is 1 or 2; each R ^1a is the same or different, and is independently selected from halogen, C _1-6 alkyl and C _1-6 alkoxy, and s1 is 0 or 1.

In some embodiments of the present disclosure, the compound represented by general formula (IIIN) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, pyridyl and pyrimidinyl; ring B is selected from 3-6 membered Heterocyclyl, phenyl and 5- or 6-membered heteroaryl; L ¹ is -O- or -C(O)-; R ^5a is hydrogen atom or C _1-6 alkyl; Y ¹ is nitrogen atom or CR ⁴ , and R ⁴ is a hydrogen atom or a halogen; R ⁰ is a hydrogen atom or a C _1-6 alkyl group; R ^4a and R ^4b are the same or different, and each independently is a hydrogen atom or a halogen; R ² is

R ¹¹ is selected from hydrogen atom, halogen and C _1-6 alkyl; R ¹² is hydrogen atom or C _1-6 alkyl; R ¹³ is hydrogen atom or C _1-6 alkyl; R ³ is C _1-6 alkane and t is 0, 1 or 2; m is 1 or 2; R ^1a is halogen or C _1-6 alkyl, and s1 is 0 or 1.

In some embodiments of the present disclosure, the compound represented by general formula (IIIN) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, pyridyl and pyrimidinyl; ring B is selected from 3-6 membered Heterocyclyl, phenyl and 5- or 6-membered heteroaryl; L ¹ is -O- or -C(O)-; R ^5a is a hydrogen atom or a C _1-6 alkyl group; Y ¹ is a nitrogen atom or CH; R ⁰ is a hydrogen atom or a C _1-6 alkyl group; R ^4a and R ^4b are the same or different, and each independently is a hydrogen atom or a halogen; R ² is

R ¹¹ is selected from hydrogen atom, halogen and C _1-6 alkyl; R ¹² is hydrogen atom or C _1-6 alkyl; R ¹³ is hydrogen atom or C _1-6 alkyl; R ³ is C _1-6 alkane base, and t is 0, 1 or 2; m is 1 or 2; s1 is 0.

for

Ring B is selected from pyridyl, pyrimidinyl and tetrahydropyrrolyl; L ¹ is -O- or -C(O)-; R ^5a is a hydrogen atom; Y ¹ is CR ⁴ , and R ⁴ is a hydrogen atom or a halogen; R ⁰ is C _1-6 alkyl; R ^4a and R ^4b are the same or different, and each independently is a hydrogen atom or halogen; R ² is

R ¹¹ is selected from hydrogen atom, halogen and C _1-6 alkyl; R ¹² is hydrogen atom or C _1-6 alkyl; R ¹³ is hydrogen atom; R ³ is C _1-6 alkyl, and t is 0 or 1; m is 1 or 2; R ^1a is halogen or C _1-6 alkyl, and s1 is 0 or 1.

for

Ring B is selected from 3 to 6 membered heterocyclyl, phenyl and 5 or 6 membered heteroaryl; L ¹ is -O- or -C(O)-; R ^5a is a hydrogen atom; Y ¹ is a nitrogen atom or CH ; R ⁰ is a hydrogen atom or a C _1-6 alkyl group; R ^4a and R ^4b are the same or different, and each independently is a hydrogen atom or a halogen; R ² is

R ¹¹ is selected from hydrogen atom, halogen and C _1-6 alkyl; R ¹² is hydrogen atom; R ¹³ is hydrogen atom; R ³ is C _1-6 alkyl, and t is 0, 1 or 2; m is 1 or 2; s1 is 0.

In some embodiments of the present disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein ring B is pyridyl or pyrimidinyl; L ¹ is -O- or -C(O) -; Y ¹ is CR ⁴ , and R ⁴ is hydrogen atom or halogen; R ⁰ is C _1-6 alkyl; R ^4a and R ^4b are both hydrogen atoms; R ¹² is hydrogen atom; R ³ is C _1-6 Alkyl, and t is 0 or 1; m is 1 or 2; each R ^1a is the same or different, and each independently selected from halogen, C _1-6 alkyl and C _1-6 alkoxy, and s1 is 0 or 1.

In some embodiments of the present disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein ring B is pyridyl or pyrimidinyl; L ¹ is -O- or -C(O) -; Y ¹ is CR ⁴ , and R ⁴ is hydrogen atom or halogen; R ⁰ is C _1-6 alkyl; R ^4a and R ^4b are both hydrogen atoms; R ¹² is hydrogen atom; R ³ is C _1-6 Alkyl, and t is 0 or 1; m is 1 or 2; R ^1a is halogen or C _1-6 alkyl, and s1 is 0 or 1.

Table A Typical compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to a compound represented by general formula (Ia) or a salt thereof,

in:

W is halogen; preferably, W is iodine;

Ring B, X, Z ¹ to Z ⁴ , L ¹ , Y ¹ to Y ³ , R ³ , m and t are as defined in the general formula (I).

Another aspect of the present disclosure relates to a compound represented by general formula (IIa) or a salt thereof,

in:

W is halogen; preferably, W is iodine;

Ring B, L ¹ , Y ¹ to Y ³ , R ⁰ , R ³ , R ⁵ , m and t are as defined in the general formula (II).

Another aspect of the present disclosure relates to a compound represented by general formula (IIIa) or a salt thereof,

in:

W is halogen; preferably, W is iodine;

Ring B, L ¹ , Y ¹ , R ⁰ , R ³ , R ^4a , R ^4b and t are as defined in the general formula (III).

Another aspect of the present disclosure relates to a compound represented by general formula (IIINa) or a salt thereof,

in:

W is halogen; preferably, W is iodine;

Ring B, L ¹ , Y ¹ , R ⁰ , R ³ , R ^4a , R ^4b , m and t are as defined in the general formula (IIIN).

Table B Typical intermediate compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to a compound represented by general formula (IIb) or a salt thereof,

in:

L ^2a is -NR ^5a -;

Ring A, ring B, L ¹ , Y ¹ to Y ³ , R ⁰ , R ^1a , R ³ , R ⁵ , R ^5a , s1, m and t are as defined in the general formula (II).

Another aspect of the present disclosure relates to a compound represented by general formula (IIINb) or a salt thereof,

in:

Ring A, ring B, L ¹ , Y ¹ , R ⁰ , R ^1a , R ³ , R ^4a , R ^4b , R ^5a , s1, m and t are as defined in the general formula (IIIN).

Table C Typical intermediate compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to a compound represented by general formula (IVc) or a salt thereof,

in:

R ^w is an alkynyl protecting group; preferably, R ^w is tert-butyldimethylsilyl (TBS);

Ring B, L ¹ , Y ¹ , R ⁰ , R ^1a , R ³ , R ^4a , R ^4b , s1, m and t are as defined in the general formula (IV).

Table D Typical intermediate compounds of the present disclosure include, but are not limited to:

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

A compound represented by general formula (Ia) or a salt thereof and a compound represented by general formula (X) or a salt thereof undergo a coupling reaction to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof;

in:

W is halogen; preferably, W is iodine;

L is

R is a hydrogen atom or a C _1-6 alkyl group;

Ring A, ring B, X, Z ¹ to Z ⁴ , L ¹ , Y ¹ to Y ³ , R ¹ , R ³ , m, s and t are as defined in the general formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, comprising the following steps:

A compound represented by general formula (IIa) or a salt thereof and a compound represented by general formula (XI) or a salt thereof undergo a coupling reaction to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;

in:

W is halogen; preferably, W is iodine;

L is

R is a hydrogen atom or a C _1-6 alkyl group;

Ring A, ring B, L ¹ , L ² , Y ¹ to Y ³ , R ⁰ , R ^1a , R ² , R ³ , R ⁵ , m, s1 and t are as defined in the general formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, comprising the following steps:

A compound represented by general formula (IIIa) or a salt thereof and a compound represented by general formula (XI) or a salt thereof undergo a coupling reaction to obtain a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof;

in:

W is halogen; preferably, W is iodine;

L is

R is a hydrogen atom or a C _1-6 alkyl group;

Ring A, ring B, L ¹ , L ² , Y ¹ , R ⁰ , R ^1a , R ² , R ³ , R ^4a , R ^4b , s1 and t are as defined in the general formula (III).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IIIN) or a pharmaceutically acceptable salt thereof, comprising the following steps:

A compound represented by general formula (IIINa) or a salt thereof and a compound represented by general formula (XII) or a salt thereof undergo a coupling reaction to obtain a compound represented by general formula (IIIN) or a pharmaceutically acceptable salt thereof;

in:

W is halogen; preferably, W is iodine;

L is

R is a hydrogen atom or a C _1-6 alkyl group;

Ring A, ring B, L ¹ , Y ¹ , R ⁰ , R ^1a , R ² , R ³ , R ^4a , R ^4b , R ^5a , s1, m and t are as defined in the general formula (IIIN).

The compound represented by general formula (IIb) or its salt reacts with the compound represented by general formula (M) or its salt to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt;

in:

L ^2a is -NR ^5a -;

L ^2b is -C(O)-;

L ² is -NR ^5a -C(O)-;

R ^x is hydroxyl or halogen; preferably, R ^x is halogen; more preferably, R ^x is a chlorine atom;

^R2 is

Preferably, ^R2 is

Ring A, Ring B, L ¹ , Y ¹ to Y ³ , R ⁰ , R ^1a , R ³ , R ⁵ , R ^5a , R ¹¹ to R ¹³ , s1, m and t are as defined in general formula (II) .

The compound represented by general formula (IIINb) or its salt reacts with the compound represented by general formula (MI) or its salt to obtain the compound represented by general formula (IIIN) or its pharmaceutically acceptable salt;

in:

^R2 is

Preferably, ^R2 is

Ring A, Ring B, L ¹ , Y ¹ , R ⁰ , R ^1a , R ³ , R ^4a , R ^4b , R ^5a , R ¹¹ to R ¹³ , s1, m and t are as defined in general formula (IIIN) .

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound represented by the general formula (IVc) or its salt is removed from the protecting group ^Rw to obtain the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;

in:

R ¹² is a hydrogen atom;

Another aspect of the present disclosure relates to a pharmaceutical composition containing the general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) of the present disclosure And the compound shown in Table A or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure further relates to compounds shown in general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) and Table A or their pharmaceutically acceptable salts or comprising Use of the pharmaceutical composition of the invention in the preparation of a medicament for inhibiting FGFR2.

The present disclosure further relates to compounds shown in general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) and Table A or their pharmaceutically acceptable salts or comprising Use of the pharmaceutical composition in the preparation of medicines for treating and/or preventing tumors.

The present disclosure also relates to a method of inhibiting FGFR2, which includes administering a therapeutically effective amount of the general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) to the patient in need And a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it.

The present disclosure also relates to a method for treating and/or preventing tumors, which comprises administering a therapeutically effective dose of general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula A compound shown in formula (IV) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a compound shown in general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, for use as a medicament.

The present disclosure further relates to compounds shown in general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) and Table A or pharmaceutically acceptable salts thereof, or comprising A pharmaceutical composition thereof for use as a FGFR2 inhibitor.

The present disclosure further relates to compounds shown in general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) and Table A or pharmaceutically acceptable salts thereof, or comprising A pharmaceutical composition thereof for inhibiting FGFR2.

The present disclosure further relates to compounds shown in general formula (I), general formula (II), general formula (III), general formula (IIIN), general formula (IV) and Table A or pharmaceutically acceptable salts thereof, or comprising A pharmaceutical composition thereof, which is used for treating and/or preventing tumors.

The tumor as described above in the present disclosure is cancer; the cancer is preferably selected from bile duct cancer, liver cancer, breast cancer, prostate cancer, lung cancer (such as non-small cell lung cancer and small cell lung cancer), thyroid cancer, gastric cancer, ovarian cancer, Colorectal cancer (eg, colon and rectum), endometrial cancer, urothelial cancer, testicular cancer, cervical cancer, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, esophageal cancer, head and neck cancer , renal cancer, pancreatic cancer, bone cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelial tumor, glioma (such as astrocytoma and glioblastoma), ependymoma, neuroblastoma, Ganglioma, medulloblastoma, pineal cell tumor, meningioma, neurofibroma, schwannoma and Wilms tumor; more preferably selected from cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, Thyroid, gastric, ovarian, colorectal, endometrial, and urothelial cancers.

The active compound may be presented in a form suitable for administration by any suitable route, preferably in unit dosage form, or in such a form that the patient can self-administer a single dose. A unit dosage form of a compound or composition of the present disclosure may be presented as a tablet, capsule, cachet, bottle, powder, granule, lozenge, suppository, reconstituted powder or liquid.

As a general guide, a suitable unit dose may be 0.1 to 1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients wait. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir. Oral compositions can be prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and palatable medicinal preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.

Oral formulations can also be provided in soft gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, or where the active ingredient is mixed with a water-soluble carrier or an oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

Oily suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil. The oily suspensions may contain a thickening agent. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be vegetable oil, mineral oil or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase, and the injection or microemulsion can be injected into the patient's bloodstream by local bulk injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. Model 5400 IV pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blended and fixed oil may be used. In addition, fatty acids are also used in the preparation of injectables.

The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

As is well known to those skilled in the art, the dosage of the drug to be administered depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the state of health of the patient, the behavior of the patient , patient's diet, administration time, administration method, rate of excretion, combination of drugs, severity of disease, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dosage of the compound or the content of the pharmaceutically acceptable salt Kinds can be validated against traditional treatment regimens.

Glossary

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

The term "alkyl" refers to a saturated linear or branched aliphatic hydrocarbon group having 1 to 20 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie C _1-20 alkyl). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (ie, a C _1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (ie, a C _1-6 alkyl group). Non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl Base-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-dimethyl 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 isomers thereof. Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, One or more of cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl group is as above. Alkenyl groups having 2 to 12 (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e. C _2-12 alkenyl) are preferred, more preferably 2 Alkenyl to 6 carbon atoms (ie C _2-6 alkenyl). Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from the group consisting of alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl One or more of radical, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as above, and it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (ie, C _2-12 alkynyl), more preferably alkynyl having 2 to 6 carbon atoms (ie, C _2-6 alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from the group consisting of alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl One or more of radical, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic full carbocycle (ie monocyclic cycloalkyl) or polycyclic ring system (ie polycyclic cycloalkyl) having 3 to 20 (eg 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 3 to 20 membered cycloalkyl). The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 ring atoms (i.e. a 3 to 12 membered cycloalkyl group), more preferably a cycloalkyl group having 3 to 8 ring atoms (i.e. a 3 to 8 membered cycloalkyl group). ), most preferably a cycloalkyl group having 3 to 6 ring atoms (ie a 3 to 6 membered cycloalkyl group).

Said monocyclic cycloalkyl, non-limiting examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl , cycloheptatrienyl and cyclooctyl, etc.

The polycyclic cycloalkyl includes: spirocycloalkyl, condensed cycloalkyl and bridged cycloalkyl.

The term "spirocycloalkyl" refers to a polycyclic ring system that shares one carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds in the ring, or may contain one or more rings selected from nitrogen, Oxygen and sulfur heteroatoms (the nitrogen may be optionally oxidized, i.e. form nitrogen oxides; the sulfur may be optionally oxo, i.e. form sulfoxides or sulfones, but excluding -O-O-, -O-S - or -S-S-), provided that it contains at least one full carbon ring and the point of attachment is on the full carbon ring, it has 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered spirocycloalkyl). The spirocycloalkyl is preferably a spirocycloalkyl having 6 to 14 ring atoms (i.e. a 6 to 14 membered spirocycloalkyl), more preferably a spirocycloalkyl having 7 to 10 ring atoms (i.e. 7 to 10 member spirocycloalkyl). The spirocycloalkyl group includes single spirocycloalkyl and polyspirocycloalkyl (such as double spirocycloalkyl, etc.), preferably single spirocycloalkyl or double spirocycloalkyl, more preferably 3-membered/4-membered, 3-membered Yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/ 6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan Single spirocycloalkyl. Non-limiting examples include:

Its connection point can be at any position;

wait.

The term "fused cycloalkyl" refers to a polycyclic ring system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl to a heterocyclic One or more of cyclic groups, aryl groups or heteroaryl groups are condensed, wherein the point of attachment is on the monocyclic cycloalkyl group, which can contain one or more double bonds in the ring, and have 5 to 20 (for example, 5 , 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered fused cycloalkyl). The condensed cycloalkyl group is preferably a fused cycloalkyl group having 6 to 14 ring atoms (i.e. a 6 to 14 membered fused cycloalkyl group), more preferably a fused cycloalkyl group having 7 to 10 ring atoms (i.e. 7 to 10 fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl , more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan , 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan Member/5-member or 7-member/6-membered bicyclic fused cycloalkyl group. Non-limiting examples include:

its connection point

can be anywhere;

wait.

The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system which shares two carbon atoms not directly connected between the rings, which may contain one or more double bonds in the ring, and has 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (ie, 5 to 20 membered bridged cycloalkyl). The bridged cycloalkyl group is preferably a bridged cycloalkyl group having 6 to 14 carbon atoms (i.e. a 6 to 14 membered bridged cycloalkyl group), more preferably a bridged cycloalkyl group having 7 to 10 carbon atoms (i.e. 7 to 10 bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl . Non-limiting examples include:

Its connection point can be anywhere.

Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkane One of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e. monocyclic heterocyclyl) or polycyclic heterocyclic ring system (i.e. polycyclic heterocyclyl) containing at least one (eg 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e. form nitrogen oxides; the sulfur may optionally be oxo, i.e. form sulfoxides or sulfone, but not including -O-O-, -O-S- or -S-S-), with 3 to 20 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 3 to 20 membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e. a 3 to 12 membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e. a 3 to 8 membered heterocyclic group) ); more preferably a heterocyclyl group having 3 to 6 ring atoms (ie, a 3- to 6-membered heterocyclyl group); most preferably a heterocyclyl group having 5 or 6 ring atoms (ie, a 5- or 6-membered heterocyclyl group).

Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl , Thiomorpholinyl and Homopiperazinyl, etc.

The polycyclic heterocyclic groups include spiro heterocyclic groups, condensed heterocyclic groups and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system that shares one atom (called a spiro atom) between the rings, which may contain one or more double bonds in the ring, and at least one (such as 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e. to form sulfoxides or sulfones, But not including -O-O-, -O-S- or -S-S-), the condition is to contain at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered spiroheterocyclyl). The spiroheterocyclyl is preferably a spiroheterocyclyl having 6 to 14 ring atoms (i.e. 6 to 14 membered spiroheterocyclyl), more preferably a spiroheterocyclyl having 7 to 10 ring atoms (i.e. 7 to 10 membered spiroheterocyclyl). The spiroheterocyclyl includes single spiroheterocyclyl and polyspiroheterocyclyl (such as double spiroheterocyclyl, etc.), preferably single spiroheterocyclyl or double spiroheterocyclyl, more preferably 3-membered/4-membered, 3-membered Yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/ 6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan Monospiroheterocyclyl. Non-limiting examples include:

wait.

The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system which shares two adjacent atoms between the rings, which may contain one or more double bonds, and which contains at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxo, i.e. to form sulfoxides or sulfones, but not Including -O-O-, -O-S- or -S-S-), which is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group with a cycloalkyl, aryl or heteroaryl One or more of the fused groups, wherein the point of attachment is on the monocyclic heterocyclic group, and there are 5 to 20 (for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered fused heterocyclyl). The fused heterocyclic group is preferably a fused heterocyclic group having 6 to 14 ring atoms (ie, a 6 to 14 membered fused heterocyclic group), more preferably a condensed heterocyclic group having 7 to 10 ring atoms (ie, 7 to 10 membered fused heterocyclyl). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably bicyclic fused heterocyclic groups or tricyclic fused heterocyclic groups, more preferably 3 Yuan/4 Yuan, 3 Yuan/5 Yuan, 3 Yuan/6 Yuan, 4 Yuan/4 Yuan, 4 Yuan/5 Yuan, 4 Yuan/6 Yuan, 5 Yuan/3 Yuan, 5 Yuan/4 Yuan, 5 Yuan/ 5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan Or a 7-membered/6-membered bicyclic condensed heterocyclic group. Non-limiting examples include:

wait.

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, and may contain one or more double bonds in the ring, and at least one (for example, 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e. to form nitrogen oxides; the sulfur may be optionally oxidized, i.e. to form sulfoxides or sulfones, but not including -O-O-, -O-S- or -S-S-), which have 5 to 20 (eg 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (ie 5 to 20 membered bridged heterocyclyl). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e. a 6 to 14 membered bridged heterocyclic group), more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e. 7 to 10 bridged heterocyclyl). According to the number of rings, it can be divided into bicyclic bridged heterocyclic group and polycyclic bridged heterocyclic group (such as tricyclic bridged heterocyclic group, tetracyclic bridged heterocyclic group, etc.), preferably bicyclic bridged heterocyclic group or tricyclic bridged heterocyclic group base. Non-limiting examples include:

wait.

The heterocyclyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkane One of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or more.

The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aryl) or a polycyclic aromatic ring system (i.e., a polycyclic aryl) having a conjugated π-electron system, which has 6 to 14 (e.g., 6 , 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (ie 6 to 14 membered aryl). The aryl group is preferably an aryl group having 6 to 10 ring atoms (ie, a 6 to 10 membered aryl group). The monocyclic aryl group, such as phenyl. Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracenyl, phenanthrenyl and the like. The polycyclic aryl also includes the condensing of phenyl with one or more of heterocyclic or cycloalkyl, or the fused of naphthyl with one or more of heterocyclic or cycloalkyl, wherein the connection point On phenyl or naphthyl, and in this case, the number of ring atoms continues to mean the number of ring atoms in a polycyclic aromatic ring system, non-limiting examples include:

wait.

Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy one or Multiple.

The term "heteroaryl" refers to a monocyclic heteroaryl ring (ie, monocyclic heteroaryl) or a polycyclic heteroaryl ring system (ie, polycyclic heteroaryl) having a conjugated π-electron system, which contains at least one (eg 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e. form nitrogen oxides; the sulfur may optionally be oxo, i.e. forming sulfoxides or sulfones, but excluding -O-O-, -O-S- or -S-S-), which have 5 to 14 (eg 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ) ring atoms (ie 5 to 14 membered heteroaryl). The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e. a 5 to 10 membered heteroaryl group), more preferably a heteroaryl group having 5 or 6 ring atoms (i.e. a 5 or 6 membered heteroaryl group). ).

Non-limiting examples of the monocyclic heteroaryl include: furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl , pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (such as

etc.), pyrazinyl, pyridazinyl, etc.

The polycyclic heteroaryl, non-limiting examples include: indolyl, indazolyl, quinolinyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene group, quinazoline group, benzothiazolyl group, carbazolyl group, etc. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aryls, wherein the point of attachment is on the aromatic ring, and in this case the number of ring atoms continues to represent the polycyclic heteroaryl The number of ring atoms in the system. The polycyclic heteroaryl also includes monocyclic heteroaryl fused with one or more of cycloalkyl or heterocyclic, wherein the point of attachment is on the monocyclic heteroaryl ring, and in this case, the ring The number of atoms continues to indicate the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include:

wait.

Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, substituents are preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkane One or more of oxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkylene" refers to a divalent cycloalkyl group, wherein cycloalkyl is as defined above.

The term "heterocyclylene" refers to a divalent heterocyclyl group, wherein heterocyclyl is as defined above.

The term "arylene" refers to a divalent aryl group, wherein aryl is as defined above.

The term "heteroarylene" refers to a divalent heteroaryl group, wherein heteroaryl is as defined above.

The term "alkynyl protecting group" refers to a group introduced on an alkynyl group which is easy to remove in order to keep the active hydrogen in acetylene or terminal alkyne unchanged when other parts of the molecule react. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), tert-butyl Dimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "alkylthio" refers to alkyl-S-, wherein alkyl 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 group is as defined above.

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

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

The term "methylene" refers to = _CH2 .

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

The term "hydroxyl" refers to -OH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "oxo" or "oxo" refers to "=O".

The term "carbonyl" refers to C=O.

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

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

Compounds of the present disclosure may exist in particular stereoisomeric forms. The term "stereoisomer" refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (e.g. racemates, mixtures of diastereomers) . Substituents in compounds of the present disclosure may be present with additional asymmetric atoms. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomer. An isomer of a certain compound in the present disclosure can be prepared by asymmetric synthesis or chiral auxiliary agents, or, when the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxyl), with appropriate optical Reactive acids or bases form diastereomeric salts, which are then resolved by conventional methods well known in the art to yield the pure isomers. Furthermore, separation of enantiomers and diastereomers is usually accomplished by chromatography.

In the chemical structures of the compounds described in this disclosure, the bond

Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond

can be

or both

Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both Z and E forms are included.

The compounds of the present disclosure may exist in different tautomeric forms and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers that exist in equilibrium and are readily converted from one isomeric form to the other. It includes all possible tautomers, i.e. present as a single isomer or as a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactam, and the like. An example of lactam-lactim equilibrium is shown below:

For example, when referring to pyrazolyl, it should be understood to include any one of the following two structures or a mixture of two tautomers:

All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomers.

Compounds of the present disclosure include all suitable isotopic derivatives of their compounds. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, etc., such as ² H (deuterium, D), respectively, ³ H (tritium, T), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N ^, ¹⁷ O, 18 O, ³² p, ³³ p, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I, and ¹³¹ I, etc., preferably deuterium.

Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic and side effects, increasing drug stability, enhancing curative effect, and prolonging the biological half-life of drugs. All permutations of isotopic composition of the disclosed compounds, whether radioactive or not, are included within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, wherein the replacement of deuterium may be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

When a position is specifically designated as deuterium D, the position is understood to have an abundance of deuterium (ie at least 15% deuterium incorporation) that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). Exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium (i.e. at least 15% deuterium incorporation), at least 2000 times more abundant deuterium (i.e. at least 30% deuterium incorporation) , at least 3000 times the abundance of deuterium (i.e. at least 45% deuterium incorporation), at least 3340 times the abundance of deuterium (i.e. at least 50.1% deuterium incorporation), at least 3500 times the abundance of deuterium (i.e. at least 52.5% deuterium incorporation), at least 4000-fold more abundant deuterium (i.e. at least 60% deuterium incorporation), at least 4500-fold more abundant deuterium (i.e. at least 67.5% deuterium incorporation), at least 5000-fold Deuterium in abundance (i.e. at least 75% deuterium incorporation), deuterium in at least 5500 times abundance (i.e. at least 82.5% deuterium incorporation), deuterium in at least 6000 times abundance (i.e. at least 90% deuterium incorporation deuterium incorporation), at least 6333.3 times the abundance of deuterium (i.e. at least 95% deuterium incorporation), at least 6466.7 times the abundance of deuterium (i.e. at least 97% deuterium incorporation), at least 6600 times the abundance of deuterium ( That is, at least 99% deuterium incorporation), at least 6633.3 times the abundance of deuterium (ie, at least 99.5% deuterium incorporation), or higher abundance of deuterium.

"Optionally" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "C _1-6 alkyl optionally (optionally) substituted by halogen or cyano" means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl The case where the group is not substituted by halogen and cyano.

"Substituted" or "substituted" means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, are independently substituted by the corresponding number of substituents. Possible or impossible substitutions can be determined (by experiment or theory) by those skilled in the art without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.

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

"Pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals, and have proper biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of the therapeutically effective dose varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate therapeutically effective dose in individual cases can be determined by those skilled in the art according to routine experiments.

As used herein, the term "pharmaceutically acceptable" means those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with patient tissues without undue toxicity, irritation, allergic reaction or Other problems or complications that have a reasonable benefit/risk ratio and are valid for the intended use.

As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it means that the parameter may vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, the numbers are generally given for illustrative purposes only, and not for limitation.

Synthetic Methods of the Disclosed Compounds

In order to accomplish the purpose of this disclosure, this disclosure adopts the following technical solutions:

Option One

The preparation method of the compound represented by the general formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:

A compound represented by general formula (Ia) or a salt thereof and a compound represented by general formula (X) or a salt thereof undergoes a Suzuki coupling reaction to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof;

in:

W is halogen; preferably, W is iodine;

L is

R is a hydrogen atom or a C _1-6 alkyl group;

Option II

The preparation method of the compound represented by the general formula (II) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:

A compound represented by general formula (IIa) or a salt thereof and a compound represented by general formula (XI) or a salt thereof undergoes a Suzuki coupling reaction to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;

in:

W is halogen; preferably, W is iodine;

L is

R is a hydrogen atom or a C _1-6 alkyl group;

third solution

The preparation method of the compound represented by the general formula (III) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:

A compound represented by general formula (IIIa) or a salt thereof and a compound represented by general formula (XI) or a salt thereof undergoes a Suzuki coupling reaction to obtain a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof;

in:

W is halogen; preferably, W is iodine;

L is

R is a hydrogen atom or a C _1-6 alkyl group;

Option four

The preparation method of the compound represented by the general formula (IIIN) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:

The compound represented by the general formula (IIINa) or its salt and the compound represented by the general formula (XII) or its salt undergo a Suzuki coupling reaction to obtain the compound represented by the general formula (IIIN) or a pharmaceutically acceptable salt thereof;

in:

W is halogen; preferably, W is iodine;

L is

R is a hydrogen atom or a C _1-6 alkyl group;

Option five

The compound represented by general formula (IIb) or its salt and the compound represented by general formula (M) or its salt are under alkaline conditions, and optionally in a condensation agent (such as 2-(7-azabenzotri In the presence of azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU)) react to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof;

in:

L ^2a is -NR ^5a -;

L ^2b is -C(O)-;

L ² is -NR ^5a -C(O)-;

^R2 is

Preferably, ^R2 is

Option six

The compound represented by the general formula (IIINb) or its salt and the compound represented by the general formula (MI) or its salt are under alkaline conditions, and optionally in a condensation agent (such as 2-(7-azabenzotri azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU)) react to obtain the compound represented by the general formula (IIIN) or a pharmaceutically acceptable salt thereof;

in:

^R2 is

Preferably, ^R2 is

Option seven

The preparation method of the compound represented by the general formula (IV) of the present disclosure or a pharmaceutically acceptable salt thereof comprises the following steps:

The compound represented by the general formula (IVc) or a salt thereof is removed in the presence of a catalyst (such as tetrabutylammonium fluoride) to remove the protecting group ^Rw to obtain the compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;

in:

R ¹² is a hydrogen atom;

In the above synthesis schemes 1 to 4, the Suzuki coupling reaction is preferably carried out in the presence of a base (such as sodium carbonate and potassium carbonate) and a metal catalyst (such as tetrakis(triphenylphosphine)palladium).

The above-mentioned metal catalysts include but are not limited to tetrakis(triphenylphosphine)palladium, 1,1'-bis(tert-butylphosphine)ferrocenepalladium chloride, palladium dichloride, palladium acetate, 1,1'-bis( Dibenzylphosphino)dichlorodipentyl iron palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1'-bis(diphenylphosphino)bis Ferrocene]dichloropalladium dichloromethane complex, tris(dibenzylideneacetone)dipalladium, etc., preferably tetrakis(triphenylphosphine)palladium or 1,1'-bis(tert-butylphosphine)dipalladium Ferrocene Palladium Chloride. In the above synthesis scheme, bases include organic bases and inorganic bases, and the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine (DIPEA), n-butyllithium, diisopropylamino Lithium, potassium acetate, sodium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; the inorganic base includes but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, hydrogen Sodium Oxide, Lithium Hydroxide Monohydrate, Lithium Hydroxide, and Potassium Hydroxide. The base described in Schemes 1 to 4 is preferably sodium carbonate, potassium carbonate and cesium fluoride; the reagent providing alkaline conditions described in Schemes 5 to 6 is preferably N,N-diisopropylethylamine (DIPEA).

The above synthesis scheme is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-Hexane, Dimethyl Sulfoxide, 1,4-Dioxane, Water, N,N-Dimethylformamide, N,N-Dimethylacetamide and mixtures thereof.

Detailed ways

The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

Example

Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). The determination of NMR is carried out with a Bruker AVANCE NEO 500M nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard is four Methylsilane (TMS).

MS was determined with Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High performance liquid chromatography (HPLC) was analyzed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatography.

Chiral HPLC analysis was performed using an Agilent 1260 DAD high performance liquid chromatograph.

High performance liquid phase preparative chromatography uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.

Chiral preparative chromatography uses a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ~0.5mm.

Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

Kinase average inhibition rate and IC ₅₀ value were measured with NovoStar microplate reader (BMG Company, Germany).

The known starting materials of the present disclosure can be used or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals, Shanghai Titan Technology Co., Ltd., China National Pharmaceutical Group Co., Ltd., Adamas Reagent Co., Ltd., Shanghai Pide Pharmaceutical Technology Co., Ltd., Shanghai Haohong Biomedical Technology Co., Ltd. and Thermo Fisher Scientific (China) Technology Ltd. and other companies.

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

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

The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.

The hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.

For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.

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, which is 20°C to 30°C.

The monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developer used for reaction, the eluent system of the column chromatography that purifies compound adopts and the developer system of thin-layer chromatography comprise: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

Example 1

N-(4-(11-methyl-7-((4-methylpyrimidin-2-yl)oxy)-5,11-dihydro-4H-1,3,4,11-tetraazadi Benzo[cd,h]azulene-10-yl)phenyl)acrylamide 1

first step

2-Bromo-5-((4-methylpyrimidin-2-yl)oxy)benzonitrile 1c

2-Bromo-5-hydroxybenzonitrile 1a (2.0g, 10.1mmol, prepared by the method disclosed on page 95 of the patent application "WO2004035556A1" specification) was dissolved in dimethyl sulfoxide, and potassium hydroxide solution ( 1.0 mL, 10M), stirred for 30 minutes. Add 2-chloro-4-methylpyrimidine 1b (1.3 g, 10.1 mmol), heat to 100° C., and stir for 3 hours. Add 100mL of water, extract with ethyl acetate (30mL×3), wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the residue is purified by CombiFlash rapid prep apparatus with eluent system B to obtain The title compound 1c (2.4 g), yield: 81.9%.

MS m/z (ESI): 290.1 [M+1].

second step

tert-butyl 2-bromo-5-((4-methylpyrimidin-2-yl)oxy)benzylcarbamate 1d

Compound 1c (1.8g, 6.20mmol) was dissolved in methanol (30mL), and di-tert-butyl dicarbonate (2.0g, 9.35mmol), anhydrous nickel chloride (81mg, 0.63mmol) and sodium borohydride (708mg , 18.7mmol), stirred for 3 hours. Concentrate, add water, extract with ethyl acetate (50mL×3), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and elute the residue with a CombiFlash Reagent system B was purified to obtain the title compound 1d (1.0 g), yield: 40.9%.

MS m/z (ESI): 393.9 [M+1].

third step

5-((4-methylpyrimidin-2-yl)oxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) tert-butyl benzylcarbamate 1e

Under argon atmosphere, compound 1d (1.0g, 2.54mmol), bipinacol borate (967mg, 3.81mmol), 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride (189mg, 255mmol ) and potassium acetate (747mg, 7.61mmol) were added to 1,4-dioxane (20mL), and stirred at 90°C for 16 hours. It was filtered through celite, washed with ethyl acetate, concentrated under reduced pressure, and the residue was purified by CombiFlash with eluent system B to obtain the title compound 1e (1.0 g), yield: 89.3%.

MS m/z (ESI): 442.0 [M+1].

the fourth step

2-(4-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-((4-methylpyrimidin-2-yl)oxy)benzylamino tert-butyl formate 1g

Under argon atmosphere, compound 1e (1.0g, 2.27mmol), 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine 1f (666mg, 2.27mmol, using patent application "WO2017046739A1" prepared by the method disclosed on pages 88-89), tetrakis (triphenylphosphine) palladium (262mg, 0.27mmol) and sodium carbonate (300mg, 2.83mmol) by adding 1,4-dioxane ( 20 mL), water (4 mL) was added, and stirred at 90° C. for 16 hours. Concentrate, add water, extract with dichloromethane/methanol (10/1) mixed solvent (20mL×3), combine organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, the residue Purification by CombiFlash with eluent system A gave the title compound 1 g (0.6 g), yield: 55.1%.

MS m/z (ESI): 481.0 [M+1].

the fifth step

11-methyl-7-((4-methylpyrimidin-2-yl)oxy)-5,11-dihydro-4H-1,3,4,11-tetraazadibenzo[cd,h ] azulene 1h

Compound 1g (0.45g, 0.94mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (5mL) was added, and stirred for 1 hour. After concentration under reduced pressure, the resulting residue was dissolved in acetonitrile (10 mL), neutralized with triethylamine, heated to 60° C., and stirred for 1 hour. It was concentrated under reduced pressure, and the residue was purified by CombiFlash with eluent system A to obtain the title compound 1h (225 mg), yield: 69.8%.

MS m/z (ESI): 345.0 [M+1].

step six

10-iodo-11-methyl-7-((4-methylpyrimidin-2-yl)oxy)-5,11-dihydro-4H-1,3,4,11-tetraazadibenzo [cd,h] azulene 1i

Compound 1h (225mg, 0.65mmol) was dissolved in dichloromethane (10mL), trifluoroacetic acid (300mg, 2.63mmol) and N-iodosuccinimide (162mg, 0.72mmol) were added successively, and stirred for 1 hour. Neutralize with saturated sodium carbonate solution, extract with dichloromethane/methanol (10/1) mixed solvent (20mL×3), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the residual The compound was purified by CombiFlash with eluent system A to obtain the title compound 1i (235 mg), yield: 76.5%.

MS m/z (ESI): 471.0 [M+1].

step seven

Under argon atmosphere, compound 1i (105 mg, 0.23 mmol), compound N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl)acrylamide 1j (64mg, 0.23mmol, prepared from the reference "Journal of Organometallic Chemistry, 2003, 680(1-2), 263-270"), tetrakis(triphenylphosphine) palladium (26mg, 0.023 mmol) and sodium carbonate (48mg, 0.45mmol) were added to 1,4-dioxane (20mL), water (4mL) was added, and stirred at 100°C for 16 hours. Concentrate under reduced pressure, add water, extract with dichloromethane/methanol (10/1) mixed solvent (20mL×3), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was purified by CombiFlash with eluent system A to afford the title compound 1 (55 mg), yield: 50.3%.

MS m/z (ESI): 490.0 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.40(s,1H),8.43(d,1H),8.18(s,1H),7.88(d,2H),7.59(s,1H),7.57 (d,2H),7.19(s,1H),7.12(d,1H),6.88-6.82(m,2H),6.51-6.46(dd,1H),6.31(d,1H),5.81(d,1H ), 4.37(d,2H), 3.60(s,3H), 2.40(s,3H).

Example 2

N-(4-(11-methyl-7-((4-methylpyrimidin-2-yl)oxy)-5,11-dihydro-4H-1,3,4,11-tetraazadi Benzo[cd,h]azulene-10-yl)phenyl)methacrylamide 2

Under argon atmosphere, compound 1i (110 mg, 0.23 mmol), N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Base) methacrylamide 2a (74mg, 0.26mmol, prepared by reference "Journal of Organometallic Chemistry, 2003, 680 (1-2), 263-270"), tetrakis (triphenylphosphine) palladium (30mg, 0.026mmol) and sodium carbonate (50mg, 0.47mmol) were added to 1,4-dioxane (20mL), water (4mL) was added, and stirred at 100°C for 16 hours. Concentrate under reduced pressure, add water, extract with dichloromethane/methanol (10/1) mixed solvent (20mL×3), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue was purified by CombiFlash with eluent system A to afford the title compound 2 (60 mg), yield: 50.9%.

MS m/z (ESI): 504.0 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.03(s,1H),8.43(d,1H),8.17(s,1H),7.01(d,2H),7.58(s,1H),7.55 (d,2H),7.18(s,1H),7.12(d,1H),6.88-6.82(m,2H),5.86(s,1H),5.57(s,1H),4.36(d,2H), 3.59(s,3H), 2.40(s,3H), 1.98(s,3H).

Example 3

2-fluoro-N-(4-(12-methyl-8-((6-methylpyridin-2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4, 12-Tetraazabenzo[7,8]octcyclo[1,2,3-cd]inden-11-yl)phenyl)acrylamide 3

first step

2-fluoro-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide 3b

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 3a (1.0 g, 4.56 mmol) and 2-fluoroacrylic acid (430 mg, 4.77mmol) was added to 20mL of dichloromethane, and then N,N-diisopropylethylamine (1.77g, 13.69mmol), 1-hydroxybenzotriazole (926mg, 6.85mmol) and 1-( 3-Dimethylaminopropyl)-3-ethylcarbodiimide (1.32g, 6.88mmol), stirred for 16 hours. After adding 30 mL of water, the liquids were separated, the aqueous phase was extracted with dichloromethane (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B , to obtain the target compound 3b (250 mg, yield: 18.8%).

second step

2-Bromo-5-((6-methylpyridin-2-yl)oxy)benzonitrile 3e

2-bromo-6-methylpyridine 3c (33g, 191.83mmol), 2-bromo-5-hydroxybenzonitrile 3d (25g, 126.25mmol) and potassium carbonate (22g, 159.18mmol) were mixed and stirred, heated to 180 °C, stirred for 6 hours. Cool to room temperature, add 1000mL of water, extract the aqueous phase with ethyl acetate (500mL×3), combine the organic phases, concentrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system B to obtain the target compound 3e (14.45g , yield: 39.6%).

MS m/z (ESI): 290.9 [M+1].

third step

2-Bromo-5-((6-methylpyridin-2-yl)oxy)benzoic acid 3f

Compound 3e (3.0g, 10.37mmol) was added to 26mL of a mixed solvent of ethanol and water (V/V=10/3), then potassium hydroxide (6g, 90.9mmol, 85% purity) was added, and heated to 110°C React for 16 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in 100 mL of water and then adjusted to pH 3 with 1M dilute hydrochloric acid. The aqueous phase was extracted with ethyl acetate (200 mL×3), and the organic phases were combined and dried over anhydrous sodium sulfate. , filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound 3f (3.21 g). The product was directly used in the next reaction without purification.

MS m/z (ESI): 308.1 [M+1].

the fourth step

(2-Bromo-5-((6-methylpyridin-2-yl)oxy)phenyl)methanol 3g

Compound 3f (3.21 g, 10.41 mmol) was added into the bottle, and borane (1M, 25 mL) was added, heated to 60° C. for 3 hours. After the reaction solution was cooled to room temperature, methanol was carefully added to quench until no bubbles were generated, and then the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 3g (2.45g , yield: 80.0%).

MS m/z (ESI): 294.0 [M+1].

the fifth step

2-(4-bromo-3-(bromomethyl)phenoxy)-6-methylpyridine 3h

Compound 3g (2.45g, 8.32mmol) was dissolved in a mixed solvent of 65mL tetrahydrofuran and dichloromethane (V/V=3/10), and triphenylphosphine (2.75g, 10.48mmol) and carbon tetrabromide were added (3.3g, 9.95mmol), stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 3h (2.38 g, yield: 80.0%).

MS m/z (ESI): 357.7 [M+1].

step six

2-(2-Bromo-5-((6-methylpyridin-2-yl)oxy)phenyl)acetonitrile 3i

Compound 3h (2.38g, 6.66mmol) was dissolved in 45mL of acetonitrile, cooled to 0°C, trimethylsilyl cyanide (856mg, 8.63mmol, 1.08mL) was added dropwise, and tetrabutylammonium fluoride (1M, 8.7 mL), stirred at 0°C for 30 minutes and then warmed to room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 3i (1.93 g, yield: 95.5%).

MS m/z (ESI): 302.8 [M+1].

step seven

(2-Bromo-5-((6-methylpyridin-2-yl)oxy)phenethyl)carbamate tert-butyl ester 3j

Compound 3i (1.43g, 4.71mmol) was dissolved in a mixed solvent of 60mL methanol and tetrahydrofuran (V/V=5/1), and nickel chloride hexahydrate (140mg, 472.3μmol) and di-tert-butyl dicarbonate ( 1.568g, 7.18mmol, 1.6mL), and sodium borohydride (536mg, 14.16mmol) was slowly added in batches, and the reaction was stirred for 2 hours after the addition. Add 30 mL of ammonium chloride aqueous solution to quench and extract with ethyl acetate (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. B was purified to obtain the target compound 3j (1 g, yield: 52.0%).

eighth step

(5-((6-methylpyridin-2-yl)oxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) phenethyl) tert-butyl carbamate 3k

Under nitrogen atmosphere, compound 3j (1 g, 2.45 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(1,3, 2-dioxaborolane) (935mg, 3.68mmol), potassium acetate (723mg, 7.36mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (180mg, 246.0μmol) into 40mL 1,4-dioxane, heated to 95°C for 16 hours. The reaction was cooled to room temperature and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 3k (776 mg, yield: 69.5%). MS m/z (ESI): 455.0 [M+1].

Ninth step

(2-(4-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-((6-methylpyridin-2-yl)oxy)phenethyl base) tert-butyl carbamate 3l

Under a nitrogen atmosphere, 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (500mg, 1.70mmol, disclosed on pages 88-89 of the patent application "WO2017046739A1" Prepared by the method), compound 3k (776mg, 1.70mmol), potassium carbonate (295mg, 2.13mmol) and tetrakis (triphenylphosphine) palladium (200mg, 173.0μmol) were added to 36mL of water and 1,4-diox Hexacyclic (V/V=1/5) mixed solvent, heated to 95°C for 16 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 31 (564 mg, yield: 66.8%).

MS m/z (ESI): 494.5 [M+1].

tenth step

12-methyl-8-((6-methylpyridin-2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4,12-tetraazabenzo[7, 8]octcyclo[1,2,3-cd]indene 3m

Compound 3l (564 mg, 1.14 mmol) was dissolved in 10 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction was concentrated under reduced pressure. The resulting residue was dissolved in 30 mL of acetonitrile, triethylamine (2.187 g, 21.61 mmol, 3 mL) was added, and the mixture was heated to 75° C. for 3 hours. The reaction liquid was cooled to room temperature and then concentrated under reduced pressure. After adding 25 mL of saturated aqueous sodium bicarbonate solution to the residue, it was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. , the residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 3m (310 mg, yield: 75.9%).

MS m/z (ESI): 358.0 [M+1].

Eleventh step

11-iodo-12-methyl-8-((6-methylpyridin-2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4,12-tetraazabenzene And[7,8]octcyclo[1,2,3-cd]indene 3n

Compound 3m (310 mg, 867.3 μmol) was dissolved in 30 mL of dichloromethane, cooled to 0° C., trifluoroacetic acid (491 mg, 4.30 mmol, 320 μL) was added, and N-iodosuccinimide (292 mg, 1.29 mmol), warming up to room temperature and stirring for 40 minutes after addition. Add 15 mL of saturated aqueous sodium bicarbonate and 5 mL of saturated aqueous sodium sulfite, separate the layers, extract the aqueous phase with dichloromethane (25 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and wash the residue with silica gel Purified by column chromatography with eluent system A to obtain the target compound 3n (392 mg, yield: 93.5%).

MS m/z (ESI): 484.4 [M+1].

Twelfth step

Under nitrogen atmosphere, compound 3b (70 mg, 240.4 μmol), compound 3n (100 mg, 206.9 μmol), potassium carbonate (43 mg, 311.1 μmol) and tetrakis(triphenylphosphine) palladium (24 mg, 20.7 μmol) were added to 24 mL In a mixed solvent of water and 1,4-dioxane (V/V=1/5), heat to 95°C to react overnight. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 3 (80 mg, yield: 74.3%). MS m/z (ESI): 520.9 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.44(s,1H),8.27(s,1H),7.82(d,2H),7.71(t,1H),7.40(d,2H),7.13 (d,1H),6.99(d,1H),6.72(d,1H),6.66(d,1H),6.65(dd,1H),6.17-6.18(m,1H),6.75(dd,1H), 5.46(dd,1H), 3.66(s,3H), 3.48(s,2H), 3.08(s,2H), 2.34(s,3H).

Example 4

N-(4-(12-methyl-8-(pyrrolidine-1-carbonyl)-4,5,6,12-tetrahydro-1,3,4,12-tetraazabenzo[7,8 ]octcyclo[1,2,3-cd]inden-11-yl)phenyl)acrylamide 4

first step

4-Bromo-3-(cyanomethyl)benzoic acid 4b

Methyl 4-bromo-3-(cyanomethyl)benzoate 4a (2.64g, 10.39mmol, prepared by the method disclosed on page 352 of the patent application "WO2017214458A2" specification) was dissolved in 62.5mL of water and tetrahydrofuran ( Lithium hydroxide (872mg, 20.77mmol) was added to the mixed solvent (V/V=1/24), heated to 50°C for 16 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure, 1M hydrochloric acid was added to the residue until the pH of the reaction solution was less than 7, the aqueous phase was extracted with ethyl acetate (50mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate Concentration under reduced pressure gave the target compound 4b (2.54 g). The product was directly used in the next reaction without purification.

MS m/z (ESI): 238.0 [M-1].

second step

2-(2-Bromo-5-(pyrrolidine-1-carbonyl)phenyl)acetonitrile 4c

Compound 4b (2.54g, 10.58mmol) was dissolved in 50mL N,N-dimethylformamide, tetrahydropyrrole (1.13g, 15.88mmol), N,N-diisopropylethylamine (2g, 15.475 mmol, 2.75mL), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.82g, 12.67mmol), stirred for 3 hours , add 50mL of water and extract with ethyl acetate (80mL×3), combine the organic phases, wash with water (50mL×3), wash with saturated sodium chloride solution (30mL×1), dry over anhydrous sodium sulfate, filter, and depressurize the filtrate After concentration, the residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 4c (2.78 g, yield: 89.6%). MS m/z (ESI): 293.1 [M+1].

third step

(2-Bromo-5-(pyrrolidine-1-carbonyl)phenethyl)carbamate tert-butyl ester 4d

Compound 4c (2.78g, 9.48mmol) was dissolved in 50mL of methanol, di-tert-butyl dicarbonate (3.1g, 14.20mmol, 3.3mL) and nickel chloride hexahydrate (281mg, 948.0μmol) were added, and then slowly separated Sodium borohydride (1.08 g, 28.54 mmol) was added in batches, and the reaction was stirred for 2 hours after the addition. After quenching by adding 15 mL of saturated ammonium chloride, the reaction solution was concentrated under reduced pressure, the residue was extracted with dichloromethane (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with silica gel Purified by column chromatography with eluent system B to obtain the target compound 4d (1.58 g, yield: 41.9%).

MS m/z (ESI): 397.2 [M+1].

the fourth step

(5-(Pyrrolidine-1-carbonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenethyl)carbamate tert-butyl ester 4e

Under nitrogen atmosphere, compound 4d (1.58g, 3.97mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(1,3 ,2-dioxaborolane) (1.3g, 5.11mmol), potassium acetate (585mg, 5.96mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( 290mg, 396.3μmol) into 50mL 1,4-dioxane, heated to 95°C for 16 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 4e (1.67 g, yield: 94.5%).

MS m/z (ESI): 445.2 [M+1].

the fifth step

(2-(4-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-(pyrrolidine-1-carbonyl)phenethyl)carbamate tert-butyl 4f

Under a nitrogen atmosphere, 4-chloro-5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.05g, 3.57mmol, using the patent application "WO2017046739A1" specification pages 88-89 prepared by the disclosed method), compound 4e (1.67g, 3.75mmol), potassium carbonate (742mg, 5.36mmol) and tetrakis(triphenylphosphine)palladium (413mg, 357.4μmol) were added to 60mL of water and 1,4- In a mixed solvent of dioxane (V/V=1/5), heat to 95° C. for 16 hours to react. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 4f (1.67 g, yield : 94.5%).

MS m/z (ESI): 484.2 [M+1].

step six

(12-Methyl-4,5,6,12-tetrahydro-1,3,4,12-tetraazabenzo[7,8]octcyclo[1,2,3-cd]indene-8 -yl) (pyrrolidin-1-yl) methyl ketone 4g

Compound 4f (640 mg, 1.32 mmol) was dissolved in 10 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 20 mL of acetonitrile, triethylamine (1.603 g, 15.84 mmol, 2.2 mL) was added, and the mixture was heated to 75° C. for 4 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. After adding 20 mL of saturated aqueous sodium bicarbonate solution to the residue, it was extracted with dichloromethane (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4 g (514 mg) of the target compound. The product was directly used in the next reaction without purification.

MS m/z (ESI): 348.3 [M+1].

step seven

(11-iodo-12-methyl-4,5,6,12-tetrahydro-1,3,4,12-tetraazabenzo[7,8]octcyclo[1,2,3-cd ] Inden-8-yl) (pyrrolidin-1-yl) methyl ketone 4h

Dissolve compound 4g (514mg, 1.47mmol) in 40mL of dichloromethane, add trifluoroacetic acid (840mg, 7.36mmol, 560μL), cool to 0°C and add N-iodosuccinimide (500mg, 2.22mmol) After the addition, the temperature was raised to room temperature and the reaction was carried out for 30 minutes. Add 10 mL of saturated aqueous sodium sulfite and 30 mL of saturated aqueous sodium bicarbonate, separate the layers, extract the aqueous phase with dichloromethane (30 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and wash the residue with silica gel Purified by column chromatography with eluent system A to obtain the target compound 4h (577 mg, yield: 82.3%).

MS m/z (ESI): 474.1 [M+1].

eighth step

Under nitrogen atmosphere, compound 1j (100 mg, 366.1 μmol), compound 4h (157 mg, 331.7 μmol), potassium carbonate (69 mg, 499.2 μmol) and tetrakis(triphenylphosphine) palladium (38 mg, 32.8 μmol) were added to 36 mL In a mixed solvent of water and 1,4-dioxane (V/V=1/5), heat to 95°C to react overnight. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 4 (100 mg, yield: 61.0%).

MS m/z (ESI): 493.3 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.31(s,1H),8.28(s,1H),7.74(d,2H),7.53(s,1H),7.35(d,2H),7.05 (d,1H),6.71(d,1H),6.45(dd,1H),6.28(dd,1H),6.17-6.18(m,1H),5.78(dd,1H),3.68(s,3H), 3.48-3.39 (m, 6H), 3.12 (m, 2H), 1.86-1.78 (m, 4H).

Example 5

N-(4-(11-methyl-7-((6-methylpyridin-2-yl)oxy)-5,11-dihydro-4H-1,3,4,11-tetraazadi Benzo[cd,h]azulene-10-yl)phenyl)acrylamide 5

first step

(2-Bromo-5-((6-methylpyridin-2-yl)oxy)benzyl)carbamate tert-butyl ester 5a

Compound 3e (1.156g, 4.00mmol) was dissolved in 25mL of methanol, nickel chloride hexahydrate (96mg, 403.89μmol) and di-tert-butyl dicarbonate (1.309g, 6.00mmol) were added, and hydroboration was added slowly in batches Sodium (454mg, 12.00mmol), after the addition was completed, the reaction was stirred for 2 hours. Add 50 mL of aqueous solution to quench and extract with ethyl acetate (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting residue is purified by silica gel column chromatography with eluent system B, The target compound 5a (658 mg, yield: 41.8%) was obtained.

MS m/z (ESI): 393.0 [M+1].

second step

(5-((6-methylpyridin-2-yl)oxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) benzyl) tert-butyl carbamate 5b

Under nitrogen atmosphere, compound 5a (658 mg, 1.67 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di(1,3, 2-dioxaborolane) (553mg, 2.18mmol), potassium acetate (493mg, 5.02mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (123mg, 168.10μmol) into 40mL 1,4-dioxane, heated to 95°C for 17 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 5b (626 mg, yield: 85.0%).

MS m/z (ESI): 441.1 [M+1].

third step

(2-(4-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-((6-methylpyridin-2-yl)oxy)benzyl base) tert-butyl carbamate 5c

Under nitrogen atmosphere, compound 1f (416 mg, 1.42 mmol), compound 5b (626 mg, 1.42 mmol), sodium carbonate (181 mg, 1.71 mmol) and tetrakis(triphenylphosphine) palladium (165 mg, 142.88 μmol) were added to 48 mL In a mixed solvent of water and 1,4-dioxane (V/V=1/5), it was heated to 100° C. for 17 hours to react. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 5c (558 mg, yield: 81.8%).

MS m/z(ESI):480.1[M+1]).

the fourth step

11-methyl-7-((6-methylpyridin-2-yl)oxy)-5,11-dihydro-4H-1,3,4,11-tetraazadibenzo[cd,h ] azulene 5d

Compound 5c (558 mg, 1.16 mmol) was dissolved in 10 mL of dichloromethane, 10 mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure. The resulting residue was dissolved in 25 mL of acetonitrile, triethylamine (706 mg, 6.98 mmol) was added, and the mixture was heated to 70° C. for 4 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. After adding 50 mL of saturated sodium chloride solution to the residue, it was extracted with dichloromethane (50 mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was washed with silica gel column chromatography. The system A was purified to obtain the target compound 5d (250 mg, yield: 62.6%).

MS m/z (ESI): 344.1 [M+1].

the fifth step

10-iodo-11-methyl-7-((6-methylpyridin-2-yl)oxy)-5,11-dihydro-4H-1,3,4,11-tetraazadibenzo [cd,h] azulene 5e

Compound 5d (250mg, 728.05μmol) was dissolved in 20mL of dichloromethane, cooled to 0°C, trifluoroacetic acid (415mg, 3.64mmol) was added, and N-iodosuccinimide (246mg, 1.09mmol) was added After the addition was completed, the temperature was raised to room temperature and the reaction was stirred for 5 hours. Add 100mL saturated sodium sulfite solution to quench, separate the layers, extract the aqueous phase with dichloromethane (100mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is eluted by silica gel column chromatography Reagent system A was purified to obtain the target compound 5e (261 mg, yield: 76.4%).

MS m/z (ESI): 470.0 [M+1].

step six

Under nitrogen atmosphere, compound 1j (88 mg, 322.19 μmol), compound 5e (125 mg, 266.37 μmol), potassium carbonate (93 mg, 672.91 μmol) and tetrakis(triphenylphosphine) palladium (31 mg, 26.83 μmol) were added to 18 mL In a mixed solvent of water and 1,4-dioxane (V/V=1/5), it was heated to 95°C for 17 hours to react. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 5 (77.7 mg, yield: 59.7%).

MS m/z (ESI): 489.1 [M+1].

¹ H NMR (500MHz,DMSO-d ₆ ):δ10.40(s,1H),8.17(s,1H),7.88-7.87(m,2H),7.71-7.67(m,1H),7.57-7.54( m,3H),7.10(d,1H),6.97-6.96(m,1H),6.85-6.84(m,1H),6.76-6.72(m,2H),6.51-6.46(m,1H),6.33- 6.29 (m, 1H), 5.81-5.79 (m, 1H), 4.36-4.35 (m, 2H), 3.58 (s, 3H), 2.30 (s, 3H).

Example 6

N-(4-(11-methyl-7-((6-methylpyridin-2-yl)oxy)-5,11-dihydro-4H-1,3,4,11-tetraazadi Benzo[cd,h]azulene-10-yl)phenyl)methacrylamide 6

Under nitrogen atmosphere, compound 5e (125 mg, 266.37 μmol), compound 2a (92 mg, 320.38 μmol), potassium carbonate (93 mg, 672.91 μmol) and tetrakis(triphenylphosphine) palladium (31 mg, 26.83 μmol) were added to 18 mL In a mixed solvent of water and 1,4-dioxane (V/V=1/5), it was heated to 95°C for 17 hours to react. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 6 (35.3 mg, yield: 26.4%).

MS m/z (ESI): 503.1 [M+1].

¹ H NMR (500MHz,DMSO-d ₆ ):δ10.03(s,1H),8.17(s,1H),7.92-7.90(m,2H),7.70-7.67(m,1H),7.57-7.53( m,3H),7.11-7.10(m,1H),6.97-6.95(m,1H),6.87-6.85(m,1H),6.76-6.71(m,2H),5.85(s,1H),5.56( s, 1H), 4.36-4.35 (m, 2H), 3.58 (s, 3H), 2.30 (s, 3H), 1.98 (s, 3H).

Example 7

N-(4-(12-methyl-8-((6-methylpyridin-2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4,12-tetraaza Heterobenzo[7,8]octcyclo[1,2,3-cd]inden-11-yl)phenyl)acrylamide 7

Using the synthetic route of compound 3 in Example 3, replacing compound 3b with compound 1j, the title compound 7 (60 mg) was obtained.

MS m/z (ESI): 503.4 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.30(s,1H),8.28(s,1H),7.75(d,2H),7.71(t,1H),7.37(d,2H),7.13 (d,1H),6.99(d,1H),6.72(d,1H),6.70-6.65(m,2H),6.44(dd,1H),6.28(dd,1H),6.16-6.17(m,1H ), 5.79(dd,1H), 3.66(s,3H), 3.47(s,2H), 3.08(s,2H), 2.34(s,3H).

Example 8

N-(4-(12-methyl-8-((6-methylpyridin-2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4,12-tetraaza Heterobenzo[7,8]octcyclo[1,2,3-cd]inden-11-yl)phenyl)methacrylamide 8

Using the synthetic route of compound 3 in Example 3, replacing compound 3b with compound 2a, the title compound 8 (70 mg) was obtained.

MS m/z (ESI): 517.4 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ9.94(s,1H),8.27(s,1H),7.77(d,2H),7.71(t,1H),7.36(d,2H),7.12 (d,1H),6.99(d,1H),6.72(d,1H),6.70-6.65(m,2H),6.15-6.16(m,1H),5.81(s,1H),5.54(s,1H ), 3.66(s,3H), 3.47(s,2H), 3.08(s,2H), 2.34(s,3H), 1.96(s,3H).

Example 9

10-(6-ethynyl-4-methylpyridin-3-yl)-11-methyl-7-((6-methylpyridin-2-yl)oxy)-5,11-dihydro-4H -1,3,4,11-Tetraazadibenzo[cd,h]azulene 9

first step

10-(6-((tert-butyldimethylsilyl)ethynyl)-4-methylpyridin-3-yl)-11-methyl-7-((6-methylpyridin-2-yl) Oxy)-5,11-dihydro-4H-1,3,4,11-tetraazadibenzo[cd,h]azulene 9b

Under nitrogen atmosphere, compound 5e (100 mg, 213.09 μmol), 2-((tert-butyldimethylsilyl)ethynyl)-4-methyl-5-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)pyridine 9a (115 mg, 321.79 μmol, prepared by the method disclosed on page 897 of the specification of the patent application "WO2020231990A1"), potassium carbonate (89 mg, 643.97μmol) and tetrakis(triphenylphosphine)palladium (50mg, 43.27μmol) were added to a mixed solvent of 12mL water and 1,4-dioxane (V/V=1/5), heated to 100°C for reaction 17 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 9b (95 mg, yield: 77.8%).

MS m/z (ESI): 573.5 [M+1].

second step

Compound 9b (95 mg, 165.86 μmol) was dissolved in 15 mL of tetrahydrofuran, cooled to 0° C., tetrabutylammonium fluoride (46 mg, 204.3 μmol) was added, and the temperature was raised to room temperature for 1 hour. 50 mL of water was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 9 (12.7 mg, yield: 16.7%).

MS m/z (ESI): 459.1 [M+1].

¹ H NMR (500MHz,DMSO-d ₆ ):δ8.62(s,1H),8.23(s,1H),7.79-7.62(m,3H),7.16-7.14(m,1H),6.99-6.98( m,1H),6.82-6.80(m,1H),6.75-6.73(m,1H),6.67-6.66(m,1H),4.48(s,1H),4.38(s,2H),3.49(s, 3H), 2.30(s,3H), 2.15(s,3H).

Example 10

2-fluoro-N-(4-(11-methyl-7-((4-methylpyrimidin-2-yl)oxy)-5,11-dihydro-4H-1,3,4,11- Tetraazadibenzo[cd,h]azulene-10-yl)phenyl)acrylamide 10

The title compound 10 (110 mg) was obtained by using the synthetic route of compound 1 in Example 1, replacing compound 1j with compound 3b in the seventh step.

MS m/z (ESI): 508.1 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.53(s,1H),8.44(d,1H),8.18(s,1H),7.97(d,2H),7.59(d,3H),7.19 (d,1H),7.13(d,1H),6.83(s,2H),5.76(dd,1H),5.48(dd,1H),4.37(s,2H),3.59(s,3H),2.40( s, 3H).

Example 11

N-(4-(11-methyl-7-((4-methylpyrimidin-2-yl)oxy)-5,11-dihydro-4H-3,4,11-tetraazadibenzo [cd,h]azulene-10-yl)phenyl)but-2-yne amide 11

first step

4-(11-methyl-7-((4-methylpyrimidin-2-yl)-oxyl)-5,11-dihydro-4H-1,3,4,11-tetraazadibenzo [cd,h]azulene-10-yl)aniline 11a

The title compound 11a (270 mg) was obtained by using the synthesis route of compound 1 in Example 1, replacing compound 1j with compound 3a in the seventh step.

second step

Compound 11a (220 mg, 0.51 mmol) and butynoic acid (45 mg, 0.54 mmol) were dissolved in N,N-dimethylformamide (10 mL), and DIPEA (131 mg, 1.01 mmol) and 2-(7-nitrogen Hexabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (232 mg, 0.61 mmol), stirred overnight. Add water, extract three times with dichloromethane/methanol mixed system (V/V=8/1), combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, the residue Purification by silica gel column chromatography with eluent system A gave the target compound 11 (32 mg, yield: 12.6%).

MS m/z (ESI): 502.1 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.87(s,1H),8.43(d,1H),8.17(d,1H),7.80(dd,2H),7.59(s,1H),7.55 (dd,2H),7.18(s,1H),7.13(d,1H),6.83(s,1H),4.36(d,2H),3.58(s,3H),2.40(s,3H),2.08( s, 3H).

Example 12

2-fluoro-N-(4-(11-methyl-7-((6-methylpyridin-2-yl)oxy)-5,11-dihydro-4H-1,3,4,11- Tetraazadibenzo[cd,h]azulene-10-yl)phenyl)acrylamide 12

Under nitrogen atmosphere, compound 5e (137 mg, 291.94 μmol), compound 3b (110 mg, 377.84 μmol), potassium carbonate (101 mg, 730.80 μmol) and tetrakis(triphenylphosphine) palladium (34 mg, 29.42 μmol) were added to 18 mL In a mixed solvent of water and 1,4-dioxane (V/V=1/5), it was heated to 100° C. for 17 hours to react. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 12 (82.0 mg, yield: 55.5%).

MS m/z (ESI): 507.2 [M+1].

¹ H NMR (500MHz,DMSO-d ₆ ):δ10.53(s,1H),8.17(s,1H),7.96-7.94(m,2H),7.71-7.67(m,1H),7.59-7.57( m,3H),7.11-7.10(m,1H),6.97-6.96(m,1H),6.84-6.82(m,1H),6.76-6.72(m,2H),5.82-5.71(m,1H), 5.49-5.45 (m, 1H), 4.36-4.35 (m, 2H), 3.59 (s, 3H), 2.30 (s, 3H).

Example 13

2-fluoro-N-(4-(12-methyl-8-(pyrrolidine-1-carbonyl)-4,5,6,12-tetrahydro-1,3,4,12-tetraazabenzene And[7,8]octcyclo[1,2,3-cd]inden-11-yl)phenyl)acrylamide 13

Using the synthetic route of compound 4 in Example 4, compound 1j in the eighth step was replaced by compound 3b to obtain the title compound 13 (120 mg).

MS m/z (ESI): 511.3 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.44(s,1H),8.28(s,1H),7.81(d,2H),7.54(s,1H),7.38(d,2H),7.04 (d,1H),6.70(d,1H),6.20-6.19(m,1H),5.75(dd,1H),5.46(dd,1H),3.67(s,3H),3.48-3.39(m,6H ), 3.13(s,2H), 1.86-1.79(m,4H).

Example 14

N-(4-(6-fluoro-11-methyl-7-((4-methylpyrimidin-2-yl)oxy)-5,11-dihydro-4H-1,3,4,11- Tetraazadibenzo[cd,h]azulene-10-yl)phenyl)acrylamide 14

first step

2-(4-Bromo-2-fluorophenoxy)-4-methylpyrimidine 14b

Potassium hydroxide (3.8 g, 57.5 mmol, 85% purity) was dissolved in 3.8 mL of water, 4-bromo-2-fluorophenol 14a (10 g, 52.3 mmol) and 60 mL of dimethylsulfoxide were added, followed by 2-chloro- 4-Methylpyrimidine (6.74g, 52.4mmol), heated to 100°C for 3 hours. Cool the reaction solution to room temperature, add 700mL ethyl acetate, wash with water (150mL×3), wash with saturated sodium chloride solution (100mL×1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purification by chromatography with eluent system B afforded the target compound 14b (12.1 g, yield: 81.6%).

MS m/z (ESI): 282.9 [M+1].

second step

6-Bromo-2-fluoro-3-((4-methylpyrimidin-2-yl)oxy)benzaldehyde 14c

Dissolve compound 14b (18.86g, 66.62mmol) in 180mL tetrahydrofuran, cool to -78°C, add lithium diisopropylamide (38mL, 2M) dropwise, stir for 30 minutes, then add N,N-dimethyl Nylformamide (7.376g, 100.9mmol, 8mL), stirred for 30 minutes, quenched by adding 50mL of saturated ammonium chloride solution, then warmed up to room temperature, separated, the aqueous phase was extracted with ethyl acetate (100mL×3), and the organic phase, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 14c (2.7 g, yield: 13.0%).

MS m/z (ESI): 311.1 [M+1].

third step

(6-Bromo-2-fluoro-3-((4-methylpyrimidin-2-yl)oxy)phenyl)methanol 14d

Compound 14c (6 g, 19.28 mmol) was dissolved in a mixed solvent of tetrahydrofuran and methanol (V/V=1/1), sodium borohydride (730 mg, 19.29 mmol) was added, and the reaction was stirred for 1 hour. Add 20 mL of saturated ammonium chloride solution to quench, concentrate under reduced pressure, add 30 mL of water to the residue, and extract with dichloromethane (50 mL×3), combine the organic phases, filter, and concentrate the filtrate under reduced pressure, and the residue is chromatographed on a silica gel column. Purification with eluent system B afforded the target compound 14d (2.65 g, yield: 43.8%).

MS m/z (ESI): 313.1 [M+1].

the fourth step

Benzyl 6-bromo-2-fluoro-3-((4-methylpyrimidin-2-yl)oxy)methylsulfonate 14e

Dissolve compound 14d (2.65g, 8.46mmol) in 60mL of dichloromethane, add triethylamine (1.31g, 12.9mmol, 1.8mL), cool to 0°C, add methanesulfonic anhydride (1.8g, 10.33mmol), The reaction was stirred for 2 hours. After adding 30mL of saturated sodium bicarbonate solution, the layers were separated, the aqueous phase was extracted with dichloromethane (50mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound 14e (3.655g). Purification was used directly in the next reaction.

MS m/z (ESI): 391.0 [M+1].

the fifth step

(6-Bromo-2-fluoro-3-((4-methylpyrimidin-2-yl)oxy)benzyl)(tert-butoxycarbonyl)carbamate tert-butyl ester 14f

Compound 14e (1.84g, 4.70mmol) was dissolved in 40mL of N,N-dimethylformamide, cesium carbonate (2.07g, 6.35mmol) and tert-butyl N-butoxycarbonylcarbamate (1.23g , 5.66mmol, Shaoyuan Chemical), stirred and reacted for 16 hours. After adding 500mL ethyl acetate to the reaction solution, filter, wash the filtrate with water (60mL×3), wash with saturated sodium chloride solution (40mL×1), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use a silica gel column to Purification by chromatography with eluent system B afforded the target compound 14f (2.122 g, yield: 88.0%).

MS m/z (ESI): 1045.1 [2M+Na].

step six

(tert-butoxycarbonyl)(2-fluoro-3-((4-methylpyrimidin-2-yl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)benzyl)carbamate tert-butyl ester 14g

Under a nitrogen atmosphere, compound 14f (2.12g, 4.13mmol) was dissolved in 50mL 1,4-dioxane, and 4,4,4',4',5,5,5',5'-Octa Methyl-2,2'-bis(1,3,2-dioxaborolane) (1.58g, 6.22mmol), potassium acetate (1.22g, 12.43mmol) and [1,1'-bis(bis(di Phenylphosphino) ferrocene] palladium dichloride (303 mg, 414.1 μmol), heated to 95 ° C for 16 hours, added 50 mL of ethyl acetate and filtered, the filtrate was concentrated under reduced pressure, and the residue was eluted by silica gel column chromatography Reagent system B was purified to obtain the target compound 14g (1.93g, yield: 83.4%).

step seven

(tert-butoxycarbonyl)(6-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-3-((4-methyl Pyrimidin-2-yl)oxy)benzyl)tert-butyl carbamate 14h

Under nitrogen atmosphere, compound 1f (550mg, 1.87mmol), compound 14g (1g, 1.78mmol), potassium carbonate (309mg, 2.23mmol) and tetrakis(triphenylphosphine)palladium (207mg, 179.1μmol) were added to 36mL In a mixed solvent of water and 1,4-dioxane (V/V=1/5), heat to 95°C for 16 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in 50 mL of dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 14h (796 mg, yield : 74.3%).

MS m/z (ESI): 621.3 [M+Na].

eighth step

6-Fluoro-11-methyl-7-((4-methylpyrimidin-2-yl)oxy)-5,11-dihydro-4H-1,3,4,11-tetraazadibenzo [cd,h] azulene 14i

Compound 14h (0.796 g, 1.32 mmol) was dissolved in 20 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 20 mL of acetonitrile, triethylamine (2.916 g, 28.8 mmol, 4 mL) was added, and the mixture was heated to 75° C. for 4 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure, 30 mL of saturated sodium bicarbonate solution was added to the residue, and then extracted with dichloromethane (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 14i (303 mg, yield: 62.9%).

MS m/z (ESI): 363.4 [M+1].

Ninth step

6-Fluoro-10-iodo-11-methyl-7-((4-methylpyrimidin-2-yl)oxy)-5,11-dihydro-4H-1,3,4,11-tetraazole Heterodibenzo[cd,h]azulene 14j

Compound 14i (303 mg, 836.1 μmol) was dissolved in 30 mL of dichloromethane, trifluoroacetic acid (480 mg, 4.21 mmol, 0.32 mL) was added, cooled to 0 °C, and N-iodosuccinimide (282 mg, 1.25 mmol), warming up to room temperature and stirring for 30 minutes, quenched by adding 5mL saturated sodium sulfite solution and 30mL saturated sodium bicarbonate solution, separating the layers, extracting the aqueous phase with dichloromethane (30mL×2), combining the organic phases, anhydrous sodium sulfate After drying and filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 14j (332 mg, yield: 81.3%).

MS m/z (ESI): 489.4 [M+1].

tenth step

Under nitrogen atmosphere, compound 1j (62 mg, 226.9 μmol), compound 14j (100 mg, 204.8 μmol), potassium carbonate (38 mg, 274.9 μmol) and tetrakis(triphenylphosphine) palladium (24 mg, 20.76 μmol) were added to 24 mL In a mixed solvent of water and 1,4-dioxane (V/V=1/5), heat to 95°C for 16 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in 50 mL of dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 14 (46 mg, yield rate: 44.2%).

MS m/z (ESI): 508.1 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.40(s,1H),8.45(d,1H),8.20(s,1H),7.89(d,2H),7.63-7.61(m,1H) ,7.58(d,2H),7.16(d,1H),7.02(t,1H),6.65(d,1H),6.49(dd,1H),6.31(d,1H),5.81(d,1H), 4.47(s,2H), 3.61(s,3H), 2.42(s,3H).

Example 15

2-fluoro-N-(4-(6-fluoro-11-methyl-7-((4-methylpyrimidin-2-yl)oxy)-5,11-dihydro-4H-1,3, 4,11-Tetraazadibenzo[cd,h]azulene-10-yl)phenyl)acrylamide 15

Using the synthetic route of compound 14 in Example 14, replacing compound 1j with compound 3b in the tenth step, the title compound 15 (40 mg) was obtained.

MS m/z (ESI): 526.1 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.54(s,1H),8.45(d,1H),8.20(s,1H),7.96(d,2H),7.64-7.60(m,3H) ,7.18(d,1H),7.02(t,1H),6.64(d,1H),5.76(dd,1H),5.48(dd,1H),4.48-4.47(m,2H),3.61(s,3H ), 2.42(s,3H).

Example 16

N-(4-(6-fluoro-11-methyl-7-((4-methylpyrimidin-2-yl)oxy)-5,11-dihydro-4H-1,3,4,11- Tetraazadibenzo[cd,h]azulene-10-yl)phenyl)methacrylamide 16

Using the synthetic route of compound 14 in Example 14, replacing compound 1j with compound 2a in the tenth step, the title compound 16 (61 mg) was obtained.

MS m/z (ESI): 522.1 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.04(s,1H),8.46(d,1H),8.19(s,1H),7.91(d,2H),7.62(t,1H),7.56 (d,2H),7.16(d,1H),7.02(t,1H),6.66(d,1H),5.85(s,1H),5.57(s,1H),4.47(d,2H),3.60( s,3H), 2.42(s,3H), 1.98(s,3H).

Example 17

N-(4-(7-fluoro-12-methyl-8-((4-methylpyrimidin-2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4, 12-Tetraazabenzo[7,8]octcyclo[1,2,3-cd]inden-11-yl)phenyl)acrylamide 17

first step

2-(6-Bromo-2-fluoro-3-((4-methylpyrimidin-2-yl)oxy)phenyl)acetonitrile 17a

Compound 14e (3.655g, 9.34mmol) was dissolved in 60mL of acetonitrile, then trimethylsilyl cyanide (991mg, 9.98mmol, 1.25mL) was added, and tetrabutylammonium fluoride (10mL, 1M ), stirring and reacting for 2 hours after adding and warming up to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 17a (2.15 g, yield: 71.4%).

MS m/z (ESI): 322.1 [M+1].

second step

(6-Bromo-2-fluoro-3-((4-methylpyrimidin-2-yl)oxy)phenethyl)carbamate tert-butyl ester 17b

Compound 17a (2.15g, 6.67mmol) was dissolved in 60mL of methanol, nickel chloride hexahydrate (790mg, 3.32mmol) and di-tert-butyl dicarbonate (2.185g, 10.01mmol, 2.3mL) were added slowly in batches Sodium borohydride (757 mg, 20.0 mmol) was added and stirred for 30 minutes. Add 20 mL of saturated ammonium chloride solution to quench and concentrate under reduced pressure. After adding 40mL water and 100mL dichloromethane to the residue, separate the liquids, extract the aqueous phase with dichloromethane (50mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purification by chromatography with eluent system B afforded the target compound 17b (1.44 g, yield: 50.6%).

MS m/z (ESI): 426.1 [M+1].

third step

(2-fluoro-3-((4-methylpyrimidin-2-yl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) phenethyl) tert-butyl carbamate 17c

Under nitrogen atmosphere, compound 17b (1.434g, 3.36mmol), potassium acetate (660mg, 6.72mmol), 4,4,4',4',5,5,5',5'-octamethyl-2 , 2'-bis(1,3,2-dioxaborolane) (855mg, 3.36mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (246mg , 336.2μmol) into 50mL 1,4-dioxane, heated to 95°C for 16 hours. The reaction solution was cooled to room temperature and then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 17c (643 mg, yield: 40.3%). MS m/z (ESI): 474.3 [M+1].

the fourth step

(6-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-3-((4-methylpyrimidin-2-yl)oxy Base) phenethyl) tert-butyl carbamate 17d

Under nitrogen atmosphere, compound 1f (400 mg, 1.36 mmol), compound 17c (643 mg, 1.35 mmol), potassium carbonate (235 mg, 1.70 mmol) and tetrakis(triphenylphosphine) palladium (157 mg, 135.8 μmol) were added to 36 mL In a mixed solvent of water and 1,4-dioxane (V/V=1/5), heat to 95°C for 16 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in 50 mL of dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 17d (675 mg, yield : 96.9%).

MS m/z (ESI): 513.2 [M+1].

the fifth step

7-fluoro-12-methyl 8-((4-methylpyrimidin-2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4,12-tetraazabenzo [7,8]octcyclo[1,2,3-cd]indene 17e

Compound 17d (675 mg, 1.31 mmol) was dissolved in 10 mL of dichloromethane, then 3 mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in 15 mL of acetonitrile, triethylamine (2.55 g, 25.2 mmol, 3.5 mL) was added, and the mixture was heated to 80° C. for 4 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. Added 30 mL of saturated sodium bicarbonate solution to the residue and extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 17e (421 mg, yield: 85.0%).

MS m/z (ESI): 377.2 [M+1].

step six

7-Fluoro-11-iodo-12-methyl-8-((4-methylpyrimidin-2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4,12- Tetraazabenzo[7,8]octcyclo[1,2,3-cd]indene 17f

Compound 17e (421mg, 1.11mmol) was dissolved in 30mL of dichloromethane, after cooling to 0°C, trifluoroacetic acid (630mg, 5.52mmol, 420μL) was added, and N-iodosuccinimide (377mg, 1.67 mmol), then warming up to room temperature and stirring for 1 hour. Add 30mL of saturated sodium bicarbonate solution and 5mL of saturated sodium sulfite solution, separate the layers, extract the aqueous phase with dichloromethane (50mL×2), combine the organic phases, and concentrate under reduced pressure to obtain the target compound 17f (606mg), which is used directly without further purification Next reaction.

MS m/z (ESI): 503.1 [M+1].

step seven

Under nitrogen atmosphere, compound 1j (90 mg, 329.5 μmol), compound 17f (150 mg, 298.6 μmol), potassium carbonate (62 mg, 448.6 μmol) and tetrakis(triphenylphosphine) palladium (35 mg, 30.28 μmol) were added to 30 mL In a mixed solvent of water and 1,4-dioxane (V/V=1/5), heat to 95°C for 10 hours to react. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in 50 mL of dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 17 (35 mg, yield : 22.4%).

MS m/z (ESI): 522.2 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.32(s,1H),8.46(d,1H),8.32(s,1H),7.77(d,2H),7.43(d,2H),7.16 (d,1H),6.95(t,1H),6.55(d,1H),6.45(dd,1H),6.29(dd,1H),6.14-6.13(m,1H),5.79(dd,1H), 3.66(s,3H), 3.46(s,2H), 3.18-3.15(m,2H), 2.43(s,3H).

Example 18

2-fluoro-N-(4-(7-fluoro-12-methyl-8-((4-methylpyrimidin-2-yl)oxy)-4,5,6,12-tetrahydro-1, 3,4,12-Tetraazabenzo[7,8]octcyclo[1,2,3-cd]inden-11-yl)phenyl)acrylamide 18

Using the synthetic route of compound 17 in Example 17, replacing compound 1j with compound 3b in the seventh step, the title compound 18 (45 mg) was obtained.

MS m/z (ESI): 540.2 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.46(s,1H),8.46(d,1H),8.32(s,1H),7.84(d,2H),7.46(d,2H),7.18 (d,1H),6.95(t,1H),6.55(d,1H),6.15-6.14(m,1H),5.75(dd,1H),5.46(dd,1H),3.66(s,3H), 3.46(s,2H), 3.18-3.16(m,2H), 2.43(s,3H).

Example 19

2-fluoro-N-(3-fluoro-4-(12-methyl-8-((6-methylpyrimidin-2-yl)oxy)-4,5,6,12-tetrahydro-1, 3,4,12-Tetraazabenzo[7,8]octcyclo[1,2,3-cd]inden-11-yl)phenyl)acrylamide 19

first step

N-(4-bromo-3-fluorophenyl)-2-fluoroacrylamide 19b

4-Bromo-3-fluoroaniline 19a (1 g, 5.26 mmol) was dissolved in 20 mL of N,N-dimethylformamide, and 2-fluoroacrylic acid (710 mg, 7.88 mmol), 2-(7-azo Benzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.0g, 7.89mmol), N,N-diisopropylethylamine (1.36g, 10.52mmol) , stirred for 17 hours. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by CombiFlash with eluent system B to afford the title compound 19b (420 mg, 30.5% yield).

MS m/z (ESI): 262.1 [M-1].

second step

N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-fluoroacrylamide 19c

Under a nitrogen atmosphere, compound 19b (420 mg, 1.60 mmol), pinacol diboronate (610 mg, 2.40 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (II) (176mg, 0.24mmol) and potassium acetate (315mg, 3.21mmol) were added to 20mL 1,4-dioxane, heated to 95°C and stirred for 16 hours. The reaction liquid was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by a CombiFlash rapid preparation apparatus with eluent system B to obtain the title compound 19c (400 mg, yield 80.7%).

MS m/z (ESI): 308.3 [M-1].

third step

Under a nitrogen atmosphere, compound 19c (113 mg, 365.5 μmol), compound 3n (160 mg, 331.0 μmol), cesium fluoride (126 mg, 829.4 μmol) and 1,1'-bis(tert-butylphosphino)ferrocene chloride Palladium chloride (45 mg, 66.0 μmol) was added to 24 mL of a mixed solvent of water and 1,4-dioxane (V/V=1/5), replaced with nitrogen three times, and heated to 95° C. for 16 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in 50 mL of dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 19 (23 mg, yield rate: 12.9%).

MS m/z (ESI): 539.5 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.64(s,1H),8.28(s,1H),7.84(d,1H),7.72(t,1H),7.64(d,1H),7.42 (s,1H),7.12(s,1H),6.99(d,1H),6.73-6.67(m,3H),6.32-6.31(m,1H),5.76(dd,1H),5.50(dd,1H ), 3.60(s,3H), 3.47-3.43(m,2H), 3.07-3.02(m,2H), 2.33(s,3H).

Example 20

11-(6-ethynyl-4-methylpyridin-3-yl)-7-fluoro-12-methyl-8-((4-methylpyrimidin-2-yl)oxy)-4,5, 6,12-Tetrahydro-1,3,4,12-tetraazabenzo[7,8]octcyclo[1,2,3-cd]indene 20

first step

11-(6-((tert-butyldimethylsilyl)ethynyl)-4-methylpyridin-3-yl)-7-fluoro-12-methyl-8-((4-methylpyrimidine- 2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4,12-tetraazabenzo[7,8]octcyclo[1,2,3-cd]indene 20b

Compound 17f (100 mg, 199.09 μmol) and 2-((tert-butyldimethylsilyl)ethynyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3 , 2-dioxaborolan-2-yl)pyridine 20a (85mg, 237.85μmol, prepared by the method disclosed in the example on page 897 of the specification in the patent application "WO2020231990A1"), tetrakis(triphenylphosphine ) Palladium (35 mg, 30.29 μmol) and potassium carbonate (55 mg, 397.96 μmol) were dissolved in 10 mL of 1,4-dioxane and 2 mL of water, heated to 100 ° C under nitrogen protection and stirred for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by a CombiFlash rapid preparation apparatus with eluent system A to obtain the title compound 20b (89 mg, yield 73.8%).

MS m/z (ESI): 606.0 [M+1].

second step

Compound 20b (89 mg, 146.92 μmol) was dissolved in 20 mL of tetrahydrofuran, tetrabutylammonium fluoride (40 mg, 177.64 μmol) was added at 0° C., and stirring was continued for 1 hour. After the reaction, it was concentrated under reduced pressure, and the residue was purified by CombiFlash with eluent system A to obtain the title compound 20 (26 mg, yield 36.0%).

MS m/z (ESI): 492.6 [M+1].

¹ H NMR (500MHz,DMSO-d ₆ )δ8.71-8.67(m,1H),8.51-8.50(s,1H),8.35(s,1H),7.59(s,1H),7.18-7.17(m ,1H),6.99-6.97(m,1H),6.51-6.49(m,1H),6.30(s,1H),4.43(s,1H),3.56(s,3H),3.43-3.41(m,2H ), 3.17-3.08(m,2H), 2.51(s,3H), 2.42(s,3H).

Example 21

10-(6-ethynyl-4-methylpyridin-3-yl)-6-fluoro-11-methyl-7-((4-methylpyrimidin-2-yl)oxy)-5,11- Dihydro-4H-1,3,4,11-tetraazadibenzo[cd,h]azulene 21

Using the synthetic route of Example 20, the compound 17f in the first step was replaced by compound 14j to obtain the title compound 21 (17 mg, yield: 12.4%).

MS m/z (ESI): 478.5 [M+1].

¹ H NMR (500MHz,DMSO-d ₆ )δ8.83(s,1H),8.47-8.45(m,1H),8.23(s,1H),7.74(s,1H),7.70-7.69(m,1H ),7.18-7.16(m,1H),7.08-7.05(m,1H),6.50-6.47(m,1H),4.48-4.46(m,3H),3.50(s,3H),2.41(s,3H ), 2.17(s,3H).

Example 22

11-(6-ethynyl-4-methoxypyridin-3-yl)-12-methyl-8-((6-methylpyridin-2-yl)oxy)-4,5,6,12 -Tetrahydro-1,3,4,12-tetraazabenzo[7,8]octcyclo[1,2,3-cd]indene 22

first step

2,5-Dibromo-4-methoxypyridine 22b

Dissolve 2,5-dibromo-4-iodopyridine 22a (6.60g, 18.24mmol), cuprous iodide (0.34g, 1.82mmol) and sodium methoxide (0.46g, 20.08mmol) in 100mL methanol and heat to reflux 12 hours. Add 50 mL of saturated sodium bicarbonate solution, filter through celite, wash the filter cake with dichloromethane (50 mL×2), and extract the aqueous phase with dichloromethane (120 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (100 mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 22b (3.80 g, yield: 85.0%).

MS m/z (ESI): 265.9 [M+1].

second step

5-Bromo-2-((tert-butyldimethylsilyl)ethynyl)-4-methoxypyridine 22c

Under nitrogen atmosphere, compound 22b (3.80g, 15.11mmol), tert-butylethynyldimethylsilane (2.31g, 16.47mmol) were dissolved in 50mL N,N-dimethylformamide, triethylamine ( 4.56g, 45.23mmol), cuprous iodide (72mg, 3.02mmol) and bis(triphenylphosphine)palladium dichloride (1.06g, 1.51mmol), react at 50°C for 2 hours. Add 100mL of water, extract with ethyl acetate (100mL×3), combine the organic phases, wash the organic phase with saturated sodium chloride solution (100mL×3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use silica gel column chromatography Purified with eluent system B to obtain the title compound 22c (3.60 g, yield: 77.4%). MS m/z (ESI): 326.0 [M+1].

third step

(6-((tert-Butyldimethylsilyl)ethynyl)-4-methoxypyridin-3-yl)boronic acid 22d

Under a nitrogen atmosphere, compound 22c (3.10 g, 9.50 mmol) was dissolved in 50 mL of tetrahydrofuran, cooled to -78 ° C, and n-butyllithium (5.7 mL, 14.25 mmol, 2.5 M n-hexane solution) was added dropwise, and stirred for 0.5 hours , then added tributyl borate (4.37g, 19mmol), returned to room temperature for 0.5 hours, and added 40mL of methanol to quench. The system was concentrated under reduced pressure and directly purified by high performance liquid chromatography to obtain the title compound 22d (906 mg, yield: 34.5%).

MS m/z (ESI): 292.1 [M+1].

¹ H NMR (400MHz, CDCl ₃ ): δ8.83(s, 1H), 6.97(s, 1H), 3.98(s, 3H), 1.01(s, 9H), 0.22(s, 6H).

the fourth step

11-(6-((tert-butyldimethylsilyl)ethynyl)-4-methoxypyridin-3-yl)-12-methyl-8-((6-methylpyridin-2-yl )oxy)-4,5,6,12-tetrahydro-1,3,4,12-tetraazabenzo[7,8]octcyclo[1,2,3-cd]indene 22e

Compound 3n (200 mg, 413.82 μmol), compound 22d (133 mg, 4556.69 μmol), tetrakis(triphenylphosphine)palladium (72 mg, 62.31 μmol) and potassium carbonate (115 mg, 832.09 μmol) were dissolved in 20 mL under nitrogen atmosphere 1,4-Dioxane and 4 mL of water were stirred at 100°C for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by a CombiFlash rapid prep apparatus with eluent system A to obtain the title compound 22e (200 mg, yield 80.1%).

MS m/z (ESI): 603.2 [M+1].

the fifth step

Compound 22e (200 mg, 331.78 μmol) was dissolved in 20 mL of tetrahydrofuran, tetrabutylammonium fluoride (90 mg, 399.69 μmol) was added at 0° C., and stirring was continued for 1 hour. After the reaction, it was concentrated under reduced pressure, and the residue was purified by CombiFlash with eluent system A to obtain the title compound 22 (36 mg, yield 22.2%).

MS m/z (ESI): 489.4 [M+1].

¹ H NMR (500MHz, CDCl3) δ8.48(s,1H),8.22(s,1H),7.53(s,1H),7.14-7.08(m,2H),6.98-6.88(m,1H),6.75 -6.71(m,2H),6.65-6.60(m,1H),4.69(s,1H),3.86(s,3H),3.68(s,3H),3.67-3.52(m,2H),3.25-3.21 (m,2H), 2.47(s,3H).

Example 23

2-fluoro-N-(4-(12-methyl-8-((4-methylpyrimidin-2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4, 12-Tetraazabenzo[7,8]octcyclo[1,2,3-cd]inden-11-yl)phenyl)acrylamide 23

first step

(2-Bromo-5-((4-methylpyrimidin-2-yl)oxy)phenyl)methanol 23b

Potassium hydroxide (1.28g, 19.39mmol, 85% purity) was dissolved in 1.2mL of water, 50mL of dimethyl sulfoxide was added, and then 4-bromo-3-(hydroxymethyl)phenol 23a (3.583g, 17.64mmol, Prepared by the method disclosed on page 88 of the patent application "US2015291629A1", and finally added 2-chloro-4-methylpyrimidine (2.269g, 17.64mmol), heated to 110°C and stirred for 3 hours. After adding 500 mL of ethyl acetate, wash with water (100 mL×3), wash with saturated aqueous sodium chloride solution (80 mL×1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is subjected to silica gel column chromatography with eluent system B Purification afforded the target compound 23b (3.5 g, yield: 67.2%).

second step

Benzyl 2-bromo-5-((4-methylpyrimidin-2-yl)oxy)methanesulfonate 23c

Dissolve compound 23b (3.5g, 11.85mmol) in 150mL of dichloromethane, add methanesulfonic anhydride (2.5g, 14.35mmol) and triethylamine (1.822g, 18.0mmol, 2.5mL) after cooling to 0°C, stir React for 2 hours. Add 50mL saturated sodium bicarbonate solution, separate the layers, extract the aqueous phase with dichloromethane (50mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and elute the residue with silica gel column chromatography Reagent system B was purified to obtain the target compound 23c (4.88g), which was directly used in the next reaction without further purification.

MS m/z (ESI): 373.0 [M+1].

third step

2-(2-Bromo-5-((4-methylpyrimidin-2-yl)oxy)phenyl)acetonitrile 23d

Compound 23c (4.88g, 13.07mmol) was dissolved in 80mL of acetonitrile, trimethylsilyl cyanide (1.5g, 15.12mmol, 1.9mL) was added, cooled to 0°C, and tetrabutylammonium fluoride (15.2mL, 1M), after the addition, the mixture was warmed up to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 23d (3.2 g, yield: 80.4%).

the fourth step

(2-Bromo-5-((4-methylpyrimidin-2-yl)oxy)phenethyl)carbamate tert-butyl ester 23e

Compound 23d (3.2g, 10.52mmol) was dissolved in 60mL of methanol, nickel chloride hexahydrate (1.56g, 5.26mmol) and di-tert-butyl dicarbonate (3.42g, 15.67mmol, 3.6mL) were added, and slowly Sodium borohydride (995mg, 26.3mmol) was added, and the reaction was stirred for 1 hour after the addition. Add 20 mL of saturated ammonium chloride aqueous solution to quench, and concentrate the reaction solution under reduced pressure. Add 20 mL of water and 50 mL of ethyl acetate to the residue, separate the layers, extract the aqueous phase with ethyl acetate (50 mL×2), combine the organic phases, and remove Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography with eluent system B to obtain the target compound 23e (2.25 g, yield: 52.3%).

MS m/z (ESI): 407.8 [M+1].

the fifth step

(5-((4-methylpyrimidin-2-yl)oxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) phenethyl) tert-butyl carbamate 23f

Under nitrogen atmosphere, compound 23e (2.25g, 5.51mmol) was dissolved in 60mL 1,4-dioxane, and biboronic acid pinacol ester (1.75g, 6.89mmol), potassium acetate (1.35g, 13.75 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (403mg, 550.7μmol), heated to 95°C for 16 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 23f (2.464 g, yield: 98.1%).

MS m/z (ESI): 456.0 [M+1].

step six

(2-(4-Chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-((4-methylpyrimidin-2-yl)oxy)phenethyl base) tert-butyl carbamate 23g

Under nitrogen atmosphere, compound 1f (1.59g, 5.41mmol), compound 23f (2.464g, 5.41mmol), potassium carbonate (1.12g, 8.10mmol) and tetrakis(triphenylphosphine)palladium (625mg, 540.8μmol) Add it into a mixed solvent of 60 mL of water and 1,4-dioxane (V/V=1/5), and heat to 95° C. for 16 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain 23g of the target compound (2.02g, yield : 75.4%).

MS m/z (ESI): 495.1 [M+1].

step seven

12-methyl-8-((4-methylpyrimidin-2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4,12-tetraazabenzo[7, 8]octcyclo[1,2,3-cd]indene 23h

Compound 23g (2.05g, 4.14mmol) was dissolved in 20mL of dichloromethane, 5mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction liquid was concentrated under reduced pressure, and the residue was dissolved in 25 mL of acetonitrile, then triethylamine (8.38 g, 82.81 mmol, 11.5 mL) was added, and heated to 85° C. for 5 hours. The reaction solution was cooled to room temperature and filtered, and the filter cake was washed with a small amount of acetonitrile to obtain the target compound 23h (554 mg, yield: 37.3%). MS m/z (ESI): 359.2 [M+1].

eighth step

11-iodo-12-methyl-8-((4-methylpyrimidin-2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4,12-tetraazabenzene And[7,8]octcyclo[1,2,3-cd]indene 23i

Dissolve compound 23h (554mg, 1.54mmol) in 60mL of dichloromethane, add trifluoroacetic acid (870mg, 7.63mmol, 0.58mL), cool to 0°C, add N-iodosuccinimide (470mg, 2.08 mmol), stirred and reacted for 1 hour after being warmed up to room temperature. Add 20 mL of saturated sodium bicarbonate solution and 2 mL of saturated sodium sulfite solution, separate the layers, extract the aqueous phase with dichloromethane (40 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target compound 23i ( 792 mg), which was directly used in the next reaction without further purification.

MS m/z (ESI): 485.0 [M+1].

Ninth step

Under nitrogen atmosphere, compound 3b (99 mg, 340.0 μmol), compound 23i (150 mg, 309.7 μmol), potassium carbonate (64 mg, 463.0 μmol) and tetrakis(triphenylphosphine) palladium (36 mg, 31.15 μmol) were added to 30 mL In a mixed solvent of water and 1,4-dioxane (V/V=1/5), heat to 95°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 23 (85 mg, yield: 52.6%).

MS m/z (ESI): 522.8 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.44(s,1H),8.44(d,1H),8.28(s,1H),7.83(d,2H),7.41(d,2H),7.20 (s,1H),7.12(d,1H),6.76-6.69(m,2H),6.15(s,1H),5.74(dd,1H),5.46(dd,1H),3.65(s,3H), 3.48(s,2H), 3.09(s,2H), 2.40(s,3H).

Example 24

11-(6-ethynyl-4-methylpyridin-3-yl)-12-methyl-8-((4-methylpyrimidin-2-yl)oxy)-4,5,6,12- Tetrahydro-1,3,4,12-tetraazabenzo[7,8]octcyclo[1,2,3-cd]indene24

Using the synthetic route of Example 20, replacing compound 17f in the first step with compound 23i, and replacing compound 20a in the first step with compound 22d, the title compound 24 (30 mg, yield: 29.8%) was prepared.

MS m/z (ESI): 490.5 [M+1].

¹ H NMR (500MHz,DMSO-d ₆ )δ8.45-8.44(m,1H),8.27(s,1H),8.13(br,1H),7.44(s,1H),7.19(s,1H), 7.13-7.12(m,1H),6.77-6.75(m,1H),6.64-6.62(m,1H),6.31(s,1H), 4.45(s,1H),3.90(s,3H),3.59- 3.54 (m, 4H), 3.35-3.30 (m, 1H), 3.20-3.15 (m, 1H), 2.96-2.93 (m, 1H), 2.40 (s, 3H).

Example 25

N-(4-(12-methyl-8-((4-methylpyrimidin-2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4,12-tetraaza Heterobenzo[7,8]octcyclo[1,2,3-cd]inden-11-yl)phenyl)acrylamide 25

Using the synthetic route of compound 23 in Example 23, replacing compound 3b with compound 1j in the ninth step, the title compound 25 (100 mg) was obtained.

MS m/z (ESI): 504.5 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.31(s,1H),8.44(d,1H),8.28(s,1H),7.75(d,2H),7.38(d,2H),7.20 (s,1H),7.12(d,1H),6.76-6.70(m,2H),6.48-6.42(m,1H),6.30-6.26(m,1H),6.13(s,1H),5.80-5.77 (m,1H), 3.65(s,3H), 3.47(s,2H), 3.09(s,2H), 2.40(s,3H).

Example 26

2-fluoro-N-(3-fluoro-4-(7-fluoro-12-methyl-8-((4-methylpyrimidin-2-yl)oxy)-4,5,6,12-tetra Hydrogen-1,3,4,12-tetraazabenzo[7,8]octcyclo[1,2,3-cd]inden-11-yl)phenyl)acrylamide 26

Using the synthetic route of compound 19 in Example 19, the third step compound 3n was replaced by compound 17f to obtain the title compound 26 (70 mg).

MS m/z (ESI): 558.7 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.66(s,1H),8.46(d,1H),8.33(s,1H),7.86-7.84(m,1H),7.67-7.66(m, 1H),7.49(s,1H),7.18(d,1H),6.99(t,1H),6.58(d,1H),6.26(s,1H),5.77(dd,1H),5.50(dd,1H ), 3.62(s,3H), 3.47(s,2H), 3.15-3.11(m,2H), 2.43(s,3H).

Example 27

N-(2-fluoro-4-(7-fluoro-12-methyl-8-((4-methylpyrimidin-2-yl)oxy)-4,5,6,12-tetrahydro-1, 3,4,12-Tetraazabenzo[7,8]octcyclo[1,2,3-cd]inden-11-yl)phenyl)acrylamide 27

first step

N-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide 27b

2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 27a (2.0 g, 8.43 mmol) was dissolved in 50 mL di Add triethylamine (2.56g, 25.30mmol) to methyl chloride, cool to 0°C, dropwise add acryloyl chloride (763mg, 8.43mmol), and stir at room temperature for 2 hours. After adding 10 mL of saturated sodium bicarbonate solution, the liquids were separated, the aqueous phase was extracted with dichloromethane (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with a CombiFlash Removal of reagent system B was purified to obtain the target compound 27b (2.2 g, yield: 89.6%).

MS m/z (ESI): 292.1 [M+1].

second step

The title compound 27 (5 mg, yield; 4.7%) was obtained by using the synthesis route of the seventh step in Example 17, replacing compound 1j with compound 27b.

MS m/z (ESI): 540.3 [M+1].

¹ H NMR (500MHz, CDCl ₃ )δ8.61-8.55(m,1H),8.48-8.45(m,1H),8.37-8.35(m,1H),7.64(s,1H),7.28-7.23(m ,1H),7.12-7.09(m,1H),6.93-6.88(m,2H),6.61-6.59(m,1H),6.52-6.48(m,1H),6.36-6.33(m,1H),5.87 -5.85 (m, 1H), 4.64 (s, 1H), 3.78 (s, 3H), 3.69-3.65 (m, 2H), 3.32-3.30 (m, 2H), 2.51 (s, 3H).

Example 28

11-(2-ethynyl-4-methylpyrimidin-5-yl)-12-methyl-8-((6-methylpyridin-2-yl)oxy)-4,5,6,12- Tetrahydro-1,3,4,12-tetraazabenzo[7,8]octcyclo[1,2,3-cd]indene28

first step

5-Bromo-2-((tert-butyldimethylsilyl)ethynyl)-4-methylpyrimidine 28b

Under nitrogen atmosphere, 5-bromo-2-chloro-4-methylpyrimidine 28a (4.00g, 19.28mmol), tert-butylethynyldimethylsilane (2.71g, 19.28mmol) were dissolved in 120mL N,N- Dimethylformamide, add triethylamine (5.84g, 57.85mmol), cuprous iodide (735mg, 3.86mmol) and bis(triphenylphosphine)palladium dichloride (2.03g, 2.89mmol), 80°C React for 17 hours. Add 250 mL of water, extract with ethyl acetate (180 mL×3), combine the organic phases, wash the organic phase with saturated sodium chloride solution (100 mL×3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use CombiFlash Purification by flash prep with eluent system B afforded the title compound 28b (3.97 g, yield: 66.2%).

MS m/z (ESI): 311.0 [M+1].

second step

2-((tert-Butyldimethylsilyl)ethynyl)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) pyrimidine 28c

Under nitrogen atmosphere, compound 28b (1.77g, 5.70mmol), pinacol diboronate (2.60g, 10.25mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium ( II) (834mg, 1.14mmol) and potassium acetate (1.68g, 17.10mmol) were added to 100mL 1,4-dioxane, heated to 85°C and stirred for 17 hours. The reaction liquid was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a crude product. The residue was purified by CombiFlash with eluent system B to obtain the title compound 28c (645 mg, yield 31.6%).

MS m/z (ESI): 358.9 [M+1].

third step

11-(2-((tert-butyldimethylsilyl)ethynyl)-4-methylpyrimidin-5-yl)-12-methyl-8-((6-methylpyridin-2-yl) Oxy)-4,5,6,12-tetrahydro-1,3,4,12-tetraazabenzo[7,8]octcyclo[1,2,3-cd]indene 28d

Under nitrogen atmosphere, compound 3n (647mg, 1.34mmol), compound 28c (400mg, 1.12mmol), 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (107mg, 0.22mmol ), Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl) Benzene)] palladium (176mg, 0.11mmol) and sodium carbonate (355mg, 3.35mmol) were dissolved in 30mL of 1,4-dioxane and 6mL of water, and stirred at 100°C for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by a CombiFlash rapid prep apparatus with eluent system A to obtain the title compound 28d (60 mg, yield 9.2%).

MS m/z (ESI): 588.2 [M+1].

the fourth step

Compound 28d (60 mg, 102.08 μmol) was dissolved in 10 mL of tetrahydrofuran, tetrabutylammonium fluoride (28 mg, 122.13 μmol) was added at 0° C., and stirring was continued for 1 hour. After the reaction, it was concentrated under reduced pressure, and the residue was purified by CombiFlash with eluent system A to obtain the title compound 28 (15 mg, yield 31.0%).

MS m/z (ESI): 474.1 [M+1].

¹ H NMR (500MHz,DMSO-d ₆ )δ8.94(br,1H),8.30(s,1H),7.74-7.70(m,1H),7.15(s,1H),7.00-6.99(m,1H ),6.75-6.70(m,2H),6.62-6.60(m,1H),6.50(s,1H),4.48(s,1H),3.61(s,3H),3.38-3.35(m,2H), 3.09-3.01(m,2H), 2.32(s,3H), 2.01(s,3H).

Example 29

N-(4-(7-fluoro-12-methyl-8-((6-methylpyridin-2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4, 12-Tetraazabenzo[7,8]octcyclo[1,2,3-cd]inden-11-yl)phenyl)acrylamide 29

first step

6-Bromo-2-fluoro-3-(methoxymethoxy)benzaldehyde 29b

4-Bromo-2-fluoro-1-(methoxymethoxy)benzene 29a (43.94g, 186.9mmol, using the method disclosed in the document "Journal of Medicinal Chemistry, 2008, 51(18), 5502-5505" prepared) was dissolved in 350mL tetrahydrofuran, cooled to -78°C, lithium diisopropylamide (108mL, 2M) was added dropwise, stirred for 30 minutes, and N,N-dimethylformamide (18.44g , 252.2mmol, 20mL), stirred for 30 minutes. Add 100mL of saturated ammonium chloride aqueous solution to quench, warm up to room temperature, separate the layers, extract the aqueous phase with ethyl acetate (150mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purified by silica gel column chromatography with eluent system B to obtain the target compound 29b (40.3 g, yield: 81.9%).

second step

4-Bromo-2-fluoro-3-(hydroxymethyl)phenol 29c

Compound 29b (40.3 g, 153.1 mmol) was dissolved in 370 mL of a mixed solvent of methanol and tetrahydrofuran (V/V=12/25), sodium borohydride (4.4 g, 116.3 mmol) was slowly added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, 150 mL of 4M hydrochloric acid was added to the residue, and the reaction was stirred for 3 hours. After filtering, the filter cake was washed with water and dried; the filtrate was extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, combined with the filter cake and dried to obtain the target compound 29c (35 g), which was directly used in the next reaction without further purification.

third step

(6-Bromo-2-fluoro-3-((6-methylpyridin-2-yl)oxy)phenyl)methanol 29d

Under nitrogen atmosphere, 6-bromo-2-picoline (32.5 g, 188.9 mmol), cesium carbonate (49.2 g, 151.0 mmol), compound 29c (27.8 g, 125.7 mmol) were added to 80 mL of dimethylsulfoxide , heated to 175°C for 5 hours. After cooling the reaction solution to room temperature, 800 mL of ethyl acetate was added and filtered, the filtrate was washed with water (150 mL×3), washed with saturated aqueous sodium chloride solution (100 mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue Purified by silica gel column chromatography with eluent system B to obtain the target compound 29d (19.05 g, yield: 48.5%).

MS m/z (ESI): 312.0 [M+1].

the fourth step

Benzyl 6-bromo-2-fluoro-3-((6-methylpyridin-2-yl)oxy)methylsulfonate 29e

Compound 29d (19.05g, 61.03mmol) was dissolved in 150mL of dichloromethane, cooled to 0°C, methanesulfonic anhydride (14.35g, 82.37mmol) and triethylamine (10.46g, 103.3mmol, 14.3mL) were added, stirred React for 2 hours. Add 100mL saturated aqueous sodium bicarbonate solution to quench, separate the layers, extract the aqueous phase with dichloromethane (60mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target compound 29e (26.18g) , which can be directly used in the next reaction without further purification.

MS m/z (ESI): 390.2 [M+1].

the fifth step

2-(6-Bromo-2-fluoro-3-((6-methylpyridin-2-yl)oxy)phenyl)acetonitrile 29f

Compound 29e (26.18g, 67.08mmol) was dissolved in 250mL acetonitrile, cooled to 0°C, and trimethylsilyl cyanide (7.93g, 79.93mmol, 10mL) and tetrabutylammonium fluoride (80.5mL, 1M) were added slowly in sequence , stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 29f (18.67 g, yield: 67.1%).

MS m/z (ESI): 321.2 [M+1].

step six

(6-Bromo-2-fluoro-3-((6-methylpyridin-2-yl)oxy)phenethyl)carbamate tert-butyl ester 29g

Compound 29f (21 g, 65.39 mmol) was dissolved in 50 mL of tetrahydrofuran, borane tetrahydrofuran complex (196 mL, 1M) was added, and heated to 60° C. for 2.5 hours. After cooling the reaction liquid to room temperature, slowly add methanol, then add 50 mL of 2M hydrochloric acid, and heat to 60° C. for 1 hour to react. The reaction solution was cooled to room temperature, 125 mL of 2M sodium hydroxide solution was added, and di-tert-butyl dicarbonate (21.375 g, 97.93 mmol, 22.5 mL) was added, and the reaction was stirred for 15 minutes. After adding 50 mL of saturated sodium chloride solution, the liquids were separated, the aqueous phase was extracted with ethyl acetate (150 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was eluted by silica gel column chromatography. Reagent system B was purified to obtain 29 g of the target compound (18.67 g, yield: 67.1%).

MS m/z (ESI): 425.2 [M+1].

step seven

(2-fluoro-3-((6-methylpyridin-2-yl)oxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) phenethyl) tert-butyl carbamate 29h

Under nitrogen atmosphere, compound 29g (18.67g, 43.89mmol), bipinacol borate (16.72g, 65.84mmol), potassium acetate (12.92g, 131.6mmol), [1,1'-bis(di Phenylphosphino)ferrocene]palladium dichloride (4.82g, 6.58mmol) was added to 250mL 1,4-dioxane, heated to 95°C for 48 hours. The reaction solution was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 29h (9.75 g, yield: 47.0%).

MS m/z (ESI): 473.3 [M+1].

eighth step

(6-(4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-fluoro-3-((6-methylpyridin-2-yl)oxy Base) phenethyl) tert-butyl carbamate 29i

Under nitrogen atmosphere, compound 1f (6.36g, 21.67mmol), compound 29h (9.75g, 20.64mmol), potassium carbonate (4.28g, 30.96mmol) and tetrakis (triphenylphosphine) palladium (2.4g, 2.07mmol ) into a mixed solvent of 240 mL of water and 1,4-dioxane (V/V=1/5), and heated to 95° C. for 68 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved by adding 200 mL of dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the target compound 29i (10.39 g, Yield: 98.3%).

MS m/z (ESI): 512.2 [M+1].

Ninth step

7-Fluoro-12-methyl-8-((6-methylpyridin-2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4,12-tetraazabenzene And[7,8]octcyclo[1,2,3-cd]indene 29j

Compound 29i (10.39 g, 20.29 mmol) was dissolved in 50 mL of dichloromethane, 20 mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 150 mL of acetonitrile, triethylamine (25.515 g, 252.1 mmol, 35 mL) was added, and the mixture was heated to 85°C for 5 hours. The reaction solution was concentrated under reduced pressure, 30 mL of acetonitrile was added to the residue and filtered, the filter cake was washed with a small amount of acetonitrile and dried to obtain the target compound 29j (5.479 g, yield: 71.9%).

MS m/z (ESI): 376.3 [M+1].

tenth step

7-Fluoro-11-iodo-12-methyl-8-((6-methylpyridin-2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4,12- Tetraazabenzo[7,8]octcyclo[1,2,3-cd]indene 29k

Compound 29j (1.1g, 2.93mmol) was dissolved in 100mL of dichloromethane, trifluoroacetic acid (1.588g, 13.92mmol, 1.05mL) was added, cooled to 0°C, and N-iodosuccinimide ( 857mg, 3.80mmol), warmed up to room temperature and reacted for 1 hour. Add 50 mL of saturated sodium bicarbonate solution and 10 mL of saturated sodium sulfite solution to quench, separate the layers, extract the aqueous phase with dichloromethane (50 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target compound 29k (1.3 g, yield: 88.5%).

MS m/z (ESI): 502.3 [M+1].

Eleventh step

Under nitrogen atmosphere, compound 1j (106 mg, 388.0 μmol), compound 29k (162 mg, 323.1 μmol), potassium carbonate (67 mg, 484.7 μmol) and tetrakis(triphenylphosphine) palladium (37 mg, 32.0 μmol) were added to 30 mL In a mixed solvent of water and 1,4-dioxane (V/V=1/5), heat to 95°C to react overnight. After the reaction was cooled to room temperature and concentrated under reduced pressure, 100 mL of dichloromethane was added to the residue to dissolve and then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 29 (65 mg, yield : 38.6%). MS m/z (ESI): 521.5 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.31(s,1H),8.31(d,1H),7.77-7.71(m,3H),7.41(d,2H),6.98(d,1H) ,6.86(t,1H),6.80(d,1H),6.53(d,1H),6.48-6.43(m,1H),6.28(d,1H),6.15(s,1H),5.79(d,1H ), 3.67(s,3H), 3.47(s,2H), 3.18-3.15(m,2H), 2.30(s,3H).

Example 30

2-fluoro-N-(4-(7-fluoro-12-methyl-8-((6-methylpyridin-2-yl)oxy)-4,5,6,12-tetrahydro-1, 3,4,12-Tetraazabenzo[7,8]octcyclo[1,2,3-cd]inden-11-yl)phenyl)acrylamide 30

Under nitrogen atmosphere, compound 3b (113 mg, 388.1 μmol), compound 29k (162 mg, 323.1 μmol), potassium carbonate (67 mg, 484.7 μmol) and tetrakis(triphenylphosphine) palladium (37 mg, 32.0 μmol) were added to 30 mL In a mixed solvent of water and 1,4-dioxane (V/V=1/5), heat to 95°C to react overnight. After the reaction was cooled to room temperature and concentrated under reduced pressure, 100 mL of dichloromethane was added to the residue to dissolve and then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the target compound 30 (120 mg, yield : 69.0%).

MS m/z (ESI): 539.5 [M+1].

¹ H NMR (500MHz,DMSO-d ₆ ):δ10.45(s,1H),8.31(s,1H),7.85-7.83(m,2H),7.74-7.71(m,1H),7.44-7.43( m,2H),6.99-6.98(m,1H),6.86-6.85(m,1H),6.81-6.80(m,1H),6.53-6.51(m,1H),6.16(s,1H),5.79- 5.70 (m, 1H), 5.48-5.44 (m, 1H), 3.67 (s, 3H), 3.50-3.44 (m, 2H), 3.18-3.16 (m, 2H), 2.30 (s, 3H).

Example 31

11-(6-ethynyl-4-methylpyridin-3-yl)-7-fluoro-12-methyl-8-((6-methylpyridin-2-yl)oxy)-4,5, 6,12-tetrahydro-1,3,4,12-tetraazabenzo[7,8]octcyclo[1,2,3-cd]indene31

first step

11-(6-((tert-butyldimethylsilyl)ethynyl)-4-methylpyridin-3-yl)-7-fluoro-12-methyl-8-((6-methylpyridine- 2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4,12-tetraazabenzo[7,8]octcyclo[1,2,3-cd]indene 31a

Under nitrogen atmosphere, compound 29k (155 mg, 309.2 μmol), 2-((tert-butyldimethylsilyl)ethynyl)-4-methyl-5-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)pyridine 9a (133 mg, 372.2 μmol, prepared by the method disclosed on page 897 of the specification of the patent application "WO2020231990A1"), potassium carbonate (64 mg, 463.1 μmol) and tetrakis (triphenylphosphine) palladium 36 mg, 31.2 μmol) were added to 30 mL of water and 1,4-dioxane (V/V = 1/5) mixed solvent, heated to 100 ° C to react 17 Hour. After cooling the reaction solution to room temperature, it was filtered and concentrated under reduced pressure to obtain the target compound 31a (187 mg, yield: 100%), which was directly used in the next reaction without purification.

second step

Compound 31a (187 mg, 309.2 μmol) was dissolved in 15 mL of tetrahydrofuran, cooled to 0° C., tetrabutylammonium fluoride (112 mg, 497.4 μmol) was added, and the temperature was raised to room temperature for 1 hour. Add 50mL water to the reaction solution, extract with ethyl acetate (30mL×3), combine the organic phases and concentrate under reduced pressure, and directly use high performance liquid chromatography (Boston Phlex C18 150*30mm, 5 μm, elution system: water (10mmol Ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30mL/min) was purified and isolated to obtain the target compound 31 (25mg, yield: 16.5%).

MS m/z (ESI): 491.1 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ8.65(s,1H),8.34(s,1H),7.75-7.72(m,1H),7.56(s,1H),7.00-6.98(m, 1H),6.91-6.87(m,1H),6.83-6.81(m,1H),6.47-6.46(m,1H),6.33(s,1H),4.43(s,1H),3.56-3.40(m, 5H), 3.17-3.07(m, 2H), 2.29(s, 3H), 1.96(s, 3H).

Example 32

N-(4-(7-fluoro-12-methyl-8-((4-methylpyrimidin-2-yl)oxy)-4,5,6,12-tetrahydro-1,3,4, 12-Tetraazabenzo[7,8]octcyclo[1,2,3-cd]inden-11-yl)phenyl)methacrylamide 32

Under nitrogen atmosphere, compound 2a (138 mg, 480.6 μmol), compound 17f (200 mg, 398.2 μmol), potassium carbonate (100 mg, 723.6 μmol) and tetrakis(triphenylphosphine) palladium (56 mg, 48.5 μmol) were added to 30 mL In a mixed solvent of water and 1,4-dioxane (V/V=1/5), heat to 95°C to react overnight. After the reaction was cooled to room temperature, it was concentrated under reduced pressure, and 100 mL of dichloromethane was added to the residue to dissolve and then filtered. 10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL/min) was purified and isolated to obtain the title compound 32 (78 mg, yield: 36.4%).

MS m/z (ESI): 536.4 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ9.97(s,1H),8.47-8.46(m,1H),8.32(s,1H),7.81-7.79(m,2H),7.41-7.40( m,2H),7.17-7.16(m,1H),6.97-6.93(m,1H),6.57-6.55(m,1H),6.13(s,1H),5.82(s,1H),5.54(s, 1H), 3.66(s,3H), 3.50-3.40(m,2H), 3.18-3.16(m,2H), 2.43(s,3H), 1.96(s,3H).

Example 33

N-(3-fluoro-4-(7-fluoro-12-methyl-8-((6-methylpyridin-2-yl)oxy)-4,5,6,12-tetrahydro-1, 3,4,12)-Tetraazabenzo[7,8]octcyclo[1,2,3-cd]inden-11-yl)phenyl)methacrylamide 33

first step

N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide 33b

3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 33a (2.0 g, 8.44 mmol) was added to 30 mL di Triethylamine (1.71 g, 16.90 mmol) was added to methyl chloride, methacryloyl chloride (970 mg, 9.28 mmol) was added dropwise under ice cooling, and the reaction was stirred at room temperature for 2 hours. After adding 30 mL of saturated sodium bicarbonate, the liquids were separated, the aqueous phase was extracted with dichloromethane (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography with eluent System B was purified to obtain the target compound 33b (2.20 g, yield: 85.5%).

MS m/z (ESI): 306.1 [M+1].

second step

Under nitrogen atmosphere, compound 33b (67 mg, 219.4 μmol), compound 29k (100 mg, 199.5 μmol), potassium carbonate (55 mg, 399.0 μmol) and tetrakis(triphenylphosphine) palladium (35 mg, 30.0 μmol) were added to 24 mL In a mixed solvent of water and 1,4-dioxane (V/V=1/5), heat to 100°C to react overnight. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and then filtered. Ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30mL/min) was purified and isolated to obtain the title compound 33 (30mg, yield: 27.2%).

MS m/z (ESI): 553.6 [M+1].

¹ H NMR(500MHz,DMSO-d ₆ ):δ10.15(s,1H),8.32(s,1H),7.83-7.81(m,1H),7.72(t,1H),7.58-7.56(m, 1H),7.43-7.30(m,1H),6.98(d,1H),6.92-6.89(m,1H),6.81-6.79(m,1H),6.57-6.55(m,1H),6.28(s, 1H),5.83(s,1H),5.58(s,1H),3.61(s,3H),3.55-3.40(m,2H),3.15-3.12(m,2H),2.29(s,3H),1.95 (s,3H).

Example 34

N-(3-fluoro-4-(7-fluoro-12-methyl-8-((4-methylpyrimidin-2-yl)oxy)-4,5,6,12-tetrahydro-1, 3,4,12)-tetraazabenzo[7,8]octcyclo[1,2,3-cd]inden-11-yl)phenyl)methacrylamide 34

Under nitrogen atmosphere, compound 33b (64 mg, 211.0 μmol), compound 17f (106 mg, 211.0 μmol), sodium carbonate (45 mg, 422.1 μmol) and tetrakis(triphenylphosphine) palladium (49 mg, 42.2 μmol) were added to 30 mL In a mixed solvent of water and 1,4-dioxane (V/V=1/5), heat to 100°C to react overnight. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and then filtered. Ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30mL/min) was purified and isolated to obtain the title compound 34 (41 mg, yield: 35.1%).

MS m/z (ESI): 554.6 [M+1].

¹ H NMR (500MHz, DMSO-d ₆ ): δ10.16(s,1H),8.47-8.46(m,1H),8.32(s,1H),7.84-7.81(m,1H),7.58-7.57( m,1H),7.46-7.30(m,1H),7.17-7.16(m,1H),7.01-6.98(m,1H),6.60-6.58(m,1H),6.24(s,1H),5.83( s,1H),5.58(s,1H),3.61(s,3H),3.50-3.40(m,2H),3.14-3.12(m,2H),2.42(s,3H),1.95(s,3H) .

biological evaluation

The following further describes and explains the present disclosure in combination with test examples, but these test examples are not meant to limit the scope of the present disclosure.

Test Example 1: Inhibition of FGFR1 and FGFR2 Kinases by Compounds of the Disclosure

The FGFR1 and FGFR2 kinase activities of the compounds to be tested were tested by using the mobility shift assay. The test concentration is 1000nM, 3-fold serial dilution, 10 concentrations, repeated hole detection.

1.1 Experimental materials

1.1.1 Reagents and consumables

试剂名称Reagent name	供货商supplier	货号Item No.	批号batch number
FGFR1FGFR1	CarnaCarna	08-13308-133	12CBS-0123K12CBS-0123K
FGFR2FGFR2	CarnaCarna	08-13408-134	13CBS-0735H13CBS-0735H

激酶底物22Kinase substrate 22	GLGL	112393112393	P200403-CL112393P200403-CL112393
DMSODMSO	SigmaSigma	D8418-1LD8418-1L	SHBG3288VSHBG3288V
384孔板384-well plate	CorningCorning	35733573	1261900312619003

1.1.2 Instruments

Centrifuge (manufacturer: Eppendorf, model: 5430)

Microplate reader (manufacturer: Perkin Elmer, model: Caliper EZ ReaderII)

Echo 550 (manufacturer: Labcyte, model: Echo 550)

1.2 Experimental steps

(1) Compounds were diluted with DMSO to a stock concentration of 10 mM. The test concentration of the compound was 1000nM, and a 3-fold serial dilution was performed, and a total of 10 concentrations were set, and the wells were repeated for detection.

(2) 100% DMSO solution diluted to 100-fold final concentration in a 384-well plate. Use a dispenser Echo550 to transfer 250 nL of 100-fold final concentration of the compound to the target plate.

(3) Prepare a 2.5-fold final concentration kinase solution with 1× kinase buffer.

(4) Add 10 μL of 2.5-fold final concentration kinase solution to compound wells and positive control wells; add 10 μL 1× kinase buffer to negative control wells.

(5) Centrifuge at 1000rpm for 30s, shake the reaction plate and incubate at room temperature for 10min.

(6) Prepare a mixed solution of ATP/kinase substrate 22 at 25/15 times final concentration with 1×kinase buffer.

(7) Add 15 μL of the mixed solution of ATP/kinase substrate 22 to start the reaction.

(8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake and mix well, and incubate at room temperature for a corresponding period of time.

(9) Add 30 μL of stop detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, shake and mix well.

(10) Read the conversion rate with a microplate reader.

Table 1 Inhibition of the disclosed compounds on FGFR1 and FGFR2 kinases

Conclusion: The disclosed compound has inhibitory effect on FGFR2.

Test Example 2: Inhibition of FGFR1, FGFR2, FGFR2_V564F, FGFR2_N549H, FGFR3 and FGFR4 Kinases by the Compounds of the Disclosure

The FGFR1, FGFR2, FGFR2_V564F, FGFR2_N549H, FGFR3 and FGFR4 kinase activities of the compounds to be tested were tested using the method of ADP GLO. The highest test concentration of FGFR2, FGFR2_V564F, FGFR2_N549H and FGFR3 was 1000nM, the highest concentration of FGFR1 and FGFR4 was 10μM, 3-fold serial dilution, 9 concentrations, repeated well detection.

2.1 Experimental materials

2.1.1 Reagents and consumables

2.1.2 Instruments

仪器名称equipment name	厂家factory	型号信息model information
离心机centrifuge	Beckman coulterBeckman coulter	Allegra X-12 centrifugeAllegra X-12 centrifuge
酶标仪Microplate reader	BMG LABTECHBMG LABTECH	PHERASTAR HSPHERASTAR HS

2.2 Experimental steps

(1) Prepare 1×kinase buffer solution (40mM Tris, pH=7.5; 20mM MgCl ₂ ; 0.1mg/mL BSA), and add 50 μM final concentration of DTT and 2mM MnCl ₂ ;

(2) Dilute the compound solution with DMSO, 3-fold serial dilution, and set a total of 9 concentration gradients; then take 1.5 μL of the compound and add it to 98.5 μL of kinase buffer;

(3) Prepare a mixed solution of ATP and PolyE4Y1 (Poly(4:1Glu, Tyr)), so that the concentration of ATP and PolyE4Y1 is 6 times the final concentration, and equal volumes are made into a reaction mixture;

(4) Dilute the FGFR1/FGFR2/FGFR2_V564F/FGFR2_N549H/FGFR3/FGFR4 kinase solution to a final concentration of 3 times with the kinase buffer;

(5) Take a 96-well plate or a 384-well plate, add 2 μL of diluted compound solution to each well, and centrifuge;

(6) Add 2 μL of kinase solution to each well, centrifuge, shake and mix for 2 minutes, and then incubate at room temperature for 60 minutes;

(7) Add 2 μL/well of the mixture of ATP and PolyE4Y1, centrifuge, shake and mix for 2 minutes, and react at room temperature for 60 minutes;

(8) Add 6 μL/well of ADP GLO stop solution, centrifuge, shake and mix for 2 minutes, and react at room temperature for 40 minutes;

(9) Add 12 μL/well kinase detection reagent, incubate at room temperature for 40 min, and detect the luminescent signal with a microplate reader.

Table 2-1 The inhibitory effect of the disclosed compounds on FGFR1, FGFR2, FGFR3 and FGFR4 kinases

Conclusion: The disclosed compound has inhibitory effect on FGFR2.

Table 2-2 The inhibitory effect of the disclosed compounds on FGFR2_V564F and FGFR2_N549H kinases

Conclusion: The disclosed compound has a good inhibitory effect on FGFR2_V564F and FGFR2_N549H.

Test Example 3: The Compounds of the Disclosure Inhibit the Proliferation of SNU-16 and Li-7 Cells

The inhibitory effect of the compound on the proliferation of SNU-16 and Li-7 cells was detected by CTG method. For SNU-16 and Li-7 cells, the highest concentration of the compound was 1000nM and 10μM, respectively, and a 3-fold serial dilution was performed, and a total of 9 concentrations were set, and repeated wells were tested.

3.1 Experimental materials

3.1.1 Reagents and consumables

材料名称material name	货号Item No.	厂家factory	批号batch number
RPMI-1640培养基RPMI-1640 Medium	22400-08922400-089	GibcoGibco	22766962276696
胎牛血清fetal bovine serum	1009114810091148	GibcoGibco	2152441P2152441P
青霉素&链霉素Penicillin & Streptomycin	15140-12215140-122	GibcoGibco	21998412199841
DPBS(1×)DPBS (1×)	14190-14414190-144	GibcoGibco	21560322156032
0.25％胰蛋白酶-EDTA(1×)0.25% Trypsin-EDTA (1×)	25200-07225200-072	GibcoGibco	21933662193366
CellTiter-GloCellTiter-Glo	G7572G7572	PromegaPromega	00003475550000347555
试剂储备,50mLReagent stock, 50mL	48704870	CorningCorning	3611712236117122
96-孔板,黑色透明底96-well plate, black transparent bottom	36033603	CorningCorning	3311804433118044
96-孔透明圆底聚苯乙烯未处理微孔板，无盖96-well clear round-bottom polystyrene untreated microplates, without lids	37953795	CorningCorning	1241805212418052
检测板,2mLAssay plate, 2mL	39603960	CorningCorning	2501800025018000

3.1.2 Instruments

仪器名称equipment name	厂家factory	型号信息model information
自动细胞计数器Automated Cell Counter	CountstarCountstar	IC1000IC1000
超净工作台Clean bench	ThermoThermo	1300AII1300AII
培养箱incubator	ThermoThermo	I160I160
酶标仪Microplate reader	BMG LABTECHBMG LABTECH	PHERASTAR HSPHERASTAR HS
离心机centrifuge	Beckman coulterBeckman coulter	Allegra X-12 centrifugeAllegra X-12 centrifuge

3.2 Experimental steps

(1) SNU-16 (ATCC cell bank, #CRL-5974) and Li-7 cells (Nanjing Kebai Biotechnology Co., Ltd., #CBP60205) were plated at a density of 1250/well, and 50 μL/well was added to 96-well black-edged cells Culture plate (Corning, #3603), edge wells blocked with 100 μL PBS. Place in a 37°C CO ₂ incubator for 24 hours;

(2) The stock solution of the compound was diluted to 500 μM or 5 mM with DMSO, and then 3-fold serial dilution was performed with DMSO, and a total of 9 concentrations were set, and DMSO was used as a negative control group. Then take 1 μL of the diluted compound and add it to 250 μL RPMI-1640 complete medium to dilute the above compound 250 times;

(3) Take 50 μL of the diluted drug and add it to the cell culture plate, so that the highest concentration of the drug for SNU-16 cells and Li-7 cells is 1000 nM and 10 uM respectively, 3-fold serial dilution, 9 concentrations, repeated hole detection, DMSO The final concentration is 0.2%;

(4) After adding the compound, the cell culture plate was placed in a 37°C _CO2 incubator to continue culturing, SNU-16 was cultured for 3 days, and Li-7 cells were cultured for 6 days;

(5) Add 50 μL of CellTiter-Glo reagent (Promega, #G7572) to each well, shake and mix for 2 minutes on a shaker, then incubate at room temperature for 28 minutes, and detect on a microplate reader after the signal is stable.

Table 3 The compounds disclosed in the present invention have inhibitory effect on the proliferation of SNU-16 and Li-7 cells

Conclusion: Compared with Li-7 cells, the disclosed compound has selective inhibitory effect on SNU-16 cells.

Claims

A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

in:

X is selected from -O-, -S-, -NR 5 - and -C(R a R b )-;

Y 1 , Y 2 and Y 3 are the same or different, and each independently is a nitrogen atom or CR 4 ;

Z 1 , Z 2 , Z 3 and Z 4 are the same or different, and each independently selected from a carbon atom, a nitrogen atom, NR 0 and CR c ;

Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

R is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein each of the alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group is independently any is selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, -NR 8 R 9 , hydroxyl, hydroxyalkyl, cycloalkyl, hetero One or more substituents in ring group, aryl group and heteroaryl group are substituted;

R c is selected from hydrogen atom, alkyl, halogen, cyano, oxo, -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -OR 10 , -S(O) p R 10 , -S(O) p NR 6 R 7 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein all The alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, - NR 8 R 9 , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;

Each R is the same or different, and each independently selected from halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, oxo, -(CR d R e ) r -NR 6 R 7 and -L 2 -R 2 ;

L 1 is selected from chemical bond, -(CR f R g ) r -, -NR 5a -, -O-, -OC(R f R g )-, -C(R f R g )-O-, -C( R f R g )-NR 5a -, -NR 5a -C(R f R g )-, -C(O)-, -OC(O)-, -C(O)-O-, -S(O ) p -, -NR 5a -C(O)-, -C(O)-NR 5a -, -C(O)-NR 5a -C(R f R g )-, -C(R f R g ) -NR 5a -C(O)-, -NR 5a -C(O)-C(R f R g )-, -NR 5a -S(O) 2 -, -S(O) 2 -NR 5a -, Cycloalkylene, heterocyclylene, arylene and heteroarylene, wherein said cycloalkylene, heterocyclylene, arylene and heteroarylene are each independently selected from halogen , oxo, alkyl, haloalkyl, methylene, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, -NR 8 R 9 , hydroxyl and hydroxyalkyl base replaced;

L 2 is selected from chemical bond, -(CR f R g ) r -, -NR 5a -, -O-, -OC(R f R g )-, -C(R f R g )-O-, -C( R f R g )-NR 5a -, -NR 5a -C(R f R g )-, -C(O)-, -OC(O)-, -C(O)-O-, -S(O ) p -, -NR 5a -C(O)-, -C(O)-NR 5a -, -C(O)-NR 5a -C(R f R g )-, -C(R f R g ) -NR 5a -C(O)-, -NR 5a -C(O)-C(R f R g )-, -NR 5a -S(O) 2 -, -S(O) 2 -NR 5a -, Cycloalkylene, heterocyclylene, arylene and heteroarylene, wherein said cycloalkylene, heterocyclylene, arylene and heteroarylene are each independently selected from halogen , oxo, alkyl, haloalkyl, methylene, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, -NR 8 R 9 , hydroxyl and hydroxyalkyl base replaced;

R 2 is selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -C(O)R 10 , -C(O)OR 10 ,
Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, One or more substituents in haloalkyl, methylene, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, -NR 8 R 9 , hydroxyl and hydroxyalkyl;

R 11 , R 12 and R 13 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, -C(O)NR 6 R 7 , -C(O)R 10 , -C(O)OR 10. -C(O)-N(R 5b )-OR 10 , cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, Aryl and heteroaryl are each independently optionally selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -NR 8 R 9 , hydroxyl, hydroxyalkyl, ring One or more substituents in alkyl, heterocyclyl, aryl and heteroaryl;

Or R 11 and R 12 form a cycloalkyl or heterocyclic group together with the connected carbon atoms, wherein each of the cycloalkyl or heterocyclic groups is independently optionally selected from halogen, oxo, alkyl, alkane Oxygen, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;

Or R 12 and R 13 form a cycloalkyl or heterocyclic group together with the connected carbon atoms, wherein each of the cycloalkyl or heterocyclic groups is independently selected from halogen, oxo, alkyl, alkane Oxygen, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;

R a , R b , R d , R e , R f and R g are the same or different, and each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkynyl group, an alkoxy group and Haloalkoxy;

Each R 3 is the same or different, and each independently selected from alkyl, halogen, cyano, oxo, -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 10 , - C(O)OR 10 , -OC(O)R 10 , -OR 10 , -S(O) p R 10 , -S(O) p NR 6 R 7 , cycloalkyl, heterocyclyl, aryl and Heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkane Oxygen, cyano, -NR 8 R 9 , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted by one or more substituents;

R 4 is the same or different at each occurrence, and is each independently selected from a hydrogen atom, an alkyl group, a halogen, a cyano group, -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -OR 10 , -S(O) p R 10 , -S(O) p NR 6 R 7 , cycloalkyl, heterocyclyl, Aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from halogen, oxo, alkyl, haloalkyl, alkoxy One or more substituents in radical, haloalkoxy, cyano, -NR 8 R 9 , hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R 5 , R 5a and R 5b are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group;

R 6 , R 7 , R 8 and R 9 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy ;

Or R 6 and R 7 form a heterocyclic group together with the connected nitrogen atom, wherein the heterocyclic group is optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano One or more substituents in radical, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Or R 8 and R 9 form a heterocyclic group together with the connected nitrogen atom, wherein the heterocyclic group is optionally selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano One or more substituents in radical, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R 10 are the same or different at each occurrence, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein said alkyl group, ring Alkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

p is 0, 1 or 2;

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

r is 0, 1, 2, 3, 4, 5 or 6;

s is 0, 1, 2, 3, 4 or 5; and

t is 0, 1, 2, 3, 4 or 5.
The compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Z 1 is a nitrogen atom, Z 2 is a carbon atom, Z 3 is NR 0 , and Z 4 is a carbon atom, wherein R 0 is as defined in claim 1.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein X is -NR 5 -, wherein R 5 is as defined in claim 1.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein at least one R 1 is -L 2 -R 2 , wherein L 2 and R 2 are as as defined in claim 1.
According to the compound represented by the general formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 4, it is the compound represented by the general formula (II) or its pharmaceutically acceptable salt:

in:

Each R 1a is the same or different, and each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano, oxo and -(CR d R e ) r -NR 6 R 7 ;

s1 is 0, 1, 2, 3 or 4;

Ring A, Ring B, L 1 , L 2 , Y 1 to Y 3 , R 0 , R d , Re , R 2 , R 3 , R 5 to R 7 , r, m and t are as claimed in claim 1 definition.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 5 is a hydrogen atom.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein m is 1 or 2.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein L 2 is a chemical bond or -NR 5a -C(O)-, wherein R 5a is as as defined in claim 1; preferably, L 2 is -NR 5a -C(O)-, wherein R 5a is as defined in claim 1 .
According to the compound represented by the general formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 8, it is the compound represented by the general formula (IIIN) or its pharmaceutically acceptable salt:

in:

Each R 1a is the same or different, and each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano, oxo and -(CR d R e ) r -NR 6 R 7 ;

R 4a and R 4b are the same or different, and each independently selected from hydrogen atom, C 1-6 alkyl, halogen, cyano, -NR 6 R 7 , -C(O)NR 6 R 7 , -C(O )R 10 , -C(O)OR 10 and -OR 10 , wherein the C 1-6 alkyl is optionally selected from halogen, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano Substituted by one or more substituents in group, -NR 8 R 9 , hydroxyl and C 1-6 hydroxyalkyl;

s1 is 0, 1, 2, 3 or 4;

m is 1 or 2;

Ring A, Ring B, L 1 , Y 1 , R 0 , R d , Re , R 2 , R 3 , R 5a , R 6 to R 10 , r and t are as defined in claim 1 .
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein ring A is 6 to 10 membered aryl or 5 to 10 membered heteroaryl; preferably Preferably, ring A is selected from phenyl, pyridyl and pyrimidyl; more preferably, ring A is phenyl or pyridyl; most preferably, ring A is phenyl.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein ring B is selected from 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclic group , 6 to 10 membered aryl and 5 to 10 membered heteroaryl; preferably, ring B is selected from 3 to 6 membered heterocyclyl, phenyl and 5 or 6 membered heteroaryl; more preferably, ring B is selected from Pyridyl, pyrimidinyl and tetrahydropyrrolyl.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl , C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, -C(O)R 10 , -C(O)OR 10 ,
wherein R 10 to R 13 are as defined in claim 1 .
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein each R 3 is the same or different, and each independently selected from C 1-6 alkyl , C 1-6 haloalkyl, halogen, cyano, oxo, -NR 6 R 7 , C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl, and t is 0, 1 or 2, wherein R 6 and R 7 are as defined in claim 1.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R 0 is a hydrogen atom or a C 1-6 alkyl group.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein Y 1 is a nitrogen atom or CR 4 , and R 4 is a hydrogen atom or a halogen.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein L 1 is -O- or -C(O)-.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 5 to 16, wherein each R 1a is the same or different, and each independently selected from halogen, C 1-6 Alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl and -(CR d R e ) r -NR 6 R 7 , and s1 is 0, 1 or 2, wherein R d , R e , R 6 , R 7 and r are as defined in claim 1 .
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 17, wherein R 4a and R 4b are the same or different, and are each independently selected from a hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, halogen, cyano, -NR 6 R 7 , C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl, wherein R 6 and R7 are as defined in claim 1.
The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, which is selected from the following compounds:
A compound represented by general formula (Ia) or a salt thereof,

in:

W is halogen; preferably, W is iodine;

Ring B, X, Z 1 to Z 4 , L 1 , Y 1 to Y 3 , R 3 , m and t are as defined in claim 1 .
A compound or a salt thereof selected from:
A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps:

A compound represented by general formula (Ia) or a salt thereof and a compound represented by general formula (X) undergo a coupling reaction to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof;

in:

W is halogen; preferably, W is iodine;

L is
R is a hydrogen atom or a C 1-6 alkyl group;

Ring A, Ring B, X, Z 1 to Z 4 , L 1 , Y 1 to Y 3 , R 1 , R 3 , m, s and t are as defined in claim 1 .
A pharmaceutical composition, which contains the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19, and one or more pharmaceutically acceptable carrier, diluent or excipient.
According to the compound represented by the general formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 19 or the pharmaceutical composition according to claim 23 in the preparation of medicines for inhibiting FGFR2 use.
According to the compound represented by the general formula (I) or its pharmaceutically acceptable salt according to any one of claims 1 to 19 or the pharmaceutical composition according to claim 23 in the preparation for the treatment and/or prevention of tumors In particular, the tumor is cancer; the cancer is preferably selected from bile duct cancer, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, colorectal cancer, intrauterine Membranous cancer, urothelial cancer, testicular cancer, cervical cancer, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, pancreatic cancer, bone cancer, lymphoma, melanoma tumor, sarcoma, peripheral neuroepithelial tumor, glioma, ependymoma, neuroblastoma, ganglioma, medulloblastoma, pineal cell tumor, meningioma, neurofibroma, schwannoma and Wilms tumor; more preferably selected from cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, gastric cancer, ovarian cancer, colorectal cancer, endometrial cancer and urothelial cancer.