CN117659006A

CN117659006A - Nitrogen-containing heteroaryl compound, preparation method thereof and application thereof in medicine

Info

Publication number: CN117659006A
Application number: CN202211059922.0A
Authority: CN
Inventors: 陆标; 桂斌; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2022-08-30
Filing date: 2022-08-30
Publication date: 2024-03-08

Abstract

The present disclosure relates to nitrogen-containing heteroaryl compounds, methods of making and their use in medicine. Specifically, the disclosure relates to nitrogen-containing heteroaryl compounds represented by general formula (I), a preparation method thereof and compounds containing the samePharmaceutical compositions and their use as therapeutic agents, in particular as FGFR2 inhibitors and for the preparation of medicaments for the treatment and/or prophylaxis of tumors.

Description

Nitrogen-containing heteroaryl compound, preparation method thereof and application thereof in medicine

Technical Field

The present disclosure belongs to the field of medicine, and relates to a nitrogen-containing heteroaryl compound, a preparation method thereof and application thereof in medicine. Specifically, the disclosure relates to a nitrogen-containing heteroaryl compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application of the compound as a therapeutic agent, particularly application of the compound as an FGFR2 inhibitor and application of the compound in preparation of medicines for treating and/or preventing tumors.

Background

Fibroblast growth factor receptors (Fibroblast growth factors receptors, FGFRs) are a member of the receptor tyrosine kinase family (RTKs), a classical class of RTKs comprising four members FGFR1, FGFR2, FGFR3 and FGFR4, each comprising three parts of an extracellular region, a transmembrane region and an intracellular tyrosine kinase region. Fibroblast Growth Factors (FGFs) bind to the FGFRs causing receptor dimerization, resulting in activation of the autophosphorylation of multiple tyrosine residues of their intracellular tyrosine kinase domain; activated FGFRs activate substrate PLC gamma and signal adapter protein FRS2 through phosphorylation, and further activate downstream RAS-RAF-MAPK, PI3K/AKT, PKC, STAT and other signal channels, thereby influencing physiological functions such as cell proliferation, differentiation, migration, angiogenesis, tissue repair and the like (Signal Transduct Targeted Ther,2020,2;5 (1): 181).

FGF in humans is divided into 6 subfamilies in total, and two major categories: classical FGFs and hormonal FGFs. Classical FGFs include FGF1-10, 16-18, 20, 22, bind to FGFR1-4, have a strong affinity for heparin, and primarily affect cell proliferation, differentiation, angiogenesis and wound repair and Cancer progression (Nat Rev Cancer,2010;10 (2): 116-129); the hormone FGFs include FGF19, 21 and 23, and are combined with FGFR1 and FGFR4 mainly, and alpha/beta-Klotho is used as a co-receptor to regulate in-vivo metabolic processes. Wherein FGF19-FGFR4 regulates cholic acid metabolism, FGF23-FGFR1 regulates calcium, phosphorus and vitamin D levels in blood (Nat Rev Drug discovery.2016; 15 (1): 51-69), which causes target-related toxicity caused by inhibition of FGFR1 and FGFR4, and causes serious adverse reactions such as high blood phosphorus and diarrhea.

When FGFR is abnormal, it causes excessive activation of FGFR signaling pathway and further induces canceration of normal cells, and FGFR gene abnormality is common in various cancers. An NGS study against 4853 types of solid tumors showed that 7% of cancers had FGFR abnormalities, including FGFR1 (49%), FGFR2 (19%), FGFR3 (26%), and FGFR4 (7%). Among them, the higher incidence of FGFR2 abnormality is endometrial Cancer, cholangiocarcinoma, and gastric Cancer (Clin Cancer Res.2016 1;22 (1): 259-267).

Currently, two pan-FGFR inhibitor drugs are marketed for FGFR in batches, namely Erdatinib of Jassen, with batch indication of local advanced or metastatic urothelial cancer with abnormalities in FGFR2 or FGFR3 (NEngl J med.2019,381 (4): 338-348); and Pemigatinib of Incyte, the indication being 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 inhibition of FGFR1 and FGFR4, pan-FGFR inhibitors mostly adopt a mode of intermittent administration to reduce the adverse reactions, so that the curative effect of the drug is greatly compromised. In addition to target-related toxicity, pan-FGFR inhibitors can also develop resistance during treatment. For example, in patients with FGFR2 fusion or mutation type cholangiocarcinoma, acquired drug resistance mutations at sites V564, N549, E565, L617, K641 etc. occur after treatment with pan-FGFR inhibitors (Cancer discover.2017, 7 (3): 252-263). These adverse effects, intermittent dosing and acquired drug resistance problems greatly limit the use of pan-FGFR inhibitors.

Currently RELAY corporation issued the only patent on FGFR2 selective inhibitors (WO 2020231990A 1). The small molecule FGFR2 inhibitor RLY4008 of RELAY in 2020 entered clinical stage one. Currently, no FGFR2 selective inhibitor drugs are approved for marketing, and thus there is still a significant unmet medical need for the relevant patient population.

Disclosure of Invention

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

wherein:

Z ¹ 、Z ² and Z ³ The same or different and are each independently a carbon atom or a nitrogen atom, at least one of which is a nitrogen atom;

w, X and Y are the same or different and are each independently selected from oxygen atom, sulfur atom, C (O), CR ^c R ^d And NR ^e ；

R ^a And R is ^b The same or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

ring a is aryl or heteroaryl;

each R is ¹ Identical OR different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, cyano, oxo, -OR ¹⁰ 、-(CR ^f R ^g ) _n -NR ⁶ R ⁷ and-L ² -R ⁴ ；

L ¹ And L ² Identical or different and are each independently selected from the group consisting of chemical bonds, - (CR) ^h R ⁱ ) _r -、-NR ^5a -, O atom, -O- (CR) ^h R ⁱ ) _r -、-(CR ^h R ⁱ ) _r -O-、-(CR ^h R ⁱ ) _r -NR ^5a -、-NR ^5a -(CR ^h R ⁱ ) _r -、-C(O)-、-O-C(O)-、-C(O)O-、-S(O) _p -、-NR ^5a -C(O)-、-C(O)-NR ^5a -、-C(O)-NR ^5a -(CR ^h R ⁱ ) _r -、-(CR ^h R ⁱ ) _r -NR ^5a -C(O)-、-NR ^5a -C(O)-(CR ^h R ⁱ ) _r -、-NR ^5a -S(O) ₂ -、-S(O) ₂ -NR ^5a -, divalent cycloalkyl, divalent heterocyclic, arylene, and heteroarylene groups, wherein each of said divalent cycloalkyl, divalent heterocyclic, arylene, and heteroarylene groups is independently optionally substituted with a member selected from the group consisting of halogen, oxo, alkyl, haloalkyl, methylene, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, -NR ⁸ R ⁹ Hydroxy group And one or more substituents in hydroxyalkyl;

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

each R is ² Identical or different and are each independently selected from the group consisting of hydrogen, alkyl, halogen, cyano, -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 each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -NR ⁸ R ⁹ One or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

each R is ³ Identical or different and are each independently selected from the group consisting of hydrogen, 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 each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -NR ⁸ R ⁹ One or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁴ Selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -C (O) R ¹⁰ 、-C(O)OR ¹⁰ 、Cycloalkyl, heterocyclyl, aryl andheteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with a member selected from the group consisting of halogen, oxo, alkyl, haloalkyl, methylene, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, -NR ⁸ R ⁹ One or more substituents of hydroxyl and hydroxyalkyl groups;

R ¹¹ 、R ¹² 、R ¹³ identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, -C (O) NR ⁶ R ⁷ 、-C(O)R ¹⁰ 、-C(O)OR ¹⁰ 、-C(O)-NR ^5b -OR ¹⁰ Cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -NR ⁸ R ⁹ One or more substituents selected from the group consisting of hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R is ¹¹ And R is ¹² Forms, together with the attached carbon atom, a cycloalkyl or heterocyclyl group, wherein each of the cycloalkyl or heterocyclyl groups formed is independently optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Or R is ¹² And R is ¹³ Forms, together with the attached carbon atom, a cycloalkyl or heterocyclyl group, wherein each of the cycloalkyl or heterocyclyl groups formed is independently optionally substituted with one or more substituents selected from halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl and haloalkoxy;

or R is ⁶ And R is ⁷ Together with the attached nitrogen atom, form a heterocyclic group, wherein the formed heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

Or R is ⁸ And R is ⁹ Together with the attached nitrogen atom, form a heterocyclic group, wherein the formed heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of halogen, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ¹⁰ selected from the group consisting of hydrogen atoms, alkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein each of said alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl groups, alkoxy groups, haloalkyl groups, and haloalkoxy groups;

R ^e selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^c 、R ^d 、R ^f 、R ^g 、R ^h and R is ⁱ The same or different and are each independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkoxy, and haloalkoxy;

m is 0, 1, 2 or 3;

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

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

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

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

p is 0, 1 or 2; and is also provided with

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

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Z ¹ Is a nitrogen atom, Z ² And Z ³ All are carbon atoms; or Z is ¹ And Z ² Is a carbon atom, Z ³ Are nitrogen atoms; or Z is ¹ And Z ³ Is a carbon atom, Z ² Are nitrogen atoms; preferably Z ¹ Is a nitrogen atom, Z ² And Z ³ Are all carbon atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, whereinSelected from->Preferably, the +>Is->Wherein W, X, Y and m are as defined in formula (I); further preferably, ->Is->Wherein W, X and m are as defined in formula (I); more preferably, the->Is->Therein W, R ^c 、R ^d And m is as defined in formula (I); most preferably, the->Selected from->Further preferably, ->Selected from->

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ^a And R is ^b Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein at least one R ¹ is-L ² -R ⁴ Wherein L is ² And R is ⁴ As defined in formula (I).

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

Wherein:

s1 is 0, 1 or 2;

ring a, ring B, ring C, L ¹ 、L ² 、W、X、Y、R ¹ To R ⁴ M, q and t are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of 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 phenyl, pyridyl, pyrazolyl, cyclohexyl, cyclohexenyl, piperidinyl and 1,2,3, 6-tetrahydropyridinyl; more preferably, ring B is phenyl or pyridinyl; most preferably, ring B is phenyl.

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein t is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof, whereinSelected from-> Preferably, the +>Is->More preferably, the->Selected from->Wherein Q is ¹ And Q ² Identical or different and are each independently CR ² Or a nitrogen atom; t1 is 0, 1 or 2; r is R ² As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof, wherein Y is CR ^c R ^d ，R ^c And R is ^d As defined in formula (I); preferably Y is CH ₂ 。

In the present disclosureIn some preferred embodiments, the compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof, wherein W is CR ^c R ^d Or NR (NR) ^e ，R ^c 、R ^d And R is ^e As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof, wherein X is CR ^c R ^d Or an oxygen atom, R ^c And R is ^d As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.

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

wherein:

Q ¹ and Q ² Identical or different and are each independently CR ² Or a nitrogen atom;

w is CR ^c R ^d Or NR (NR) ^e ；

X is CR ^c R ^d Or an oxygen atom;

m is 0 or 1;

s1 is 0, 1 or 2;

t1 is 0, 1 or 2;

ring a, ring C, L ¹ 、L ² 、R ¹ To R ⁴ 、R ^c 、R ^d 、R ^e And q is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein Selected from->Preferably, the +>Is->Wherein t1 is 0, 1 or 2; r is R ² As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein W is CR ^c R ^d Or NR (NR) ^e And X is CR ^c R ^d ，R ^c 、R ^d And R is ^e As defined in formula (I); or W is CR ^c R ^d And X is an oxygen atom, R ^c And R is ^d As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein ring a is a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl; preferably, ring a is selected from phenyl, pyridinyl and pyrimidinyl; more preferably, ring a is phenyl.

In some preferred embodiments of the present disclosure, the compound of formula (II), formula (III), or a pharmaceutically acceptable salt thereof, whereinSelected from-> Preferably, the method comprises the steps of,is->Wherein s1 is 0, 1 or 2; l (L) ² 、R ¹ And R is ⁴ As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein L ¹ Is an oxygen atom or C (O), preferably L ¹ Is an oxygen atom.

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

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, R ^5a Is a hydrogen atom or C _1-6 Alkyl, preferably R ^5a Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), or a pharmaceutically acceptable salt thereof, wherein R ⁴ 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 is ¹⁰ To R ¹³ As defined in formula (I); preferably, R ⁴ Is->Wherein R is ¹¹ To R ¹³ As defined in formula (I).

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

wherein:

w is CR ^c R ^d Or NR (NR) ^e ；

m is 0 or 1;

s1 is 0, 1 or 2;

t1 is 0, 1 or 2;

ring C, R ¹ To R ³ 、R ^5a 、R ¹¹ To R ¹³ 、R ^c 、R ^d 、R ^e And q is as defined in formula (I).

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

Wherein:

m is 0 or 1;

s1 is 0, 1 or 2;

t1 is 0, 1 or 2;

ring C, R ¹ To R ³ 、R ^5a 、R ¹¹ To R ¹³ 、R ^c 、R ^d And q is as defined in formula (I).

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

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), formula (V), or a pharmaceutically acceptable salt thereof, wherein ring C is selected from 3 to 10 membered cycloalkyl, 3 to 10 membered heterocyclyl, 6 to 10 membered aryl, or 5 to 10 membered heteroaryl; preferably, ring C is selected from 3 to 8 membered cycloalkyl, 4 to 7 membered heterocyclyl, phenyl and 5 or 6 membered heteroaryl; preferably, ring C is selected from phenyl, 5 or 6 membered heteroaryl and 5 or 6 membered heterocyclyl; preferably, ring C is selected from phenyl, pyridyl, pyrimidinyl and tetrahydropyrrolyl.

In some preferred embodiments of the present disclosure, the compound of formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof, wherein each R ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, C _1-6 Hydroxyalkyl and-NR ⁶ R ⁷ Wherein R is ⁶ And R is ⁷ As defined in formula (I); preferably, R ¹ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof, wherein each R ² Identical or different and are each independently selected from hydrogen atoms, 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 is ⁶ And R is ⁷ As defined in formula (I); preferably, R ² Is a hydrogen atom or a halogen.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof, wherein each R ³ Identical or different and are each independently selected from hydrogen atoms, 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, wherein R is ⁶ And R is ⁷ As defined in formula (I); preferably, R ³ Is a hydrogen atom or C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the chemical formula (I), formula (II), formula (III), formula (IV), formula (V) A compound or pharmaceutically acceptable salt thereof, wherein R ^c And R is ^d Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; preferably, R ^c And R is ^d Identical or different and are each independently a hydrogen atom or C _1-6 An alkyl group; further preferably R ^c And R is ^d Each hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV) or a pharmaceutically acceptable salt thereof, wherein R ^e Is a hydrogen atom or C _1-6 An alkyl group; preferably, R ^e Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof, wherein R ^5a Is a hydrogen atom or C _1-6 An alkyl group; preferably, R ^5a Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof, wherein R ¹¹ Selected from hydrogen atoms, 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 Hydroxy and C _1-6 Substituted with one or more substituents in hydroxyalkyl, wherein R ⁶ To R ¹⁰ As defined in formula (I); preferably, R ¹¹ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; further preferably, R ¹¹ Is a hydrogen atom or C _1-6 An alkyl group; most preferably, R ¹¹ Is a hydrogen atom.

In some embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof, wherein R ¹¹ Halogen is preferably a fluorine atom.

At the bookIn some preferred embodiments, the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof is disclosed, wherein R ¹² Selected from hydrogen atoms, 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 Hydroxy and C _1-6 Substituted with one or more substituents in hydroxyalkyl, wherein R ⁶ To R ¹⁰ As defined in formula (I); preferably, R ¹² Is a hydrogen atom or C _1-6 An alkyl group; further preferably, R ¹² Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof, wherein R ¹³ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; preferably, R ¹³ Is a hydrogen atom or C _1-6 An alkyl group; further preferably, R ¹³ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof, wherein R ⁶ And R is ⁷ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Hydroxyalkyl, 3-to 8-membered cycloalkyl and 3-to 12-membered heterocyclyl, wherein said C _1-6 Alkyl, 3-to 8-membered cycloalkyl and 3-to 12-membered heterocyclyl are each independently optionally selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof, wherein R ⁸ And R is ⁹ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Hydroxyalkyl group, 3To 8 membered cycloalkyl and 3 to 12 membered heterocyclyl, wherein said C _1-6 Alkyl, 3-to 8-membered cycloalkyl and 3-to 12-membered heterocyclyl are each independently optionally selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 One or more substituents in the haloalkoxy group.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 Hydroxyalkyl groups.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III), formula (IV), formula (V) or a pharmaceutically acceptable salt thereof, wherein q is 0, 1 or 2; preferably q is 0 or 1. In some preferred embodiments of the present disclosure, the compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein,

y is CH ₂ ，

W is CR ^c R ^d Or NR (NR) ^e ，

X is CR ^c R ^d Or an oxygen atom, or a group of oxygen atoms,

m is 0 or 1;

R ^c and R is ^d Identical or different and are each independently a hydrogen atom or C _1-6 An alkyl group;

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

ring B is phenyl or 5 or 6 membered heteroaryl;

L ¹ is an oxygen atom or C (O);

ring C is selected from phenyl, 5 or 6 membered heteroaryl, and 5 or 6 membered heterocyclyl;

R ³ is a hydrogen atom or C _1-6 An alkyl group;

ring a is selected from phenyl, pyridinyl and pyrimidinyl;

L ² is a chemical bond or-NR ^5a -；

R ^5a Is a hydrogen atom or C _1-6 An alkyl group, a hydroxyl group,

R ⁴ is that

R ¹¹ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group;

R ¹² Is a hydrogen atom or C _1-6 An alkyl group;

R ¹³ is a hydrogen atom or C _1-6 An alkyl group;

R ¹ is a hydrogen atom;

q is 0, 1 or 2.

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 the general formula (IIa) or a salt thereof,

wherein:

L ² is-NR ^5a -；

Ring a, ring B, ring C, L ¹ 、W、X、Y、R ¹ To R ³ 、R ^5a S1, m, q and t are as defined in formula (II).

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

wherein:

L ² is-NR ^5a -；

Ring a, ring C, L ¹ 、W、X、Q ¹ 、Q ² 、R ¹ To R ³ 、R ^5a S1, t1, m and q are as defined in formula (III).

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

wherein:

ring C, W, R ¹ To R ³ 、R ^5a 、R ^c 、R ^d M, s1, t1 and q are as defined in formula (IV).

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

wherein:

ring C, R ¹ To R ³ 、R ^5a 、R ^c 、R ^d M, s1, t1 and q are as defined in formula (V).

Table B 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 (II) or a pharmaceutically acceptable salt thereof, comprising:

reacting a compound represented by the general formula (IIa) or a salt thereof with a compound represented by the general formula (X) to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;

Wherein:

l is halogen or OH; preferably, L is halogen; preferably, L is a chlorine atom;

L ² is-NR ^5a -；

R ⁴ Is that

Ring a, ring B, ring C, L ¹ 、W、X、Y、R ¹ To R ³ 、R ^5a 、R ¹¹ To R ¹³ S1, m, q and t are as defined in 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:

reacting a compound represented by the general formula (IIIa) or a salt thereof with a compound represented by the general formula (X) to obtain a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;

wherein:

l is halogen or OH; preferably, L is halogen; preferably, L is a chlorine atom;

L ² is-NR ^5a -；

R ⁴ Is that

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:

reacting a compound represented by the general formula (IVa) or a salt thereof with a compound represented by the general formula (XI) to obtain a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;

wherein:

l is halogen or OH; preferably, L is halogen; preferably, L is a chlorine atom;

ring C, W, R ¹ To R ³ 、R ^5a 、R ¹¹ To R ¹³ 、R ^c 、R ^d M, s1, t1 and q are as defined in formula (IV).

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

Reacting a compound represented by the general formula (Va) or a salt thereof with a compound represented by the general formula (XI) to obtain a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof;

wherein:

l is halogen or OH; preferably, L is halogen; preferably, L is a chlorine atom;

ring C, R ¹ To R ³ 、R ^5a 、R ¹¹ To R ¹³ 、R ^c 、R ^d M, s1, t1 and q are as defined in formula (V).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III), formula (IV), formula (V) and table a or a pharmaceutically acceptable salt thereof of the present disclosure, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting FGFR 2.

The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV), formula (V) and formula (V) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for the preparation of a medicament for the treatment and/or prevention of a tumor.

The present disclosure also relates to a method of inhibiting FGFR2 comprising administering to a patient in need thereof an effective inhibiting amount of a compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method of treating and/or preventing a tumor comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a compound represented by general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V) and table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The disclosure further relates to compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), and table a, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as FGFR2 inhibitors.

The present disclosure further relates to compounds of general formula (I), general formula (II), general formula (III), general formula (IV), general formula (V), and table a or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment and/or prevention of tumors.

The tumor as described above in the present disclosure is a cancer; the cancer is preferably selected from cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), thyroid cancer, stomach cancer, ovarian cancer, colorectal cancer (e.g., colon cancer and rectal cancer), 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 nerve epithelial tumor, glioma (e.g., astrocytoma and glioblastoma), ependymoma, neuroblastoma, gangliocytoma, pineal tumor, meningioma, neurofibroma, schwanms tumor; more preferably selected from the group consisting of cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, stomach cancer, ovarian cancer, colorectal cancer, endometrial cancer, and urothelial cancer. The active compounds may be formulated in a form suitable for administration by any suitable route, preferably in unit dosage form, or in a form whereby the patient may self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation.

As a general guideline, suitable unit doses may be from 0.1 to 1000mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of the active compound.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or 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. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

The oil suspensions may be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickener. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which injectable solution or microemulsion may be injected into the blood stream of a patient by topical bolus injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare injections.

The compounds of the present disclosure 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 amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

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

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group (i.e., C) containing from 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms _1-12 Alkyl groups), more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C _1-6 Alkyl). Non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl 3, 3-dimethylhexyl, 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-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

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

The term "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups containing 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred, and alkynyl groups containing 2 to 6 carbon atoms are more preferred. Alkynyl groups may be substituted or unsubstituted and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated all-carbon monocyclic or multicyclic ring system comprising 3 to 20 ring atoms (i.e., a 3 to 20 membered cycloalkyl group), preferably comprising 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms (i.e., a 3 to 12 membered cycloalkyl group), preferably comprising 3 to 8 ring atoms (i.e., a 3 to 8 membered cycloalkyl group), more preferably comprising 3 to 6 ring atoms (i.e., a 3 to 6 membered cycloalkyl group).

Non-limiting examples of said all-carbon monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like.

The cycloalkyl group of the polycyclic ring system includes: spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl. Cycloalkyl groups of the polycyclic ring system also include all-carbon monocyclic cycloalkyl, spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups as described above fused to one or more aryl, heteroaryl, or heterocyclic groups, wherein the point of attachment is on the ring of the all-carbon monocyclic cycloalkyl, spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups, and in such cases the number of carbon atoms continues to represent the number of carbon atoms in the polycyclic ring system, non-limiting examples include: Etc.; preferably

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic ring system, which may contain one or more double bonds, sharing one carbon atom between the monocyclic rings (referred to as the spiro atom). Preferably 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 members), more preferably 7 to 10 members. The spirocycloalkyl groups are classified into single spirocycloalkyl groups or multiple spirocycloalkyl groups (e.g., double spirocycloalkyl groups) according to the number of common spiro atoms between rings, and preferably single spirocycloalkyl groups and double spirocycloalkyl groups. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/4-membered, 6-membered/5-membered or 6-membered/6-membered monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused ring alkyl" refers to a 5 to 20 membered polycyclic ring system wherein each ring shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the ring systems may contain one or more double bonds. Preferably 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 members), more preferably 7 to 10 members. The polycyclic condensed ring alkyl groups may be classified as bicyclic, tricyclic, tetracyclic, etc., depending on the number of constituent ring systems, but are preferably bicyclic or tricyclic condensed ring alkyl groups, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered bicyclic condensed ring alkyl groups. Non-limiting examples of fused ring alkyl groups include:

The term "bridged cycloalkyl" refers to a 5-to 20-membered polycyclic ring system, which may contain one or more double bonds, in which any two rings share two carbon atoms which are not directly attached. Preferably 6 to 14 membered (e.g. 6, 7, 8, 9, 10, 11, 12, 13 or 14 membered), more preferably 7 to 10 membered. Polycyclic cycloalkyl groups which can be classified into bicyclic, tricyclic, tetracyclic and the like according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:

cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of a D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated, mono-or polycyclic ring system containing from 3 to 20 ring atoms in which one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., forms a sulfoxide or sulfone), but does not include the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon atoms, and the point of attachment being either a carbon atom or a nitrogen atom (i.e., a 3 to 20 membered heterocyclyl) on the basis of satisfaction of valence theory. Preferably from 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 4 (e.g., 1,2,3, and 4) are heteroatoms (i.e., 3 to 12 membered heterocyclyl); more preferably 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which 1 to 3 are heteroatoms (e.g., 1,2, and 3) (i.e., 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms (i.e., 3 to 6 membered heterocyclyl); most preferably contain 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e., 5 or 6 membered heterocyclyl).

Non-limiting examples of such monocyclic heterocyclic groups include: pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.

The heterocyclic groups of the polycyclic ring system include spiro heterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups. The heterocyclic groups of the polycyclic ring system also include monocyclic heterocyclic groups, spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups as described above fused to one or more aryl, heteroaryl, or cycloalkyl groups, where the point of attachment is on the ring in which the heterocyclic groups, spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups of the monocyclic ring system are located, and in which case the number of ring atoms continues to represent the number of ring atoms in the polycyclic ring system, non-limiting examples of which include:

etc.

The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic ring system having a single ring sharing one atom (referred to as the spiro atom) wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon atoms, and the point of attachment being either a carbon atom or a nitrogen atom, on the basis of satisfaction of valence theory. Which may contain one or more double bonds. Preferably 6 to 14 membered (e.g. 6, 7, 8, 9, 10, 11, 12, 13 or 14 membered), more preferably 7 to 10 membered. The spiroheterocyclyl groups are classified into single spiroheterocyclyl groups or multiple spiroheterocyclyl groups (e.g., double spiroheterocyclyl groups) according to the number of common spiro atoms between rings, and are preferably single spiroheterocyclyl groups and double spiroheterocyclyl groups. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl groups include:

The term "fused heterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic ring system in which each ring shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon atoms, and the point of attachment being either a carbon atom or a nitrogen atom, on the basis of satisfaction of valence theory. Preferably 6 to 14 membered (e.g. 6, 7, 8, 9, 10, 11, 12, 13 or 14 membered), more preferably 7 to 10 membered. The number of constituent rings may be classified into a polycyclic fused heterocyclic group such as a bicyclic, tricyclic, tetracyclic and the like, preferably a bicyclic or tricyclic fused heterocyclic group, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 5-membered/7-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, 6-membered/6-membered, 6-membered/7-membered, 7-membered/5-membered or 7-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

the term "bridged heterocyclyl" refers to a 5-to 14-membered polycyclic heterocyclic ring system in which any two rings share two atoms which are not directly connected, which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon atoms, and the point of attachment being either a carbon atom or a nitrogen atom, on the basis of satisfaction of valence theory. Preferably 6 to 14 membered (e.g. 6, 7, 8, 9, 10, 11, 12, 13 or 14 membered), more preferably 7 to 10 membered. Polycyclic bridged heterocyclic groups which can be classified as bicyclic, tricyclic, tetracyclic, etc., depending on the number of ring systems involved, are preferred, and bicyclic, tricyclic or tetracyclic bridged heterocyclic groups are more preferred. Non-limiting examples of bridged heterocyclyl groups include:

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

The term "aryl" refers to a 6 to 14 membered mono-or polycyclic (which share rings adjacent pairs of carbon atoms) ring system with conjugated pi-electron systems, preferably 6 to 10 membered (e.g., 6, 7, 8, 9 or 10 membered). The monocyclic aryl group is, for example, phenyl. Non-limiting examples of aryl groups of the polycyclic ring system include: naphthyl, and the like. The aryl groups of the polycyclic ring system also include aryl groups of phenyl and polycyclic ring systems as described above fused with one or more heterocyclic or cycloalkyl groups, wherein the point of attachment is on the ring in which the aryl groups of the phenyl and polycyclic ring systems are located, and in such cases the number of ring atoms continues to represent the number of ring atoms in the polycyclic ring system, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a monocyclic or polycyclic ring system having a conjugated pi-electron system which contains 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4) selected from oxygen, sulfur, and nitrogen, 5 to 14 ring atoms. Preferably a 5 to 10 membered (e.g. 5, 6, 7, 8, 9 or 10 membered) heteroaryl, more preferably a 5 or 6 membered heteroaryl.

Non-limiting examples of such monocyclic heteroaryl groups include: furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like.

Non-limiting examples of heteroaryl groups of the polycyclic systems include: indolyl, quinolinyl, carbazolyl, and the like. The heteroaryl group of the polycyclic system also includes monocyclic heteroaryl groups as described above and polycyclic systems in which the heteroaryl group of the polycyclic system is fused with one or more aryl groups, wherein the point of attachment is not limited, and in which case the number of ring atoms continues to represent the number of ring atoms in the polycyclic system. The heteroaryl groups of the polycyclic ring system also include monocyclic heteroaryl groups as described above and polycyclic ring systems in which the heteroaryl groups of the polycyclic ring system are fused to one or more cycloalkyl or heterocyclyl groups, wherein the points of attachment are on the ring in which the heteroaryl groups of the monocyclic heteroaryl and polycyclic ring systems are located, and in which case the number of ring atoms continues to represent the number of ring atoms in the polycyclic ring system. Non-limiting examples of which include:

Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The cycloalkyl, heterocyclyl, aryl and heteroaryl groups described above include residues derived from the removal of one hydrogen atom from a ring atom of the parent ring system, or residues derived from the removal of two hydrogen atoms from the same ring atom or two different ring atoms of the parent, i.e. "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

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

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

The term "deuterated alkyl" 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 hydroxyl groups, wherein alkyl is as defined above.

The term "methylene" refers to =ch ₂ 。

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

The term "hydroxy" refers to-OH.

The term "amino" refers to-NH ₂ 。

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

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

The term "carbonyl" refers to c=o.

The compounds of the present disclosure may exist in particular stereoisomeric forms. The term "stereoisomer" refers to an isomer that is identical in structure but differs in the arrangement of atoms in space. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformational isomers and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in compounds of the present disclosure may present additional asymmetric carbon atoms. All such stereoisomers, and mixtures thereof, are included within the scope of the present disclosure. For all carbon-carbon double bonds, Z and E are included even if only one configuration is named. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers and (D) -and (L) -isomers can be prepared by chiral syntheses or chiral reagents or other conventional techniques. An isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, or when a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl) is contained in the molecule, a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is performed by conventional methods known in the art to give the pure isomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography.

In the chemical structure of the compounds of the present disclosure, the bondIndicating the unspecified configuration, i.e.the bond +.>Can be +.>Or->Or at the same time contain->And->Two configurations.

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound wherein at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, and the like, e.g., respectively ² H (deuterium, D), 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., deuterium is preferred.

Compared with non-deuterated medicines, deuterated medicines have the advantages of reducing toxic and side effects, increasing medicine stability, enhancing curative effect, prolonging biological half-life of medicines and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed 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 replacement of deuterium may be partial or complete, with partial replacement of deuterium meaning that at least one hydrogen is replaced by at least one deuterium.

"optionally" or "optionally" is intended to mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example "C optionally substituted by halogen or cyano _1-6 Alkyl "means that halogen or cyano may be, but need not be, present, and this description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

"substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, such as physiological/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure, which may be selected from inorganic salts or organic salts. Such salts are safe and effective when used in mammals and have desirable biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate groups with an appropriate 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 and organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent to achieve, or at least partially achieve, the desired effect. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and are effective for the intended use.

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

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is shown that the parameter may vary by + -10%, and sometimes more preferably within + -5%. As will be appreciated by those skilled in the art, where parameters are not critical, numerals are generally given for illustration purposes only and are not limiting.

Methods of synthesizing compounds of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical scheme:

scheme one

A process for the preparation of a compound of formula (II) or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

reacting a compound represented by the general formula (IIa) or a salt thereof with a compound represented by the general formula (X) under alkaline conditions to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

l is halogen; preferably, L is a chlorine atom;

L ² is-NR ^5a -；

R ⁴ Is that

Scheme II

A process for the preparation of a compound of formula (III) or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

Reacting a compound represented by the general formula (IIIa) or a salt thereof with a compound represented by the general formula (X) under alkaline conditions to obtain a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;

wherein:

l is halogen; preferably, L is a chlorine atom;

L ² is-NR ^5a -；

R ⁴ Is that

Scheme III

A process for the preparation of a compound of formula (IV) or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

reacting a compound represented by the general formula (IVa) or a salt thereof with a compound represented by the general formula (XI) under alkaline conditions to obtain a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;

wherein:

l is halogen; preferably, L is a chlorine atom;

Scheme IV

A process for the preparation of a compound of formula (V) or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

/>

reacting a compound represented by the general formula (Va) or a salt thereof with a compound represented by the general formula (XI) under alkaline conditions to obtain a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof;

wherein:

l is halogen; preferably, L is a chlorine atom;

Scheme five

reacting a compound represented by the general formula (IIa) or a salt thereof with a compound represented by the general formula (X) in the presence of a condensing agent under alkaline conditions to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof;

wherein:

l is-OH; l (L) ² is-NR ^5a -；

R ⁴ Is that

Scheme six

reacting a compound represented by the general formula (IIIa) or a salt thereof with a compound represented by the general formula (X) under alkaline conditions in the presence of a condensing agent to obtain a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;

wherein:

l is-OH;

L ² is-NR ^5a -；

R ⁴ Is that

Scheme seven

reacting a compound represented by the general formula (IVa) or a salt thereof with a compound represented by the general formula (XI) in the presence of a condensing agent under alkaline conditions to obtain a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof;

Wherein:

l is-OH;

Scheme eight

reacting a compound represented by the general formula (Va) or a salt thereof with a compound represented by the general formula (XI) in the presence of a condensing agent under alkaline conditions to obtain a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof;

wherein:

l is-OH;

In the above synthetic schemes, the base includes organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, preferably triethylamine and N, N-diisopropylethylamine; the inorganic base includes, but is not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide, and potassium hydroxide.

In the above synthetic schemes, the condensing agent includes, but is not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N '-dicyclohexylcarbodiimide, N, N' -diisopropylcarbodiimide, O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol, O-benzotriazol-N, N, N ', N' -tetramethyluronium hexafluorophosphate, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), 2- (7-benzotriazol-N, N, N ', N' -tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxy-tripyrrolidinylphosphine; preferably HATU.

The above synthetic schemes are preferably carried out in solvents including, but 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-dimethylformamide, N-dimethylacetamide, and mixtures thereof.

Detailed Description

The present disclosure is further described below in conjunction with the examples, which are not intended to limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus or Bruker AVANCE NEO M with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS).

MS was determined using an Agilent 1200/1290DAD-6110/6120 Quadrapol MS liquid chromatography-mass spectrometry (manufacturer: agilent, MS model: 6110/6120 Quadrapol MS).

waters ACQuity UPLC-QD/SQD (manufacturers: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)

Thermo Ultimate 3000-Q exact (manufacturer: thermo, MS model: thermo Qexact)

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC1200 DAD, agilent HPLC1200VWD, and Waters HPLC e2695-2489 high performance liquid chromatography.

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

The high performance liquid phase was prepared by using a Waters 2545-2767, waters 2767-SQ Detector 2, shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.

Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash flash rapid prep instrument used CombiFlash Rf200 (teldyne ISCO).

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were measured using a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemicals, and the like.

The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.

An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses a Parr 3916 model EKX hydrogenometer and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: n-hexane/ethyl acetate system, B: the volume ratio of the methylene dichloride to the methanol is adjusted according to the polarity of the compound, and can be adjusted by adding a small amount of alkaline or acidic reagents such as triethylamine, acetic acid and the like.

Example 1

3- (4-acrylamidophenyl) -2- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5,6,7, 8-tetrahydroindolizine-1-carboxamide 1

First step

2- (4-bromo-2-fluorophenoxy) -4-methylpyrimidine 1c

Potassium hydroxide (1.8 g,27.27mmol,85% purity) was dissolved in 1.8mL of water, 4-bromo-2-fluorophenol 1a (5 g,26.17mmol, adamas) and 60mL of dimethyl sulfoxide were added, and 2-chloro-4-methylpyrimidine 1b (3.36 g,26.13mmol, medicine) was further added, and the mixture was heated to 100℃to react for 3 hours. The reaction solution was cooled to room temperature, diluted with 750mL of ethyl acetate, washed with water (100 mL. Times.3), then with saturated sodium chloride solution (100 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the objective compound 1c (6.1 g, yield: 82.3%).

MS m/z(ESI):284.9[M+1]。

Second step

2- (2-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) phenoxy) -4-methylpyrimidine 1d

Compound 1c (6.1 g,21.54 mmol), pinacol biborate (8.2 g,32.29mmol, shaoshan chemical), potassium acetate (6.3 g,64.19 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (1.6 g,2.18mmol, adamas) were added to 150ml of 1, 4-dioxane under nitrogen and heated to 95 ℃ for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the objective compound 1d (7.19 g, yield: > 100%).

MS m/z(ESI):331.0[M+1]。

Third step

3- (4- ((Boc) amino) phenyl) -5,6,7, 8-tetrahydroindolizine-1-carboxylic acid ethyl ester 1f

Ethyl 5,6,7, 8-tetrahydroindolizine-1-carboxylate 1e (1.5 g,7.76mmol, prepared by well-known methods "Journal of Organic Chemistry,1977,42 (5), 909-910"), tert-butyl N- (4-bromophenyl) carbamate (2.53 g,9.29mmol, shao-chemical), bis (triphenylphosphine) palladium dichloride (545 mg, 776.4. Mu. Mol, adamas), potassium acetate (1.5 g,15.28 mmol) were added to 50mL of N, N-dimethylacetamide under nitrogen, heated to 120℃and stirred for 17 h. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the objective compound 1f (460 mg, yield: 15.4%).

MS m/z(ESI):385.0[M+1]。

Fourth step

3- (4- ((Boc) amino) phenyl) -5,6,7, 8-tetrahydroindolizine-1-carboxylic acid 1g

Compound 1f (460 mg,1.19 mmol) was dissolved in 18mL of methanol and water (V: V=5:1), sodium hydroxide (480 mg,12 mmol) was added, and the mixture was heated to 80℃for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, 1N diluted hydrochloric acid was added until the pH of the solution was less than 7, filtered, and the cake was dried in vacuo to give 1g of the objective compound (367 mg, yield: 86.0%).

MS m/z(ESI):357.0[M+1]。

Fifth step

(4- (1-carboxamide-5, 6,7, 8-tetrahydroindolizin-3-yl) phenyl) carbamic acid tert-butyl ester 1h

1g (367 mg,1.02 mmol) of the compound was dissolved in 20mL of N, N-dimethylformamide, and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (470 mg,1.23 mmol), triethylamine (160 mg,1.58mmol,0.22 mL) and 5mL of a 1, 4-dioxane solution of 0.4M ammonia were added thereto and reacted at room temperature with stirring for 2 hours. 50mL of water was added and extracted with ethyl acetate (80 mL. Times.3), the organic phases were combined, washed with water (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 1h (367 mg, yield: 100%).

MS m/z(ESI):356.1[M+1]。

Sixth step

(4- (2-bromo-1-carboxamido-5, 6,7, 8-tetrahydroindolizin-3-yl) phenyl) carbamic acid tert-butyl ester 1i

Compound 1h (367 mg,1.03 mmol) was dissolved in 30mL of dichloromethane, N-bromosuccinimide (180 mg,1.01 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After addition of 10mL of saturated sodium bicarbonate solution and 5mL of saturated sodium thiosulfate solution, the liquid was separated, the aqueous phase was extracted with methylene chloride (30 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the objective compound 1i (387 mg, yield: 86.2%).

Seventh step (4- (1-carboxamide-2- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5,6,7, 8-tetrahydroindolizin-3-yl) phenyl) carbamic acid tert-butyl ester 1j

Compound 1d (294 mg,890.4 μmol), compound 1i (387 mg,891.0 μmol), potassium carbonate (166 mg,1.20 mmol) and tetrakis (triphenylphosphine) palladium (103 mg,89.1 μmol) were added to 18mL of water and 1, 4-dioxane (V: v=1:5) under a nitrogen atmosphere, and heated to 95 ℃ for reaction for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, 50mL of methylene chloride was added to the residue to dissolve, and then, filtration was carried out, and the obtained residue was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to give the objective compound 1j (280 mg, yield: 56.3%).

MS m/z(ESI):558.9[M+1]。

Eighth step

3- (4-aminophenyl) -2- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -5,6,7, 8-tetrahydroindolizine-1-carboxamide 1k

Compound 1j (280 mg, 502.1. Mu. Mol) was dissolved in 10mL of methylene chloride, 3mL of trifluoroacetic acid was added thereto, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, a saturated sodium hydrogencarbonate solution was added to the residue to give a solution having a pH of more than 7, the aqueous phase was extracted with methylene chloride (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the objective compound 1k (220 mg, yield: 95.7%).

MS m/z(ESI):458.1[M+1]。

Ninth step

Compound 1k (105 mg, 229.5. Mu. Mol) was dissolved in 15mL of methylene chloride, triethylamine (219 mg,2.16mmol,0.3 mL) was added thereto, and then acryloyl chloride (112 mg,1.23mmol,0.1 mL) was added dropwise thereto, and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the objective compound 1 (60 mg, yield: 51.1%).

MS m/z(ESI):512.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.35(d,1H),7.65(s,1H),7.56(d,2H),7.16-7.12(m,3H),7.06-7.02(m,2H),6.92(d,1H),6.45(dd,1H),6.28(dd,1H),5.78(dd,1H),5.21(s,2H),3.77(t,2H),3.26(t,2H),2.49(s,3H),1.96-1.89(m,4H)。

Example 2

5- (4-Acylaminophenyl) -6- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -2, 3-dihydro-1H-pyrrolizine-7-carboxamide 2

Using the synthetic route for compound 1 in example 1, substituting starting compound 1e from the third step with starting compound 2, 3-dihydro-1H-pyrroline-7-carboxylic acid ethyl ester (prepared using well-known methods "Synthesis,2002, (16), 2450-2456"), the title compound 2 (40 mg) was prepared.

MS m/z(ESI):498.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.37(d,1H),7.54-7.52(m,2H),7.37(s,1H),7.23(t,1H),7.14-7.12(m,4H),6.95(d,1H),6.45(dd,1H),6.26(dd,1H),5.80(dd,1H),5.25(s,2H),4.04(t,2H),3.22-3.24(m,2H),2.55-2.58(m,2H),2.51(s,3H)。

Example 3

6- (4-Acylaminophenyl) -7- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -3, 4-dihydro-1H-pyrrolo [2,1-c ] [1,4] oxazine-8-carboxamide 3

First step

4-formyl-morpholine-3-carboxylic acid 3b

Morpholine-3-carboxylic acid 3a (1.5 g,11.44mmol, after completion) was dissolved in 20mL formic acid and acetic anhydride (7.1 g,69.35mmol, chinese medicine) was added dropwise at 0deg.C and reacted for 3 hours. 2mL of water was added and the mixture was dried by spinning to give the objective compound 3b (1.8 g, yield: 100%), which was used in the next step without purification.

Second step

3, 4-dihydro-1H-pyrrolo [2,1-c ] [1,4] oxazine-8-carboxylic acid ethyl ester 3c

Compound 3b (1.8 g,11.31 mmol) and ethyl propiolate (2.2 g,22.42 mmol) were added to 20mL acetic anhydride and reacted for 2 hours at 120℃under nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the objective compound 3c (2.0 g, yield: 90.5%), which was used in the next step without purification.

Third step

6- (4- ((Boc) amino) phenyl) -3, 4-dihydro-1H-pyrrolo [2,1-c ] [1,4] oxazine-8-carboxylic acid ethyl ester 3d

Under nitrogen, compound 3c (2 g,10.24 mmol), N-butoxycarbonyl-4-bromoalanine (3.4 g,12.38mmol, shao Yuan chemical), bis (triphenylphosphine) palladium dichloride (1.1 g,1.52mmol, adamas), potassium acetate (2.1 g,21.39mmol, obtained) were added to 50mL of N, N-dimethylacetamide, heated to 120℃and stirred for 17 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the objective compound 3d (600 mg, yield: 15.2%). MS m/z (ESI) 387.1[ M+1].

Fourth step

6- (4- ((Boc) amino) phenyl) -3, 4-dihydro-1H-pyrrolo [2,1-c ] [1,4] oxazine-8-carboxylic acid 3e

Compound 3d (600 mg,1.55 mmol) was dissolved in 30mL of methanol and water (V: v=5:1), sodium hydroxide (310 mg,7.76mmol, chinese medicine) was added, and the mixture was heated to 80 ℃ to react for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, 1N diluted hydrochloric acid was added until the pH of the solution was less than 7, filtered, and the cake was dried in vacuo to give the objective compound 3e (550 mg, yield: 98.8%).

MS m/z(ESI):359.0[M+1]。

Fifth step (tert-butyl 4- (8-carboxamide-3, 4-dihydro-1H-pyrrolo [2,1-c ] [1,4] oxazin-6-yl) phenyl) carbamate 3f

Compound 3e (500 mg,1.39 mmol) was dissolved in 20mL of N, N-dimethylformamide, and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (795 mg,2.09mmol, pichia), N, N-diisopropylethylamine (360 mg,2.79mmol, adamas) and 7mL of a 0.4M 1, 4-dioxane solution of ammonia were added thereto and the mixture was stirred at room temperature to react for 2 hours. After 50mL of water was added, the mixture was extracted with ethyl acetate (80 mL. Times.3), the organic phases were combined, washed with water (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the objective compound 3f (500 mg, yield: 100%). MS m/z (ESI) 358.1[ M+1].

Sixth step

(4- (7-bromo-8-carboxamido-3, 4-dihydro-1H-pyrrolo [2,1-c ] [1,4] oxazin-6-yl) phenyl) carbamic acid tert-butyl ester 3g

Compound 3f (400 mg,1.12 mmol) was dissolved in 30mL of methylene chloride, N-bromosuccinimide (199mg, 1.12 mmol) was added, and the reaction was stirred at room temperature for 1 hour. After addition of 10mL of saturated sodium bicarbonate solution and 5mL of saturated sodium thiosulfate solution, the liquid was separated, the aqueous phase was extracted with methylene chloride (30 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give 3g of the objective compound (480 mg, yield: 98.3%).

Seventh step

(4- (8-carboxamide-7- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -3, 4-dihydro-1H-pyrrolo [2,1-c ] [1,4] oxazin-6-yl) phenyl) carbamic acid tert-butyl ester 3H

3g (300 mg, 687.6. Mu. Mol) of compound 1d (227 mg, 687.6. Mu. Mol), sodium carbonate (146 mg,1.37 mmol) and tetrakis (triphenylphosphine) palladium (1599 mg, 137.5. Mu. Mol) were added to 30mL of water and 1, 4-dioxane (V: V=1:5) under a nitrogen atmosphere, and the mixture was heated to 95℃to react for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, 50mL of methylene chloride was added to the residue to dissolve, and then, filtration was carried out, and the obtained residue was concentrated under reduced pressure, and purified by silica gel column chromatography with eluent system B to give the objective compound (210 mg, yield: 54.5%).

MS m/z(ESI):560.0[M+1]。

Eighth step

6- (4-aminophenyl) -7- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -3, 4-dihydro-1H-pyrrolo [2,1-c ] [1,4] oxazine-8-carboxamide 3i

Compound 3h (210 mg, 375.3. Mu. Mol) was dissolved in 10mL of dichloromethane, 3mL of trifluoroacetic acid was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, a saturated sodium hydrogencarbonate solution was added to the residue to give a solution having a pH of more than 7, the aqueous phase was extracted with methylene chloride (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the objective compound 3i (170 mg, yield: 98.6%).

MS m/z(ESI):459.5[M+1]。

Ninth step

Compound 3i (70 mg, 152.3. Mu. Mol) was dissolved in 15mL of methylene chloride, triethylamine (46 mg, 457.0. Mu. Mol, national drug) was added thereto, and then acryloyl chloride (69 mg, 761.8. Mu. Mol, aldamos) was added dropwise thereto, and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the objective compound 3 (26 mg, yield: 33.2%).

MS m/z(ESI):514.1[M+1]。

¹ H NMR(500MHz,DMSO)δ10.21(s,1H),8.46(d,1H),7.67-7.64(m,2H),7.25-7.10(m,5H),7.00-6.98(m,2H),6.45-6.39(m,2H),6.27-6.24(m,1H),5.94(s,1H),5.76(dd,1H),4.98(s,2H),3.95(t,2H),3.77(t,2H),2.40(s,2H)。

Example 4

7- (3-fluoro-4- ((4-methylpyrimidin-2-yl) oxy) phenyl) -6- (4- (2-fluoroacrylamide) phenyl) -3, 4-dihydro-1H-pyrrolo [2,1-c ] [1,4] oxazine-8-carboxamide 4

Compound 3i (50 mg, 108.82. Mu. Mol) and 2-fluoroacrylic acid (19.6 mg, 217.54. Mu. Mol, adamas), N, N-diisopropylethylamine (360 mg,2.79mmol, adamas) were dissolved in 20mL of N, N-dimethylformamide, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (83 mg, 217.66. Mu. Mol, bi.) was added at 0℃and the reaction was stirred at room temperature for 2 hours. After 50mL of water was added, the mixture was extracted with ethyl acetate (80 mL. Times.3), the organic phases were combined, washed with water (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the objective compound 4 (10 mg, yield: 17.3%).

MS m/z(ESI):532.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.35(s,1H),7.95(s,1H),7.57(t,2H),7.21-7.15(m,3H),7.08-7.05(m,2H),6.93(d,1H),5.89-5.79(m,2H),5.29-5.25(m,4H),4.03(t,2H),3.86(t,2H),2.49(s,3H)。

Example 5

5- (4-acrylamidophenyl) -6- (4- ((6-methylpyridin-2-yl) oxy) phenyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-7-carboxamide 5

First step

2- (4-bromophenoxy) -6-methylpyridine 5c

A mixture of 2-bromo-6-methylpyridine 5a (10.05 g,58.42mmol, after medicine), anhydrous potassium carbonate (12 g,86.82 mmol) and 4-bromophenol 5b (15.16 g,87.62mmol, after medicine) was heated to 200℃under nitrogen atmosphere and stirred for reaction for 6 hours. The reaction mixture was cooled to room temperature, 500mL of water was added, the mixture was extracted with ethyl acetate (300 mL. Times.3), and the organic phases were combined and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave a residue which was purified by silica gel column chromatography with eluent system a to give the objective compound 5c (12.5 g, yield 81%).

Second step

(E) -3- (4- ((6-methylpyridin-2-yl) oxy) phenyl) acrylic acid ethyl ester 5d

Compound 5c (11 g,41.64 mmol), ethyl acrylate (7.36 g,73.59mmol,8 mL), triethylamine (8.45 g,83.56mmol,11.6 mL) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (2.8 g,4.16 mmol) were added to 150mL of N, N-dimethylformamide under nitrogen and heated to 100deg.C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system a to give the objective compound 5d (6.6 g, yield 58.8%).

Third step

4- (4- ((6-methylpyridin-2-yl) oxy) phenyl) -1H-pyrrole-3-carboxylic acid ethyl ester 5e

P-toluenesulfonylmethyloisonitrile (8.77 g,44.91mmol, shaotong chemical) was dissolved in 150mL tetrahydrofuran, cooled to-78℃and hexamethyl diamido lithium silyl (45 mL,45mmol, 1M) was added and the reaction stirred for 30 min. Compound 5d (8.06 g,29.93 mmol) was added thereto, and the mixture was warmed to room temperature after the addition, followed by stirring for 3 hours. 80mL of water was added and the solution was separated, the aqueous phase was extracted with ethyl acetate (300 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the objective compound 5e (5.4 g, yield: 55.9%).

Fourth step

1- (2- ((tert-Butoxycarbonyl) amino) ethyl) -4- (4- ((6-methylpyridin-2-yl) oxy) phenyl) -1H-pyrrole-3-carboxylic acid ethyl ester 5f

Compound 5e (4.9 g,15.20 mmol) was dissolved in 100mL of tetrahydrofuran, sodium hydrogen (730 mg,18.37mmol, 60% purity) was added, and the reaction was stirred for 0.5 h. Then, 1,2, 3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2, 2-dioxide (3.75 g,16.79mmol, medical stone technology) was added, and the mixture was stirred and reacted for 1 hour, and the temperature was raised to 50℃for 3 hours. The reaction solution was cooled to room temperature, 10% aqueous citric acid was added to a solution pH of less than 7, the solution was separated, the aqueous phase was extracted with ethyl acetate (300 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the objective compound 5f (7.5 g, yield 105.9%) which was used in the next reaction without further purification.

MS m/z(ESI):466.1[M+1]。

Fifth step

1- (2-aminoethyl) -4- (4- ((6-methylpyridin-2-yl) oxy) phenyl) -1H-pyrrole-3-carboxylic acid ethyl ester 5g

Compound 5f (7.5 g,16.11 mmol) was dissolved in 50mL of dichloromethane, 10mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, a saturated sodium hydrogencarbonate solution was added to the residue to a pH of more than 7, 50mL of methylene chloride was added, the mixture was separated, the aqueous phase was extracted with methylene chloride (50 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give 5g (3.5 g, yield: 59.4%) of the objective compound.

MS m/z(ESI):366.3[M+1]。

Sixth step

1- (2- ((tert-Butoxycarbonyl) amino) ethyl) -4- (4- ((6-methylpyridin-2-yl) oxy) phenyl) -1H-pyrrole-3-carboxylic acid 5H

5g (3.5 g,9.57 mmol) of the compound was dissolved in a mixed solvent of 48mL of water and methanol (V: V=1:5), sodium hydroxide (2 g,50 mmol) was added, and the mixture was heated to 80℃to react overnight. The reaction mixture was cooled to room temperature, followed by addition of di-tert-butyl dicarbonate (3.23 g,14.79mmol,3.4 mL), stirring for 1 hour, and then additional addition of di-tert-butyl dicarbonate (3.23 g,14.79mmol,3.4 mL) was performed twice, and stirring was continued for 3 hours. 1N hydrochloric acid was carefully added to adjust the pH of the solution to less than 7, dichloromethane extraction (80 mL. Times.3) was added, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the objective compound for 5h (3.5 g, yield 83.5%). It was used in the next reaction without further purification.

MS m/z(ESI):438.4[M+1]。

Seventh step

(2- (3-carboxamide-4- (4- ((6-methylpyridin-2-yl) oxy) phenyl) -1H-pyrrol-1-yl) ethyl) carbamic acid tert-butyl ester 5i

Compound 5h (3.5 g,8.00 mmol) was dissolved in 100mL of N, N-dimethylformamide, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (4.56 g,11.99 mmol), diisopropylethylamine (1.53 g,11.83mmol,2.1 mL) and a 1, 4-dioxane solution of ammonia (39.9 mL, 0.4M) were added and the reaction stirred for 16 h. The reaction solution was diluted with 800mL of ethyl acetate, washed with water (150 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the objective compound 5i (3 g, yield: 85.9%).

MS m/z(ESI):437.4[M+1]。

Eighth step (tert-butyl 2- (2-bromo-4-carboxamido-3- (4- ((6-methylpyridin-2-yl) oxy) phenyl) -1H-pyrrol-1-yl) ethyl) carbamate 5j

Compound 5i (3 g,6.87 mmol) was dissolved in 80mL of dichloromethane and N-bromosuccinimide (978 mg,5.49 mmol) was added slowly in portions and the reaction was stirred for 2 hours. After adding 30mL of a saturated sodium hydrogencarbonate solution and 5mL of a saturated sodium thiosulfate solution, the liquid was separated, the aqueous phase was extracted with methylene chloride (30 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the objective compound 5j (2.61 g, yield: 73.6%).

MS m/z(ESI):514.8[M+1]。

Ninth step

(2- (2-bromo-4-cyano-3- (4- ((6-methylpyridin-2-yl) oxy) phenyl) -1H-pyrrol-1-yl) ethyl) carbamic acid tert-butyl ester 5k

Compound 5j (932 mg,1.80 mmol) was dissolved in 40mL of dichloromethane, triethylamine (1.82 g,18.00mmol,2.5 mL) was added, and trifluoroacetic anhydride (0.6 g,2.85mmol,0.4 mL) was added dropwise and the reaction was stirred for 2 hours. Saturated sodium bicarbonate solution was added, the solution was separated, the aqueous phase was extracted with dichloromethane (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the objective compound 5k (737 mg, yield: 81.9%).

MS m/z(ESI):497.5[M+1]。

Tenth step

(2- (4-cyano-3- (4- ((6-methylpyridin-2-yl) oxy) phenyl) -2- (4-nitrophenyl) -1H-pyrrol-1-yl) ethyl) carbamic acid tert-butyl ester 5l

4-Nitrophenyl boronic acid (500 mg,2.99 mmol), compound 5k (1.24 g,2.49 mmol), potassium carbonate (516 mg,3.73 mmol), and Tetratriphenylphosphine palladium (288 mg, 249.2. Mu. Mol) were added to a mixed solvent of 48mL of water and 1, 4-dioxane (V: V=1:5) under a nitrogen atmosphere, and the mixture was heated to 95℃for 16 hours. The reaction solution was cooled to this point and concentrated under reduced pressure. 60mL of methylene chloride was added to the residue to dissolve it, and the resulting residue was filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give 5L (1.24 g, yield: 92.1%) of the objective compound.

MS m/z(ESI):540.4[M+1]。

Eleventh step

(2- (2-bromo-3-cyano-4- (4- ((6-methylpyridin-2-yl) oxy) phenyl) -5- (4-nitrophenyl) -1H-pyrrol-1-yl) ethyl) carbamic acid tert-butyl ester 5m

Compound 5l (1.24 g,2.29 mmol) was dissolved in 40mL chloroform, N-bromosuccinimide (440 mg,2.47 mmol) was added, and the mixture was heated to 60℃to react for 3 hours. After cooling the reaction solution to room temperature, 10mL of a saturated sodium sulfite solution was added, and the solution was separated, the aqueous phase was extracted with methylene chloride (30 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the objective compound 5m (1.38 g, yield: 97%).

MS m/z(ESI):618.0[M+1]。

Twelfth step

7-cyano-6- (4- ((6-methylpyridin-2-yl) oxy) phenyl) -5- (4-nitrophenyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-1-carboxylic acid tert-butyl ester 5n

Compound 5m (1.38 g,2.23 mmol) was dissolved in 40mL of 1, 4-dioxane under nitrogen, cesium carbonate (1.09 g,3.34 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropyloxy-1, 1 '-biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (463 mg, 557.1. Mu. Mol) were added and heated to 100℃for reaction for 48 hours. The reaction solution was cooled to room temperature, then filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the objective compound 5n (904 mg, yield: 75.3%).

Thirteenth step

6- (4- ((6-methylpyridin-2-yl) oxy) phenyl) -5- (4-nitrophenyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-7-carboxamide 5o

Compound 5n (466 mg, 866.8. Mu. Mol) was added to 12mL of 85% phosphoric acid and reacted for 2.5 hours at 100 ℃. The reaction solution was cooled to room temperature, diluted with water, and then added with aqueous ammonia until the pH of the reaction solution became more than 7, extracted with methylene chloride (40 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the objective compound 5o (293 mg, yield: 74.2%). MS m/z (ESI): 456.4[ M+1].

Fourteenth step

5- (4-aminophenyl) -6- (4- ((6-methylpyridin-2-yl) oxy) phenyl) -2, 3-dihydro-1H-pyrrolo [1,2-a ] imidazole-7-carboxamide 5p

Compound 5o (360 mg,790.4 μmol) was dissolved in a mixed solvent of 100mL of tetrahydrofuran and methanol (V: v=1:1) under a hydrogen atmosphere, 10% palladium on carbon (106 mg,996 μmol) was added, and the reaction was stirred for 16 hours. The filtrate was filtered, and concentrated under reduced pressure to the objective compound 5p (338 mg, yield: 100%). It was used in the next reaction without further purification.

Fifteenth step

Compound 5p (156 mg, 366.6. Mu. Mol) was dissolved in 10mL of N, N-dimethylformamide, and acrylic acid (29 mg, 402.4. Mu. Mol), N, N-diisopropylethylamine (95 mg, 735.0. Mu. Mol, 130. Mu.L) and 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (210 mg, 552.2. Mu. Mol) were added and the mixture was stirred for 2 hours. 50mL of ethyl acetate was added, followed by dilution and washing with water (20 mL. Times.3), saturated sodium chloride washing (20 mL. Times.1), drying over anhydrous sodium sulfate, and concentrating under reduced pressure, and the residue was purified by preparative chromatography to give the objective compound 5 (30 mg, yield: 17.0%).

MS m/z(ESI):480.4[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ7.61(t,1H),7.46(d,1H),7.37(s,1H),7.34-7.31(m,2H),7.12-7.09(m,2H),7.08-7.06(m,2H),6.93(d,1H),6.67(d,1H),6.44(dd,1H),6.25(dd,1H),5.78(dd,2H),5.25(s,1H),5.01(s,2H),4.17-4.14(m,2H),4.06-4.02(m,2H),2.48(s,3H)。

Example 6

7- (3-fluoro-4- (pyrrolidine-1-carbonyl) phenyl) -6- (4- (2-fluoroacrylamide) phenyl) -3, 4-dihydro-1H-pyrrolo [2,1-c ] [1,4] oxazine-8-carboxamide 6

First step

(2-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) phenyl) (pyrrolidin-1-yl) methanone 6b

(4-bromo-2-fluorophenyl) (pyrrolidin-1-yl) methanone 6a (6.1 g,22.51mmol, aikang), pinacol biborate (11.4 g,45.02mmol, shaosheng chemical), potassium acetate (6.6 g,67.53 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (2.1 g,2.25mmol, adamas) was added to 150mL of 1, 4-dioxane under nitrogen and heated to 95℃for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to give the objective compound 6b (8.2 g, yield: > 100%).

The second step (tert-butyl 4- (8-carboxamido-7- (3-fluoro-4- (pyrrolidine-1-carbonyl) phenyl) -3, 4-dihydro-1H-pyrrolo [2,1-c ] [1,4] oxazin-6-yl) carbamate 6c

3g (300 mg, 687.6. Mu. Mol) of compound 6b (284 mg, 693.89. Mu. Mol), sodium carbonate (146 mg,1.37 mmol) and tetrakis (triphenylphosphine) palladium (1599 mg, 137.5. Mu. Mol) were added to 30mL of water and 1, 4-dioxane (V: V=1:5) under a nitrogen atmosphere, and heated to 95℃for reaction for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, 50mL of methylene chloride was added to the residue to dissolve, and then, filtration was carried out, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the objective compound 6c (280 mg, yield: 74.2%).

MS m/z(ESI):549.1[M+1]。

Third step

6- (4-aminophenyl) -7- (3-fluoro-4- (pyrrolidine-1-carbonyl) phenyl) -3, 4-dihydro-1H-pyrrolo [2,1-c ] [1,4] oxazine-8-carboxamide 6d

Compound 6c (280 mg, 510.38. Mu. Mol) was dissolved in 10mL of methylene chloride, 3mL of trifluoroacetic acid was added thereto, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, a saturated sodium hydrogencarbonate solution was added to the residue to give a solution having a pH of more than 7, the aqueous phase was extracted with methylene chloride (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the objective compound 6d (200 mg, yield: 87.4%).

MS m/z(ESI):449.2[M+1]。

Fourth step

7- (3-fluoro-4- (pyrrolidine-1-carbonyl) phenyl) -6- (4- (2-fluoroacrylamide) phenyl) -3, 4-dihydro-1H-pyrrolo [2,1-c ] [1,4] oxazine-8-carboxamide oxa 6

Compound 6d (180 mg, 401.34. Mu. Mol) and 2-fluoroacrylic acid (72.3 mg, 802.75. Mu. Mol, adamas), N, N-diisopropylethylamine (319 mg,2.00mmol, adamas) were dissolved in 20mL of N, N-dimethylformamide, 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (305 mg, 802.7. Mu. Mol, bi) was added at 0℃and the reaction was stirred at room temperature for 2 hours. 50mL of water was added and extracted with ethyl acetate (80 mL. Times.3), the organic phases were combined, washed with water (30 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the objective compound 6 (5 mg, yield: 2.4%).

MS m/z(ESI):521.3[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ7.93(s,1H),7.54(t,2H),7.37-7.34(m,2H),7.13-7.09(m,2H),6.98-6.95(m,1H),5.88-5.78(dd,2H),5.29-5.25(m,1H),5.22(s,1H),5.09(s,2H),4.02(t,2H),3.83(t,2H),3.63(t,2H),3.29(t,2H),1.98-1.89(m,4H)。

Biological evaluation

The present disclosure is explained in further detail below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1: inhibition of FGFR2 kinase by the compounds of the present disclosure

FGFR2 kinase activity of the test compounds was tested using the mobility shift method (Mobility shift assay). The test concentration was 1000nM, 3-fold dilution, 10 concentrations, multiplex assay.

1.1 Experimental materials

1.1.1 reagents and consumables

Reagent name	Suppliers of goods	Goods number	Lot number
				FGFR2	Carna	08-134	13CBS-0735H
Kinase substrate 22	GL	112393	P200403-CL112393
				DMSO	Sigma	D8418-1L	SHBG3288V
384 well plate	Corning	3573	12619003

1.1.2 instruments

Centrifuge (manufacturer: eppendorf type 5430)

Enzyme label instrument (manufacturer: perkin Elmer model Caliper EZ ReaderII)

Echo550 (manufacturer: labcyte, model: echo 550)

1.2 Experimental procedure

(1) The compound was diluted with DMSO and stock concentration was 10mM. Compound test concentration was 1000nM, 3-fold gradient dilution was performed, 10 concentrations were set up and multiplex well detection was performed.

(2) 100% DMSO solutions were diluted to 100-fold final concentration in 384 well plates. The final concentration of 250nL of compound was transferred 100-fold to the plate of interest 3573 using a dispenser Echo 550.

(3) A2.5-fold final concentration of kinase solution was prepared with 1 Xkinase buffer.

(4) Adding 10 mu L of kinase solution with 2.5 times of final concentration to each of the compound well and the positive control well; mu.L of 1 Xkinase buffer was added to the negative control wells.

(5) Centrifugation at 1000rpm for 30s, shaking and mixing the reaction plate, and incubating for 10min at room temperature.

(6) A25/15 fold final concentration of the mixed solution of ATP/kinase substrate 22 was prepared with 1 Xkinase buffer.

(7) The reaction was initiated by adding 15. Mu.L of the mixed solution of ATP/kinase substrate 22.

(8) The 384-well plate was centrifuged at 1000rpm for 30 seconds, and after shaking and mixing, incubated at room temperature for a corresponding period of time.

(9) The kinase reaction was stopped by adding 30. Mu.L of stop detection solution, centrifuging at 1000rpm for 30 seconds, and shaking and mixing.

(10) The conversion was read with Caliper EZ Reader.

TABLE 1 inhibition of FGFR2 kinase by the compounds of the present disclosure

Conclusion: the compounds of the present disclosure have inhibitory effects on FGFR 2.

Test example 2: inhibition of FGFR1 and FGFR2 kinases by compounds of the present disclosure

The FGFR1 and FGFR2 kinase activities of the test compounds were tested using the ADP GLO method. FGFR2 was tested at 1000nm and FGFR1 at 10 μm, 3-fold gradient dilution, 10 concentrations, multiplex well assay.

2.1 Experimental materials

2.1.1 reagents and consumables

2.1.2 instruments

Instrument name	Manufacturer' s	Model information
			Centrifugal machine	Beckman coulter	Allegra X-12 centrifuge
Enzyme label instrument	BMG LABTECH	PHERASTAR HS

2.2 Experimental procedure

(1) 1 Xkinase buffer (40 mM Tris, pH= 7.5;20mM MgCl2;0.1mg/mL BSA) was prepared and 50. Mu.M final concentration of DTT and 2mM MnCl2 was added;

(2) Diluting the compound solution with DMSO, and performing 3-time gradient dilution to set 10 concentration gradients in total; then 1.5. Mu.L of the compound was added to 98.5. Mu.L of kinase buffer;

(3) Preparing a mixed solution of ATP and PolyE4Y1 (Poly (4:1 Glu, tyr)) so that the concentration of ATP and PolyE4Y1 is 6 times of the final concentration, and preparing a reaction mixed solution in an equal volume;

(4) Diluting the FGFR1/FGFR2 kinase solution to 3 times of final concentration respectively by using a kinase buffer solution;

(5) Taking a 96-well plate or a 384-well plate, adding 2 mu L of diluted compound solution into each well, and centrifuging;

(6) Adding 2 mu L of kinase solution into each hole, centrifuging, shaking and mixing for 2min, and then incubating for 60min at room temperature;

(7) Adding 2 mu L/hole of mixed solution of ATP and PolyE4Y1, centrifuging, shaking and mixing for 2min, and reacting at room temperature for 60min;

(8) Adding 6 mu L/hole ADP GLO stop solution, centrifuging, shaking and mixing for 2min, and reacting at room temperature for 40min;

(9) Adding 12 mu L/Kong Jimei detection reagent, incubating for 40min at room temperature, and detecting a luminescence signal by using an enzyme-labeled instrument.

TABLE 2 inhibition of FGFR1 and FGFR2 kinases by the compounds of the present disclosure

Test example 3: proliferation inhibitory effects of the disclosed compounds on SNU-16 and Li-7 cells

The proliferation inhibition of SNU-16 and Li-7 cells by the compounds was examined using the CTG method. For SNU-16 and Li-7 cells, the highest concentration of the compound was 1000nM and 10. Mu.M, respectively, and 3-fold gradient dilutions were performed, setting 9 concentrations in total, and multiplex assay.

3.1 Experimental materials

3.1.1 reagents and consumables

3.1.2 instruments

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3.2 Experimental procedure

(1) SNU-16 (ATCC cell Bank, #CRL-5974) and Li-7 fineCells (Bai Biotechnology Co., nanjing, # CBP 60205) were plated at a density of 1250/well, 50. Mu.L/well in 96 Kong Heibian cell culture plates (Corning, # 3603) and the peripheral wells were blocked with 100. Mu.L PBS. Placed at 37 degrees CO ₂ Culturing in an incubator for 24 hours;

(2) Compound stock was diluted to 500 μm or 5mM with DMSO, and 3-fold gradient dilution was performed with DMSO, and 9 concentrations were set up in total, DMSO as a negative control group. Then 1. Mu.L of the diluted compound was added to 250. Mu.L of RPMI-1640 complete medium, and the above compound was diluted 250-fold;

(3) Adding 50 mu L of diluted medicines into a cell culture plate, so that the highest concentration of SNU-16 cell medicines and Li-7 cell medicines is 1000nM and 10uM respectively, carrying out gradient dilution by 3 times, carrying out multi-well detection on 9 concentrations, and the final concentration of DMSO is 0.2%;

(4) After the compound was added, the cell culture plate was placed in 37 degrees CO ₂ Culturing in an incubator, SNU-16 culturing for 3 days, and culturing Li-7 cells for 6 days;

(5) 50. Mu.L CellTiter-Glo reagent (Promega, #G7572) was added to each well, and the mixture was stirred on a shaker for 2min, incubated at room temperature for 28min, and detected on an ELISA reader after the signal had stabilized.

TABLE 3 proliferation inhibition of SNU-16 and Li-7 cells by the compounds of the present disclosure

Conclusion: the compounds of the present disclosure have selective inhibition of SNU-16 cells relative to Li-7 cells.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

Z ¹ 、Z ² and Z ³ Identical or different and eachIndependently a carbon atom or a nitrogen atom, at least one of which is a nitrogen atom;

ring a is aryl or heteroaryl;

L ¹ And L ² Identical or different and are each independently selected from the group consisting of chemical bonds, - (CR) ^h R ⁱ ) _r -、-NR ^5a -, O atom, -O- (CR) ^h R ⁱ ) _r -、-(CR ^h R ⁱ ) _r -O-、-(CR ^h R ⁱ ) _r -NR ^5a -、-NR ^5a -(CR ^h R ⁱ ) _r -、-C(O)-、-O-C(O)-、-C(O)O-、-S(O) _p -、-NR ^5a -C(O)-、-C(O)-NR ^5a -、-C(O)-NR ^5a -(CR ^h R ⁱ ) _r -、-(CR ^h R ⁱ ) _r -NR ^5a -C(O)-、-NR ^5a -C(O)-(CR ^h R ⁱ ) _r -、-NR ^5a -S(O) ₂ -、-S(O) ₂ -NR ^5a -, divalent cycloalkyl, divalent heterocyclic, arylene, and heteroarylene groups, wherein each of said divalent cycloalkyl, divalent heterocyclic, arylene, and heteroarylene groups is independently optionally substituted with a member selected from the group consisting of halogen, oxo, alkyl, haloalkyl, methylene, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, -NR ⁸ R ⁹ One or more substituents of hydroxyl and hydroxyalkyl groups;

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

ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁴ selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, -C (O) R ¹⁰ 、-C(O)OR ¹⁰ 、Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with a member selected from the group consisting of halogen, oxoAlkyl, haloalkyl, methylene, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, -NR ⁸ R ⁹ One or more substituents of hydroxyl and hydroxyalkyl groups;

R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ identical or different and are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl And heteroaryl, wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, and haloalkoxy;

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

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

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

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

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

p is 0, 1 or 2; and is also provided with

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

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Z ¹ Is a nitrogen atom, Z ² And Z ³ Are all carbon atoms.

3. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R ^a And R is ^b Are all hydrogen atoms.

4. A compound of 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 ⁴ Wherein L is ² And R is ⁴ As defined in claim 1.

5. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a compound of general formula (II):

wherein:

s1 is 0, 1 or 2;

ring a, ring B, ring C, L ¹ 、L ² 、W、X、Y、R ¹ To R ⁴ M, q and t are as defined in claim 1.

6. A compound of general formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl or pyridinyl.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein Y is CR ^c R ^d ，R ^c And R is ^d Of the general formula(I) Is defined in (a); preferably Y is CH ₂ 。

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein W is CR ^c R ^d Or NR (NR) ^e ，R ^c 、R ^d And R is ^e As defined in claim 1.

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein X is CR ^c R ^d Or an oxygen atom, R ^c And R is ^d As defined in claim 1.

10. A compound of general formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (III):

wherein:

w is CR ^c R ^d Or NR (NR) ^e ；

X is CR ^c R ^d Or an oxygen atom;

m is 0 or 1;

s1 is 0, 1 or 2;

t1 is 0, 1 or 2;

ring a, ring C, L ¹ 、L ² 、R ¹ To R ⁴ 、R ^c 、R ^d 、R ^e And q is as defined in claim 1.

11. A compound of general formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein ring a is phenyl.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein L ¹ Is an oxygen atom or C (O); preferably L ¹ Is an oxygen atom.

13. A compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein L ² is-NR ^5a -, wherein R is ^5a As defined in claim 1.

14. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R ⁴ Is thatWherein R is ¹¹ To R ¹³ As defined in claim 1.

15. A compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from phenyl, pyridinyl, pyrimidinyl and tetrahydropyrrolyl; preferably ring C is selected from phenyl, pyridyl and pyrimidinyl.

16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 15, wherein each R ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, C _1-6 Hydroxyalkyl and-NR ⁶ R ⁷ Wherein R is ⁶ And R is ⁷ As defined in claim 1.

17. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein each R ² Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl, halogenPlain, cyano, -NR ⁶ R ⁷ 、C _1-6 Alkoxy, C _1-6 Haloalkoxy and C _1-6 Hydroxyalkyl, wherein R is ⁶ And R is ⁷ As defined in claim 1.

18. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein each R ³ Identical or different and are each independently selected from hydrogen atoms, 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, wherein R is ⁶ And R is ⁷ As defined in claim 1.

19. A compound of general formula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

20. a compound represented by the general formula (IIa) or a salt thereof,

wherein:

L ² is-NR ^5a -；

Ring a, ring B, ring C, L ¹ 、W、X、Y、R ¹ To R ³ 、R ^5a S1, m, q and t are as defined in claim 5.

21. The compound of claim 20, or a salt thereof, selected from the following compounds:

22. a process for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, comprising:

wherein:

l is halogen or OH; preferably, L is halogen; further preferably, L is a chlorine atom;

L ² is-NR ^5a -；

R ⁴ Is that

Ring a, ring B, ring C, L ¹ 、W、X、Y、R ¹ To R ³ 、R ^5a 、R ¹¹ To R ¹³ S1, m, q and t are as defined in claim 5.

23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

24. Use of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, in the manufacture of a medicament for inhibiting FGFR 2.

25. Use of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, in the manufacture of a medicament for the treatment and/or prevention of a tumor; preferably the tumour is a cancer; the cancer is preferably selected from the group consisting of cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, stomach cancer, ovarian cancer, colorectal cancer, 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 nerve epithelium tumor, glioma, ependymoma, neuroblastoma, gangliocytoma, neuroblastoma, pineal tumor, meningioma, neurofibroma, schwannoma, and wilms' tumor; more preferably selected from the group consisting of cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, thyroid cancer, stomach cancer, ovarian cancer, colorectal cancer, endometrial cancer, and urothelial cancer.