Heterocyclic derivative inhibitor as well as preparation method and application thereof

Abstract

The invention relates to a heterocyclic derivative inhibitor as well as a preparation method and application thereof. In particular, the present invention relates to a compound represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and uses of the compound as an inhibitor in preparation of drugs for treatment and / or prevention of cancer and cartilage hypoplasia related diseases.

Description

Heterocyclic derivative inhibitor, preparation method and application thereof Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a heterocyclic derivative inhibitor, a preparation method and an application thereof. Background Art

[0002] FGFR (Fibroblast Growth Factor Receptor) is a tyrosine kinase, comprising four isoforms: FGFR1, FGFR2, FGFR3, and FGFR4. Upon ligand binding, FGFR dimerizes and autophosphorylates, activating downstream signaling pathways including RAS-RAF-MAPK, PI3K-AKT, STAT, and PLCγ. FGFR-mediated signaling plays a crucial role in cell proliferation, migration, differentiation, and survival.

[0003] Overactivation caused by various mutations of FGFR is widely present in many tumors, and inhibition of FGFR is a potential target for the treatment of various cancers. A study published in Clinical Cancer Research in 2015 (Clin Cancer Res; 22(1) January 1, 2016) showed that approximately 7.1% of cancers have FGFR aberrations. FGFR1 amplification aberrations are present in approximately 20% of lung squamous cell carcinomas and approximately 20% of breast cancers. FGFR2 rearrangement aberrations are present in approximately 15% of bile duct carcinomas, FGFR2 point mutations are present in approximately 10% of endometrial cancers, and FGFR2b amplification is present in approximately 10% of gastric cancers. FGFR3 point mutations are present in approximately 20% of metastatic urothelial carcinomas.

[0004] FGFR inhibitors hold great promise as a promising drug in the pharmaceutical industry, potentially becoming a first-line treatment for cholangiocarcinoma and a new option for targeted cancer therapy across a wide range of cancer types. They are also expected to be effective for patients with a variety of FGFR aberrations. However, the current standard treatment for cholangiocarcinoma is chemotherapy, which carries a poor prognosis and lacks a second-line treatment option. The main challenges with FGFR inhibitors include the development of drug resistance in patients approximately seven months after treatment, and the toxicity of drugs targeting the FGFR1 target, which can cause hyperphosphatemia.

[0005] Currently, two pan-FGFR inhibitors are available globally. In April 2019, Johnson & Johnson's Balversa (erdafitinib, JNJ-42756493) was approved for patients with locally metastatic or metastatic bladder cancer harboring FGFR3 or FGFR2 point mutations. In April 2020, Incyte's Pemazyre (pemigatinib, INCB054828) was approved for patients with previously treated advanced cholangiocarcinoma harboring FGFR2 gene fusions or rearrangements.

[0006] Although FGFR inhibitors have been reported to have therapeutic effects on various cancers, potent and highly selective FGFR inhibitors have not yet been discovered. The present invention aims to provide novel compounds that have FGFR inhibitory activity and are useful as anticancer agents.

[0007] Summary of the Invention

[0008] The object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) has the following structure:

[0009] in:

[0010] Ring A is a monocyclic heteroaryl group;

[0011] M1 is N or CR m1 ;

[0012] M2 is N or CR m2 ;

[0013] L1, L2 and L3 are each independently selected from a bond, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, -(CH2) n C(O)(CR aa R bb ) n1 -、-(CH2) n C(O)NR aa (CR aa R bb ) n1 -、-(CH2) n (CR aa R bb ) n2 -、-(CR aa R bb ) n O(CH2) n1 -、-(CH2) n S(CR aa R bb ) n3 -、-(CR aa Rbb ) n3 (CH2) n NR cc -、-(CH2) n NR aa (CR bb R cc ) n -、-(CH2) n NR aa C(O)-、-(CH2) n P(O) p R aa -、-(CH2) n S(O) m -、-(CH2) n S(O) m NR aa -、-C(=NR aa )NR aa -、-C(=CR bb R cc )-、-C(=S)NR aa - and -(CH2) n NR aa S(O) m -;

[0014] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR a 、-C(O)R a 、-SR a 、S(O)R a or S(O)2R a , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0015] R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR b 、-C(O)R b 、-SR b 、S(O)R b or S(O)2R b , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0016] R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0017] R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR d 、-C(O)R d 、-SR d 、S(O)R d or S(O)2R d , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0018] R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR e 、-C(O)R e 、-SR e 、S(O)R e or S(O)2R e , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0019] R m1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR f 、-C(O)R f 、-SR f 、S(O)R f or S(O)2Rf , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0020] R m2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR g 、-C(O)R g 、-SR g 、S(O)R g or S(O)2R g , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0021] Alternatively, one of R2 and one of R3 are linked to adjacent atoms to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, and the cycloalkyl, heterocyclic, aryl and heteroaryl group may optionally be further substituted;

[0022] Alternatively, one R3 and one R4 are linked to adjacent atoms to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, and the cycloalkyl, heterocyclic, aryl and heteroaryl group may optionally be further substituted;

[0023] R a 、R b 、R c 、R d 、R e 、R f and R g each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0024] R aa 、R bb and R cceach independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0025] Or, R aa With R bb Together with adjacent atoms, they form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

[0026] Or, R bb With R cc Together with adjacent atoms, they form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

[0027] x is 0, 1, 2, 3, 4, 5, or 6;

[0028] y is 0, 1, 2, 3, 4, 5, or 6;

[0029] z is 0, 1, 2, 3, 4, 5, or 6;

[0030] p is 0, 1, 2, or 3;

[0031] m is 0, 1, 2, or 3;

[0032] n, n1, n2, n3 and n4 are each independently 0, 1, 2 or 3.

[0033] In certain embodiments of the present invention, the compound is as shown in formula (II), formula (II-1), formula (II-2) or formula (II-3),

[0034] in,

[0035] Ring A is a heteroaryl group, which is a monocyclic heteroaryl group or a polycyclic heteroaryl group;

[0036] L1 is selected from -(CH2) n C(O)(CR aa R bb ) n1 -、-(CH2) n C(O)NR aa (CR aa R bb ) n1 -、-(CH2) n (CR aa Rbb ) n2 -or-(CR aa R bb ) n O(CH2) n1 -;

[0037] R aa and R bb Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0038] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 Aryl, 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl;

[0039] Preferably, R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 Aryl, 5-14 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl;

[0040] R2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0041] R3 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 3-8 Cycloalkyl substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -C 1-6 Alkyl-R c 、-NHR c 、-OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c ; Preferably, R3 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 3-8 Cycloalkyl substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 Aryl, 5-14 membered heteroaryl, -OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c ;

[0042] R c independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1- 6 alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, hydroxyl, C 1-6 Alkyl-substituted amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are optionally substituted with hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 one or more substitutions of aryl or 5-14 membered heteroaryl;

[0043] Preferably, R c independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0044] R4 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0045] R6, R7 and R8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- 6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 Aryl, 5-14 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl;

[0046] Alternatively, one of R2 and one of R3 are connected to adjacent atoms to form C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1- 6 alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 one or more substitutions of aryl or 5-14 membered heteroaryl;

[0047] Alternatively, one of R3 and one of R4 are connected to adjacent atoms to form C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1- 6 alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 one or more substitutions of aryl or 5-14 membered heteroaryl;

[0048] x is 0, 1, 2, 3, 4, 5, or 6;

[0049] y is 0, 1, 2, 3, 4, 5, or 6;

[0050] z is 0, 1, 2, 3, 4, 5, or 6;

[0051] n is 0, 1, 2, or 3;

[0052] n1 is 0, 1, 2 or 3; and

[0053] n2 is 0, 1, 2 or 3.

[0054] In certain embodiments of the present invention,

[0055] Ring A is selected from a monocyclic heteroaryl group or a polycyclic heteroaryl group;

[0056] The monocyclic heteroaryl group is preferably a 5-12-membered heteroaryl group; more preferably a 5-membered or 6-membered heteroaryl group; further preferably a 5-membered or 6-membered heteroaryl group containing 1-3 N, O or S atoms;

[0057] The monocyclic heteroaryl group is preferably

[0058] The monocyclic heteroaryl group is more preferably the following group:

[0059] In certain embodiments of the present invention, the compound is represented by formula (III), formula (III-1), formula (III-2), formula (III-3), formula (III-4), formula (III-5), formula (III-6), formula (III-7) or formula (III-8):

[0060] Ring B is independently a 5-10 membered heterocyclic group, preferably a nitrogen-containing 5-10 membered heterocyclic group, more preferably a 5-7 membered heterocyclic group containing one nitrogen atom, and further preferably

[0061] Ring C is a 5-10 membered heterocyclic group, preferably a nitrogen-containing 5-10 membered heterocyclic group, more preferably a 3-6 membered heterocyclic group containing one nitrogen atom, and further preferably

[0062] L1 is selected from -(CH2) n C(O)(CR aa R bb ) n1 -、-(CH2) n C(O)NR aa (CR aa R bb ) n1 -、-(CH2) n (CR aa R bb ) n2 -or-(CR aa R bb ) n O(CH2) n1 -;

[0063] L4 is selected from -(CH2) n C(O)(CR aa R bb ) n1 -、-(CH2) n C(O)NR aa (CR aa R bb ) n1 -、-(CH2) n (CR aa R bb ) n2 -or-(CR aa R bb ) n O(CH2) n1 -, preferably -C(O)-;

[0064] R aa and R bb Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-6 hydroxyalkyl;

[0065] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, cyano substituted C 1-3 Alkyl, C 1-3 Alkyl-CO-, halogenated C 1-3 Alkyl, halogenated C 2-4 Alkenyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl;

[0066] Preferably, R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1- 3 alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl;

[0067] More preferably, R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl, 5-6 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl;

[0068] R2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0069] R 31 、R 32 and R 33 are each independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 3-8 Cycloalkyl substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -C 1-6 Alkyl-R c 、-NHR c 、-OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c Preferably, R 31 、R 32 and R 33 are each independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, -C 1-3 Alkyl-R c 、-NHR c or -C(O)R c ;

[0070] Preferably, R 31 、R 32 and R 33 are each independently selected from hydrogen, deuterium, halogen, amino, C 1-6Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 3-8 Cycloalkyl substituted C 1- 6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c Preferably, R 31 、R 32 and R 33 are each independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or -C(O)R c ;

[0071] R c independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1- 6 alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0072] R4, R 10 、R 11 and R 12are each independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1- 6 alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0073] R6, R7, R8 and R9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 Aryl, 5-14 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl;

[0074] u is 0, 1, 2, 3, 4, 5, or 6;

[0075] v is 0, 1, 2, 3, 4, 5, or 6;

[0076] w is 0, 1, 2, 3, 4, 5, or 6;

[0077] x is 0, 1, 2, 3, 4, 5, or 6;

[0078] z is 0, 1, 2, 3, 4, 5, or 6;

[0079] n is 0, 1, 2, or 3;

[0080] n1 is 0, 1, 2 or 3; and

[0081] n2 is 0, 1, 2 or 3.

[0082] In certain embodiments of the present invention, the compound is represented by formula (IV):

[0083] in:

[0084] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 Aryl, 5-15 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 One or more substitutions of aryl, 5-14 membered heteroaryl;

[0085] R2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0086] R 32 Selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 3-8 Cycloalkyl substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -C 1-6 Alkyl-R c 、-NHR c 、-OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c ;

[0087] R c independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1- 6 alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0088] R4 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0089] R6, R7, R8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1- 6 alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1- 6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C1- 3 alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl;

[0090] x is 0, 1, 2, 3, 4, 5, or 6;

[0091] z is 0, 1, 2, 3, 4, 5 or 6.

[0092] In certain embodiments of the present invention, the compound is represented by formula (V):

[0093] In certain embodiments of the present invention, R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, oxo, thioxo, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3- 6-membered cycloalkyl, 3-8-membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl;

[0094] R2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl or 5-10 membered heteroaryl;

[0095] R 32 Selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 3-6 Cycloalkyl substituted C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-6 Alkyl-R c 、-NHR c 、-OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c ;

[0096] R c independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0097] R4 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0098] R6 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1- 3 alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, or one or more 5- to 6-membered heteroaryl groups.

[0099] In certain embodiments of the present invention, the compound is represented by formula (VI):

[0100] in,

[0101] R 11 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group;

[0102] R2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group;

[0103] R 32 Selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 3-6 Cycloalkyl substituted C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group;

[0104] R4 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group;

[0105] R6 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group;

[0106] q is 1, 2, 3 or 4.

[0107] In certain embodiments of the present invention, R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, thiol, cyano, nitro, oxo, thioxo, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3- 6-membered cycloalkyl, 3-8-membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, or one or more 5- to 6-membered heteroaryl groups.

[0108] In certain embodiments of the present invention, R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1- 3 alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, or one or more 5- to 6-membered heteroaryl groups.

[0109] In certain embodiments of the present invention, R1 is selected from C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl or 5-6 membered heteroaryl, the C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy and C 1-3 is substituted by one or more hydroxyalkyl groups.

[0110] In certain embodiments of the present invention, R1 is selected from C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy and C 1-3 is substituted by one or more hydroxyalkyl groups.

[0111] In certain embodiments of the present invention, R1 is selected from

[0112] In certain embodiments of the present invention, R1 is selected from

[0113] In certain embodiments of the present invention, R1 is selected from or cyclobutyl, said Or cyclobutyl can be further optionally substituted by hydrogen or methyl. In certain embodiments of the present invention, L1 is -O-, -C(O)NHCH2- or -C(O)NH-.

[0114] In certain embodiments of the present invention, L1 is -O- or -C(O)NHCH2-.

[0115] In certain embodiments of the present invention, R2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl.

[0116] In certain embodiments of the present invention, R2 is independently selected from hydrogen, fluoro, methoxy, or deuterated methoxy.

[0117] In certain embodiments of the present invention, R2 is independently selected from hydrogen, fluoro or methoxy.

[0118] In certain embodiments of the present invention, L2 is a bond.

[0119] In certain embodiments of the present invention, R3 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 3-6 Cycloalkyl substituted C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c .

[0120] In certain embodiments of the present invention, R c independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, C1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl.

[0121] In certain embodiments of the present invention, R3 is independently selected from hydrogen, methyl, -C(O)NH2, ethyl, vinyl, ethynyl, cyclopropyl, trifluoromethyl, methoxy, amino, oxo, cyclopropyl-methyl-, -NHCH3, -NH-tert-butyl or

[0122] In certain embodiments of the present invention, R3 is independently selected from methyl, -C(O)NH2, ethyl, ethynyl, cyclopropyl, trifluoromethyl, methoxy, amino, oxo, cyclopropyl-methyl-, -NHCH3 or

[0123] In certain embodiments of the present invention, R4 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl.

[0124] In certain embodiments of the present invention, R4 is independently selected from hydrogen, fluoro, methyl or methoxy.

[0125] In certain embodiments of the present invention, R4 is independently selected from hydrogen, fluoro, and methyl.

[0126] In certain embodiments of the present invention, R 10 independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl.

[0127] In certain embodiments of the present invention, R 11 independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl.

[0128] In certain embodiments of the present invention, R 12 independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl.

[0129] In certain embodiments of the present invention, L3 is a bond.

[0130] In certain embodiments of the present invention, one R2 and one R3 are linked to adjacent atoms to form C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 When aryl or 5-8 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-8 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy and C 1-3 One or more substitutions in the hydroxyalkyl group.

[0131] In certain embodiments of the present invention, one R3 and one R4 are linked to adjacent atoms to form a C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 When aryl or 5-8 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-8 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy and C 1-3 One or more substitutions in the hydroxyalkyl group.

[0132] In certain embodiments of the present invention, one R3 and one R4 are linked to adjacent atoms to form

[0133] In certain embodiments of the present invention, R6, R7, R8 and R9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6-membered cycloalkyl, 3-8-membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, or one or more 5- to 6-membered heteroaryl groups.

[0134] In certain embodiments of the present invention, R6, R7, R8 and R9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 Alkoxy; the C 1-3 Alkyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 The alkoxy group may optionally be further substituted with hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio and C 1-3 One or more substitutions in the alkyl group.

[0135] In certain embodiments of the present invention, R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl or one or more substitutions; preferably, R3 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 3-6 Cycloalkyl substituted C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, 3-8 membered heterocyclic group, -OR c or -C(O)R c .

[0136] In certain embodiments of the present invention, R 31 For hydrogen, deuterium, C 1-3 alkyl.

[0137] In certain embodiments of the present invention, R 32 C 1-3 Alkyl, C 2-4 Alkenyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl.

[0138] In certain embodiments of the present invention, R 33 -C(O)R c .

[0139] In certain embodiments of the present invention, R c independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, or one or more 5- to 6-membered heteroaryl groups.

[0140] In certain embodiments of the present invention, one R3 and one R4 are linked to adjacent atoms to form a C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3- 6-membered cycloalkyl, 3-8-membered heterocyclic group, C 6-10 aryl, or one or more 5- to 6-membered heteroaryl groups.

[0141] In certain embodiments of the present invention, R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OR a 、-C(O)R a 、-SR a 、S(O)R a or S(O)2R a , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, 5-6 membered heteroaryl, one or more substitutions; preferably, R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, -OR a or -C(O)R a .

[0142] In certain embodiments of the present invention, R a independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, or one or more 5- to 6-membered heteroaryl groups.

[0143] In certain embodiments of the present invention, Ring B is C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; preferably, ring B is C 3-6 Cycloalkyl or 5-6 membered heteroaryl.

[0144] In certain embodiments of the present invention, Ring B is or cyclobutyl.

[0145] In certain embodiments of the present invention, R8 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OR h 、-C(O)R h 、-SR h 、S(O)Rh or S(O)2R h , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl or one or more substitutions; preferably, R8 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, -OR h or -C(O)R h .

[0146] In certain embodiments of the present invention, R h independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14Aryl and 5-14 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, or one or more 5- to 6-membered heteroaryl groups.

[0147] In certain embodiments of the present invention, R8 is independently hydrogen or methyl.

[0148] In certain embodiments of the present invention, L1 is selected from a bond, -(CH2) n C(O)(CR aa R bb ) n1 -、-(CH2) n C(O)NR aa (CR aa R bb ) n1 -、-(CH2) n (CR aa R bb ) n2 -、-(CR aa R bb ) n O(CH2) n1 -、-(CH2) n O(CR aa R bb ) n1 -、-(CR aa R bb ) n3 (CH2) n NR cc -、-(CH2) n NR aa (CR bb R cc ) n -、-(CH2) n NR aa C(O)-.

[0149] In certain embodiments of the present invention, R aa 、R bb and R ccare each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3- 8-cycloalkyl, 3-12-membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, or one or more 5- to 6-membered heteroaryl groups.

[0150] In certain embodiments of the present invention, L1 is -O- or -C(O)NHCH2-.

[0151] In certain embodiments of the present invention, R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OR b 、-C(O)R b 、-SRb 、S(O)R b or S(O)2R b , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl or one or more substitutions; preferably, R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, -OR b or -C(O)R b .

[0152] In certain embodiments of the present invention, R b independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C6-14 Aryl and 5-14 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, or one or more 5- to 6-membered heteroaryl groups.

[0153] In certain embodiments of the present invention, R2 is independently hydrogen, fluoro or methoxy.

[0154] In certain embodiments of the present invention, R2 is independently hydrogen, fluoro, methoxy, or deuterated methoxy.

[0155] In certain embodiments of the present invention, R6 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OR f 、-C(O)R f 、-SR f 、S(O)R f or S(O)2R f , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl or one or more substitutions; preferably, R6 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 3-6 Cycloalkyl substituted C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, 3-8 membered heterocyclic group, -OR f or -C(O)R f .

[0156] In certain embodiments of the present invention, R f independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, or one or more 5- to 6-membered heteroaryl groups.

[0157] In certain embodiments of the present invention, R6 is hydrogen, fluorine or methyl, preferably fluorine.

[0158] In certain embodiments of the present invention, R6 is hydrogen or fluoro.

[0159] In certain embodiments of the present invention, R7 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OR g 、-C(O)R g 、-SR g 、S(O)R g or S(O)2R g , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl or one or more substitutions; preferably, R7 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 3-6 Cycloalkyl substituted C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C1-3 Hydroxyalkyl, 3-8 membered heterocyclic group, -OR g or -C(O)R g .

[0160] In certain embodiments of the present invention, R g independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, or one or more 5- to 6-membered heteroaryl groups.

[0161] In certain embodiments of the present invention, R7 is hydrogen or fluoro.

[0162] In certain embodiments of the present invention, L3 is a bond.

[0163] In certain embodiments of the present invention, R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OR d 、-C(O)R d 、-SR d 、S(O)R d or S(O)2R d , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl and 5-6 membered heteroaryl; preferably, R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl.

[0164] In certain embodiments of the present invention, R d independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more of aryl and 5-6 membered heteroaryl are substituted.

[0165] In certain embodiments of the present invention, R4 is independently selected from hydrogen, fluoro, methyl or methoxy.

[0166] In certain embodiments of the present invention, R4 is independently selected from hydrogen, fluorine and methyl. In certain embodiments of the present invention, R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OR e 、-C(O)R e 、-SR e 、S(O)R e or S(O)2R e , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1- 6 alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl are substituted with one or more; preferably, R5 is independently selected from C 2-6 Alkenyl or C 2-6 Alkynyl, the C 2-6 Alkenyl and C 2-6 Alkynyl is optionally substituted with hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl and C 1-3 One or more substitutions in the hydroxyalkyl group.

[0167] In certain embodiments of the present invention, R5 is vinyl,

[0168] In certain embodiments of the present invention, L1 is selected from -(CH2) n C(O)(CR aa R bb ) n1 -、-(CH2) n C(O)NR aa (CR aa R bb ) n1 -、-(CH2) n (CR aa R bb ) n2 -or-(CR aa R bb ) n O(CH2) n1 -;

[0169] R aa and R bb Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, thio, C 1-3 Alkyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3Alkoxy; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, oxo, thioxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy;

[0170] R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-6 membered heteroaryl containing 1-3 N, O or S atoms, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1- 3 alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl groups may be further substituted with one or more of hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, mercapto, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methyl substituted with 1-3 fluorine, chlorine or bromine groups, ethyl substituted with 1-3 fluorine, chlorine or bromine groups, propyl substituted with 1-3 fluorine, chlorine or bromine groups, isopropyl substituted with 1-3 fluorine, chlorine or bromine groups, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups;

[0171] Preferably, R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C6-10 Aryl or 5-6 membered heteroaryl containing 1-3 N, O or S atoms, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1- 3 alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl groups may be further substituted with one or more of hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methyl substituted with 1-3 fluorine, chlorine or bromine groups, ethyl substituted with 1-3 fluorine, chlorine or bromine groups, propyl substituted with 1-3 fluorine, chlorine or bromine groups, isopropyl substituted with 1-3 fluorine, chlorine or bromine groups, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups;

[0172] More preferably, R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methyl containing 1-3 fluorine, chlorine or bromine substituted groups, ethyl containing 1-3 fluorine, chlorine or bromine substituted groups, propyl containing 1-3 fluorine, chlorine or bromine substituted groups, isopropyl containing 1-3 fluorine, chlorine or bromine substituted groups, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, The methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, optionally further substituted with fluorine, chlorine, bromine, hydroxy, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy or propoxy;

[0173] R2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, C 1-3Alkyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy or C 1-3 Hydroxyalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, hydroxy, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, deuterated methoxy, deuterated ethoxy, deuterated propoxy, methyl substituted with 1-3 fluorine, chlorine or bromine, ethyl substituted with 1-3 fluorine, chlorine or bromine, propyl substituted with 1-3 fluorine, chlorine or bromine, isopropyl substituted with 1-3 fluorine, chlorine or bromine;

[0174] R 31 、R 32 and R 33 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methyl-substituted amino, ethyl-substituted amino, propyl-substituted amino, hydroxy, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl substituted with 1-3 fluorine, chlorine or bromine, propyl substituted with 1-3 fluorine, chlorine or bromine, isopropyl substituted with 1-3 fluorine, chlorine or bromine, methoxy, ethoxy, propoxy, ethoxy substituted with 1-3 fluorine, chlorine or bromine, propoxy substituted with 1-3 fluorine, chlorine or bromine, isopropoxy substituted with 1-3 fluorine, chlorine or bromine, hydroxymethyl, hydroxyethyl, hydroxypropyl, -C 1-3 Alkyl-R c 、-NHR c or -C(O)R c Preferably, R 31 、R 32 and R 33 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methyl-substituted amino, ethyl-substituted amino, propyl-substituted amino, hydroxy, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl substituted with 1-3 fluorine, chlorine or bromine, propyl substituted with 1-3 fluorine, chlorine or bromine, isopropyl substituted with 1-3 fluorine, chlorine or bromine, methoxy, ethoxy, propoxy, ethoxy substituted with 1-3 fluorine, chlorine or bromine, propoxy substituted with 1-3 fluorine, chlorine or bromine, isopropoxy substituted with 1-3 fluorine, chlorine or bromine, hydroxymethyl, hydroxyethyl, hydroxypropyl or -C(O)R c ;

[0175] R c independently selected from hydrogen, deuterium, halogen, amino, C1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, the amino, C 1-3 Alkyl-substituted amino, hydroxy, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl are optionally substituted with hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl; preferably, R c independently selected from hydrogen, fluorine, chlorine, bromine, amino, methyl-substituted amino, ethyl-substituted amino, propyl-substituted amino, hydroxy, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl substituted with 1-3 fluorine, chlorine or bromine, propyl substituted with 1-3 fluorine, chlorine or bromine, isopropyl substituted with 1-3 fluorine, chlorine or bromine, methoxy, ethoxy, propoxy, ethoxy substituted with 1-3 fluorine, chlorine or bromine, propoxy substituted with 1-3 fluorine, chlorine or bromine, isopropoxy substituted with 1-3 fluorine, chlorine or bromine, hydroxymethyl, hydroxyethyl, hydroxypropyl,

[0176] Preferably, R c independently selected from hydrogen, fluorine, chlorine, bromine, amino, methyl-substituted amino, ethyl-substituted amino, propyl-substituted amino, hydroxy, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl substituted with 1-3 fluorine, chlorine or bromine, propyl substituted with 1-3 fluorine, chlorine or bromine, isopropyl substituted with 1-3 fluorine, chlorine or bromine, methoxy, ethoxy, propoxy, ethoxy substituted with 1-3 fluorine, chlorine or bromine, propoxy substituted with 1-3 fluorine, chlorine or bromine, isopropoxy substituted with 1-3 fluorine, chlorine or bromine, hydroxymethyl, hydroxyethyl or hydroxypropyl;

[0177] R4, R 10 、R 11 and R 12 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl substituted with 1-3 fluorine, chlorine or bromine, propyl substituted with 1-3 fluorine, chlorine or bromine, isopropyl substituted with 1-3 fluorine, chlorine or bromine, methoxy, ethoxy, propoxy, ethoxy substituted with 1-3 fluorine, chlorine or bromine, propoxy substituted with 1-3 fluorine, chlorine or bromine, isopropoxy substituted with 1-3 fluorine, chlorine or bromine, hydroxymethyl, hydroxyethyl or hydroxypropyl;

[0178] R6, R7, R8 and R9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl or 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl, 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, fluorine, chlorine, bromine, amino, methyl substituted amino, ethyl substituted amino, propyl substituted amino, hydroxy, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl substituted with 1-3 fluorine, chlorine or bromine, propyl substituted with 1-3 fluorine, chlorine or bromine, isopropyl substituted with 1-3 fluorine, chlorine or bromine, substituted with one or more of methoxy, ethoxy, propoxy, ethoxy containing 1-3 fluorine, chlorine or bromine substituted, propoxy containing 1-3 fluorine, chlorine or bromine substituted, isopropoxy containing 1-3 fluorine, chlorine or bromine substituted, hydroxymethyl, hydroxyethyl, hydroxypropyl and 6-membered heterocyclic groups; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, More preferably, hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl,

[0179] Preferably, R6, R7, R8 and R9 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl may be further optionally substituted by one or more of hydrogen, deuterium, fluorine, chlorine, bromine, amino, methyl substituted amino, ethyl substituted amino, propyl substituted amino, hydroxy, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl substituted with 1-3 fluorine, chlorine or bromine, propyl substituted with 1-3 fluorine, chlorine or bromine, isopropyl substituted with 1-3 fluorine, chlorine or bromine, methoxy, ethoxy, propoxy, ethoxy substituted with 1-3 fluorine, chlorine or bromine, propoxy substituted with 1-3 fluorine, chlorine or bromine, isopropoxy substituted with 1-3 fluorine, chlorine or bromine, hydroxymethyl, hydroxyethyl or hydroxypropyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl or hydroxypropyl;

[0180] u is 0, 1, 2, 3, 4, 5, or 6;

[0181] v is 0, 1, 2, 3, 4, 5, or 6;

[0182] w is 0, 1, 2, 3, 4, 5, or 6;

[0183] x is 0, 1, 2, 3, 4, 5, or 6;

[0184] z is 0, 1, 2, 3, 4, 5, or 6;

[0185] n is 0, 1, 2, or 3;

[0186] n1 is 0, 1, 2 or 3; and

[0187] n2 is 0, 1, 2 or 3.

[0188] In certain preferred embodiments of the present invention, L1 is selected from -O-, -C(O)-, -C(O)NHCH2- or -C(O)NH-.

[0189] In certain preferred embodiments of the present invention, R1 is selected from

[0190] In certain preferred embodiments of the present invention, R2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methoxy, deuterated ethoxy, deuterated propoxy, cyano, ethoxy, and difluoromethoxy.

[0191] In certain preferred embodiments of the present invention, R31 It is hydrogen, deuterium, methyl, ethyl, and propyl.

[0192] In certain preferred embodiments of the present invention, R 32 is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, cyano, -COCH2CH3, -COCH3, vinyl, cyclopropyl, Isopropyl, or -CD3.

[0193] In certain preferred embodiments of the present invention, R 33 It is -C(O)NH2.

[0194] In certain preferred embodiments of the present invention, R4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, cyano, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, propyl, methoxy or cyclopropyl.

[0195] In certain preferred embodiments of the present invention, R4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, cyano, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, propyl or methoxy.

[0196] In certain preferred embodiments of the present invention, R 10 are independently selected from hydrogen, deuterium, fluorine, chlorine or bromine.

[0197] In certain preferred embodiments of the present invention, R 11 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine or hydroxy.

[0198] In certain preferred embodiments of the present invention, R 12 are independently selected from hydrogen or cyano.

[0199] In certain preferred embodiments of the present invention, R6, R7, R8 and R9 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH2OH, -CH2OCH3, -CF3, -CH2N(CH3)2, Preferably, R6, R7, R8 and R9 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH2OH, -CH2OCH3, -CF3, -CH2N(CH3)2, Preferably, R6, R7 and R8 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl or cyano.

[0200] In certain preferred embodiments of the present invention, R6 is independently selected from hydrogen, fluorine, methyl, -CH2OH, -CH2OCH3, -CF3.

[0201] In certain preferred embodiments of the present invention, R7 is independently selected from hydrogen.

[0202] In certain preferred embodiments of the present invention, R8 is independently selected from hydrogen, -CH2N(CH3)2 or

[0203] In certain preferred embodiments of the present invention, R9 is methyl.

[0204] In certain preferred embodiments of the present invention,

[0205] L1 is selected from -O-, -C(O)-, -C(O)NHCH2- or -C(O)NH-;

[0206] R1 is selected from

[0207] R2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methoxy, deuterated ethoxy or deuterated propoxy; preferably fluorine, methoxy, -OCD3;

[0208] R 31 is hydrogen, deuterium, methyl, ethyl, propyl;

[0209] R 32 is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, cyano, -COCH2CH3, -COCH3, vinyl, cyclopropyl, Preferably, R 32 is hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl, methoxy, -COCH2CH3, -COCH3, vinyl, cyclopropyl

[0210] More preferably, R 32 is hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl, methoxy, vinyl or cyclopropyl;

[0211] R 33 is -C(O)NH2;

[0212] R4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, cyano, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, propyl, methoxy or cyclopropyl; preferably, R4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, propyl or methoxy; more preferably, R4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl or methoxy;

[0213] R 10 independently selected from hydrogen, deuterium, fluorine, chlorine or bromine;

[0214] R 11 are independently selected from hydrogen, deuterium, fluorine, chlorine, bromine or hydroxyl;

[0215] R 12 independently selected from hydrogen or cyano;

[0216] R6, R7, R8 and R9 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH2OH, -CH2OCH3, -CF3, -CH2N(CH3)2, Preferably, R6, R7, R8 and R9 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH2OH, -CH2OCH3, -CF3, -CH2N(CH3)2, Preferably, R6, R7, R8 and R9 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH2OH, -CH2OCH3, -CF3, -CH2N(CH3)2.

[0217] In certain preferred embodiments of the present invention, R6 is independently selected from hydrogen, fluorine, methyl, -CH2OH, -CH2OCH3, -CF3; R7 is independently selected from hydrogen; R8 is independently selected from hydrogen, -CH2N(CH3)2 or R9 is methyl.

[0218] In certain preferred embodiments of the present invention,

[0219] L1 is selected from -O-, -C(O)-, -C(O)NHCH2- or -C(O)NH-;

[0220] R1 is selected from

[0221] R2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methoxy, deuterated ethoxy or deuterated propoxy;

[0222] R31 is hydrogen, deuterium, methyl, ethyl, propyl;

[0223] R 32 is hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl, methoxy, vinyl or cyclopropyl;

[0224] R 33 is -C(O)NH2;

[0225] R4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl or methoxy;

[0226] R6, R7 and R8 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl or cyano.

[0227] In certain preferred embodiments of the present invention,

[0228] L1 is selected from -O-, -C(O)NHCH2- or -C(O)NH-;

[0229] R1 is selected from

[0230] R2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methoxy, deuterated ethoxy or deuterated propoxy;

[0231] R 31 is hydrogen, deuterium, methyl, ethyl, propyl;

[0232] R 32 is hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl, methoxy, vinyl or cyclopropyl;

[0233] R 33 is -C(O)NH2;

[0234] R4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl or methoxy;

[0235] R6, R7 and R8 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl or cyano.

[0236] The present invention also provides a method for preparing the compound represented by formula (III) as described above, its stereoisomers or pharmaceutically acceptable salts thereof, which comprises the following steps: reacting the compound represented by formula (V) and the compound represented by formula (VI) under the action of a condensing agent,

[0237] Among them, R1, L1, R2, x, R 31 、R 32、R 33 , R4, z, R6, R7, and R8 are the same as described above.

[0238] The present invention also provides a method for preparing the compound represented by formula (IV) as described above, its stereoisomers or pharmaceutically acceptable salts thereof, which comprises the following steps: reacting the compound represented by formula (VII) and the compound represented by formula (VI) under the action of a condensing agent,

[0239] Among them, R1, R2, x, R 32 , R4, z, R6, R7, and R8 are the same as described above.

[0240] The present invention also provides a compound represented by formula (V) or a stereoisomer thereof, or a compound represented by formula (VII) or a stereoisomer thereof:

[0241] Among them, R1, L1, R2, x, R 31 、R 32 、R 33 , R4, z are the same as described above.

[0242] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of the compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0243] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, has a weight percentage of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof of 0.1% to 95%, preferably 90%, 85%, 80%, 75%, 70%, 60% or 50%.

[0244] In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections, and preferably further comprises a filler, optionally a disintegrant, or further comprises one or more of a glidant or a lubricant.

[0245] In certain embodiments of the present invention, the pharmaceutical composition is a rapid-release formulation or a sustained-release formulation.

[0246] In certain embodiments of the present invention, the pharmaceutical composition, calculated as the free base, the unit dose of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is 1-1000 mg, preferably 1-500 mg, or preferably 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

[0247] In certain embodiments of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, can be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition adjusted accordingly.

[0248] In certain embodiments of the present invention, the compound, its stereoisomers or pharmaceutically acceptable salts thereof can be formulated into liquid or solid preparations, such as syrups, suspensions, emulsions, tablets, capsules, powders, granules, or lozenges.

[0249] The present invention further relates to the use of the compound of general formula (I), its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of FGFR1-4 inhibitor drugs.

[0250] In certain embodiments of the present invention, the FGFR1-4 inhibitor is a FGFR2 / 3 inhibitor.

[0251] On the other hand, the present invention also aims to provide a method for preparing a drug for treating and / or preventing cancer, bone dysplasia and other related diseases comprising a compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0252] The present invention also relates to a method for treating and / or preventing cancer, chondrodysplasia, and other related diseases. In another aspect, the present invention also provides the use of a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in treating and / or preventing cancer, chondrodysplasia, and other related diseases.

[0253] In the above technical scheme, the cancer-related disease is selected from solid tumors, colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, head and neck cancer, brain cancer, glioma, glioblastoma, hepatocellular carcinoma, lung cancer, melanoma, myeloma, pancreatic cancer, renal cell carcinoma, cervical cancer, urothelial cancer, prostate cancer, ovarian cancer, breast cancer, leukemia or lymphoma.

[0254] After structural optimization, the parent nucleus of each general formula compound, its stereoisomer or pharmaceutically acceptable salt described in the present invention is modified into a monocyclic structure, thereby improving the inhibitory activity at the FGFR2 enzyme level while having inhibitory activity at the FGFR3 enzyme and cellular levels, while still maintaining selectivity for FGFR1.

[0255] Detailed Description of the Invention

[0256] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0257] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred.

[0258] The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc.

[0259] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.

[0260] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0261] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0262] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; further preferably, it is a 3-8 membered heterocyclic group containing 1-3 nitrogen atoms, optionally substituted with 1-2 oxygen atoms, sulfur atoms, or oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups, or nitrogen-containing fused heterocyclic groups.

[0263] Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl, etc., preferably pyrrolidinyl, morpholinyl, piperidinyl, azepanyl, 1,4-diazepanyl and piperazinyl. Polycyclic heterocyclic groups include spirocyclic, fused ring and bridged heterocyclic groups; wherein the spirocyclic, fused ring and bridged heterocyclic groups are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring. Non-limiting examples of monocyclic heterocyclic groups include:

[0264] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0265] wait.

[0266] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0267] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably, phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, including benzo 5- to 10-membered heteroaryl, benzo 3- to 8-membered cycloalkyl, and benzo 3- to 8-membered heteroalkyl, preferably benzo 5- to 6-membered heteroaryl, benzo 3- to 6-membered cycloalkyl, and benzo 3- to 6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.

[0268] Wherein the ring connecting to the parent structure is an aryl ring, non-limiting examples of which include:

[0269] wait.

[0270] The aryl group may be substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0271] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably a monocyclic heteroaryl group, which is 5 to 12-membered, more preferably 5-membered or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl. The heteroaryl group can be a polycyclic heteroaryl group, which is formed by condensing the monocyclic heteroaryl group to an aryl, heteroaryl, heterocyclic or cycloalkyl ring and connecting to the parent structure. The polycyclic heteroaryl group can be bicyclic or tricyclic or more. Non-limiting examples include:

[0272] wait.

[0273] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0274] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0275] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0276] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0277] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0278] "Alkenyl" refers to a chain alkenyl group, also known as an alkene group, wherein the alkenyl group can be further substituted with other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0279] "Alkynyl" refers to (CH≡C-), wherein the alkynyl can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0280] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0281] The hydrogen atoms described in the present invention can all be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0282] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0283] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0284] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0285] "Pharmaceutically acceptable salt" or "pharmaceutically usable salt" refers to a salt of the compound of the present invention, which is safe and effective when used in mammals and has the desired biological activity. DETAILED DESCRIPTION

[0286] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0287] Example

[0288] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as the solvents, with tetramethylsilane (TMS) as the internal standard.

[0289] Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed on an Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0290] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0291] The starting materials in the examples of the present invention are known and can be purchased commercially, or can be synthesized using or according to methods known in the art.

[0292] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, with dry solvents and reaction temperatures in degrees Celsius.

[0293] Example 1

[0294] 4-(4-Acryloylamidophenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0295] Step 1: Preparation of methyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate

[0296] Methyl 5-methyl-1H-pyrrole-2-carboxylate (5.06 g, 36.36 mmol) was dissolved in dichloromethane (100 mL). The reaction solution was cooled to 0°C in an ice-water bath. N-bromosuccinimide (6.86 g, 38.55 mmol) was added with stirring. The reaction solution was stirred at 0°C for 40 minutes. 2N aqueous sodium hydroxide solution (70 mL) was added with stirring at 0°C and stirred for 2 minutes. The mixture was allowed to stand for stratification. The aqueous phase was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next reaction.

[0297] MS m / z(ESI):216.0,218.0[MH] - .

[0298] Step 2: Preparation of 1-(tert-butyl) 2-methyl 4-bromo-5-methyl-1H-pyrrole-1,2-dicarboxylate

[0299] Methyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (7.93 g, 36.37 mmol) was dissolved in acetonitrile (50 mL), and 4-dimethylaminopyridine (444.31 mg, 3.64 mmol) was added. Tert-butoxycarbonyl tert-butyl carbonate (8.73 g, 40.01 mmol) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 5 hours, concentrated under reduced pressure to remove the solvent, and the residue was dispersed in dichloromethane, washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (10.67 g, 92%).

[0300] MS m / z(ESI):318.0,320.0[M+H] + .

[0301] Step 3: Preparation of methyl 5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate

[0302] 1-(tert-Butyl)-2-methyl-4-bromo-5-methyl-1H-pyrrole-1,2-dicarboxylate (10.67 g, 33.54 mmol), 4-nitrophenylboronic acid (11.20 g, 67.07 mmol), Pd(PPh3)4 (3.87 g, 3.35 mmol), and anhydrous sodium carbonate (35.55 g, 335.36 mmol) were dispersed in a mixture of DMF (100 mL) and water (20 mL). The reaction solution was protected by nitrogen and heated to 90°C with stirring for 4 hours, then to 110°C with stirring for 12 hours. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was slurried in ethyl acetate to obtain the title compound (5.6 g, 64%).

[0303] MS m / z(ESI):261.1[M+H] + .

[0304] Step 4: Preparation of methyl 3-bromo-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate

[0305] Methyl 5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate (2.85 g, 10.95 mmol) was dissolved in DMF (40 mL), and N-bromosuccinimide (2.05 g, 11.50 mmol) was added with stirring at room temperature. The reaction solution was stirred at room temperature for 1 hour and the reaction solution was directly used in the next reaction.

[0306] MS m / z(ESI):339.0,341.0[M+H] + .

[0307] Step 5: Preparation of 1-(tert-butyl)2-methyl-3-bromo-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-1,2-dicarboxylate

[0308] To the reaction mixture of the previous step were added 4-dimethylaminopyridine (268 mg, 2.19 mmol) and tert-butoxycarbonyl tert-butyl carbonate (5.98 g, 27.38 mmol) in sequence. The reaction mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (3.75 g, two-step yield 78%).

[0309] MS m / z(ESI):439.0,441.0[M+H] + .

[0310] Step 6: Preparation of methyl 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate

[0311] 1-(tert-butyl) 2-methyl 3-bromo-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-1,2-dicarboxylate (2 g, 4.55 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methylpyrimidine (2.71 g, 8.20 mmol), Pd(PPh3)4 (1.05 g, 910.63 μmol) were dispersed in To DMF (100 mL) was added a mixed solution of anhydrous sodium carbonate (3.86 g, 36.43 mmol) in water (10 mL). The reaction solution was replaced with nitrogen, heated to 90°C and stirred for 2 hours, then stirred at 110°C for 4 hours. The reaction solution was diluted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (1.6 g, 76%).

[0312] MS m / z(ESI):463.1,465.1[M+H] + .

[0313] Step 7: Preparation of 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylic acid

[0314] Methyl 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate (1.6 g, 3.46 mmol) was dissolved in a mixed solvent of ethanol (30 mL) and tetrahydrofuran (30 mL). A solution of sodium hydroxide (138 mg, 3.46 mmol) in water (20 mL) was added with stirring at room temperature. The reaction solution was heated to 50°C and stirred for 4 hours. The organic solvent was removed by concentration under reduced pressure. The residue was acidified with acetic acid and extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The residue was slurried with ethyl acetate to obtain the title compound (564 mg, 36%).

[0315] MS m / z(ESI):447.1[MH] - .

[0316] Step 8: Preparation of 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxamide

[0317] 3-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylic acid (564 mg, 1.26 mmol), diisopropylethylamine (488 mg, 3.77 mmol, 657.24 μL), HOBt (340 mg, 2.52 mmol) and EDCI (482 mg, 2.52 mmol, hydrochloride) were added sequentially to dichloromethane (50 mL) and stirred at room temperature for 16 hours. The solvent was removed by concentration under reduced pressure, and the residue was dispersed in saturated ammonium chloride solution, slurried, filtered, and the filter residue was collected. The filter residue was washed with water, collected, and dried under reduced pressure to obtain the title compound (562.76 mg, 100%).

[0318] MS m / z(ESI):448.1[M+H] + .

[0319] Step 9: Preparation of 4-(4-aminophenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0320] 3-(3-Fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxamide (563 mg, 1.26 mmol) was dissolved in a mixed solvent of dioxane (30 mL) and ethanol (30 mL). Iron powder (7.02 g, 125.78 mmol) and a solution of ammonium chloride (3.36 g, 62.89 mmol) in water (20 mL) were added sequentially. The reaction solution was heated to 50°C under nitrogen and stirred for 1 hour. The solvent was removed by concentration under reduced pressure. The residue was dispersed in water and extracted with dichloromethane. The combined dichloromethane layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (338 mg, 64%).

[0321] MS m / z(ESI):418.2[M+H] + .

[0322] Step 10: Preparation of 4-(4-acryloylamidophenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0323] 4-(4-Aminophenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-5-methyl-1H-pyrrole-2-carboxamide (60 mg, 143.73 μmol) was dissolved in DMF (5 mL) and cooled to 0°C in an ice-water bath. Triethylamine (15 mg, 143.73 μmol, 20.05 μL) and acryloyl chloride (13 mg, 143.73 μmol) were added sequentially with stirring. The reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was directly purified by ODS-Flash column chromatography to obtain the title compound (21.2 mg, 28%).

[0324] MS m / z(ESI):472.2[M+H] + .

[0325] 1 H NMR (400MHz, DMSO-d6) δ11.52 (s, 1H), 10.08 (s, 1H), 8.47 (d, J = 5.0Hz, 1H), 7. 54(d,J=8.4Hz,2H),7.24(t,J=8.4Hz,1H),7.17(d,J=4.9Hz,1H),7.14-7.07( m,1H),7.02-6.93(m,3H),6.41(dd,J=16.9,10.0Hz,1H),6.23(dd,J=17.1,1. 5Hz,1H),6.02(s,1H),5.73(dd,J=10.0,1.6Hz,1H),2.41(s,3H),2.22(s,3H).

[0326] Example 2

[0327] 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-(4-methacryloylamidophenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0328] 4-(4-Aminophenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-5-methyl-1H-pyrrole-2-carboxamide (60 mg, 143.73 μmol) was dissolved in DMF (5 mL) and cooled to 0°C in an ice-water bath. Triethylamine (73 mg, 718.67 μmol, 100.24 μL) and 2-methacryloyl chloride (15 mg, 143.73 μmol) were added sequentially with stirring. The reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was directly purified by ODS-Flash column chromatography to obtain the title compound (22.2 mg, 29%).

[0329] MS m / z(ESI):486.2[M+H]+ .

[0330] 1 H NMR (400MHz, DMSO-d6) δ11.52(s,1H),9.71(s,1H),8.47(d,J=4.9Hz,1H),7.54(d,J=8.5Hz,2H),7.24(t,J=8.4Hz,1H),7.17(d,J=4.9Hz,1H), 7.14-7.07(m,1H),6.99(d,J=8.7Hz,1H),6.94(d,J=8.5Hz,2H),6.01(s ,1H),5.75(s,1H),5.48(s,1H),2.41(s,3H),2.22(s,3H),1.93(s,3H).

[0331] Example 3

[0332] 3-(3-Fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-4-(4-(2-fluoroprop-2-enoylamino)phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0333] 2-Fluoroacrylic acid (16 mg, 179.67 μmol), HOBt (25 mg, 179.67 μmol), triethylamine (61 mg, 598.90 μmol, 83.53 μL) and HATU (68 mg, 179.67 μmol) were added to DMF (1 mL) in sequence, and the reaction solution was stirred at room temperature for 10 minutes. The mixture was then added to a solution of 4-(4-aminophenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-1H-pyrrole-2-carboxamide (50 mg, 119.78 μmol) in DMF (2 mL). The reaction solution was stirred at room temperature for 1 hour, filtered, and the filtrate was separated by ODS-Flash column chromatography to obtain the title compound (21 mg, 35%).

[0334] 1H NMR (400MHz, DMSO-d6) δ11.53(s,1H),10.22(s,1H),8.47(d,J=5.0Hz,1H),7.59(d,J=8.6Hz,2H),7.25(t,J=8.4Hz,1H),7.17(d,J=5.0Hz,1H),7. 12(dd,J=11.6,1.8Hz,1H),7.02-6.94(m,3H),6.02(s,1H),5.68(dd,J=4 7.7,3.6Hz,1H),5.40(dd,J=15.6,3.6Hz,1H),2.41(s,3H),2.22(s,3H).

[0335] MS m / z(ESI):490.2[M+H] + .

[0336] Example 4

[0337] 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-5-methyl-4-(4-(2-(trifluoromethyl)acryloylamido)phenyl)-1H-pyrrole-2-carboxamide

[0338] 4-(4-Aminophenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-1H-pyrrole-2-carboxamide (50 mg, 119.78 μmol) and 2-(trifluoromethyl)prop-2-enoic acid (50 mg, 359.34 μmol) were dissolved in DMF (3 mL). EDCI (69 mg, 359.34 μmol, hydrochloride) and 4-dimethylaminopyridine (3 mg, 23.96 μmol) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was directly separated by ODS-Flash column chromatography to obtain the target compound (40.6 mg, 58%).

[0339] MS m / z(ESI):540.2[M+H] + .

[0340] 1H NMR (400MHz, DMSO-d6) δ11.53(s,1H),10.37(s,1H),8.47(d,J=5.0Hz,1H),7.52(d,J=8.5Hz,2H),7.25(t,J=8.4Hz,1H),7.17(d, J=5.0Hz,1H),7.12(dd,J=11.6,1.8Hz,1H),6.98(d,J=8.5Hz,4H),6.48(d,J=11.2Hz,2H),6.03(s,1H),2.41(s,3H),2.22(s,3H).

[0341] Example 5

[0342] 4-(4-(2-chloroacryloylamino)phenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0343] 4-(4-Aminophenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-1H-pyrrole-2-carboxamide (50 mg, 119.78 μmol) and 2-chloroprop-2-enoic acid (19 mg, 179.67 μmol) were dissolved in DMF (3 mL) in sequence. Triethylamine (61 mg, 598.90 μmol, 83.53 μL) and HATU (68 mg, 179.67 μmol) were added in sequence with stirring at room temperature. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was separated by ODS-Flash column chromatography to obtain the title compound (5.5 mg, 9%).

[0344] MS m / z(ESI):506.2[M+H] + .

[0345] 1 H NMR (400MHz, DMSO-d6) δ11.53(s,1H),10.14(s,1H),8.47(d,J=5.0Hz,1H),7.53(d,J=8.4Hz,2H),7.25(t,J=8.4Hz,1H),7.17(d ,J=5.0Hz,1H),7.14-7.08(m,1H),6.98(d,J=8.5Hz,4H),6.38(d,J=2.3Hz,1H),6.06(d,J=2.2Hz,2H),2.41(s,3H),2.22(s,3H).

[0346] Example 10

[0347] 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-(2-fluoro-4-methacryloylamidophenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0348] Step 1: Preparation of O1-tert-butyl O2-methyl 4-bromo-3-iodo-5-methyl-pyrrole-1,2-dicarboxylate

[0349] Methyl 5-methyl-1H-pyrrole-2-carboxylate (5.06 g, 36.36 mmol) was dissolved in dichloromethane (100 mL), cooled to 0°C in an ice-water bath, and N-bromosuccinimide (6.80 g, 38.18 mmol) was added in portions under stirring. The reaction solution was stirred at 0°C for 1 hour, and N-iodosuccinimide (9.00 g, 40.00 mmol) was added in portions. The reaction solution was stirred at 0°C for 30 minutes, and then the ice-water bath was removed. The mixture was transferred to room temperature and stirred for 30 minutes. 4-Dimethylaminopyridine (4.44 g, 36.36 mmol) and tert-butoxycarbonyl tert-butyl carbonate (23.81 g, 109.09 mmol) were added in sequence. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was washed with saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (11.6 g, 72%).

[0350] MS m / z(ESI):444.0,446.0[M+H] + .

[0351] Step 2: Preparation of methyl 4-bromo-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-1H-pyrrole-2-carboxylate

[0352] O1-tert-butyl O2-methyl 4-bromo-3-iodo-5-methyl-pyrrole-1,2-dicarboxylate (11.6 g, 26.12 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methyl-pyrimidine (15.52 g, 47.02 mmol), tetrakis(triphenylphosphine)palladium (3.02 g, 2.61 mmol) were added to DMF (70 mL), the reaction solution was protected with nitrogen, and potassium phosphate (16.63 g, 78.37 mmol) was added to water under stirring at room temperature. (10mL) solution, the resulting reaction solution was replaced once with nitrogen, transferred to 50°C and stirred for 24 hours, the reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated, the residue was dissolved in dichloromethane (10mL), trifluoroacetic acid (10mL) was added, stirred at room temperature for 30 minutes, and concentrated under reduced pressure to remove the solvent, the residue was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated by silica gel column chromatography to obtain the title compound (710 mg, 6%).

[0353] MS m / z(ESI):420.1[M+H] + .

[0354] Step 3: Preparation of 4-bromo-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-1H-pyrrole-2-carboxylic acid

[0355] Methyl 4-bromo-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-1H-pyrrole-2-carboxylate (710 mg, 1.69 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL). A solution of sodium hydroxide (68 mg, 1.69 mmol) in water (10 mL) was added with stirring at room temperature. The resulting reaction solution was transferred to 90°C and stirred for 1 hour. The solvent was removed by concentration under reduced pressure. The residue was dispersed in water, the pH was adjusted to acidic by adding acetic acid, and the mixture was extracted with dichloromethane. The dichloromethane extracts were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used directly in the next reaction.

[0356] MS m / z(ESI):406.1[M+H] + .

[0357] Step 4: Preparation of N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-prop-2-enamide

[0358] 3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.05 g, 4.43 mmol) was dissolved in dichloromethane (20 mL) and cooled to 0°C in an ice-water bath. Diisopropylethylamine (859 mg, 6.64 mmol, 1.16 mL) and 2-methylprop-2-enoyl chloride (556 mg, 5.31 mmol) were added sequentially with stirring. The reaction solution was stirred at 0°C for 30 minutes. The reaction solution was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (1.2 g, 89%).

[0359] MS m / z(ESI):306.2[M+H] + .

[0360] Step 5: Preparation of tert-butyl 4-bromo-2-carbamoyl-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-pyrrole-1-carboxylate

[0361] 4-Bromo-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-1H-pyrrole-2-carboxylic acid (687 mg, 1.69 mmol) was dissolved in DMF (15 mL), and HOBt (457 mg, 3.38 mmol), triethylamine (513 mg, 5.07 mmol, 707.14 μL), EDCI (648 mg, 3.38 mmol, hydrochloride) and ammonium chloride (452 ​​mg, 8.45 mmol) were added in sequence under stirring at room temperature. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was washed with acetic acid. The mixture was diluted with ethyl ester, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in acetonitrile (50 mL), and tert-butoxycarbonyl tert-butyl carbonate (1.11 g, 5.07 mmol) and 4-dimethylaminopyridine (207 mg, 1.69 mmol) were added sequentially with stirring at room temperature. The resulting reaction solution was stirred at room temperature for 2 hours, concentrated under reduced pressure to remove the solvent, and the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the target compound (390 mg, 46%).

[0362] MS m / z(ESI):505.1,507.1[M+H] + .

[0363] Step 6: Preparation of 4-(2-fluoro-4-(2-methylprop-2-enoylamino)phenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0364] Tert-butyl 4-bromo-2-carbamoyl-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-pyrrole-1-carboxylate (130 mg, 257.25 μmol), N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-prop-2-enamide (157 mg, 514.51 μmol) and Pd(dppf)Cl2 (38 mg, 51.45 μmol) were added to DMF (10 mL). The reaction solution was protected by nitrogen and a solution of potassium carbonate (107 mg, 771.76 μmol) in water (1 mL) was added under stirring at room temperature. The reaction solution was replaced with nitrogen and transferred to an oil bath, heated to 100°C and stirred for 2 hours. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative TLC and prep-HPLC to obtain the title compound (0.9 mg, 1%).

[0365] MS m / z(ESI):504.2[M+H] + .

[0366] Example 12

[0367] 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-(4-methacryloylamido-2-methylphenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0368] Step 1: Preparation of methyl 5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylate

[0369] To DMF (100 mL) were added O1-tert-butyl O2-methyl 4-bromo-5-methyl-pyrrole-1,2-dicarboxylate (6.05 g, 19.02 mmol), 4,4,5,5-tetramethyl-2-(2-methyl-4-nitro-phenyl)-1,3,2-dioxaborolane (7.50 g, 28.52 mmol), and tetrakis(triphenylphosphine)palladium (2.20 g, 1.90 mmol). A solution of sodium carbonate (20.15 g, 190.15 mmol) in water (20 mL) was added with stirring at room temperature. The resulting reaction solution was heated to 90°C under nitrogen and stirred for 16 hours. The reaction mixture was filtered through celite, and the residue was washed with ethyl acetate. The filtrate was collected, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (4.22 g, 81%).

[0370] MS m / z(ESI):275.1[M+H] + .

[0371] Step 2: Preparation of O1-tert-butyl O2-methyl 3-bromo-5-methyl-4-(2-methyl-4-nitro-phenyl)pyrrole-1,2-dicarboxylate

[0372] Methyl 5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylate (4.22 g, 15.39 mmol) was dissolved in DMF (30 mL). N-bromosuccinimide (2.79 g, 15.69 mmol) was added portionwise with stirring at room temperature. The reaction solution was stirred at room temperature for 1 hour. Tert-butoxycarbonyl tert-butyl carbonate (6.72 g, 30.77 mmol) and 4-dimethylaminopyridine (1.88 g, 15.39 mmol) were added sequentially to the reaction solution. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (3.65 g, 52%).

[0373] MS m / z(ESI):453.1[M+H] + .

[0374] Step 3: Preparation of 3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylate

[0375] O1-tert-butyl O2-methyl 3-bromo-5-methyl-4-(2-methyl-4-nitro-phenyl)pyrrole-1,2-dicarboxylate (1 g, 2.21 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methyl-pyrimidine (1.09 g, 3.31 mmol) and Pd(dppf)Cl2 (323 mg, 441.23 μg) were added to the mixture. mol) was dispersed in DMF (15 mL). The reaction solution was protected by nitrogen. A solution of potassium carbonate (914 mg, 6.62 mmol) in water (1.5 mL) was added under stirring at room temperature. The reaction solution was further replaced with nitrogen once, and the mixture was transferred to 90°C and stirred for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (922 mg, 88%).

[0376] MS m / z(ESI):477.2[M+H] + .

[0377] Step 4: Preparation of 3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylic acid

[0378] 3-(3-Fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylate (922 mg, 1.94 mmol) was dissolved in a mixed solvent of methanol (25 mL) and tetrahydrofuran (25 mL). A solution of sodium hydroxide (774 mg, 19.35 mmol) in water (15 mL) was added under stirring. The resulting reaction solution was transferred to 50° C. and stirred for 4 hours. The organic solvent was removed by concentration under reduced pressure. The residue was diluted with water and the pH was adjusted to neutral with acetic acid under stirring. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and shrunk. The residue was used directly in the next reaction.

[0379] MS m / z(ESI):463.1[M+H] + .

[0380] Step 5: Preparation of 4-(4-amino-2-methyl-phenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0381] 3-(3-Fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylic acid (894 mg, 1.93 mmol) was dissolved in DMF (15 mL). Diisopropylethylamine (749 mg, 5.80 mmol, 1.01 mL), HOBt (522 mg, 3.87 mmol), EDCI (741 mg, 3.87 mmol, hydrochloride) and ammonium chloride (517 mg, 9.67 mmol) were added in sequence under stirring at room temperature. The reaction solution was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate and saturated sodium chloride. The mixture was washed with an aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in a mixed solvent of dioxane (25 mL) and ethanol (25 mL), and iron powder (5.40 g, 96.66 mmol) and a solution of ammonium chloride (3.10 g, 58.00 mmol) in water (20 mL) were added in sequence. The reaction solution was protected with nitrogen, heated to 50°C and stirred for 2 hours. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in dichloromethane and filtered through celite. The filter residue was washed with dichloromethane, the filtrate was collected, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the target compound (465 mg, 56%).

[0382] MS m / z(ESI):432.2[M+H] + .

[0383] Step 6: Preparation of 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-(4-methacryloylamido-2-methylphenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0384] 4-(4-Amino-2-methyl-phenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-1H-pyrrole-2-carboxamide (100 mg, 231.77 μmol) was dissolved in dry DMF (5 mL) and cooled to 0°C in an ice-water bath. Diisopropylethylamine (45 mg, 347.66 μmol) and 2-methylprop-2-enoyl chloride (27 mg, 254.95 μmol) were added sequentially with stirring. The reaction solution was transferred to room temperature and stirred for 30 minutes. The reaction solution was separated by ODS-Flash column chromatography to obtain the title compound (23 mg, 17%).

[0385] MS m / z(ESI):500.2[M+H] + .

[0386] 1H NMR (400MHz, DMSO-d6) δ11.46(s,1H),9.65(s,1H),8.45(d,J=5.0Hz,1H),7.47(s,1H),7.44(d,J=8.3Hz,1H),7.16(t,J=7.6Hz,2H),7.04(dd,J=11.9 ,1.4Hz,2H),6.97(d,J=8.2Hz,1H),6.93(d,J=8.2Hz,1H),6.23(s,1H),5.7 6(s,1H),5.47(s,1H),2.39(s,3H),2.02(s,3H),1.93(s,3H),1.88(s,3H).

[0387] Example 13

[0388] 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0389] 2-Fluoroprop-2-enoic acid (63 mg, 695.31 μmol) was dissolved in dry DMF (5 mL). EDCI (133 mg, 695.31 μmol, hydrochloride), HOBt (31 mg, 231.77 μmol) and 4-dimethylaminopyridine (14 mg, 115.89 μmol) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for several minutes. 4-(4-amino-2-methyl-phenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-1H-pyrrole-2-carboxamide (100 mg, 231.77 μmol) was added. The reaction mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by prep-HPLC to obtain the title compound (6.5 mg, 6%).

[0390] MS m / z(ESI):504.2[M+H] + .

[0391] 1H NMR (400MHz, DMSO-d6) δ11.50(s,1H),10.16(s,1H),8.44(d,J=5.0Hz,1H),7.52(s,1H),7.50-7.44(m,1H),7.16(dd,J=9.3,6.9Hz,2H),7.03(dd,J= 17.1,4.9Hz,2H),6.96-6.87(m,1H),6.25(s,1H),5.68(dd,J=47.6,3.5Hz ,1H),5.39(dd,J=15.6,3.5Hz,1H),2.39(s,3H),2.02(s,3H),1.89(s,3H).

[0392] Example 14

[0393] 4-(4-(2-chloroacryloylamino)-2-methylphenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0394] 2-Chloroprop-2-enoic acid (49 mg, 463.54 μmol) was dissolved in DMF (5 mL). Dicyclohexylcarbodiimide (96 mg, 463.54 μmol) and diisopropylethylamine (60 mg, 463.54 μmol) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for several minutes. 4-(4-amino-2-methyl-phenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl-1H-pyrrole-2-carboxamide (100 mg, 231.77 μmol) was added. The resulting reaction solution was stirred at room temperature for 12 hours. The reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative TLC and prep-HPLC to obtain the title compound (26.5 mg, 22%).

[0395] MS m / z(ESI):520.2[M+H] + .

[0396] 1H NMR (400MHz, DMSO-d6) δ11.49(s,1H),10.08(s,1H),8.45(d,J=5.0Hz,1H),7.44(dd,J=11.8,3.4Hz,2H),7.17(dd,J=10.1,6.8Hz,2H),7.0 4(dd,J=17.6,5.0Hz,3H),6.93(dd,J=8.3,0.8Hz,1H),6.39(d,J=2.5Hz,2H),6.05(d,J=2.5Hz,1H),2.39(s,3H),2.02(s,3H),1.90(s,3H).

[0397] Example 15

[0398] 5-ethyl-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-4-(4-(2-fluoroacryloylamido)phenyl)-1H-pyrrole-2-carboxamide

[0399] Step 1: Preparation of O1-tert-butyl O2-methyl 4-bromopyrrole-1,2-dicarboxylate

[0400] Methyl 4-bromo-1H-pyrrole-2-carboxylate (7.7 g, 37.74 mmol) and tert-butoxycarbonyl tert-butyl carbonate (10.71 g, 49.06 mmol) were dissolved in acetonitrile (50 mL), and 4-dimethylaminopyridine (4.61 g, 37.74 mmol) was added. The reaction solution was stirred at room temperature under nitrogen for 2 hours, and the solvent was removed by concentration under reduced pressure. The residue was separated by silica gel column chromatography to obtain the target compound (11.1 g, 97%).

[0401] MS m / z(ESI):304.1,306.1[M+H] + .

[0402] Step 2: Preparation of methyl 4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate

[0403] To a mixed solvent of DMF (100 mL) and water (20 mL) was added O1-tert-butyl O2-methyl 4-bromopyrrole-1,2-dicarboxylate (7.8 g, 25.65 mmol), 4-nitrophenylboronic acid (8.56 g, 51.29 mmol), tetrakistriphenylphosphine palladium (2.96 g, 2.56 mmol) and anhydrous sodium carbonate (27.19 g, 256.46 mmol). The reaction solution was replaced with nitrogen, heated to 90°C and stirred for 3 hours, then heated to 110°C and stirred for 3 hours. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was slurried with ethyl acetate to obtain the target compound (4.65 g, 74%).

[0404] MS m / z(ESI):247.1[M+H] + .

[0405] Step 3: Preparation of O1-tert-butyl O2-methyl 5-bromo-3-iodo-4-(4-nitrophenyl)pyrrole-1,2-dicarboxylate

[0406] Methyl 4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate (2.77 g, 11.23 mmol) was dissolved in DMF (35 mL) and cooled to 0°C in an ice-water bath. N-bromosuccinimide (2 g, 11.23 mmol) was added portionwise with stirring. The ice-water bath was removed and the reaction solution was transferred to room temperature and stirred for 4 hours. N-iodosuccinimide (2.53 g, 11.23 mmol) was added and the reaction solution was stirred at room temperature for 2 hours. 4-Dimethylaminopyridine (1.37 g, 11.23 mmol) and tert-butoxycarbonyl tert-butyl carbonate (9.8 g, 44.91 mmol) were added respectively and the reaction solution was stirred at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (5.5 g, 89%).

[0407] MS m / z(ESI):551.1,553.1[M+H] + .

[0408] Step 4: Preparation of methyl 5-bromo-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate

[0409] O1-tert-butyl O2-methyl 5-bromo-3-iodo-4-(4-nitrophenyl)pyrrole-1,2-dicarboxylate (3.3 g, 5.99 mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4-methyl-pyrimidine (3.56 g, 10.78 mmol), tetrakis(triphenylphosphine)palladium (6.92 g, 5.99 mmol) were dissolved in DMF (60 The reaction solution was protected by nitrogen, and a solution of anhydrous potassium phosphate (1.27 g, 5.99 mmol) in water (6 mL) was added under stirring at room temperature. The reaction solution was replaced with nitrogen, transferred to an oil bath, heated to 55° C., and stirred for 16 hours. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in dichloromethane. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (3.16 g, 100%).

[0410] MS m / z(ESI):527.1,529.1[M+H] + .

[0411] Step 5: Preparation of methyl 3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-4-(4-nitrophenyl)-5-vinyl-1H-pyrrole-2-carboxylate

[0412] Methyl 5-bromo-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate (1 g, 1.90 mmol), potassium vinyl fluoroborate (1.26 g, 9.48 mmol), Pd(dppf)Cl2 (277 mg, 379.29 μmol) and tetrabutylammonium bromide (122 mg, 379.29 μmol) were added to dioxane (15 mL). Anhydrous potassium carbonate (785 mg, 5.69 mmol) in water (3 mL) was added. The resulting reaction solution was replaced with nitrogen and transferred to a microwave synthesizer. The mixture was heated to 100°C and stirred for 4 hours. The solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was isolated by silica gel column chromatography to obtain the title compound (355 mg, 39%).

[0413] MS m / z(ESI):475.2[M+H] + .

[0414] Step 6: Preparation of 3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-4-(4-nitrophenyl)-5-vinyl-1H-pyrrole-2-carboxylic acid

[0415] Methyl 3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-4-(4-nitrophenyl)-5-vinyl-1H-pyrrole-2-carboxylate (355 mg, 748.25 μmol) was dissolved in methanol (5 mL), and a solution of lithium hydroxide monohydrate (94 mg, 2.24 mmol) in water (5 mL) was added with stirring at room temperature. The reaction solution was transferred to a 70°C oil bath and heated for 5 hours. The organic solvent was removed by concentration under reduced pressure. The residue was diluted with water and adjusted to pH = 5 with 2N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used directly in the next reaction.

[0416] MS m / z(ESI):461.1[M+H] + .

[0417] Step 7: Preparation of 3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-4-(4-nitrophenyl)-5-vinyl-1H-pyrrole-2-carboxamide

[0418] 3-(3-Fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-4-(4-nitrophenyl)-5-vinyl-1H-pyrrole-2-carboxylic acid (344 mg, 747.15 μmol) was dissolved in DMF (10 mL). HOBt (201.91 mg, 1.49 mmol), triethylamine (227 mg, 2.24 mmol, 312.63 μL), EDCI (287 mg, 1.49 mmol, hydrochloride) and ammonium chloride (200 mg, 3.74 mmol) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for 2 hours. The solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used directly in the next reaction.

[0419] MS m / z(ESI):460.2[M+H] + .

[0420] Step 8: Preparation of 4-(4-aminophenyl)-5-ethyl-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-1H-pyrrole-2-carboxamide

[0421] 3-(3-Fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-4-(4-nitrophenyl)-5-vinyl-1H-pyrrole-2-carboxamide (775 mg, 1.69 mmol) was dissolved in a mixed solvent of ethanol (15 mL), ethyl acetate (10 mL) and dichloromethane (5 mL). Palladium on carbon (200 mg) was added, and the reaction solution was replaced with hydrogen. The reaction was stirred at room temperature in the presence of hydrogen for 12 hours, filtered through celite, and concentrated under reduced pressure to remove the solvent. The residue was separated by silica gel column chromatography to obtain the title compound (244 mg, 34%).

[0422] MS m / z(ESI):432.2[M+H] + .

[0423] Step 9: Preparation of 5-ethyl-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-4-(4-(2-fluoroprop-2-enoylamino)phenyl)-1H-pyrrole-2-carboxamide

[0424] 2-Fluoroprop-2-enoic acid (38 mg, 417.19 μmol) was dissolved in DMF (3 mL). EDCI (80 mg, 417.19 μmol, hydrochloride) and 4-dimethylaminopyridine (5 mg, 41.72 μmol) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for several minutes, and then 4-(4-aminophenyl)-5-ethyl-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-1H-pyrrole-2-carboxamide (60 mg, 139.06 μmol) was added. The reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by prep-HPLC to obtain the title compound (2.7 mg, 4%).

[0425] MS m / z(ESI):504.2[M+H] + .

[0426] 1H NMR (400MHz, DMSO-d6) δ11.44(s,1H),10.23(s,1H),8.46(d,J=5.0Hz,1H),7.60(d ,J=8.5Hz,2H),7.22(t,J=8.5Hz,1H),7.17(d,J=5.0Hz,1H),7.11(dd,J=11.9,1.4H z,1H),6.98(dd,J=8.6,2.4Hz,4H),6.13(s,1H),5.68(dd,J=47.8,3.5Hz,1H),5.40 (dd,J=15.8,5.5Hz,1H),2.56(q,J=7.6Hz,2H),2.41(s,3H),1.13(t,J=7.6Hz,3H).

[0427] Example 16

[0428] 4-(4-(2-chloroacryloylamino)phenyl)-5-ethyl-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-1H-pyrrole-2-carboxamide

[0429] 2-Chloroprop-2-enoic acid (91 mg, 852.92 μmol) was dissolved in DMF (5 mL). Dicyclohexylcarbodiimide (176 mg, 852.92 μmol) and diisopropylethylamine (110 mg, 852.92 μmol, 148.56 μL) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for several minutes. 4-(4-aminophenyl)-5-ethyl-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-1H-pyrrole-2-carboxamide (184 mg, 426.46 μmol) was added. The reaction solution was stirred at room temperature for 2 hours, filtered, and the filtrate was collected, diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative TLC and prep-HPLC to obtain the title compound (33 mg, 15%).

[0430] MS m / z(ESI):520.2[M+H] + .

[0431] 1H NMR (400MHz, DMSO-d6) δ11.44(s,1H),10.15(s,1H),8.46(d,J=5.0Hz,1H),7.54(d,J=8.5Hz,2H),7.22(t,J=8.4Hz,1H),7.17(d,J=5.0Hz,1H),7. 11(d,J=11.7Hz,1H),7.06-6.90(m,4H),6.38(d,J=2.4Hz,1H),6.08(t,J =17.0Hz,2H),2.57(q,J=7.5Hz,2H),2.41(s,3H),1.13(t,J=7.5Hz,3H).

[0432] Example 17

[0433] 3-(3-Fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-4-(4-(prop-2-enoylamino)phenyl)-5-vinyl-1H-pyrrole-2-carboxamide

[0434] Step 1: Preparation of 4-(4-aminophenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-vinyl-1H-pyrrole-2-carboxamide

[0435] 3-(3-Fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-4-(4-nitrophenyl)-5-vinyl-1H-pyrrole-2-carboxamide (343 mg, 746.58 μmol) was dissolved in a mixture of dioxane (10 mL) and ethanol (10 mL). Iron powder (1.25 g, 22.40 mmol) and a solution of ammonium chloride (599.13 mg, 11.20 mmol) in water (10 mL) were added sequentially with stirring at room temperature. The reaction solution was protected with nitrogen and transferred to a 50°C oil bath with heating and stirring for 1 hour. The reaction solution was concentrated under reduced pressure to remove most of the organic solvent. The residue was dispersed in water and extracted with dichloromethane. The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (113 mg, 35%).

[0436] MS m / z(ESI):430.2[M+H] + .

[0437] Step 2: Preparation of 3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-4-(4-(prop-2-enoylamino)phenyl)-5-vinyl-1H-pyrrole-2-carboxamide

[0438] 4-(4-Aminophenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-vinyl-1H-pyrrole-2-carboxamide (37 mg, 86.16 μmol) was dissolved in DMF (3 mL) and cooled to 0°C in an ice-water bath. Triethylamine (44 mg, 430.79 μmol, 60.08 μL) and acryloyl chloride (8 mg, 86.16 μmol) were added sequentially with stirring. The reaction mixture was stirred at 0°C for 1 hour. The reaction solution was directly separated by ODS-Flash column chromatography to obtain the title compound (13.1 mg, 29%).

[0439] MS m / z(ESI):484.2[M+H] + .

[0440] 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),10.13(s,1H),8.46(d,J=5.0Hz,1H),7.58(d,J= 8.3Hz,2H),7.25-7.20(m,1H),7.18-7.16(m,1H),7.10(d,J=12.4Hz,1H),6.96(t,J=8. 9Hz,3H),6.70(s,1H),6.42(ddd,J=16.8,10.6,3.3Hz,2H),6.24(d,J=17.1Hz,1H),5.8 6(d,J=17.8Hz,1H),5.74(dd,J=10.2,1.1Hz,1H),5.14(d,J=11.6Hz,1H),2.41(s,3H).

[0441] Example 18

[0442] 3-(3-Fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-4-(4-(2-methylprop-2-enoylamino)phenyl)-5-vinyl-1H-pyrrole-2-carboxamide

[0443] 4-(4-Aminophenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-vinyl-1H-pyrrole-2-carboxamide (37 mg, 86.16 μmol) was dissolved in DMF (3 mL) and cooled to 0°C in an ice-water bath. Triethylamine (44 mg, 430.79 μmol, 60.08 μL) and 2-methacryloyl chloride (9 mg, 86.16 μmol) were added sequentially with stirring. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was directly separated by ODS-Flash chromatography to obtain the title compound (10.8 mg, 23%).

[0444] 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),9.76(s,1H),8.46(d,J=5.0Hz,1H),7.59(d,J =8.5Hz,2H),7.23-7.18(m,1H),7.17(d,J=5.0Hz,1H),7.10(dd,J=11.6,1.7Hz,1H) ,6.96(d,J=8.4Hz,3H),6.65(s,1H),6.42(dd,J=17.8,11.6Hz,1H),5.86(d,J=17.9 Hz,1H),5.79(s,1H),5.49(s,1H),5.14(d,J=12.0Hz,1H),2.41(s,3H),1.93(s,3H).

[0445] MS m / z(ESI):498.2[M+H] + .

[0446] Example 19

[0447] 3-(3-Fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-4-(4-(2-fluoroprop-2-enoylamino)phenyl)-5-vinyl-1H-pyrrole-2-carboxamide

[0448] 2-Fluoroacrylic acid (12 mg, 129.24 μmol), HOBt (17 mg, 129.24 μmol), triethylamine (44 mg, 430.79 μmol, 60.08 μL) and HATU (49 mg, 129.24 μmol) were added to DMF (1 mL) in sequence, and the reaction solution was stirred at room temperature for 10 minutes. The mixture was then added to a solution of 4-(4-aminophenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-vinyl-1H-pyrrole-2-carboxamide (37 mg, 86.16 μmol) in DMF (2 mL). The reaction solution was stirred at room temperature for 1 hour, filtered, and the filtrate was separated by ODS-Flash column chromatography to obtain the title compound (12.4 mg, 28.7%).

[0449] MS m / z(ESI):502.2[M+H] + .

[0450] 1H NMR(400MHz,DMSO-d6)δ11.63(s,1H),10.27(s,1H),8.46(d,J=4.8Hz,1H),7 .64(d,J=8.2Hz,2H),7.24-7.19(m,1H),7.19-7.15(m,1H),7.10(dd,J=11.5, 0.9Hz,1H),6.98(dd,J=17.7,8.3Hz,3H),6.64(s,1H),6.42(dd,J=17.3,11.6Hz,1H),5.86(d,J=1 7.6Hz,1H),5.69(dd,J=47.4,2.8Hz,1H),5.48-5.37(m,1H),5.15(d,J=11.9Hz,1H),2.41(s,3H).

[0451] Example 28

[0452] 4-(4-Acryloylamidophenyl)-3-(4-((cyclobutylmethyl)carbamoyl)phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0453] Step 1: Preparation of N-(cyclobutylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

[0454] 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1 g, 4.03 mmol) was dissolved in dichloromethane (20 mL). HOBt (164 mg, 1.21 mmol), diisopropylethylamine (1.56 g, 12.09 mmol, 2.11 mL) and EDCI (1.16 g, 6.05 mmol, hydrochloride) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for a few minutes, and then cyclobutylmethylamine (412 mg, 4.84 mmol) was added. The resulting reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane, washed with saturated aqueous sodium chloride solution and saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (1 g, 79%).

[0455] MS m / z(ESI):316.2[M+H] + .

[0456] Step 2: Preparation of methyl 3-(4-(cyclobutylmethylcarbamoyl)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate

[0457] N-(cyclobutylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1 g, 3.17 mmol), O1-tert-butyl O2-methyl 3-bromo-5-methyl-4-(4-nitrophenyl)pyrrole-1,2-dicarboxylate (1.5 g, 3.41 mmol), and Pd(dppf)Cl2 (0.5 g, 683.99 μmol) were added to DMF (20 mL). The resulting reaction solution was protected with nitrogen and a solution of potassium carbonate (1.41 g, 10.22 mmol) in water (2 mL) was added under stirring at room temperature. The reaction solution was replaced with nitrogen once, transferred to 90°C and stirred for 3 hours, and then concentrated under reduced pressure to remove the solvent. The residue was dissolved in dichloromethane, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (1.42 g, 100%).

[0458] MS m / z(ESI):448.2[M+H] + .

[0459] Step 3: Preparation of 3-(4-(cyclobutylmethylcarbamoyl)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylic acid

[0460] Methyl 3-(4-(cyclobutylmethylcarbamoyl)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate (1.42 g, 3.17 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL). A solution of sodium hydroxide (381 mg, 9.52 mmol) in water (10 mL) was added with stirring at room temperature. The resulting reaction solution was transferred to 90°C and stirred for 8 hours. The organic solvent was removed by concentration under reduced pressure. The residue was diluted with water and the pH was adjusted to acidic by adding acetic acid. The resulting precipitate was filtered, dried under reduced pressure, and washed with a small amount of ethyl acetate. The resulting solid was collected and dried under reduced pressure to obtain the title compound (1.02 g, 74%).

[0461] MS m / z(ESI):434.2[M+H] + .

[0462] Step 4: Preparation of 4-(4-aminophenyl)-3-(4-(cyclobutylmethylcarbamoyl)phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0463] 3-(4-(Cyclobutylmethylcarbamoyl)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylic acid (1.02 g, 2.35 mmol) was dissolved in DMF (15 mL). Diisopropylethylamine (911 mg, 7.05 mmol), HOBt (636 mg, 4.7 mmol), EDCI (901 mg, 4.7 mmol, hydrochloride) and ammonium chloride (629 mg, 11.75 mmol) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in a mixed solvent of ethanol (10 mL) and dioxane (10 mL), and iron powder (6.58 g, 117.5 mmol) and a solution of ammonium chloride (3.77 g, 70.5 mmol) in water (10 mL) were added sequentially. The resulting reaction solution was transferred to 90°C and heated for 2 hours. The reaction mixture was filtered through celite, and the filter residue was washed with ethyl acetate. The filtrate was collected and dried under reduced pressure. The residue was dissolved in dichloromethane, washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and shrunk. The residue was separated by silica gel column chromatography to obtain the title compound (947 mg, 100%).

[0464] MS m / z(ESI):403.2[M+H] + .

[0465] Step 5: Preparation of 3-(4-(cyclobutylmethylcarbamoyl)phenyl)-5-methyl-4-(4-(prop-2-enoylamino)phenyl)-1H-pyrrole-2-carboxamide

[0466] 4-(4-Aminophenyl)-3-(4-(cyclobutylmethylcarbamoyl)phenyl)-5-methyl-1H-pyrrole-2-carboxamide (100 mg, 248.45 μmol) was dissolved in DMF (2 mL). Diisopropylethylamine (32 mg, 248.45 μmol) and acryloyl chloride (33.73 mg, 372.68 μmol) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for 30 minutes and filtered. The filtrate was separated by prep-HPLC to obtain the title compound (31.3 mg, 27.6%).

[0467] MS m / z(ESI):457.2[M+H] + .

[0468] 1H NMR (400MHz, DMSO-d6) δ11.52(s,1H),10.03(s,1H),8.41(t,J=5.6Hz,1H),7.73(d,J=8.1Hz,2 H),7.47(d,J=8.4Hz,2H),7.22(d,J=8.1Hz,2H),6.91(d,J=8.5Hz,3H),6.39(dd,J=17.0,10.1H z,1H),6.21(dd,J=17.0,1.7Hz,1H),5.72(dd,J=10.1,1.7Hz,2H),3.27(t,J=6.3Hz,2H),2.58 -2.50(m,1H),2.22(s,3H),2.04-1.90(m,2H),1.81(dt,J=14.1,7.2Hz,2H),1.76-1.64(m,2H).

[0469] Example 29

[0470] 3-(4-((cyclobutylmethyl)carbamoyl)phenyl)-4-(4-methacryloylamidophenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0471] 4-(4-Aminophenyl)-3-(4-(cyclobutylmethylcarbamoyl)phenyl)-5-methyl-1H-pyrrole-2-carboxamide (100 mg, 248.45 μmol) was dissolved in DMF (2 mL). Diisopropylethylamine (32 mg, 248.45 μmol) and 2-methylprop-2-enoyl chloride (26 mg, 248.45 μmol) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for 30 minutes and filtered. The filtrate was separated by prep-HPLC to obtain the title compound (33.6 mg, 27%).

[0472] MS m / z(ESI):471.2[M+H] + .

[0473] 1H NMR (400MHz, DMSO-d6) δ11.53(s,1H),9.67(s,1H),8.41(t,J=5.6Hz,1H),7.7 3(d,J=8.1Hz,2H),7.47(d,J=8.5Hz,2H),7.22(d,J=8.1Hz,2H),6.89(d,J=8.5 Hz,3H),5.74(s,2H),5.47(s,1H),3.30-3.25(m,2H),2.58-2.51(m,1H),2.22 (s,3H),2.03-1.94(m,2H),1.91(s,3H),1.86-1.76(m,2H),1.76-1.62(m,2H).

[0474] Example 30

[0475] 3-(4-((cyclobutylmethyl)carbamoyl)phenyl)-4-(4-(2-fluoroacryloylamido)phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0476] 2-Fluoroprop-2-enoic acid (67 mg, 745.36 μmol) was dissolved in DMF (2 mL). EDCI (95 mg, 496.91 μmol, hydrochloride) and 4-dimethylaminopyridine (15 mg, 124.23 μmol) were added sequentially with stirring at room temperature. The reaction mixture was stirred at room temperature for 5 minutes. 4-(4-aminophenyl)-3-(4-(cyclobutylmethylcarbamoyl)phenyl)-5-methyl-1H-pyrrole-2-carboxamide (100 mg, 248.45 μmol) was added. The reaction mixture was stirred at room temperature for 30 minutes and filtered. The filtrate was separated by prep-HPLC to obtain the title compound (9.1 mg, 7%).

[0477] MS m / z(ESI):475.2[M+H] + .

[0478] 1H NMR (400MHz, DMSO-d6) δ11.55(s,1H),10.18(s,1H),8.41(t,J=5.6Hz,1H),7.73(d,J=8 .2Hz,2H),7.52(d,J=8.5Hz,2H),7.22(d,J=8.1Hz,2H),6.93(d,J=8.5Hz,3H),5.67(dd ,J=47.7,3.5Hz,2H),5.39(dd,J=15.6,3.5Hz,1H),3.29-3.25(m,2H),2.54(d,J=7.4Hz ,1H),2.22(s,3H),1.98(td,J=14.8,7.7Hz,2H),1.88-1.74(m,2H),1.75-1.63(m,2H).

[0479] Example 31

[0480] 4-(4-(2-chloroacryloylamino)phenyl)-3-(4-((cyclobutylmethyl)carbamoyl)phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0481] 2-Chloroprop-2-enoic acid (159 mg, 1.49 mmol) was dissolved in DMF (6 mL). EDCI (286 mg, 1.49 mmol, hydrochloride) and 4-dimethylaminopyridine (61 mg, 496.91 μmol) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for a few minutes. 4-(4-aminophenyl)-3-(4-(cyclobutylmethylcarbamoyl)phenyl)-5-methyl-1H-pyrrole-2-carboxamide (200 mg, 496.91 μmol) was added and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative TLC and prep-HPLC to obtain the title compound (2.4 mg, 1%).

[0482] MS m / z(ESI):491.2[M+H] + .

[0483] 1H NMR (400MHz, DMSO-d6) δ11.54(s,1H),10.09(s,1H),8.40(t,J=5.6Hz,1H),7.73(d,J =8.1Hz,2H),7.46(d,J=8.4Hz,2H),7.22(d,J=8.0Hz,2H),6.93(d,J=8.4Hz,3H),6.3 6(d,J=2.3Hz,1H),6.04(d,J=2.3Hz,1H),5.67(s,1H),3.26(d,J=6.5Hz,2H),2.54(d ,J=7.7Hz,1H),2.22(s,3H),2.03-1.90(m,2H),1.87-1.76(m,2H),1.75-1.63(m,2H).

[0484] Example 32

[0485] 4-(4-Acryloylamido-2-methylphenyl)-3-(4-((cyclobutylmethyl)carbamoyl)-3-methoxyphenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0486] Step 1: Preparation of 4-bromo-N-(cyclobutylmethyl)-2-methoxy-benzamide

[0487] 4-Bromo-2-methoxy-benzoic acid (5 g, 21.64 mmol) was dissolved in DMF (20 mL). Diisopropylethylamine (5.59 g, 43.28 mmol, 7.54 mL), HOBt (585 mg, 4.33 mmol) and EDCI (5.39 g, 28.13 mmol, hydrochloride) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for several minutes. Cyclobutylmethylamine hydrochloride (3.16 g, 25.97 mmol) was added and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain the title compound (6.45 g, 100%). The residue was used directly in the next step without further purification.

[0488] MS m / z(ESI):298.0,300.0[M+H] + .

[0489] Step 2: Preparation of N-(cyclobutylmethyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

[0490] 4-Bromo-N-(cyclobutylmethyl)-2-methoxy-benzamide (6.45 g, 21.64 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan-2-yl (6.59 g, 25.97 mmol), Pd(dppf)Cl2 (791 mg, 1.08 mmol) and potassium acetate (4.24 g, 43.28 mmol) were dispersed in dioxane (100 mL). The reaction solution was protected by dry nitrogen and heated to 100°C with stirring for 20 hours. The reaction was concentrated under reduced pressure to remove the solvent. The residue was separated by silica gel column chromatography to obtain the title compound (7.47 g, 100%).

[0491] MS m / z(ESI):346.2[M+H] + .

[0492] Step 3: Preparation of methyl 3-(4-(cyclobutylmethylcarbamoyl)-3-methoxy-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylate

[0493] 1-(tert-Butyl) 2-methyl 3-bromo-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-1,2-dicarboxylate (1 g, 2.28 mmol), N-(cyclobutylmethyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.18 g, 3.41 mmol) and Pd(dppf)Cl2 (332.84 mg, 455.3 1μmol) was dissolved in DMF (15mL), and a solution of potassium carbonate (942.50mg, 6.83mmol) in water (2.5mL) was added under nitrogen protection. The resulting reaction solution was replaced with nitrogen. The reaction solution was heated to 90°C under nitrogen protection and stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (980mg, 88%).

[0494] MS m / z(ESI):492.2[M+H] + .

[0495] Step 4: Preparation of 3-(4-(cyclobutylmethylcarbamoyl)-3-methoxy-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylic acid

[0496] Methyl 3-(4-(cyclobutylmethylcarbamoyl)-3-methoxy-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylate (980 mg, 1.99 mmol) was dissolved in a mixed solvent of tetrahydrofuran (25 mL) and methanol (25 mL). A solution of sodium hydroxide (797.50 mg, 19.94 mmol) in water (15 mL) was added with stirring at room temperature. The reaction solution was transferred to an oil bath, heated to 50° C., and stirred for 16 hours. The organic solvent was removed by concentration under reduced pressure. The residue was diluted with water, and the pH was adjusted to neutral by adding acetic acid with stirring at room temperature. The mixture was extracted with ethyl acetate. The organic phase was washed sequentially with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used directly in the next reaction.

[0497] MS m / z(ESI):478.2[M+H] + .

[0498] Step 5: Preparation of 4-(4-amino-2-methyl-phenyl)-3-(4-(cyclobutylmethylcarbamoyl)-3-methoxy-phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0499] 3-(4-(Cyclobutylmethylcarbamoyl)-3-methoxy-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylic acid (952 mg, 1.99 mmol) was dissolved in DMF (15 mL), and HOBt (538.77 mg, 3.99 mmol), diisopropylethylamine (772.99 mg, 5.98 mmol, 1.04 mL), EDCI (764.38 mg, 3.99 mmol, hydrochloride) and ammonium chloride (533.31 mg, 9.97 mmol) were added in sequence under stirring at room temperature. The reaction solution was stirred at room temperature for 1 hour, diluted with ethyl acetate, and saturated chlorination was performed. The mixture was washed with sodium aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in a mixed solvent of dioxane (25 mL) and ethanol (25 mL). Iron powder (5.57 g, 99.68 mmol) and a solution of ammonium chloride (3.20 g, 59.81 mmol) in water (20 mL) were added sequentially with stirring. The reaction solution was protected with nitrogen, heated to 50°C and stirred for 1 hour. The solvent was removed by concentration under reduced pressure. The residue was dispersed in water, and the pH was adjusted to alkaline by adding saturated sodium bicarbonate aqueous solution. The product was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (890 mg, 99%).

[0500] MS m / z(ESI):447.2[M+H]+ .

[0501] Step 6: Preparation of 3-(4-(cyclobutylmethylcarbamoyl)-3-methoxy-phenyl)-5-methyl-4-(2-methyl-4-(prop-2-enoylamino)phenyl)-1H-pyrrole-2-carboxamide

[0502] 4-(4-Amino-2-methyl-phenyl)-3-(4-(cyclobutylmethylcarbamoyl)-3-methoxy-phenyl)-5-methyl-1H-pyrrole-2-carboxamide (100 mg, 223.94 μmol) was dissolved in dry DMF (5 mL) and cooled to 0°C in an ice-water bath. Diisopropylethylamine (43.41 mg, 335.92 μmol, 58.51 μL) and acryloyl chloride (22.30 mg, 246.34 μmol) were added sequentially with stirring. The reaction mixture was transferred to room temperature and stirred for 30 minutes. The reaction mixture was separated by ODS-Flash column chromatography to obtain the title compound (28 mg, 23%).

[0503] MS m / z(ESI):501.2[M+H] + .

[0504] 1 H NMR (400MHz, DMSO-d6) δ11.49(s,1H),10.00(s,1H),8.01(t,J=5.6Hz,1H),7.57(d,J=12.5Hz,1H),7.41(d,J= 7.3Hz,2H),6.99(d,J=8.4Hz,2H),6.88-6.79(m,1H),6.73(s,1H),6.40(dd,J=16.9,10.0Hz,1H),6.22(dd,J= 17.0,1.8Hz,1H),6.00(s,1H),5.72(dd,J=10.1,1.8Hz,1H),3.59(s,3H),3.26(d,J=6.7Hz,2H),2.47-2.43(m ,1H),2.02(s,3H),1.94(dd,J=15.2,8.4Hz,2H),1.86(s,3H),1.80(dd,J=15.0,7.1Hz,2H),1.73-1.65(m,2H).

[0505] Example 33

[0506] 3-(4-((cyclobutylmethyl)carbamoyl)-3-methoxyphenyl)-4-(4-methacryloylamido-2-methylphenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0507] 4-(4-Amino-2-methyl-phenyl)-3-(4-(cyclobutylmethylcarbamoyl)-3-methoxy-phenyl)-5-methyl-1H-pyrrole-2-carboxamide (100 mg, 223.94 μmol) was dissolved in dry DMF (5 mL) and cooled to 0°C in an ice-water bath. Diisopropylethylamine (44 mg, 335.92 μmol) and 2-methylprop-2-enoyl chloride (26 mg, 246.34 μmol) were added sequentially with stirring. The reaction solution was transferred to room temperature and stirred for 30 minutes. The reaction solution was separated by ODS-Flash column chromatography to obtain the title compound (27 mg, 22%).

[0508] MS m / z(ESI):515.2[M+H] + .

[0509] 1 H NMR (400MHz, DMSO-d6) δ11.50(s,1H),9.62(s,1H),8.02(t,J=5.8Hz,1H),7.56(d,J=7.9Hz,1 H),7.40(d,J=9.2Hz,2H),6.97(d,J=8.0Hz,2H),6.83(d,J=8.2Hz,1H),6.75(s,1H),6.00(s,1 H),5.76(s,1H),5.47(s,1H),3.61(s,3H),3.27-3.24(m,2H),2.46(d,J=7.6Hz,1H),2.01(d,J =8.9Hz,3H),1.99-1.90(m,5H),1.86(s,3H),1.80(dd,J=15.0,7.2Hz,2H),1.74-1.63(m,2H).

[0510] Example 34

[0511] 3-(4-((cyclobutylmethyl)carbamoyl)-3-methoxyphenyl)-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0512] 2-Fluoroprop-2-enoic acid (61 mg, 671.83 μmol) was dissolved in dry DMF (5 mL). EDCI (129 mg, 671.83 μmol, hydrochloride), HOBt (30 mg, 223.94 μmol) and 4-dimethylaminopyridine (14 mg, 111.97 μmol) were added sequentially at room temperature. The reaction mixture was stirred at room temperature for several minutes. 4-(4-amino-2-methyl-phenyl)-3-(4-(cyclobutylmethylcarbamoyl)-3-methoxy-phenyl)-5-methyl-1H-pyrrole-2-carboxamide (100 mg, 223.94 μmol) was added. The reaction mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by prep-HPLC to obtain the title compound (15.2 mg, 13%).

[0513] MS m / z(ESI):519.2[M+H] + .

[0514] 1 H NMR (400MHz, DMSO-d6) δ11.51(s,1H),10.14(s,1H),8.02(t,J=5.7Hz,1H),7.56(d,J=7.9Hz,1H),7. 52-7.31(m,2H),7.02(d,J=8.2Hz,2H),6.87-6.80(m,1H),6.73(s,1H),6.00(s,1H),5.67(dd,J=47.7 ,3.5Hz,1H),5.39(dd,J=15.6,3.5Hz,1H),3.60(s,3H),3.26(t,J=6.4Hz,2H),2.49-2.42(m,1H),2.0 2(s,3H),1.94(dd,J=14.2,7.7Hz,2H),1.87(s,3H),1.80(dd,J=14.9,7.1Hz,2H),1.73-1.61(m,2H).

[0515] Example 35

[0516] 4-(4-(2-chloroacryloylamino)-2-methylphenyl)-3-(4-((cyclobutylmethyl)carbamoyl)-3-methoxyphenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0517] 2-Chloroacrylic acid (48 mg, 447.89 μmol) was dissolved in dry tetrahydrofuran (1 mL). Dicyclohexylcarbodiimide (46 mg, 223.94 μmol) and diisopropylethylamine (29 mg, 223.94 μmol, 39.01 μL) were added sequentially. The reaction mixture was stirred at room temperature for 10 minutes and then added to a solution of 4-(4-amino-2-methyl-phenyl)-3-(4-(cyclobutylmethylcarbamoyl)-3-methoxy-phenyl)-5-methyl-1H-pyrrole-2-carboxamide (100 mg, 223.94 μmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 12 hours and filtered. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by preparative TLC and prep-HPLC to obtain the title compound (6.6 mg, 5%).

[0518] MS m / z(ESI):535.2[M+H] + .

[0519] 1 H NMR (400MHz, DMSO-d6) δ11.51(s,1H),10.06(s,1H),8.02(t,J=5.7Hz,1H),7.56(d,J=7.9Hz,1H) ,7.40(d,J=8.2Hz,2H),7.02(d,J=7.9Hz,2H),6.83(dd,J=7.9,1.1Hz,1H),6.75(s,1H),6.39(d, J=2.4Hz,1H),6.05(d,J=2.4Hz,2H),3.61(s,3H),3.28-3.23(m,2H),2.50-2.43(m,1H),2.02(s, 3H),1.95(dd,J=14.6,8.0Hz,2H),1.88(s,3H),1.83-1.75(m,2H),1.69(dt,J=16.3,7.2Hz,2H).

[0520] Example 52

[0521] Step 1: Preparation of ethyl 2-(4-bromo-3-methoxybenzoyl)-3-(dimethylamino)prop-2-enoate

[0522] Disperse 4-bromo-3-methoxybenzoic acid (20 g, 86.56 mmol) in dry dichloromethane (150 mL). Protect the reaction solution with dry nitrogen and cool it to 0°C in an ice-water bath. Add N,N-dimethylformamide (1 mL) under stirring. After cooling for a few minutes, add oxalyl chloride (19.78 g, 155.82 mmol) dropwise. After the addition is complete, transfer the reaction solution to room temperature and stir for 16 hours. Concentrate under reduced pressure to remove the solvent. Disperse the residue in dry toluene (150 mL), protect it with dry nitrogen, and stir it at room temperature. Ethyl 3-(dimethylamino)prop-2-enoate (14.87 g, 103.88 mmol) and triethylamine (26.28 g, 259.69 mmol, 36.22 mL) were added simultaneously. The resulting reaction solution was stirred at room temperature for a few minutes, then transferred to an oil bath and heated to 110°C with stirring for 4 hours. The solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (24.60 g, 80%).

[0523] MS m / z(ESI):356.2[M+H] + .

[0524] Step 2: Preparation of ethyl 5-(4-bromo-3-methoxy-phenyl)isoxazole-4-carboxylate

[0525] Ethyl 2-(4-bromo-3-methoxybenzoyl)-3-(dimethylamino)prop-2-enoate (24.60 g, 69.06 mmol) was dissolved in methanol (250 mL). Hydroxylamine hydrochloride (4.80 g, 69.06 mmol) was added with stirring at room temperature. The resulting reaction solution was stirred at room temperature for 16 hours, concentrated under reduced pressure to remove part of the solvent, and an equal amount of water was added. The mixture was slurried and filtered. The filter residue was washed with water, collected, and dried under reduced pressure to give the title compound (16.40 g, 73%).

[0526] MS m / z(ESI):326.0[M+H] + .

[0527] Step 3: Preparation of 5-(4-bromo-3-methoxyphenyl)-2-tert-butyl-4-ethoxyformylisoxazole perchlorate

[0528] A mixture of ethyl 5-(4-bromo-3-methoxy-phenyl)isoxazole-4-carboxylate (1.76 g, 5.40 mmol) and tert-butanol (480 mg, 6.48 mmol) was cooled to -20°C and perchloric acid (2.71 g, 26.98 mmol) was added under stirring. The reaction solution was transferred to room temperature and stirred for 16 hours. The reaction solution was diluted with ice water and extracted with dichloromethane. The dichloromethane layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was directly used in the next reaction.

[0529] MS m / z(ESI):382.1,384.1[M] + .

[0530] Step 4: Preparation of ethyl 5-(4-bromo-3-methoxy-phenyl)-3-(tert-butylamino)-1-(2-methyl-4-nitro-phenyl)pyrazole-4-carboxylate

[0531] 5-(4-Bromo-3-methoxyphenyl)-2-tert-butyl-4-ethoxycarbonylisoxazole perchlorate (2.07 g, 5.40 mmol) and 2-methyl-4-nitrophenylhydrazine (903 mg, 5.40 mmol) were dispersed in ethanol (40 mL). The reaction solution was protected with dry nitrogen and heated to 100°C with stirring for 2 hours. The solvent was removed by concentration under reduced pressure. The residue was dissolved in methyl tert-butyl ether and washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. The residue was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (1.25 g, 44%).

[0532] MS m / z(ESI):531.2[M+H] + .

[0533] Step 5: Preparation of 5-(4-bromo-3-methoxy-phenyl)-3-(tert-butylamino)-1-(2-methyl-4-nitro-phenyl)pyrazole-4-carboxylic acid

[0534] Ethyl 5-(4-bromo-3-methoxy-phenyl)-3-(tert-butylamino)-1-(2-methyl-4-nitro-phenyl)pyrazole-4-carboxylate (1.25 g, 2.35 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (20 mL). A solution of sodium hydroxide (941 mg, 23.52 mmol) in water (15 mL) was added with stirring at room temperature. The resulting reaction solution was transferred to 70°C and stirred for 5 hours. The organic solvent was removed by concentration under reduced pressure. The residue was diluted with water, cooled to 0°C in an ice-water bath, and the pH was adjusted to weak acidity with dilute hydrochloric acid under stirring. The product was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.18 g, 100%) as the residue, which was used directly in the next reaction.

[0535] MS m / z(ESI):503.2[M+H] + .

[0536] Step 6: Preparation of 5-(4-bromo-3-methoxy-phenyl)-3-(tert-butylamino)-1-(2-methyl-4-nitro-phenyl)pyrazole-4-carboxamide

[0537] 5-(4-Bromo-3-methoxy-phenyl)-3-(tert-butylamino)-1-(2-methyl-4-nitro-phenyl)pyrazole-4-carboxylic acid (1.18 g, 2.34 mmol) was dissolved in N,N-dimethylformamide (20 mL). N,N'-Carbonyldiimidazole (1.9 g, 11.72 mmol) was added with stirring at room temperature. The reaction solution was stirred at room temperature under dry nitrogen for 4 hours. Ammonium chloride (1.25 g, 23.44 mmol) and diisopropylethylamine (1.51 g, 11.72 mmol, 2.04 mL) were added. The reaction solution was stirred at room temperature for 16 hours. The mixture was transferred to an oil bath and heated to 60°C with stirring for 8 hours. The reaction solution was diluted with ethyl acetate and washed sequentially with saturated aqueous sodium chloride solution, saturated aqueous sodium carbonate solution, and saturated aqueous sodium chloride solution. The residue was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (590 mg, 50%).

[0538] MS m / z(ESI):502.2[M+H] + .

[0539] Step 7: Preparation of 1-(4-amino-2-methyl-phenyl)-3-(tert-butylamino)-5-(4-(isobutylcarbamoyl)-3-methoxy-phenyl)pyrazole-4-carboxamide

[0540] Take dry microwave reaction tube A and add 5-(4-bromo-3-methoxy-phenyl)-3-(tert-butylamino)-1-(2-methyl-4-nitro-phenyl)pyrazole-4-carboxamide (502 mg, 999 μmol), 2-methyl-1-propylamine (219 mg, 3.00 mmol), Pd(dppf)Cl2 (730 mg, 999 μmol), triethylamine (202 mg, 2.00 mmol, 279 μL) and dioxane (10 mL), and seal the reaction solution; take another microwave reaction tube B and add hexacarbonyl molybdenum (2.64 g, 9.99 mmol) and dioxane (10 mL), seal it, connect microwave reaction tubes A and B with a double-ended needle, protect the reaction system with dry nitrogen, and add DBU (4.56 g, 29.98 mmol, 4.5 The reaction solution was transferred to 90°C and heated with stirring for 4 hours. The reaction solution was cooled to room temperature. The compound in microwave reaction tube A was taken and concentrated under reduced pressure. The title compound (235 mg, 48%) was obtained after separation on a silica gel column.

[0541] MS m / z(ESI):493.3[M+H] + .

[0542] Step 8: Preparation of 3-amino-1-(4-amino-2-methyl-phenyl)-5-(4-(isobutylcarbamoyl)-3-methoxy-phenyl)pyrazole-4-carboxamide

[0543] 1-(4-Amino-2-methyl-phenyl)-3-(tert-butylamino)-5-(4-(isobutylcarbamoyl)-3-methoxy-phenyl)pyrazole-4-carboxamide (235 mg, 477 μmol) was dissolved in trifluoromethanesulfonic acid (3 mL) and stirred at room temperature for 4 hours. The reaction solution was quenched by adding ice water, and the pH was adjusted to alkaline by adding ammonia water. The aqueous solution was extracted several times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (69 mg, 33%).

[0544] MS m / z(ESI):437.3[M+H] + .

[0545] Step 9: Preparation of 3-amino-1-(4-(2-fluoroprop-2-enoylamino)-2-methyl-phenyl)-5-(4-(isobutylcarbamoyl)-3-methoxy-phenyl)pyrazole-4-carboxamide

[0546] 2-Fluoroacrylic acid (9.7 mg, 108 μmol) was dissolved in N,N-dimethylformamide (3 mL). N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (47 mg, 108 μmol) and triethylamine (11 mg, 108 μmol, 15 μL) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for several minutes and then added to 3-amino-1-(4-amino-2-methyl-phenyl)-5-(4-(isobutylcarbamoyl)-3-methoxy-phenyl)pyrazole-4-carboxamide (47 mg, 108 μmol). The reaction solution was stirred at room temperature for 30 minutes and filtered. The filtrate was separated by prep-HPLC to obtain the title compound (7.5 mg, 13%).

[0547] MS m / z(ESI):509.3[M+H] + .

[0548] 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),8.12(t,J=5.9Hz,1H),7.58(s,1H),7.57(d,J=5.9Hz, 1H),7.50(d,J=2.3Hz,1H),7.26(d,J=8.6Hz,1H),7.03(d,J=1.1Hz,2H),6.97(dd,J=7.8,1. 3Hz,1H),5.69(dd,J=47.6,3.7Hz,1H),5.58(s,2H),5.42(dd,J=15.6,3.7Hz,1H),3.72(s,3 H), 3.04 (t, J = 6.4Hz, 2H), 1.98 (s, 3H), 1.78 (dp, J = 13.4, 6.7Hz, 1H), 0.86 (d, J = 6.7Hz, 6H).

[0549] Example 67

[0550] Methyl 4-(2-carbamoyl-4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoate

[0551] Step 1: Preparation of methyl 3-bromo-1-(4-methoxybenzyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate

[0552] Methyl 3-bromo-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylate (2.10 g, 5.95 mmol) and 1-(chloromethyl)-4-methoxy-benzene (1.40 g, 8.92 mmol) were dissolved in anhydrous acetonitrile (30 mL), and anhydrous potassium carbonate (2.46 g, 17.84 mmol) was added. The reaction solution was protected with dry nitrogen, heated to 110°C and stirred for 5 hours. The solvent was removed by concentration under reduced pressure, and the residue was dispersed in water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound, which was directly used in the next reaction.

[0553] MS m / z(ESI):473.1[M+H] + .

[0554] Step 2: Preparation of 3-bromo-1-(4-methoxybenzyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylic acid

[0555] Methyl 3-bromo-1-(4-methoxybenzyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate (2.81 g, 5.94 mmol) was dissolved in a mixed solution of tetrahydrofuran (20 mL) and methanol (40 mL). A solution of sodium hydroxide (712 mg, 17.81 mmol) in water (20 mL) was added with stirring at room temperature. The resulting reaction solution was heated to 50°C and stirred for 18 hours. The organic solvent was removed by concentration under reduced pressure. The residue was diluted with water, the pH was adjusted to acidic with dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used directly in the next reaction.

[0556] MS m / z(ESI):459.2[M+H] + .

[0557] Step 3: Preparation of 3-bromo-1-(4-methoxybenzyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxamide

[0558] 3-Bromo-1-(4-methoxybenzyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylic acid (2.73 g, 5.94 mmol) was dissolved in N,N-dimethylformamide (30 mL). Diisopropylethylamine (2.30 g, 17.83 mmol, 3.11 mL), 1-hydroxybenzotriazole (803 mg, 5.94 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.42 g, 17.83 mmol) and ammonium chloride (1.59 g, 29.72 mmol) were added sequentially with stirring at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (1.68 g, 62%).

[0559] MS m / z(ESI):458.1[M+H] + .

[0560] Step 4: Preparation of methyl 4-(2-carbamoyl-1-(4-methoxybenzyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrol-3-yl)-2-methoxybenzoate

[0561] 3-Bromo-1-(4-methoxybenzyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxamide (1.68 g, 3.67 mmol), methyl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.94 g, 6.64 mmol) and Pd(dppf)Cl2 (647 mg, 885.59 μmol) were added. Dissolve in N,N-dimethylformamide (20 mL), add anhydrous potassium carbonate (1.83 g, 13.28 mmol) in water (2 mL) with stirring at room temperature, heat to 100°C under nitrogen protection and stir for 2 hours, cool to room temperature, dilute the reaction solution with ethyl acetate, wash the organic phase with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is separated by silica gel column chromatography to obtain the title compound (732 mg, 30%).

[0562] MS m / z(ESI):544.2[M+H] + .

[0563] Step 5: Preparation of methyl 4-(4-(4-amino-2-methylphenyl)-2-carbamoyl-1-(4-methoxybenzyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoate

[0564] Methyl 4-(2-carbamoyl-1-(4-methoxybenzyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrol-3-yl)-2-methoxybenzoate (732 mg, 1.35 mmol) was dissolved in a mixed solvent of tetrahydrofuran (60 mL) and methanol (30 mL). Palladium / carbon (200 mg) was added, and the resulting reaction solution was stirred in the presence of hydrogen for 16 hours. The reaction mixture was filtered through celite, and the residue was used directly in the next reaction.

[0565] MS m / z(ESI):514.2[M+H] + .

[0566] Step 6: Preparation of methyl 4-(4-(4-amino-2-methylphenyl)-2-carbamoyl-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoate

[0567] Methyl 4-(4-(4-amino-2-methylphenyl)-2-carbamoyl-1-(4-methoxybenzyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoate (691 mg, 1.35 mmol) was dissolved in trifluoroacetic acid (10 mL), heated to 60°C with stirring for 5 hours, and concentrated under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used directly in the next reaction.

[0568] MS m / z(ESI):394.2[M+H] + .

[0569] Step 7: Preparation of methyl 4-(2-carbamoyl-4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoate

[0570] 2-Fluoroacrylic acid (243 mg, 2.70 mmol) was dissolved in N,N-dimethylformamide (10 mL). HATU (1.02 g, 2.70 mmol) and triethylamine (410 mg, 4.05 mmol, 565 μL) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for several minutes. Methyl 4-(4-(4-amino-2-methylphenyl)-2-carbamoyl-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoate (531 mg, 1.35 mmol) was added. The resulting reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate and washed sequentially with supersaturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated. 15 mg of the crude residue was used to obtain 6 mg of the pure title compound.

[0571] MS m / z(ESI):466.2[M+H] + .

[0572] 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),10.16(s,1H),7.53-7.42(m,3H),7.00(d,J=8.1Hz,1H),6.80(d,J=8.1Hz,1H),6.71(s,1H ),6.21(s,1H),5.68(dd,J=47.5,3.5Hz,1H),5.40(dd,J=15.6,3.5Hz,1H),3.72(s,3H),3.51(s,3H),2.03(s,3H),1.85(s,3H).

[0573] Example 68

[0574] 3-(4-((cyclopropylmethyl)carbamoyl)-3-methoxyphenyl)-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0575] Step 1: Preparation of 4-(2-carbamoyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoic acid

[0576] Methyl 4-(2-carbamoyl-4-(4-(2-fluoroprop-2-enoylamino)-2-methyl-phenyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxy-benzoate (628 mg, 1.35 mmol) was dissolved in tetrahydrofuran (30 mL). A solution of lithium hydroxide monohydrate (283 mg, 6.75 mmol) in water (10 mL) was added with stirring at room temperature. The reaction solution was stirred at room temperature for 5 hours, concentrated under reduced pressure to remove the organic solvent, and the residue was separated by prep-HPLC to obtain the title compound (50 mg, 8%).

[0577] MS m / z(ESI):452.2[M+H] + .

[0578] Step 2: Preparation of 3-(4-((cyclopropylmethyl)carbamoyl)-3-methoxyphenyl)-4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0579] 4-(2-Carbamoyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoic acid (25 mg, 55 μmol) and cyclopropylmethylamine (8 mg, 111 μmol) were dissolved in N,N-dimethylformamide (3 mL). Triethylamine (171 mg, 166 μmol, 23 μL) and HATU (42 mg, 111 μmol) were added sequentially with stirring at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, filtered, and the filtrate was separated by prep-HPLC to obtain the title compound (11 mg, 38%).

[0580] MS m / z(ESI):505.2[M+H] + .

[0581] 1H NMR (400MHz, DMSO-d6) δ11.52(s,1H),10.16(s,1H),8.12(t,J=5.7Hz,1H),7.61(d,J=7.9Hz,1 H),7.45(dd,J=11.4,3.2Hz,2H),7.02(d,J=8.2Hz,1H),6.88-6.81(m,1H),6.72(s,1H),6.03( s,1H),5.67(dd,J=47.7,3.6Hz,1H),5.40(dd,J=15.6,3.6Hz,1H),3.60(s,3H),3.12(t,J=6.2 Hz,2H),2.02(s,3H),1.86(s,3H),1.06-0.92(m,1H),0.44-0.35(m,2H),0.20(q,J=4.9Hz,2H).

[0582] Example 78

[0583] 4-(4-(2-Fluoroprop-2-enoylamino)-2-methyl-phenyl)-3-(4-(isobutylcarbamoyl)-3-(methoxy-d3)phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0584] Step 1: Preparation of methyl 4-bromo-2-(methoxy-d3)benzoate

[0585] Methyl 4-bromo-2-hydroxybenzoate (2.00 g, 8.66 mmol), deuterated iodomethane (1.51 g, 10.39 mmol) and cesium carbonate (5.62 g, 17.32 mmol) were added to DMF (20 mL) and stirred for 14 hours. The reaction solution was diluted with saturated aqueous sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain a crude product (2.10 g, 98%).

[0586] MS m / z(ESI):248.1,250.1[M+H] + .

[0587] Step 2: Preparation of methyl 2-(methoxy-d3)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0588] Methyl 4-bromo-2-(methoxy-d3)benzoate (2.10 g, 8.35 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan-2-yl (2.79 g, 11 mmol), Pd(dppf)Cl2.dichloromethane complex (0.68 g, 0.84 mmol) and anhydrous potassium acetate (1.64 g, 16.7 mmol) were added to dioxane (30 mL). The reaction solution was heated to 90°C and stirred for 14 hours. The solvent was removed by concentration under reduced pressure. The residue was dispersed in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (2.30 g, 92%).

[0589] MS m / z(ESI):296.2[M+H] + .

[0590] Step 3: Preparation of methyl 3-(methoxy-d3)-4-(methoxycarbonyl)phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylate

[0591] O1-tert-Butyl O2-methyl 3-bromo-5-methyl-4-(2-methyl-4-nitro-phenyl)pyrrole-1,2-dicarboxylate (1.28 g, 2.82 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(methoxy-d3)benzoate (1 g, 3.39 mmol) and Pd(dppf)Cl2 (413 mg, 564.77 μmol) were added to N,N-dimethylformamide (15 mL) ), the reaction solution was protected by dry nitrogen, and a solution of anhydrous potassium carbonate (1.17 g, 8.47 mmol) in water (1.5 mL) was stirred at room temperature. The resulting reaction solution was replaced with nitrogen once, transferred to an oil bath at 100°C and heated for 2 hours. The reaction solution was filtered through diatomaceous earth, and the filter residue was washed with ethyl acetate. The combined filtrate was collected and diluted with ethyl acetate, washed with a saturated sodium chloride aqueous solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (859 mg, 69%).

[0592] MS m / z(ESI):442.2[M+H] + .

[0593] Step 4: Preparation of 2-(methoxy-d3)-4-(2-(methoxycarbonyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrol-3-yl)benzoic acid

[0594] Methyl 3-(methoxy-d3)-4-(methoxycarbonyl)phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylate (859 mg, 1.95 mmol) was dissolved in tetrahydrofuran (15 mL), and a solution of lithium hydroxide monohydrate (245 mg, 5.84 mmol) in water (5 mL) was added with stirring at room temperature. The resulting reaction solution was heated to 30°C and stirred for 8 hours. The organic solvent was removed by concentration under reduced pressure, and the residue was diluted with water, and the pH was adjusted to weak acidity with 1N aqueous hydrochloric acid solution. The aqueous solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was directly used in the next reaction.

[0595] MS m / z(ESI):428.2[M+H] + .

[0596] Step 5: Preparation of methyl 3-(4-(isobutylcarbamoyl)-3-(methoxy-d3)phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylate

[0597] 2-(Methoxy-d3)-4-(2-(methoxycarbonyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrol-3-yl)benzoic acid (832 mg, 1.95 mmol) was dissolved in N,N-dimethylformamide (20 mL). 2-Methyl-1-propylamine (142 mg, 1.95 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (734 mg, 1.95 mmol) and triethylamine (394 mg, 3.89 mmol, 543 μL) were added sequentially with stirring at room temperature. The resulting reaction solution was stirred at room temperature for 30 minutes. The reaction solution was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was a mixture of three compounds and was directly used in the next reaction.

[0598] MS m / z(ESI):483.3[M+H] + .

[0599] Step 6: Preparation of 3-(4-(isobutylcarbamoyl)-3-(methoxy-d3)phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylic acid

[0600] Methyl 3-(4-(isobutylcarbamoyl)-3-(methoxy-d3)phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylate (553 mg, 1.15 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (20 mL). A solution of sodium hydroxide (46 mg, 1.15 mmol) in water (10 mL) was added with stirring at room temperature. The resulting reaction solution was heated to 50°C and stirred for 16 hours. The organic solvent was removed by concentration under reduced pressure. The residue was dispersed in ethyl acetate and the pH was adjusted to acidic by adding 1N aqueous hydrochloric acid. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used directly in the next reaction.

[0601] MS m / z(ESI):469.2[M+H] + .

[0602] Step 7: Preparation of 3-(4-(isobutylcarbamoyl)-3-(methoxy-d3)phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxamide

[0603] 3-(4-(Isobutylcarbamoyl)-3-(methoxy-d3)phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylic acid (537 mg, 1.15 mmol) was dissolved in N,N-dimethylformamide (20 mL), and ammonium chloride (613 mg, 11.46 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.10 g, 5.73 mmol), 1-hydroxybenzotriazole (155 mg, 1.15 mmol) and triethylamine (580 mg, 5.73 mmol, 799 μL) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was directly used in the next reaction.

[0604] MS m / z(ESI):468.2[M+H] + .

[0605] Step 8: Preparation of 4-(4-amino-2-methyl-phenyl)-3-(4-(isobutylcarbamoyl)-3-(methoxy-d3)phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0606] 3-(4-(Isobutylcarbamoyl)-3-(methoxy-d3)phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxamide (536 mg, 1.15 mmol) was dissolved in methanol (30 mL). Palladium / carbon (200 mg, 1.65 mmol) was added under nitrogen protection. The reaction system was replaced with hydrogen and the reaction was stirred at room temperature for 2 hours. The reaction was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography to obtain the title compound (305 mg, 61%).

[0607] MS m / z(ESI):438.2[M+H] + .

[0608] Step 9: Preparation of 4-(4-(2-fluoroprop-2-enoylamino)-2-methyl-phenyl)-3-(4-(isobutylcarbamoyl)-3-(methoxy-d3)phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0609] 2-Fluoroacrylic acid (82 mg, 906.19 μmol) was dissolved in N,N-dimethylformamide (5 mL). N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (342 mg, 906 μmol) and triethylamine (212 mg, 2.09 mmol, 292 μL) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for a few minutes and then added to 4-(4-amino-2-methyl-phenyl)-3-(4-(isobutylcarbamoyl)-3-(methoxy-d3)phenyl)-5-methyl-1H-pyrrole-2-carboxamide (305 mg, 697 μmol). The reaction solution was stirred at room temperature for 20 minutes and filtered. The filtrate was separated by prep-HPLC to obtain the title compound (220 mg, 61%).

[0610] MS m / z(ESI):510.2[M+H] + .

[0611] 1H NMR (400MHz, DMSO-d6) δ11.51(s,1H),10.15(d,J=0.9Hz,1H),8.04(t,J=5.9Hz,1H),7.55(d, J=7.9Hz,1H),7.51-7.40(m,2H),7.02(d,J=8.2Hz,2H),6.83(dd,J=7.9,1.4Hz,1H),6.73(d,J =1.3Hz,1H),5.99(s,1H),5.67(dd,J=47.7,3.6Hz,1H),5.39(dd,J=15.6,3.6Hz,1H),3.06(t ,J=6.4Hz,2H),2.02(s,3H),1.87(s,3H),1.77(tq,J=13.0,6.7Hz,1H),0.86(d,J=6.7Hz,6H).

[0612] Example 90

[0613] 3-(4-((cyclopropylmethyl)carbamoyl)-3-fluorophenyl)-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0614] Step 1: Preparation of tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

[0615] Tert-butyl 4-bromo-2-fluoro-benzoate (25 g, 90.87 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan-2-yl (32.31 g, 127.22 mmol), Pd(dppf)Cl2 dichloromethane complex (2.22 g, 2.73 mmol) and anhydrous potassium acetate (26.72 g, 272.61 mmol) were added to dioxane (200 mL). The reaction solution was protected with dry nitrogen, heated to 95°C and stirred for 18 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the residue was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain the title compound (29 g, 99%).

[0616] MS m / z(ESI):323.2[M+H] + .

[0617] Step 2: Preparation of O1-tert-butyl O2-methyl 3-(4-tert-butoxycarbonyl-3-fluoro-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)pyrrole-1,2-dicarboxylate

[0618] Dissolve O1-tert-butyl O2-methyl 3-bromo-5-methyl-4-(2-methyl-4-nitro-phenyl)pyrrole-1,2-dicarboxylate (1.60 g, 3.53 mmol), tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.27 g, 7.06 mmol), Pd(dppf)Cl2 (516 mg, 706 μmol) in N,N-dimethyl To formamide (16 mL) was added a solution of anhydrous potassium carbonate (1.46 g, 10.59 mmol) in water (1.6 mL) under nitrogen protection. The reaction solution was replaced with nitrogen once, transferred to 90°C and stirred for 1 hour. The mixture was filtered through celite and the filter residue was washed with ethyl acetate. The filtrate was collected and diluted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (2.01 g).

[0619] MS m / z(ESI):469.2[M+H] + .

[0620] Step 3: Preparation of 3-(4-tert-butoxycarbonyl-3-fluoro-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylic acid

[0621] Dissolve O1-tert-butyl O2-methyl 3-(4-tert-butoxycarbonyl-3-fluoro-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)pyrrole-1,2-dicarboxylate (2.01 g, 3.54 mmol) in dioxane (30 mL), add a solution of sodium hydroxide (707 mg, 17.68 mmol) in water (10 mL), and heat the resulting reaction solution to 50°C with stirring for 48 hours. The organic solvent is removed by concentration under reduced pressure, and the residue is diluted with water, and the pH is adjusted to weak acidity by adding acetic acid. The organic phase is extracted with ethyl acetate, and the organic phase is washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is directly used in the next reaction.

[0622] MS m / z(ESI):453.1[MH] - .

[0623] Step 4: tert-Butyl 4-(2-carbamoyl-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrol-3-yl)-2-fluoro-benzoate

[0624] 3-(4-tert-Butoxycarbonyl-3-fluoro-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylic acid (1.61 g, 3.54 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.39 g, 17.70 mmol) and 1-hydroxybenzotriazole (2.39 g, 17.70 mmol) were dissolved in N,N-dimethylformamide (20 mL). Diisopropylethylamine (1.37 g, 10.62 mmol, 1.85 mL) and ammonium chloride (947 mg, 17.70 mmol) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed sequentially with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (1.61 g, 100%).

[0625] MS m / z(ESI):454.2[M+H] + .

[0626] Step 5: Preparation of tert-butyl 4-(4-(4-amino-2-methyl-phenyl)-2-carbamoyl-5-methyl-1H-pyrrol-3-yl)-2-fluoro-benzoate

[0627] Tert-butyl 4-(2-carbamoyl-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrol-3-yl)-2-fluoro-benzoate (1.61 g, 3.55 mmol) was dissolved in methanol (20 mL), and palladium / carbon (200 mg) was added. The resulting reaction solution was replaced with hydrogen, and the reaction was stirred at room temperature in the presence of hydrogen for 2 hours. The mixture was filtered, the filtrate was collected, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (572 mg, 38%).

[0628] MS m / z(ESI):424.2[M+H] + .

[0629] Step 6: Preparation of tert-butyl 4-(2-carbamoyl-4-(4-(2-fluoroprop-2-enoylamino)-2-methyl-phenyl)-5-methyl-1H-pyrrol-3-yl)-2-fluoro-benzoate

[0630] 2-Fluoroacrylic acid (365 mg, 4.05 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (777 mg, 4.05 mmol), and 1-hydroxybenzotriazole (183 mg, 1.35 mmol) were dissolved in N,N-dimethylformamide (10 mL). 4-Dimethylaminopyridine (83 mg, 676 μmol) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for several minutes. Tert-butyl 4-(4-(4-amino-2-methyl-phenyl)-2-carbamoyl-5-methyl-1H-pyrrol-3-yl)-2-fluoro-benzoate (572 mg, 1.35 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (297 mg, 44%).

[0631] MS m / z(ESI):496.2[M+H] + .

[0632] Step 7: Preparation of 4-(2-carbamoyl-4-(4-(2-fluoroprop-2-enoylamino)-2-methyl-phenyl)-5-methyl-1H-pyrrol-3-yl)-2-fluoro-benzoic acid

[0633] Tert-butyl 4-(2-carbamoyl-4-(4-(2-fluoroprop-2-enoylamino)-2-methyl-phenyl)-5-methyl-1H-pyrrol-3-yl)-2-fluoro-benzoate (297 mg, 599 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added with stirring at room temperature. The reaction solution was stirred at room temperature for 2 hours, and the solvent was removed by concentration under reduced pressure. The residue was directly used in the next reaction.

[0634] MS m / z(ESI):440.1[M+H] + .

[0635] Step 8: Preparation of 3-(4-((cyclopropylmethyl)carbamoyl)-3-fluorophenyl)-4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0636] 4-(2-Carbamoyl-4-(4-(2-fluoroprop-2-enoylamino)-2-methyl-phenyl)-5-methyl-1H-pyrrol-3-yl)-2-fluoro-benzoic acid (66 mg, 150 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 451 μmol), and 1-hydroxybenzotriazole (20 mg, 150 μmol) were dissolved in DMF (3 mL). Diisopropylethylamine (97 mg, 751 μmol, 131 μL) and cyclopropylmethylamine (32 mg, 451 μmol) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for 2 hours, filtered, and the filtrate was separated by prep-HPLC to obtain the title compound (13.7 mg, 18%).

[0637] MS m / z(ESI):493.2[M+H] + .

[0638] 1 H NMR (400MHz, DMSO-d6) δ11.53(s,1H),10.16(s,1H),8.27(td,J=5.4,2.0Hz,1H),7.50(d,J=1.7Hz,1H ),7.45(dd,J=8.2,2.0Hz,1H),7.41(t,J=7.9Hz,1H),6.99(d,J=8.2Hz,1H),6.96(dd,J=7.9,1.3Hz,1H ),6.92(d,J=11.8Hz,1H),6.26(s,1H),5.68(dd,J=47.7,3.6Hz,1H),5.40(dd,J=15.6,3.6Hz,1H),3.0 9(t,J=6.2Hz,2H),2.01(s,3H),1.88(s,3H),1.05-0.92(m,1H),0.43-0.36(m,2H),0.22-0.16(m,2H).

[0639] Example 108

[0640] 4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0641] The preparation of 4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-5-methyl-1H-pyrrole-2-carboxamide can be referred to Example 13 or 68.

[0642] You can also synthesize it as follows:

[0643] 4-(2-Carbamoyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoic acid (20 mg, 44 μmol) and (1-fluorocyclopropyl)methanamine hydrochloride (6 mg, 49 μmol) were dissolved in DMF (3 mL). DIPEA (28 mg, 221 μmol) and HATU (25 mg, 66 μmol) were added sequentially with stirring at medium temperature. The reaction solution was stirred for 30 minutes and filtered. The filtrate was separated by prep-HPLC to obtain the title compound (11 mg, 47%).

[0644] MS m / z(ESI):523.2[M+H] + .

[0645] 1 H NMR (400MHz, DMSO-d6) δ11.53(s,1H),10.16(d,J=1.8Hz,1H),8.32(t,J=5.9Hz, 1H),7.62(d,J=7.9Hz,1H),7.51-7.39(m,2H),7.02(d,J=8.2Hz,2H),6.86(dd,J= 8.0,1.4Hz,1H),6.74(s,1H),5.75-5.60(m,1H),5.40(dd,J=15.5,3.6Hz,1H),3. 80-3.53(m,5H),2.03(s,3H),1.87(s,3H),1.02-0.89(m,2H),0.83-0.70(m,2H).

[0646] Example 109

[0647] 4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-3-(4-((2-fluoropropyl)carbamoyl)-3-methoxyphenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0648] The preparation of 4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-3-(4-((2-fluoropropyl)carbamoyl)-3-methoxyphenyl)-5-methyl-1H-pyrrole-2-carboxamide can be referred to Example 13 or 68.

[0649] You can also refer to the following synthesis operations:

[0650] HATU (25 mg, 66 μmol) was added to a solution of 4-(2-carbamoyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoic acid (20 mg, 44.30 μmol), 2-fluoropropane-1-amine hydrochloride (5.5 mg, 49 μmol) and DIPEA (29 mg, 222 μmol) in DMF (4.3 mL). The reaction mixture was stirred for 1 hour and then separated and purified by prep-HPLC to give the title compound (10.1 mg, 44%).

[0651] MS m / z(ESI):511.2[M+H] + .

[0652] 1 H NMR (400MHz, DMSO-d6) δ11.52(s,1H),10.15(s,1H),8.23(t,J=5.9Hz,1H),7.62(d,J=7.9Hz, 1H),7.50-7.40(m,2H),7.02(d,J=8.2Hz,2H),6.85(d,J=8.0Hz,1H),6.74(s,1H),6.06(s,1H ),5.68(dd,J=47.7,3.6Hz,1H),5.40(dd,J=15.6,3.6Hz,1H),4.78(ddd,J=49.2,11.3,6.0Hz ,1H),3.60(s,3H),3.51-3.39(m,2H),2.03(s,3H),1.87(s,3H),1.27(dd,J=24.0,6.2Hz,3H).

[0653] The following examples 109-1 and 109-2 were prepared with reference to examples 13 or 68.

[0654] Example 111

[0655] 3-(4-(((2,2-difluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0656] The preparation of 3-(4-(((2,2-difluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-5-methyl-1H-pyrrole-2-carboxamide can be referred to Example 13 or 68.

[0657] You can also refer to the following synthesis operations:

[0658] HATU (44 mg, 116 μmol) was added to a solution of 4-(2-carbamoyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoic acid (35 mg, 78 μmol), (2,2-difluorocyclopropyl)methanamine hydrochloride (13 mg, 93 μmol), and DIPEA (50 mg, 388 μmol) in DMF (2.5 mL). The reaction mixture was stirred for 1 hour. The reaction mixture was directly separated and purified by prep-HPLC to obtain the title compound (18 mg, 42%).

[0659] MS m / z(ESI):541.2[M+H] + .

[0660] 1 H NMR (400MHz, DMSO-d6) δ11.53(s,1H),10.17(d,J=1.8Hz,1H),8.31(t,J=5.8Hz,1H),7.62(d,J=7 .9Hz,1H),7.52-7.39(m,2H),7.02(d,J=8.1Hz,2H),6.85(dd,J=7.9,1.5Hz,1H),6.73(d,J=1.4Hz ,1H),6.05(s,1H),5.68(dd,J=47.7,3.6Hz,1H),5.40(dd,J=15.6,3.6Hz,1H),3.60(s,3H),3.41( d,J=6.9Hz,2H),2.03(s,4H),1.86(s,3H),1.54(dtd,J=12.2,7.8,4.0Hz,1H),1.37-1.25(m,1H).

[0661] The following examples 111-1 and 111-2 were prepared with reference to examples 13 or 68.

[0662] Example 157

[0663] 4-(4-(But-2-ynylamino)-2-methylphenyl)-3-(4-(isobutylcarbamoyl)-3-methoxyphenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0664] The preparation of 4-(4-(but-2-ynylamino)-2-methylphenyl)-3-(4-(isobutylcarbamoyl)-3-methoxyphenyl)-5-methyl-1H-pyrrole-2-carboxamide can be performed by referring to Example 13 or 78.

[0665] You can also refer to the following synthesis operations:

[0666] HATU (26 mg, 69 μmol) was added to a solution of 4-(4-amino-2-methyl-phenyl)-3-[4-(isobutylcarbamoyl)-3-methoxy-phenyl]-5-methyl-1H-pyrrole-2-carboxamide (20 mg, 46 μmol, prepared as described in Example 78, Step 8), but-2-ynoic acid (3.9 mg, 46 μmol), and DIPEA (17.8 mg, 138 μmol) in DMF (2.5 ml). The reaction mixture was stirred for 2 hours. The reaction mixture was directly separated and purified by prep-HPLC to give the title compound (9.1 mg, 39%).

[0667] MS m / z(ESI):501.2[M+H] + .

[0668] 1 H NMR (400MHz, DMSO-d6) δ11.50(s,1H),10.47(s,1H),8.04(t,J=5.9Hz,1H),7.55(d,J=7.9Hz,1H),7.41-7.24(m,2H),6.98(d,J=8.2Hz,2H),6. 82(d,J=8.0Hz,1H),6.73(s,1H),5.98(s,1H),3.60(s,3H),3.06(t,J=6.4Hz,2H),2.01(d,J=10.7Hz,6H),1.85(s,4H),0.87(d,J=6.6Hz,6H).

[0669] Example 159

[0670] (E)-4-(4-(4-(dimethylamino)but-2-enoylamino)-2-methylphenyl)-3-(4-(isobutylcarbamoyl)-3-methoxyphenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0671] The preparation of (E)-4-(4-(4-(dimethylamino)but-2-enoylamino)-2-methylphenyl)-3-(4-(isobutylcarbamoyl)-3-methoxyphenyl)-5-methyl-1H-pyrrole-2-carboxamide can be carried out by referring to Example 13 or 78.

[0672] You can also refer to the following synthesis operations:

[0673] HATU (26 mg, 69 μmol) was added to a DMF solution of 4-(4-amino-2-methyl-phenyl)-3-[4-(isobutylcarbamoyl)-3-methoxy-phenyl]-5-methyl-1H-pyrrole-2-carboxamide (20 mg, 46 μmol, prepared as described in Example 78, Step 8), (Z)-4-(dimethylamino)but-2-enoic acid (5.9 mg, 46 μmol), and DIPEA (18 mg, 138 μmol). The reaction mixture was stirred for 2 hours. The reaction mixture was directly separated and purified by prep-HPLC to obtain the title compound (6.0 mg, 22%).

[0674] MS m / z(ESI):546.2[M+H] + .

[0675] 1 H NMR (400MHz, DMSO-d6) δ11.50(s,1H),9.93(s,1H),8.04(t,J=5.9Hz,1H),7.56(d,J= 7.9Hz,1H),7.47-7.32(m,2H),6.98(d,J=8.2Hz,2H),6.84(dd,J=7.8,1.5Hz,1H),6.7 6-6.64(m,2H),6.27-6.20(m,1H),5.99(s,1H),3.60(s,3H),3.17-2.93(m,5H),2.18( s,5H),2.01(s,3H),1.86(s,3H),1.78(dt,J=13.4,6.7Hz,1H),0.86(d,J=6.7Hz,6H).

[0676] Example 164

[0677] 5-ethyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-3-(4-(isobutylcarbamoyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide

[0678] Prepare with reference to Example 13 or according to the following steps:

[0679] Step 1: Preparation of methyl 4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate

[0680] 1-(tert-Butyl) 2-methyl 4-bromo-1H-pyrrole-1,2-dicarboxylate (8.0 g, 26.30 mmol), 4,4,5,5-tetramethyl-2-(2-methyl-4-nitro-phenyl)-1,3,2-dioxaborolane (13.84 g, 52.61 mmol), tetrakis(triphenylphosphine)palladium (3.04 g, 2.63 mmol) and anhydrous sodium carbonate (27.88 g, 263.0 mmol) were added to a mixed solvent of DMF (200 mL) and water (30 mL). The reaction solution was replaced with nitrogen, heated to 90°C and stirred for 4 hours. The solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was slurried with ethyl acetate to obtain the title compound (5.5 g, 80%).

[0681] MS m / z(ESI):261.1[M+H] + .

[0682] Step 2: Preparation of 1-(tert-butyl)2-methyl-5-bromo-3-iodo-4-(2-methyl-4-nitrophenyl)pyrrole-1,2-dicarboxylate

[0683] Methyl 4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate (2.5 g, 9.61 mmol) was dissolved in DMF (35 mL) and cooled to 0°C in an ice-water bath. N-bromosuccinimide (1.71 g, 9.61 mmol) was added portionwise with stirring. The ice-water bath was removed, and the reaction solution was transferred to room temperature and stirred for 4 hours. N-iodosuccinimide (2.16 g, 9.61 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. 4-Dimethylaminopyridine (1.41 g, 11.53 mmol) and tert-butoxycarbonyl tert-butyl carbonate (4.15 g, 19.21 mmol) were added separately, and the reaction solution was stirred at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (2.0 g, 37%).

[0684] MS m / z(ESI):565.1,567.1[M+H] + .

[0685] Step 3: Preparation of methyl 5-bromo-3-(4-(isobutylcarbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylate

[0686] 1-(tert-Butyl)2-methyl-5-bromo-3-iodo-4-(2-methyl-4-nitrophenyl)pyrrole-1,2-dicarboxylate (1.0 g, 1.77 mmol), N-isobutyl-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.65 g, 1.95 mmol), Pd(dppf)Cl2 (129 mg, 177 μmol) were dissolved in dioxane (3 The reaction solution was protected by nitrogen, and a solution of anhydrous potassium carbonate (0.73 g, 5.31 mmol) in water (5 mL) was added under stirring at room temperature. The reaction solution was replaced with nitrogen, transferred to an oil bath, heated to 90°C, and stirred for 16 hours. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in dichloromethane. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the target compound (600 mg, 63%).

[0687] MS m / z(ESI):544.1,546.1[M+H] + .

[0688] Step 4: Preparation of methyl 3-(4-(isobutylcarbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitro-phenyl)-5-vinyl-1H-pyrrole-2-carboxylate

[0689] Methyl 5-bromo-3-(4-(isobutylcarbamoyl)-3-methoxy-phenyl)-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylate (400 mg, 734.76 μmol), potassium vinyl fluoroborate (197 mg, 1.47 mmol), Pd(dppf)Cl2 (54 mg, 73.48 μmol) and tetrabutylammonium bromide (23 mg, 73.48 μmol) were added to dioxane (15 mL). Anhydrous potassium carbonate (304 mg, 2.20 mmol) in water (3 mL) was added. The resulting reaction solution was replaced with nitrogen and transferred to a microwave synthesizer. The mixture was heated to 100°C and stirred for 4 hours. The solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was isolated by silica gel column chromatography to obtain the title compound (250 mg, 69%).

[0690] MS m / z(ESI):492.2[M+H] + .

[0691] Step 5: Preparation of 3-(4-(isobutylcarbamoyl)-3-methoxy-phenyl)-4-(2-methyl-4-nitro-phenyl)-5-vinyl-1H-pyrrole-2-carboxylic acid

[0692] Methyl 3-(4-(isobutylcarbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitro-phenyl)-5-vinyl-1H-pyrrole-2-carboxylate (400 mg, 813.78 μmol) was dissolved in methanol (5 mL), and a solution of lithium hydroxide monohydrate (171 mg, 4.07 mmol) in water (5 mL) was added with stirring at room temperature. The reaction solution was transferred to a 70°C oil bath and heated for 5 hours. The organic solvent was removed by concentration under reduced pressure, and the residue was diluted with water and adjusted to pH = 5 with 2N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used directly in the next reaction.

[0693] MS m / z(ESI):478.2[M+H] + .

[0694] Step 6: Preparation of 3-(4-(isobutylcarbamoyl)-3-methoxy-phenyl)-4-(2-methyl-4-nitro-phenyl)-5-vinyl-1H-pyrrole-2-carboxamide

[0695] 3-(4-(Isobutylcarbamoyl)-3-methoxy-phenyl)-4-(2-methyl-4-nitro-phenyl)-5-vinyl-1H-pyrrole-2-carboxylic acid (200 mg, 418.84 μmol) was dissolved in DMF (10 mL). HOBt (201.91 mg, 1.49 mmol), triethylamine (227 mg, 2.24 mmol, 312.63 μL), EDCI (287 mg, 1.49 mmol, hydrochloride) and ammonium chloride (200 mg, 3.74 mmol) were added sequentially with stirring at room temperature. The reaction solution was stirred at room temperature for 2 hours and concentrated under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used directly in the next reaction.

[0696] MS m / z(ESI):477.2[M+H] + .

[0697] Step 7: Preparation of 4-(4-amino-2-methyl-phenyl)-5-ethyl-3-(4-(isobutylcarbamoyl)-3-methoxy-phenyl)-1H-pyrrole-2-carboxamide

[0698] 3-(4-(Isobutylcarbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitrophenyl)-5-vinyl-1H-pyrrole-2-carboxamide (170 mg, 356.75 μmol) was dissolved in a mixed solvent of ethanol (15 mL), ethyl acetate (10 mL) and dichloromethane (5 mL). Palladium on carbon (50 mg) was added, and the reaction solution was replaced with hydrogen. The reaction mixture was stirred at room temperature in the presence of hydrogen for 12 hours, filtered through celite, and concentrated under reduced pressure to remove the solvent. The residue was separated by silica gel column chromatography to obtain the title compound (130 mg, 81%).

[0699] MS m / z(ESI):449.2[M+H] + .

[0700] Step 8: Preparation of 5-ethyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-3-(4-(isobutylcarbamoyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide

[0701] 2-Fluoroacrylic acid (16 mg, 179.67 μmol), triethylamine (61 mg, 598.90 μmol, 83.53 μL) and HATU (68 mg, 179.67 μmol) were added to DMF (1 mL) in sequence, and the reaction solution was stirred at room temperature for 10 minutes. The mixture was then added to a solution of 4-(4-amino-2-methyl-phenyl)-5-ethyl-3-(4-(isobutylcarbamoyl)-3-methoxy-phenyl)-1H-pyrrole-2-carboxamide (70 mg, 156.06 μmol) in DMF (2 mL). The reaction solution was stirred at room temperature for 1 hour, filtered, and the filtrate was separated by prep-HPLC to obtain the title compound (40 mg, 49%).

[0702] MS m / z(ESI):521.2[M+H] + .

[0703] 1H NMR (400MHz, DMSO-d6) δ11.45(s,1H),10.14(d,J=1.9Hz,1H),8.03(t,J=5.9Hz,1H),7.55(d,J=7.9Hz,1H),7.51 -7.42(m,2H),7.08(d,J=8.1Hz,1H),6.84(dd,J=7.9,1.5Hz,1H),6.74(d,J=1.5Hz,1H),6.05(s,1H),5.73(d,J=3 .6Hz,1H),5.62(d,J=3.6Hz,1H),5.44-5.29(m,1H),3.60(s,3H),3.11-3.02(m,2H),1.99(dt,J=13.3,6.8Hz,1H ),1.85(s,1H),1.77(dq,J=13.4,6.7Hz,1H),1.24(d,J=3.2Hz,3H),1.02(t,J=7.5Hz,3H),0.86(d,J=6.7Hz,6H).

[0704] Example 167

[0705] 5-ethyl-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-1H-pyrrole-2-carboxamide

[0706] The preparation of 5-ethyl-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-1H-pyrrole-2-carboxamide can be performed by referring to Example 13 or 164.

[0707] You can also refer to the following synthesis operations:

[0708] DIPEA (33 mg, 257 μmol) was added to a solution of 4-(4-amino-2-methyl-phenyl)-5-ethyl-3-[4-[(2-fluoro-2-methyl-propyl)carbamoyl]-3-methoxy-phenyl]-1H-pyrrole-2-carboxamide (40 mg, 86 μmol, prepared as described in Example 164, Step 7), 2-fluoroprop-2-enoic acid (9.3 mg, 103 μmol), and HATU (48.9 mg, 129 μmol) in DMF (3 mL). The reaction mixture was stirred for 1 hour. The reaction mixture was directly separated and purified by prep-HPLC to give the title compound (19.7 mg, 42%).

[0709] MS m / z(ESI):539.2[M+H]+ .

[0710] 1 H NMR (400MHz, DMSO-d6) δ11.47(s,1H),10.16(d,J=1.9Hz,1H),8.16(t,J=6.2Hz,1H),7.60(d,J=7. 9Hz,1H),7.51-7.39(m,2H),7.09(d,J=8.1Hz,2H),6.86(dd,J=7.9,1.5Hz,1H),6.77(d,J=1.5Hz,1 H),6.10(s,1H),5.68(dd,J=47.7,3.6Hz,1H),5.40(dd,J=15.6,3.6Hz,1H),3.61(s,3H),3.50-3.4 3(m,2H),2.38(dt,J=28.0,7.1Hz,2H),1.84(s,3H),1.31(d,J=21.5Hz,6H),1.03(t,J=7.5Hz,3H).

[0711] Example 169

[0712] 5-Ethyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide

[0713] The preparation of 5-ethyl-4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide can be performed by referring to Example 13 or 164.

[0714] You can also refer to the following synthesis operations:

[0715] 2-Fluoroacrylic acid (80 mg, 895 μmol), triethylamine (305 mg, 3.00 mmol, 420 μL) and HATU (340 mg, 895 μmol) were added to DMF (2 mL) in sequence. The reaction mixture was stirred for 10 minutes and then added to a solution of 4-(4-amino-2-methylphenyl)-5-ethyl-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide (362 mg, 780 μmol) in DMF (4 mL). The mixture was stirred for 1 hour and filtered. The filtrate was separated by prep-HPLC to obtain the title compound (250 mg, 60%).

[0716] MS m / z(ESI):537.2[M+H] + .

[0717] 1 H NMR (400MHz, DMSO-d6) δ11.47(s,1H),10.16(d,J=1.9Hz,1H),8.33(t,J=5.9H z,1H),7.62(d,J=8.0Hz,1H),7.52-7.42(m,2H),7.09(d,J=8.2Hz,1H),7.01( s,1H),6.87(dd,J=8.0,1.5Hz,1H),6.75(d,J=1.5Hz,1H),6.12(s,1H),5.74( d,J=3.6Hz,1H),5.62(d,J=3.6Hz,1H),5.40(dd,J=15.6,3.6Hz,1H),3.69(dd, J=20.4,6.0Hz,2H),3.61(s,3H),2.38(dh,J=29.4,7.4Hz,2H),2.01(q,J=7.2Hz,1H),1.84(s,2H),1.24(s,3H),0.90-0.72(m,3H).

[0718] Example 170

[0719] 5-Ethyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-3-(4-(((1-(fluoromethyl)cyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide

[0720] The preparation of 5-ethyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-3-(4-(((1-(fluoromethyl)cyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide can be performed by referring to Example 13 or 164.

[0721] You can also refer to the following synthesis operations:

[0722] 4-(2-Carbamoyl-5-ethyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (30 mg, 64.5 μmol, prepared as described in Example 68, step 1) was dissolved in DMF (1 mL). HATU (29 mg, 77 μmol) and DIPEA (42 mg, 322 μmol) were added with stirring, and the reaction mixture was stirred for 30 minutes. (1-(Fluoromethyl)cyclopropyl)methanamine hydrochloride (8.0 mg, 77 μmol) was added to the reaction mixture, and the reaction mixture was stirred for 1 hour. The reaction mixture was separated and purified by reverse-phase column chromatography to obtain the title compound (8.0 mg, 23%).

[0723] MS m / z(ESI):551.2[M+H] + .

[0724] 1 H NMR (400MHz, DMSO-d6) δ11.41(s,1H),10.09(d,J=1.9Hz,1H),8.11(t,J=5.7Hz,1H),7.50(d,J=7.9H z,1H),7.44-7.35(m,2H),7.10-6.95(m,1H),6.78(dd,J=7.9,1.4Hz,1H),6.68(d,J=1.4Hz,1H),5.61 (dd,J=47.7,3.6Hz,1H),5.33(dd,J=15.6,3.6Hz,1H),4.21(d,J=48.9Hz,2H),3.53(s,3H),3.20-318 (m,2H),2.40-2.20(m,2H),1.78(s,3H),0.96(t,J=7.5Hz,3H),0.59-0.51(m,2H),0.45-0.43(m,2H).

[0725] Example 190

[0726] 4-(4-Acryloylamido-2-methylphenyl)-3-(3-methoxy-4-(3-methylbutyrylamino)phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0727] Step 1: Preparation of N-(4-bromo-2-methoxyphenyl)-3-methylbutanamide

[0728] TEA (500 mg, 4.95 mmol) was added to a solution of 4-bromo-2-methoxyaniline (1 g, 4.95 mmol) and isovaleryl chloride (597 mg, 4.95 mmol) in acetonitrile (20 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered and washed with ethyl acetate. The organic phase was dried, filtered, and concentrated. The residue was separated by column chromatography to obtain the title compound (1.2 g, 85%).

[0729] MS m / z(ESI):286.2[M+H] + .

[0730] Step 2: Preparation of N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylbutanamide

[0731] [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (64 mg, 88.71 μmol) was added to a solution of N-(4-bromo-2-methoxyphenyl)-3-methylbutanamide (600 mg, 2.10 mmol), pinacol diboron (692 mg, 2.73 mmol), and potassium acetate (261 mg, 2.66 mmol) in 1'4-dioxane (20 mL). The mixture was heated to 90°C under nitrogen for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried, filtered, and concentrated. The residue was separated by column chromatography to obtain the title compound (600 mg, 86%).

[0732] MS m / z(ESI):334.3[M+H] + .

[0733] Step 3: Preparation of methyl 3-(3-methoxy-4-(3-methylbutyrylamino)phenyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate

[0734] [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (80 mg, 110.31 μmol) was added to a solution of 1-(tert-butyl)-2-methyl-3-bromo-5-methyl-4-(2-methyl-4-nitrophenyl)pyrrole-1,2-dicarboxylate (500 mg, 1.10 mmol), N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylbutanamide (478 mg, 1.43 mmol), and potassium carbonate (305 mg, 2.21 mmol) in DMF (12 mL) and water (2 mL). The mixture was purged with nitrogen three times and heated to 90°C under nitrogen for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was dried, filtered, and concentrated. The residue was separated by column chromatography to obtain the title compound (430 mg, 81%).

[0735] MS m / z(ESI):480.2[M+H] + .

[0736] Step 4: Preparation of 3-(3-methoxy-4-(3-methylbutyrylamino)phenyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylic acid

[0737] Sodium hydroxide (359 mg, 8.97 mmol) was added to a solution of methyl 3-(3-methoxy-4-(3-methylbutyrylamino)phenyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate (430 mg, 896.72 μmol) in THF (3 mL), water (1 mL), and methanol (3 mL). The reaction mixture was heated to 50°C and stirred for 16 hours. The reaction mixture was then dried by vortexing, poured into water, and the pH was adjusted to 5 with 2N hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phase was dried and vortexed to obtain the title compound (230 mg, 55%).

[0738] MS m / z(ESI):466.1[M+H] + .

[0739] Step 5: Preparation of 3-(3-methoxy-4-(3-methylbutyrylamino)phenyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxamide

[0740] DIPEA (191 mg, 1.48 mmol) was added to a solution of 3-(3-methoxy-4-(3-methylbutyrylamino)phenyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylic acid (230 mg, 494.10 μmol), ammonium chloride (132 mg, 2.47 mmol), 1-hydroxybenzotriazole (133 mg, 988.19 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (189 mg, 988.19 μmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried, filtered, and concentrated to yield the title compound (120 mg, 52%).

[0741] MS m / z(ESI):465.1[M+H] + .

[0742] Step 6: Preparation of 4-(4-amino-2-methylphenyl)-3-(3-methoxy-4-(3-methylbutyrylamino)phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0743] Wet palladium on carbon (10 mg) was added to a solution of 3-(3-methoxy-4-(3-methylbutyrylamino)phenyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxamide (60 mg, 129.17 μmol) in methanol (5 mL). The reaction mixture was reacted at room temperature under a hydrogen balloon for 2 hours. The reaction mixture was filtered and concentrated to dryness to obtain the title compound (30 mg, 53%).

[0744] MS m / z(ESI):435.2[M+H] + .

[0745] Step 7: Preparation of 4-(4-acryloylamino-2-methylphenyl)-3-(3-methoxy-4-(3-methylbutyrylamino)phenyl)-5-methyl-1H-pyrrole-2-carboxamide

[0746] Acryloyl chloride (4.50 mg, 49.71 μmol) was added to a solution of 4-(4-amino-2-methylphenyl)-3-(3-methoxy-4-(3-methylbutyrylamino)phenyl)-5-methyl-1H-pyrrole-2-carboxamide (18 mg, 41.42 μmol) and sodium bicarbonate (35 mg, 414.24 μmol) in water (1 mL) and DCM (2 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by prep-HPLC to yield the title compound (3.7 mg, 18%).

[0747] MS m / z(ESI):489.2[M+H] + .

[0748] 1 H NMR(400MHz,DMSO-d6)δ11.48(s,1H),10.05(s,1H),8.97(s,1H),7.87(d,J=8.2Hz,1H),7.45(d,J=7.1Hz,2H),7.04(d,J=8.7Hz,1H),6.83-6.76(m,1H),6.70(d,J=1.8Hz,1H),6.47(dd,J=16.9,10.1Hz,1H),6.28(dd,J=17.0,2.1Hz,1H),5.78(dd,J=10.1,2.1Hz,2H),5.38(d,J=4.6Hz,1H),3.62(s,3H),2.27(d,J=7.2Hz,2H),2.08(s,4H),1.94(s,3H),0.96(d,J=6.6Hz,6H).

[0749] The preparation of Examples 6, 7, 8, 9, 60, and 64 is referred to Example 1; the preparation of Examples 11, 27, 94, and 96 is referred to Example 10; the preparation of Examples 20, 21, 22, 23, and 24 is referred to Example 15; the preparation of Examples 25, 49, 50, 51, 65, 66, and 97 is referred to Example 3; the preparation of Example 26 is referred to Example 12; the preparation of Examples 36, 40, 41, 42, 43, 44, 45, 46, 47, and 48 is referred to Example 30; The preparation of Example 37 refers to Example 34; the preparation of Example 38 refers to Example 32; the preparation of Example 39 refers to Example 33; the preparation of Examples 53, 54, 55, 56, 57, 58, 59, and 63 refers to Example 52; the preparation of Examples 61 and 98 refers to Example 2; the preparation of Examples 62, 93, 95, 99, 100, 101, 103, and 104 refers to Example 13; the preparation of Examples 69, 70, 71, 72, 73, 74, 75, 76, The preparation of 77, 80, 81, 82, 83, 84, 85, 86-89, 142 is referred to Example 68; the preparation of Example 79 is referred to Example 78; the preparation of Examples 91 and 92 is referred to Example 90; the preparation of Examples 102 and 105 is referred to Example 12 or 13; the preparation of Examples 106, 107, 109, 110-117, 119, 120, 122-141, 143-146 is referred to Example 68; For the preparation of Examples 13 or 68, refer to Example 13 or 78; for the preparation of Examples 147-153, 157-163, 193-195, refer to Example 13 or 78; for the preparation of Examples 154-156, refer to Example 13 or 33; for the preparation of Examples 165-168, 171-189, refer to Example 13 or 164; for the preparation of Examples 191 and 192, refer to Example 13 or 190; for the preparation of Examples 196-225, refer to Example 164.

[0750] The following Examples 226-355 were synthesized with reference to the preparation method of Example 78, and Examples 356-411 were synthesized with reference to the preparation method of Example 78 or 249:

[0751] The preparation of Examples 227, 228, 229, and 230 can also refer to Example 159.

[0752] The preparation of Examples 259 and 260 can also refer to Example 164.

[0753] The preparation of Examples 325, 328-330 can also refer to Example 108.

[0754] The preparation of Example 231 refers to Example 78, and can also be synthesized according to the following steps:

[0755] 2-Fluoroacrylic acid (8 mg, 89.5 μmol), triethylamine (61 mg, 300 μmol) and HATU (34 mg, 89.5 μmol) were added to DMF (2 mL) in sequence, and the reaction mixture was stirred for 10 minutes. The mixture was then added to a solution of 4-(4-amino-2-methylphenyl)-5-cyclopropyl-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide (37 mg, 78 μmol, prepared as described in Example 78, Step 8) in DMF (4 mL). The reaction mixture was stirred for 1 hour, filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (20 mg, 47%).

[0756] MS m / z(ESI):551.2[M+H] + .

[0757] 1H NMR (400MHz, DMSO-d6) δ11.54(s,1H),10.17(d,J=1.9Hz,1H),8.18(t,J=6.2Hz,1H),7.61(d,J=8.0Hz,1H ),7.50-7.41(m,2H),7.03(d,J=8.1Hz,2H),6.85(dd,J=7.9,1.5Hz,1H),6.77(d,J=1.5Hz,1H),6.05(s,1 H),5.74(d,J=3.6Hz,1H),5.40(dd,J=15.7,3.6Hz,1H),3.90(s,3H),3.49(d,J=6.3Hz,1H),3.44(d,J=6. 3Hz,1H),2.06-1.90(m,1H),1.88(s,3H),1.34(s,3H),1.28(s,3H),1.21-1.15(m,2H),1.15-0.99(m,2H).

[0758] The preparation of Example 234 is based on Example 78, and can also be synthesized according to the following steps:

[0759] Step 1: Preparation of methyl 5-cyano-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate

[0760] Methyl 5-bromo-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate (500 mg, 891 μmol, prepared as described in Example 164, step 3), zinc cyanide (1.04 g, 8.91 mmol) and tetrakistriphenylphosphine palladium (103 mg, 89 μmol) were added to DMA (10 mL). The resulting reaction solution was replaced with nitrogen, transferred to a microwave synthesizer, heated to 140° C., and stirred for 4 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (250 mg, 55%).

[0761] MS m / z(ESI):509.2[M+H] + .

[0762] Step 2: Preparation of 5-cyano-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylic acid

[0763] Methyl 5-cyano-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate (250 mg, 492 μmol) was dissolved in methanol (5 mL), and a solution of lithium hydroxide monohydrate (206 mg, 4.92 mmol) in water (5 mL) was added with stirring at room temperature. The reaction solution was transferred to a 70°C oil bath and heated for 5 hours. The organic solvent was removed by concentration under reduced pressure. The residue was diluted with water and adjusted to pH = 5 with 2N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used directly in the next reaction.

[0764] MS m / z(ESI):495.2[M+H] + .

[0765] Step 3: Preparation of 5-cyano-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxamide

[0766] 5-Cyano-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylic acid (207 mg, 419 μmol) was dissolved in DMF (10 mL). HOBt (202 mg, 1.49 mmol), triethylamine (227 mg, 2.24 mmol), EDCI (287 mg, 1.49 mmol, hydrochloride) and ammonium chloride (200 mg, 3.74 mmol) were added sequentially with stirring. The reaction solution was stirred for 2 hours and then concentrated under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was used directly in the next reaction.

[0767] MS m / z(ESI):494.2[M+H] + .

[0768] Step 4: Preparation of 4-(4-amino-2-methylphenyl)-5-cyano-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide

[0769] 5-Cyano-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxamide (162 mg, 330 μmol) was added to a mixture of ethanol and water (V / V = 5:1) (9 mL). Iron powder (130 mg, 2.19 mol) and ammonium chloride (120 mg, 2.19 mol) were added. The reaction temperature was raised to 80°C and stirred for 2 hours. After cooling to room temperature, the reaction solution was slowly poured into DCM (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was isolated by silica gel column chromatography to obtain the title compound (50 mg, 33%).

[0770] MS m / z(ESI):464.2[M+H] + .

[0771] Step 5: Preparation of 5-cyano-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-4-(4-(2-fluoroacryloylamido)-2-methylphenyl)-1H-pyrrole-2-carboxamide

[0772] 2-Fluoroacrylic acid (16 mg, 180 μmol), triethylamine (61 mg, 599 μmol) and HATU (68 mg, 180 μmol) were added to DMF (1 mL) in sequence and stirred for 10 minutes. The mixture was then added to a solution of 4-(4-amino-2-methylphenyl)-5-cyano-3-(4-((2-fluoro-2-methylpropyl)carbamoyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide (50 mg, 108 μmol) in DMF (2 mL). The reaction mixture was stirred for 1 hour and filtered. The filtrate was separated and purified by prep-HPLC to obtain the title compound (10 mg, 16%).

[0773] MS m / z(ESI):536.2[M+H] + .

[0774] 1 H NMR (400MHz, DMSO-d6) δ10.14(s,1H),8.23(s,1H),8.09(s,1H),7.52-7.39(m,4H),7.02(d,J=7.9Hz,1H),6.74(d,J=9.6Hz,2H),5.69( s,1H),5.34(dd,J=15.7,3.6Hz,1H),5.26(t,J=4.8Hz,1H),3.53(s,3H),1.82(s,3H),1.39(s,2H),1.27(s,3H),0.79(t,J=6.5Hz,3H).

[0775] The preparation of Example 244 is based on Example 78, and can also be synthesized according to the following steps:

[0776] 2-Fluoroacrylic acid (400 mg, 4.47 mmol), triethylamine (3.05 g, 15.00 mmol, 2.1 mL) and HATU (1.70 g, 4.47 mmol) were added to DMF (10 mL) in sequence, and the reaction solution was stirred for 10 minutes. The mixture was then added to a DMF (4 mL) solution of 4-(4-amino-2-methylphenyl)-5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-(methoxy-d3)phenyl)-1H-pyrrole-2-carboxamide (1.77 g, 3.90 mmol, prepared as described in Example 78, Step 8). The reaction solution was stirred for 1 hour, filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (1.43 g, 70%).

[0777] MS m / z(ESI):526.2[M+H] + .

[0778] 1 H NMR (400MHz, DMSO-d6) δ11.52(s,1H),10.15(s,1H),8.18(t,J=5.8Hz,1H),7.57(d,J=7.9Hz,1H) ,7.47(d,J=1.9Hz,1H),7.44(dd,J=8.3,2.0Hz,1H),7.02(d,J=8.2Hz,2H),6.84(dd,J=7.9,1.4H z,1H),6.74(d,J=1.2Hz,1H),6.02(s,1H),5.67(dd,J=47.7,3.6Hz,1H),5.39(dd,J=15.6,3.6Hz ,1H),3.34(s,2H),2.02(s,3H),1.87(s,3H),0.62(dt,J=8.8,4.6Hz,2H),0.50(t,J=4.9Hz,2H).

[0779] The preparation of Example 245 can be prepared by referring to Example 78, or by following the steps below:

[0780] 2-Fluoroacrylic acid (8 mg, 89.5 μmol), triethylamine (61 mg, 300 μmol) and HATU (34 mg, 89.5 μmol) were added to DMF (2 mL) in sequence, and the reaction mixture was stirred for 10 minutes. The mixture was then added to a solution of 4-(4-amino-2-methylphenyl)-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-5-(methoxymethyl)-1H-pyrrole-2-carboxamide (37 mg, 78 μmol, prepared as described in Step 8 of Example 78) in DMF (4 mL). The reaction mixture was stirred for 1 hour, filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (4.2 mg, 10%).

[0781] MS m / z(ESI):553.2[M+H] + .

[0782] The preparation of Example 247 is based on Example 78, and can also be synthesized according to the following steps:

[0783] 2-Fluoroacrylic acid (8 mg, 89.5 μmol), triethylamine (61 mg, 300 μmol) and HATU (34 mg, 89.5 μmol) were added to DMF (2 mL) in sequence, and the reaction mixture was stirred for 10 minutes. The mixture was then added to a solution of 4-(4-amino-2-methylphenyl)-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide (34 mg, 78 μmol, prepared as described in Step 8 of Example 78) in DMF (4 mL). The reaction mixture was stirred for 1 hour, filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (10 mg, 25%).

[0784] MS m / z(ESI):509.2[M+H] + .

[0785] 1H NMR (400MHz, DMSO-d6) δ11.52(s,1H),10.15(s,1H),8.18(t,J=5.8Hz,1H),7.78(d,J=7.9Hz,1H),7.5 7(d,J=7.9Hz,1H),7.47(d,J=1.9Hz,1H),7.44(dd,J=8.3,2.0Hz,1H),7.02(d,J=8.2Hz,2H),6.84(dd, J=7.9,1.4Hz,1H),6.74(d,J=1.2Hz,1H),6.02(s,1H),5.67(dd,J=47.7,3.6Hz,1H),5.39(dd,J=15.6, 3.6Hz,1H),3.34(s,3H),3.28(s,2H),2.57(s,3H),0.62(dt,J=8.8,4.6Hz,2H),0.50(t,J=4.9Hz,2H).

[0786] Example 249

[0787] 5-Chloro-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide

[0788] Example 249 was prepared by referring to Example 78, and can also be synthesized according to the following steps:

[0789] Step 1: Preparation of methyl 5-chloro-3-iodo-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate

[0790] Methyl 4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate (0.5 g, 1.92 mmol) was dissolved in DMF (10 mL). N-chlorosuccinimide (256 mg, 1.92 mmol) was added portionwise in an ice-water bath. The reaction solution was stirred at 50°C for 4 hours, cooled to room temperature, and N-iodosuccinimide (0.43 g, 1.92 mmol) was added. The reaction solution was stirred for 2 hours, diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was directly used in the next reaction.

[0791] MS m / z(ESI):421.0[M+H] + .

[0792] Step 2: Preparation of 1-(tert-butyl)2-methyl-5-chloro-3-iodo-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-1,2-dicarboxylate

[0793] Methyl 5-chloro-3-iodo-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate (0.81 g, 1.92 mmol) was dissolved in DCM (10 mL), and 4-dimethylaminopyridine (47 mg, 0.38 mmol) was added. Tert-butoxycarbonyl tert-butyl carbonate (498 mg, 2.30 mmol) and triethylamine (388 mg, 3.84 mmol) were added with stirring. The mixture was stirred for 6 hours and concentrated under reduced pressure to remove the solvent. The residue was dispersed in DCM, washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (900 mg, 90%).

[0794] MS m / z(ESI):521.0[M+H] + .

[0795] Step 3: Preparation of methyl 5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate

[0796] 1-(tert-Butyl)2-methyl-5-chloro-3-iodo-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-1,2-dicarboxylate (900 mg, 1.72 mmol), N-((1-fluorocyclopropyl)methyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.72 g, 2.06 mmol), Pd(dppf)Cl2 (125 mM) g, 172 μmol) was dissolved in DMF (18 mL). Under nitrogen protection, a solution of anhydrous potassium phosphate (0.73 g, 3.44 mmol) in water (3 mL) was added. The reaction solution was replaced with nitrogen and then transferred to an oil bath, heated to 85°C, and stirred for 2 hours. The reaction solution was then dissolved in DCM, and the organic phase was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the title compound (600 mg, 67%).

[0797] MS m / z(ESI):516.1[M+H] + .

[0798] Step 4: Preparation of 5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylic acid

[0799] Methyl 5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate (600 mg, 1.16 mmol) was dissolved in a mixed solvent of methanol (6 mL) and tetrahydrofuran (6 mL). A solution of sodium hydroxide (928 mg, 23.2 mmol) in water (3 mL) was added with stirring. The reaction solution was heated to 60°C and stirred for 14 hours. The organic solvent was removed by concentration under reduced pressure. The residue was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The crude product was directly used in the next reaction.

[0800] MS m / z(ESI):502.1[M+H] + .

[0801] Step 5: Preparation of 5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxamide

[0802] 5-Chloro-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylic acid (210 mg, 419 μmol) was dissolved in DMF (10 mL). HOBt (201.91 mg, 1.49 mmol), triethylamine (227 mg, 2.24 mmol, 313 μL), EDCI (287 mg, 1.49 mmol, hydrochloride) and ammonium chloride (200 mg, 3.74 mmol) were added sequentially with stirring at room temperature. The reaction solution was stirred for 4 hours and concentrated under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was used directly in the next reaction.

[0803] MS m / z(ESI):501.1[M+H] + .

[0804] Step 6: Preparation of 4-(4-amino-2-methylphenyl)-5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide

[0805] 5-Chloro-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxamide (200 mg, 0.40 mmol) was dissolved in a mixed solvent of dioxane (10 mL) and ethanol (10 mL). Iron powder (224 mg, 4.0 mmol) and a solution of ammonium chloride (220 mg, 4.0 mmol) in water (5 mL) were added sequentially. The reaction solution was heated to 60°C under nitrogen and stirred for 2 hours. The solvent was then concentrated under reduced pressure. The residue was dispersed in water and extracted with DCM. The DCM layers were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was isolated by silica gel column chromatography to obtain the title compound (100 mg, 53%).

[0806] MS m / z(ESI):471.2[M+H] +

[0807] Step 7: Preparation of 5-chloro-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide

[0808] 2-Fluoroacrylic acid (16 mg, 179.67 μmol), triethylamine (61 mg, 598.90 μmol, 83.53 μL) and HATU (68 mg, 179.67 μmol) were added sequentially to DMF (1 mL). The reaction solution was stirred at room temperature for 10 minutes. The mixture was then added to a solution of 4-(4-amino-2-methyl-phenyl)-3-(4-(isobutylcarbamoyl)-3-methoxy-phenyl)-5-ethyl-1H-pyrrole-2-carboxamide (73 mg, 156.06 μmol) in DMF (2 mL). The reaction solution was stirred at room temperature for 1 hour, filtered, and the filtrate was separated by prep-HPLC to obtain the title compound (10 mg, 12%).

[0809] MS m / z(ESI):543.2[M+H] + .

[0810] 1H NMR (400MHz, DMSO-d6) δ12.45(s,1H),10.12(d,J=1.9Hz,1H),8.26(t,J=5.9Hz,1H),7.54(d,J=7.9Hz,1H ),7.44(d,J=2.2Hz,1H),7.39(dd,J=8.3,2.2Hz,1H),7.19(s,1H),6.97(d,J=8.2Hz,1H),6.78(dd,J=7.9 ,1.5Hz,1H),6.71(d,J=1.5Hz,1H),6.29(s,1H),5.34(dd,J=15.6,3.7Hz,1H),3.64(d,J=6.0Hz,1H),3.6 0(s,3H),3.59(d,J=6.0Hz,1H),1.93(q,J=6.8Hz,2H),1.17(s,2H),0.96-0.83(m,2H),0.82-0.65(m,2H).

[0811] The preparation of Example 261 can be prepared by referring to Example 78, or by following the steps below:

[0812] HATU (50.14 mg, 132.91 μmol) was added to a solution of 4-(2-carbamoyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoic acid (40 mg, 88.60 μmol), [1-(trifluoromethyl)cyclopropyl]methanamine hydrochloride (17.11 mg, 97.46 μmol), and DIPEA (57.26 mg, 443.02 μmol) in DMF (2.5 mL). The reaction mixture was stirred for 1 hour. The reaction mixture was directly separated and purified by prep-HPLC to obtain the title compound (19.6 mg, 38.55%).

[0813] MS m / z(ESI):573.0[M+H] + .

[0814] 1H NMR (400MHz, DMSO-d6) δ11.51 (s, 1H), 10.14 (s, 1H), 8.22 (t, J = 6.2Hz, 1H), 7.57 (d, J=7.9Hz,1H),7.49-7.38(m,2H),7.02(d,J=8.2Hz,2H),6.85(dd,J=8.0,1.4Hz,1H) ,6.75(d,J=1.5Hz,1H),6.02(s,1H),5.68(dd,J=47.6,3.6Hz,1H),5.40(dd,J=15.6 ,3.6Hz,1H),3.62-3.55(m,4H),3.29(s,1H),2.02(s,3H),1.87(s,3H),0.89(s,4H).

[0815] The preparation of Example 270 can be prepared by referring to Example 78, or by following the steps below:

[0816] HATU (50.14 mg, 132.91 μmol) was added to a solution of 4-(2-carbamoyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoic acid (40 mg, 88.60 μmol), (1-fluorocyclobutyl)methanamine hydrochloride (13.61 mg, 97.46 μmol), and DIPEA (57.26 mg, 443.02 μmol) in DMF (2.5 mL). The reaction mixture was stirred for 1 hour. The reaction mixture was directly separated and purified by prep-HPLC to obtain the title compound (20.1 mg, 42.02%).

[0817] MS m / z(ESI):537.0[M+H] + .

[0818] 1H NMR (400MHz, DMSO-d6) δ11.52(s,1H),10.14(s,1H),8.18(d,J=6.2Hz,1H),7.63(d,J=8.0H z,1H),7.50-7.40(m,2H),7.02(d,J=8.2Hz,2H),6.86(dd,J=7.9,1.4Hz,1H),6.75(d,J=1.5 Hz,1H),6.06(s,1H),5.67(dd,J=47.7,3.6Hz,1H),5.39(dd,J=15.6,3.6Hz,1H),3.69-3.53 (m,5H),2.22-2.10(m,4H),2.02(s,3H),1.87(s,3H),1.80-1.68(m,1H),1.56-1.45(m,1H).

[0819] The preparation of Example 273 can be prepared with reference to Example 78, or according to the following steps:

[0820] HATU (50.14 mg, 132.91 μmol) was added to a solution of 4-(2-carbamoyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoic acid (40 mg, 88.60 μmol), 1-(aminomethyl)cyclopropanecarbonitrile (12.92 mg, 97.46 μmol), and DIPEA (57.26 mg, 443.02 μmol) in DMF (2.5 mL). The reaction mixture was stirred for 1 hour. The reaction mixture was directly separated and purified by prep-HPLC to obtain the title compound (26.3 mg, 55.38%).

[0821] MS m / z(ESI):530.0[M+H] + .

[0822] 1H NMR (400MHz, DMSO-d6) δ11.52(s,1H),10.15(d,J=1.8Hz,1H),8.40(t,J=6.2Hz,1H),7.5 8(d,J=7.9Hz,1H),7.50-7.41(m,2H),7.03(d,J=8.1Hz,2H),6.86(dd,J=7.9,1.4Hz,1H) ,6.75(d,J=1.5Hz,1H),6.07(s,1H),5.68(dd,J=47.7,3.6Hz,1H),5.39(dd,J=15.6,3.6 Hz,1H),3.61(s,3H),3.42(d,J=6.3Hz,2H),2.03(s,3H),1.87(s,3H),1.22-1.04(m,4H).

[0823] The preparation of Example 274 can be prepared with reference to Example 78, and can also be synthesized according to the following steps:

[0824] 4-(2-Carbamoyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoic acid (30 mg, 66.7 μmol), DIPEA (26 mg, 199.9 μmol) and HATU (38 mg, 100.0 μmol) were added to DMF (1 mL) in sequence, and the reaction solution was stirred for 10 minutes. To the reaction solution was added (1-methoxycyclopropyl)methanamine (13 mg, 127 μmol), and the reaction solution was stirred for 1 hour. The reaction solution was filtered and the filtrate was separated and purified by prep-HPLC to obtain the title compound (16 mg, 45%).

[0825] MS m / z(ESI):535.2[M+H] + .

[0826] 1H NMR (400MHz, DMSO-d6) δ11.46 (s, 1H), 10.10 (s, 1H), 8.09 (t, J = 5.7Hz, 1H), 7. 57(d,J=7.9Hz,1H),7.38(d,J=9.3Hz,2H),6.96(d,J=8.0Hz,1H),6.79(dd,J= 7.9,1.5Hz,1H),6.67(d,J=1.5Hz,1H),5.71-5.64(m,1H),5.58-5.48(m,1H), 5.38-5.22(m,2H),3.54(s,3H),3.42(d,J=5.8Hz,2H),3.15(s,3H),1.98-1.87 (m,3H),1.79(s,3H),0.82-0.75(m,2H),0.64-0.47(m,2H).

[0827] The preparation of Example 276 can be prepared by referring to Example 78, or by following the steps below:

[0828] HATU (107 mg, 283 μmol) was added to a solution of 4-(4-amino-2-chloro-phenyl)-3-[4-[(1-fluorocyclopropyl)methylcarbamoyl]-3-methoxy-phenyl]-5-methyl-1H-pyrrole-2-carboxamide (89 mg, 189 μmol), 2-fluoroprop-2-enoic acid (25 mg, 283 μmol), and DIPEA (73 mg, 567 μmol) in DMF (10 mL). The reaction mixture was stirred for 1 hour. The reaction mixture was directly separated and purified by prep-HPLC to obtain the title compound (23 mg, 22%).

[0829] MS m / z(ESI):523.0[M+H] + .

[0830] 1 H NMR (400MHz, DMSO-d6) δ11.61 (s, 1H), 10.38 (s, 1H), 8.33 (t, J = 6.0Hz, 1H), 7. 87(d,J=2.1Hz,1H),7.67-7.39(m,2H),7.10(d,J=8.4Hz,2H),6.89-6.71(m,2H ),5.98(s,1H),5.71(dd,J=47.6,3.8Hz,1H),5.44(dd,J=15.6,3.8Hz,1H),3. 96-3.48(m,5H),2.06(s,3H),0.95(dd,J=18.9,6.4Hz,2H),0.84-0.60(m,2H).

[0831] The preparation of Example 277 can be prepared by referring to Example 78, or by following the steps below:

[0832] HATU (42 mg, 111 μmol) was added to a solution of 4-[2-carbamoyl-4-[2-chloro-4-(2-fluoroprop-2-enoylamino)phenyl]-5-methyl-1H-pyrrol-3-yl]-2-methoxy-benzoic acid (35 mg, 74 μmol, prepared as described in Example 68, step 1), 1-(aminomethyl)cyclopropanecarbonitrile hydrochloride (11 mg, 82 μmol), and DIPEA (48 mg, 371 μmol) in DMF (2.5 mL). The reaction mixture was stirred for 1 hour. The reaction mixture was directly separated and purified by prep-HPLC to obtain the title compound (11 mg, 27%).

[0833] MS m / z(ESI):550.0[M+H] + .

[0834] The preparation of Example 279 can be prepared by referring to Example 78, or by following the steps below:

[0835] 4-(2-Carbamoyl-5-chloro-4-(2-chloro-4-(2-fluoroacryloylamino)phenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (25 mg, 51 μmol, prepared as described in Example 68, step 1) was dissolved in DMF (1 mL). (1-Fluorocyclopropyl)methanamine (10 mg, 76 μmol), DIPEA (20 mg, 152 μmol), and HATU (38 mg, 102 μmol) were then added. The reaction mixture was stirred for 10 minutes. The reaction mixture was filtered, and the residue was purified by prep-HPLC to afford the title compound (7.8 mg, 27%).

[0836] MS m / z(ESI):563.2[M+H] + .

[0837] 1H NMR(400MHz,DMSO-d6)δ12.61(s,1H),10.43(s,1H),8.34(t,J=5.9Hz,1H),7 .88(d,J=2.0Hz,1H),7.64-7.53(m,2H),7.20(t,J=14.8Hz,2H),6.84(d,J=7. 6Hz,2H),6.38(s,1H),5.72(dd,J=47.6,3.7Hz,1H),5.45(dd,J=15.6,3.7Hz ,1H),3.74-3.63(m,5H),0.96(dt,J=18.9,6.7Hz,2H),0.77(q,J=8.0Hz,2H).

[0838] The preparation of Example 280 can be prepared by referring to Example 78, or by following the steps below:

[0839] 4-(2-Carbamoyl-5-chloro-4-(2-chloro-4-methacryloylamidophenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (25 mg, 51 μmol, prepared as described in Example 68, step 1) was dissolved in DMF (1 mL). 1-(Aminomethyl)cyclopropanecarbonitrile (11 mg, 76 μmol), DIPEA (20 mg, 152 μmol), and HATU (38 mg, 102 μmol) were then added. The reaction mixture was stirred for 10 minutes. The reaction mixture was filtered, and the residue was purified by prep-HPLC to yield the title compound (9.8 mg, 33%).

[0840] MS m / z(ESI):570.2[M+H] + .

[0841] 1H NMR (400MHz, DMSO-d6) δ12.62(s,1H),10.43(s,1H),8.43(t,J=6.1Hz,1H),7. 89(d,J=2.0Hz,1H),7.61-7.53(m,2H),7.21(t,J=20.1Hz,2H),6.84(d,J=7.7 Hz,2H),6.36(s,1H),5.72(dd,J=47.6,3.7Hz,1H),5.45(dd,J=15.5,3.7Hz,1 H),3.67(s,3H),3.42(d,J=6.1Hz,2H),1.20-1.13(m,2H),1.12-1.05(m,2H).

[0842] The preparation of Example 282 can be prepared with reference to Example 78, or according to the following steps:

[0843] 4-(2-Carbamoyl-5-chloro-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (30 mg, 64 μmol, prepared as described in Example 68, step 1), DIPEA (24 mg, 191 μmol) and HATU (36 mg, 96 μmol) were added sequentially to DMF (1 mL), and the reaction solution was stirred for 10 minutes. 1-(Aminomethyl)cyclopropane-1-carbonitrile hydrochloride (17 mg, 127 μmol) was added to the reaction solution, and the reaction was continued with stirring for 1 hour. The reaction was filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (16 mg, 45%).

[0844] MS m / z(ESI):550.2[M+H] + .

[0845] 1 H NMR (400MHz, DMSO-d6) δ12.45(s,1H),10.12(d,J=1.9Hz,1H),8.26(t,J=5.9Hz,1H),7.54(d,J=7.9 Hz,1H),7.44(d,J=2.2Hz,1H),7.39(dd,J=8.3,2.2Hz,1H),7.19(s,1H),6.97(d,J=8.2Hz,1H),6.78 (dd,J=7.9,1.5Hz,1H),6.71(d,J=1.5Hz,1H),6.29(s,1H),5.34(dd,J=15.6,3.7Hz,1H),3.90(s,3 H),3.64(d,J=6.0Hz,1H),3.59(d,J=6.0Hz,2H),1.87(s,3H),0.96-0.83(m,2H),0.82-0.65(m,2H).

[0846] The preparation of Example 283 can be prepared by referring to Example 78, or by following the steps below:

[0847] 4-(2-Carbamoyl-5-chloro-4-(2-fluoro-4-(2-fluoroacryloylamino)phenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (50 mg, 105 μmol, prepared as described in Example 68, step 1) was dissolved in DMF (1 mL). HATU (55.5 mg, 147 μmol) and DIPEA (68 mg, 525 μmol) were added with stirring, and the reaction mixture was stirred for 30 minutes. 1-(Aminomethyl)cyclopropane-1-carbonitrile hydrochloride (20 mg, 152 μmol) was added to the reaction mixture, and stirring was continued for 1 hour. The reaction mixture was separated and purified by reverse phase chromatography to yield the title compound (12.8 mg, 22%).

[0848] MS m / z(ESI):554.1[M+H] + .

[0849] 1 H NMR (400MHz, DMSO-d6) δ12.65 (s, 1H), 10.45 (s, 1H), 8.45 (t, J = 6.1Hz, 1H), 7.64-7. 56(m,2H),7.45(dd,J=8.5,2.1Hz,1H),7.27(s,1H),7.12(t,J=8.4Hz,1H),6.89(d,J =1.4Hz,1H),6.82(dd,J=7.9,1.5Hz,1H),6.33(s,1H),5.72(dd,J=47.7,3.7Hz,1H), 5.45(dd,J=15.6,3.7Hz,1H),3.69(s,3H),3.43(d,J=6.2Hz,2H),1.26-1.06(m,4H).

[0850] The preparation of Example 284 can be prepared by referring to Example 78, or by following the steps below:

[0851] 2-Fluoroacrylic acid (8 mg, 89.5 μmol), triethylamine (61 mg, 300 μmol) and HATU (34 mg, 89.5 μmol) were added to DMF (2 mL) in sequence, and the mixture was stirred for 10 minutes. The mixture was then added to a solution of 4-(4-amino-2-chlorophenyl)-5-ethyl-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide (37 mg, 78 μmol, prepared as described in Step 8 of Example 78) in DMF (4 mL). The reaction mixture was stirred for 1 hour, filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (25 mg, 60%).

[0852] MS m / z(ESI):557.2[M+H]+ .

[0853] 1 H NMR (400MHz, DMSO-d6) δ11.36(s,1H),10.20(s,1H),8.14(t,J=5.9Hz,1H),7.65(d,J=2.1Hz,1H),7.41(d,J=7.9Hz,2H),7.35(dd,J=8.4,2.2Hz,1H), 6.96(d,J=8.4Hz,1H),6.87(s,1H),6.62(s,2H),5.57(d,J=3.7Hz,1H),5.24(dd,J=15.6,3.8Hz,1H),3.47(s,3H),3.4 3(d,J=16.2Hz,2H),2.20(ddt,J=17.4,14.5,7.3Hz,2H),1.08(t,J=7.5Hz,3H),1.06-1.00(m,2H),0.88-0.70(m,2H).

[0854] The preparation of Example 287 can be prepared by referring to Example 78, or by following the steps below:

[0855] 2-Fluoroacrylic acid (8 mg, 89.5 μmol), triethylamine (61 mg, 300 μmol) and HATU (34 mg, 89.5 μmol) were added to DMF (2 mL) in sequence, and the mixture was stirred for 10 minutes. The mixture was then added to a solution of 4-(4-amino-2-chlorophenyl)-5-ethyl-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-methoxyphenyl)-1H-pyrrole-2-carboxamide (36 mg, 78 μmol, prepared as described in Step 8 of Example 78) in DMF (4 mL). The reaction mixture was stirred for 1 hour, filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (24 mg, 57%).

[0856] MS m / z(ESI):541.2[M+H] + .

[0857] 1H NMR (400MHz, DMSO-d6) δ11.59(s,1H),10.42(s,1H),8.36(t,J=5.9Hz,1H),7.63(d,J=7.9Hz,1H),7.5 7(dd,J=11.9,2.0Hz,1H),7.42(dd,J=8.3,2.0Hz,1H),7.22(s,1H),7.06(t,J=8.5Hz,1H),6.88-6.78( m,1H),6.68(s,1H),5.80-5.74(m,1H),5.65(d,J=3.7Hz,1H),5.33(t,J=4.8Hz,1H),3.69(s,3H),2.4 5(t,J=7.5Hz,2H),1.46(d,J=7.6Hz,2H),1.08(t,J=7.5Hz,3H),1.06-1.00(m,2H),0.88-0.70(m,2H),

[0858] The preparation of Example 352 is based on Example 78, and can also be synthesized according to the following steps:

[0859] HATU (87 mg, 231 μmol) was added to a solution of 4-(4-amino-2-fluoro-phenyl)-3-[4-[(1-fluorocyclopropyl)methylcarbamoyl]-3-methoxy-phenyl]-5-methyl-1H-pyrrole-2-carboxamide (70 mg, 154 μmol, prepared as described in Example 78, Step 8), 2-fluoroprop-2-enoic acid (21 mg, 231 μmol), and DIPEA (60 mg, 462 μmol) in DMF (2 mL). The reaction mixture was stirred for 1 hour. The reaction mixture was directly separated and purified by prep-HPLC to obtain the title compound (13.5 mg, 15%).

[0860] MS m / z(ESI):527.0[M+H] + .

[0861] 1H NMR (400MHz, DMSO-d6) δ11.65(s,1H),10.40(s,1H),8.36(t,J=5.9Hz,1H),7.6 9-7.55(m,2H),7.40(dd,J=8.5,2.1Hz,1H),7.02(t,J=8.5Hz,2H),6.89-6.78(m ,2H),5.96(s,1H),5.71(dd,J=47.6,3.7Hz,1H),5.44(dd,J=15.6,3.7Hz,1H),3 .77-3.60(m,5H),2.12(s,3H),0.96(dd,J=18.8,6.3Hz,2H),0.85-0.73(m,2H).

[0862] The preparation of Example 354 is based on Example 78, and can also be synthesized according to the following steps:

[0863] 4-(2-Carbamoyl-5-chloro-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (30 mg, 64 μmol, prepared as described in Example 68, step 1), DIPEA (24 mg, 191 μmol), and HATU (36 mg, 96 μmol) were added sequentially to DMF (1 mL) and stirred for 10 minutes. 2-Fluoro-2-methylpropane-1-amine hydrochloride (17 mg, 127 μmol) was added to the reaction solution, stirred for 1 hour, filtered, and the filtrate purified by prep-HPLC to obtain the title compound (19 mg, 54%).

[0864] MS m / z(ESI):545.2[M+H] + .

[0865] 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.11(t,J=6.2Hz,1H),7.52(d,J=7.9Hz,1H),7 .44(d,J=2.1Hz,1H),7.42-7.35(m,1H),6.97(d,J=8.3Hz,1H),6.81-6.71(m,2H),6. 60(s,1H),5.71-5.65(m,1H),5.56(d,J=3.6Hz,1H),5.34(dd,J=15.7,3.7Hz,1H),5. 26(t,J=4.7Hz,1H),3.56(s,3H),3.45-3.35(m,2H),1.87(s,3H),1.29-1.15(m,6H).

[0866] The preparation of Example 355 can refer to Example 78 or 249, and can also be synthesized according to the following steps:

[0867] 4-(2-Carbamoyl-5-chloro-4-(2-chloro-4-(2-fluoroacryloylamino)phenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (25 mg, 51 μmol, prepared as described in Example 68, step 1) was dissolved in DMF (1 mL). 2-Fluoro-2-methyl-propane-1-amine (10 mg, 77 μmol), DIPEA (20 mg, 152 μmol), and HATU (38 mg, 102 μmol) were then added. The reaction mixture was stirred for 10 minutes. The reaction mixture was filtered, and the residue was purified by prep-HPLC to yield the title compound (9.3 mg, 32%).

[0868] MS m / z(ESI):565.2[M+H] + .

[0869] 1 H NMR (400MHz, DMSO-d6) δ12.59(s,1H),10.43(s,1H),8.19(t,J=6.2Hz,1H),7 .89(d,J=2.0Hz,1H),7.63-7.54(m,2H),7.41-7.09(m,2H),6.84(dd,J=12.6 ,4.7Hz,2H),6.36(s,1H),5.72(dd,J=47.6,3.7Hz,1H),5.45(dd,J=15.6,3. 7Hz, 1H), 3.67 (s, 3H), 3.46 (dd, J=19.8, 6.2Hz, 2H), 1.31 (d, J=21.5Hz, 6H).

[0870] The preparation of Example 364 can refer to Example 78 or 249, and can also be synthesized according to the following steps:

[0871] 4-(2-Carbamoyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoic acid (30 mg, 67 μmol), DIPEA (26 mg, 200 μmol) and HATU (38 mg, 100 μmol) were added sequentially to DMF (1 mL) and stirred for 10 minutes. 3-Amino-2,2-dimethylpropionitrile (12 mg, 127 μmol) was added to the reaction solution, and the reaction solution was stirred for 1 hour. The reaction solution was filtered and the filtrate was separated and purified by prep-HPLC to obtain the title compound (15 mg, 42%).

[0872] MS m / z(ESI):532.2[M+H] + .

[0873] 1 H NMR (400MHz, DMSO-d6) δ12.18(s,1H),10.12(d,J=1.9Hz,1H),8.26(t,J=5.9Hz,1H),7.54(d,J=7.9 Hz,1H),7.44(d,J=2.2Hz,1H),7.39(dd,J=8.3,2.2Hz,1H),7.19(s,1H),6.97(d,J=8.2Hz,1H),6.78 (dd,J=7.9,1.5Hz,1H),6.71(d,J=1.5Hz,1H),6.29(s,1H),5.34(dd,J=15.6,3.7Hz,1H),3.64(d,J= 6.0Hz,1H),3.60(s,3H),3.59(d,J=6.0Hz,1H),3.45(s,2H),2.64(s,3H),2.58(s,3H),1.43(s,6H).

[0874] The preparation of Example 365 can refer to Example 78 or 249, and can also be synthesized according to the following steps:

[0875] 4-(2-Carbamoyl-5-chloro-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (30 mg, 64 μmol), DIPEA (24 mg, 191 μmol) and HATU (36 mg, 96 μmol) were added to DMF (1 mL) in sequence and stirred for 10 minutes. 3-Amino-2,2-dimethylpropionitrile (12 mg, 127 μmol) was added to the reaction solution, and the reaction solution was stirred for 1 hour. The reaction solution was filtered and the filtrate was separated and purified by prep-HPLC to obtain the title compound (13 mg, 37%).

[0876] MS m / z(ESI):552.2[M+H] + .

[0877] 1H NMR (400MHz, DMSO-d6) δ12.45(s,1H),10.12(d,J=1.9Hz,1H),8.26(t,J=5.9Hz,1H),7.54(d,J=7 .9Hz,1H),7.44(d,J=2.2Hz,1H),7.39(dd,J=8.3,2.2Hz,1H),7.19(s,1H),6.97(d,J=8.2Hz,1H) ,6.78(dd,J=7.9,1.5Hz,1H),6.71(d,J=1.5Hz,1H),6.29(s,1H),5.34(dd,J=15.6,3.7Hz,1H),3 .64(d,J=6.0Hz,1H),3.60(s,3H),3.59(d,J=6.0Hz,1H),3.45(s,2H),2.57(s,3H),1.42(s,6H),

[0878] The preparation of Example 366 can refer to Example 78 or 249, and can also be synthesized according to the following steps:

[0879] 4-(2-Carbamoyl-5-chloro-4-(2-chloro-4-(2-fluoroacryloylamino)phenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (25 mg, 51 μmol) was dissolved in DMF (1 mL). 3-Amino-2,2-dimethylpropionitrile (10 mg, 76 μmol), DIPEA (20 mg, 152 μmol), and HATU (38 mg, 102 μmol) were added. The reaction mixture was stirred for 10 minutes. The reaction mixture was filtered and the residue was purified by prep-HPLC to yield the title compound (8.2 mg, 28%).

[0880] MS m / z(ESI):572.2[M+H] + .

[0881] 1 H NMR (400MHz, DMSO-d6) δ12.62(s,1H),10.43(s,1H),8.38(t,J=6.5Hz,1H),7.89(d,J=2.0Hz,1H),7.58(dd,J=11.8,5.0Hz,2H),7.21(t,J=14.4Hz ,2H),6.90-6.80(m,2H),6.36(s,1H),5.72(dd,J=47.6,3.7Hz,1H),5.45 (dd,J=15.6,3.7Hz,1H),3.68(s,3H),3.45(d,J=6.5Hz,2H),1.30(s,6H).

[0882] The preparation of Example 367 can refer to Example 78 or 249, and can also be synthesized according to the following steps:

[0883] 4-(2-Carbamoyl-5-chloro-4-(2-fluoro-4-(2-fluoroacryloylamido)phenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (50 mg, 105 μmol, prepared as described in Example 68, step 1) was dissolved in DMF (1 mL). DIPEA (68 mg, 525 μmol) and HATU (52 mg, 137 μmol) were added with stirring, and stirring was continued for 30 minutes. 3-Amino-2,2-dimethylpropionitrile (21 mg, 210 μmol) was added. The reaction mixture was stirred for another hour. The reaction mixture was separated and purified by reverse-phase column chromatography to obtain the title compound (11.3 mg, 19%).

[0884] MS m / z(ESI):556.2[M+H] + .

[0885] 1 H NMR(400MHz,DMSO-d6)δ10.46(d,J=1.9Hz,1H),8.40(t,J=6.5Hz,1H),8.24(s,1H),7 .64-7.54(m,2H),7.45(dd,J=8.4,2.1Hz,1H),7.26(s,1H),7.12(t,J=8.4Hz,1H),6. 92(d,J=1.5Hz,1H),6.82(dd,J=7.9,1.5Hz,1H),6.38(s,1H),5.72(dd,J=47.6,3.8H z,1H),5.45(dd,J=15.6,3.7Hz,1H),3.70(s,3H),3.47(d,J=6.5Hz,2H),1.31(s,6H).

[0886] The preparation of Example 368 can refer to Example 78 or 249, and can also be synthesized according to the following steps:

[0887] 4-(2-Carbamoyl-5-chloro-4-(2-fluoro-4-(2-fluoroacryloylamino)phenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (50 mg, 105 μmol) was dissolved in DMF (1 mL). HATU (52 mg, 137 μmol) and DIPEA (68 mg, 525 μmol) were added with stirring. The mixture was stirred for 30 minutes. 2-Methylpropane-1-amine (8 mg, 105 μmol) was then added, and the reaction mixture was stirred for 1 hour. The reaction mixture was separated by reverse-phase column chromatography to obtain the title compound (12.8 mg, 23%).

[0888] MS m / z(ESI):531.1[M+H] + .

[0889] 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),8.23(s,1H),8.08(t,J=5.9Hz,1H),7.64-7.46(m,2 H),7.45(dd,J=8.4,2.0Hz,1H),7.27(s,1H),7.11(t,J=8.4Hz,1H),6.88(d,J=1.5Hz,1H) ,6.80(dd,J=7.9,1.5Hz,1H),6.31(s,1H),5.72(dd,J=47.6,3.7Hz,1H),5.45(dd,J=15.6 ,3.7Hz,1H),3.68(s,3H),3.07(t,J=6.4Hz,2H),1.85-1.74(m,1H),0.88(d,J=6.6Hz,6H).

[0890] The preparation of Example 369 can be prepared by referring to Example 78 or 249, or by following the steps below:

[0891] Dissolve 4-(2-carbamoyl-5-chloro-4-(2-fluoro-4-(2-fluoroacryloylamino)phenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (600 mg, 1.26 mmol) in DMF (10 mL). Add HATU (618 mg, 1.64 mmol) and DIPEA (815 mg, 6.30 mmol) with stirring. The reaction mixture is stirred for 30 minutes. 2-Fluoro-2-methylpropane-1-amine hydrochloride (161 mg, 1.77 mmol) is added, and stirring is continued for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and isolated by reverse-phase column chromatography to obtain the title compound (167.2 mg, 24%).

[0892] MS m / z(ESI):549.1[M+H] + .

[0893] 1H NMR (400MHz, DMSO-d6) δ12.63 (s, 1H), 10.45 (s, 1H), 8.21 (t, J = 6.2Hz, 1H), 7.65-7.55 ( m,2H),7.45(dd,J=8.4,2.0Hz,1H),7.28(s,1H),7.12(t,J=8.4Hz,1H),6.91(d,J=1.5H z,1H),6.82(dd,J=8.0,1.4Hz,1H),6.32(s,1H),5.72(dd,J=47.6,3.8Hz,1H),5.45(dd ,J=15.6,3.7Hz,1H),3.70(s,3H),3.47(dd,J=19.8,6.2Hz,2H),1.32(d,J=21.5Hz,6H).

[0894] The preparation of Example 372 can be referred to Example 78 or 249, or can be synthesized according to the following steps:

[0895] Dissolve 4-(2-carbamoyl-5-chloro-4-(2-fluoro-4-(2-fluoroacryloylamino)phenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (1 g, 2.1 mmol) in DMF (20 mL). Add HATU (1.03 g, 2.73 mmol) and DIPEA (1.36 g, 10.5 mmol) with stirring. The reaction mixture is stirred for 30 minutes. Then, (1-fluorocyclopropyl)methylamine hydrochloride (262 mg, 2.94 mmol) is added and stirring is continued for 1 hour. The reaction mixture is diluted with ethyl acetate, and the organic phase is washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse-phase column chromatography to obtain the title compound (320.4 mg, 28%).

[0896] MS m / z(ESI):547.1[M+H] + .

[0897] 1H NMR (400MHz, DMSO-d6) δ12.56 (s, 1H), 10.38 (s, 1H), 8.30 (t, J = 5.9Hz, 1H), 7.59-7.4 9(m,2H),7.38(dd,J=8.4,2.1Hz,1H),7.20(s,1H),7.04(t,J=8.4Hz,1H),6.82(d,J= 1.5Hz,1H),6.75(dd,J=8.0,1.5Hz,1H),6.25(s,1H),5.65(dd,J=47.6,3.7Hz,1H),5 .38(dd,J=15.6,3.7Hz,1H),3.68-3.57(m,5H),0.96-0.84(m,2H),0.79-0.66(m,2H).

[0898] The preparation of Example 373 can refer to Example 78 or 249, and can also be synthesized according to the following steps:

[0899] 4-(2-Carbamoyl-5-chloro-4-(2-fluoro-4-(2-fluoroacryloylamino)phenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (50 mg, 105 μmol) was dissolved in DMF (1 mL). HATU (52 mg, 137 μmol) and DIPEA (68 mg, 526 μmol) were added with stirring. The reaction mixture was stirred for 30 minutes. 1-(1-(Aminomethyl)cyclopropyl)ethan-1-one hydrochloric acid (18 mg, 158 μmol) was then added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was separated and purified by reverse-phase column chromatography to obtain the title compound (9.4 mg, 16%).

[0900] MS m / z(ESI):571.1[M+H] + .

[0901] 1H NMR (400MHz, DMSO-d6) δ12.66 (s, 1H), 10.46 (s, 1H), 8.36 (t, J = 5.9Hz, 1H), 7.68-7.56 (m, 2H), 7.45(dd,J=8.4,2.0Hz,1H),7.30(d,J=11.2Hz,1H),7.11(t,J=8.4Hz,1H),6.89(d,J=1.5Hz,1H ),6.80(dd,J=8.0,1.5Hz,1H),6.32(s,1H),5.74(dd,J=47.6,3.8Hz,1H),5.48(dd,J=15.4,3.8 Hz,1H),3.69(s,3H),3.49(d,J=5.9Hz,2H),1.95(s,3H),1.25-1.22(m,2H),1.04-1.01(m,2H).

[0902] The preparation of Example 374 can refer to Example 78 or 249, and can also be synthesized according to the following steps:

[0903] HATU (48 mg, 126 μmol) was added to a solution of 4-(2-carbamoyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoic acid (38 mg, 84 μmol), 1-[1-(aminomethyl)cyclopropyl]ethanone hydrochloride (15 mg, 101 μmol), and DIPEA (54 mg, 421 μmol) in DMF (2.5 mL). The reaction mixture was stirred for 1 hour. The reaction mixture was directly separated and purified by prep-HPLC to give the title compound (18.5 mg, 40%).

[0904] MS m / z(ESI):547.0[M+H] + .

[0905] 1H NMR (400MHz, DMSO-d6) δ11.53(s,1H),10.16(s,1H),8.32(t,J=6.0Hz,1H),7.63(d,J=8.0Hz,1H ),7.48-7.41(m,2H),7.02(d,J=8.1Hz,2H),6.84(dd,J=7.9,1.5Hz,1H),6.74(d,J=1.5Hz,1H),6 .04(s,1H),5.68(dd,J=47.7,3.6Hz,1H),5.40(dd,J=15.6,3.6Hz,1H),3.61(s,3H),3.47(d,J= 6.0Hz,2H),2.02(s,3H),1.94(s,3H),1.86(s,3H),1.23(q,J=4.4Hz,2H),1.01(q,J=4.5Hz,2H).

[0906] The preparation of Example 375 can refer to Example 78 or 249, and can also be synthesized according to the following steps:

[0907] 4-(2-Carbamoyl-5-chloro-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (30 mg, 63.7 μmol), DIPEA (24 mg, 191 μmol) and HATU (36 mg, 96 μmol) were added to DMF (1 mL) in sequence and stirred for 10 minutes. Cyclopropylmethylamine (9 mg, 127 μmol) was added and the reaction mixture was stirred for 1 hour. The mixture was filtered and the filtrate was separated and purified by prep-HPLC to obtain the title compound (18 mg, 51%).

[0908] MS m / z(ESI):525.2[M+H] + .

[0909] 1H NMR (400MHz, DMSO-d6) δ12.45(s,1H),10.12(d,J=1.9Hz,1H),8.26(t,J=5.9Hz,1H),7.54(d,J=7.9Hz,1H),7. 44(d,J=2.2Hz,1H),7.39(dd,J=8.3,2.2Hz,1H),7.19(s,1H),6.97(d,J=8.2Hz,1H),6.78(dd,J=7.9,1.5Hz,1 H),6.71(d,J=1.5Hz,1H),6.29(s,1H),5.34(dd,J=15.6,3.7Hz,1H),3.64(d,J=6.0Hz,1H),3.60(s,3H),3.59 (d,J=6.0Hz,1H),1.93(q,J=6.8Hz,2H),1.17(s,2H),1.21-1.01(m,1H),0.96-0.83(m,2H),0.82-0.65(m,2H).

[0910] The preparation of Example 376 can refer to Example 78 or 249, and can also be synthesized according to the following steps:

[0911] 4-(2-Carbamoyl-5-chloro-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (30 mg, 64 μmol), DIPEA (24 mg, 191 μmol) and HATU (36 mg, 96 μmol) were added to DMF (1 mL) in sequence and stirred for 10 minutes. 2,2-difluoropropane-1-amine (12 mg, 127 μmol) was added and the reaction mixture was stirred for 1 hour. The mixture was filtered and the filtrate was separated and purified by prep-HPLC to obtain the title compound (16 mg, 45%).

[0912] MS m / z(ESI):549.1[M+H] + .

[0913] 1H NMR (400MHz, DMSO-d6) δ10.20(s,1H),8.36(t,J=6.3Hz,1H),7.57(d,J=7.9Hz,1H),7.53-7.42(m,2H),7.23(s,1H) ,7.04(d,J=8.3Hz,1H),6.85(dd,J=7.9,1.5Hz,1H),6.80(d,J=1.5Hz,1H),6.41(s,1H),5.75(d,J=3.6Hz,1H),5.63 (d,J=3.6Hz,1H),5.41(dd,J=15.6,3.6Hz,1H),3.71(td,J=14.0,6.4Hz,2H),3.62(s,3H),1.94(s,3H),1.54(t,J=20Hz,3H).

[0914] The preparation of Example 381 can refer to Example 78 or 249, and can also be synthesized according to the following steps:

[0915] 4-(2-Carbamoyl-5-chloro-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (50 mg, 106 μmol) was dissolved in DMF (2 mL). [1-(difluoromethyl)cyclopropyl]methanamine (25 mg, 159 μmol), DIPEA (28 mg, 212 μmol), and HATU (60 mg, 159 μmol) were added. The reaction mixture was stirred for 10 minutes. The reaction mixture was filtered and the residue was purified by prep-HPLC to yield the title compound (14 mg, 22%).

[0916] MS m / z(ESI):575.2[M+H] + .

[0917] 1 H NMR (400MHz, DMSO-d6) δ12.55(s,1H),10.19(s,1H),8.21(t,J=5.8Hz,1H),7.58(d, J=7.9Hz,1H),7.50(s,1H),7.45(dd,J=8.4,1.7Hz,1H),7.22(s,1H),7.03(d,J=8.3 Hz,1H),6.84(d,J=7.9Hz,1H),6.79(s,1H),6.37(s,1H),6.01-5.57(m,2H),5.41(d d,J=15.6,3.6Hz,1H),3.61(s,3H),3.45(d,J=6.0Hz,2H),1.94(s,3H),0.70(s,4H).

[0918] The preparation of Example 383 can refer to Example 78 or 249, and can also be synthesized according to the following steps:

[0919] 4-(2-Carbamoyl-5-chloro-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (25 mg, 53 μmol) was dissolved in DMF (1 mL). [1-(Fluoromethyl)cyclopropyl]methanamine (9 mg, 64 μmol), DIPEA (14 mg, 106 μmol), and HATU (30 mg, 80 μmol) were added. The reaction mixture was stirred for 10 minutes. The reaction mixture was filtered and the residue was purified by prep-HPLC to yield the title compound (8 mg, 27%).

[0920] MS m / z(ESI):557.2[M+H] + .

[0921] 1 H NMR (400MHz, DMSO-d6) δ12.51(s,1H),10.20(s,1H),8.19(t,J=5.8Hz,1H),7.56(d,J=7.9Hz ,1H),7.51(s,1H),7.48-7.43(m,1H),7.27(s,1H),7.04(d,J=8.3Hz,1H),6.83(d,J=8.0Hz,1 H),6.78(s,1H),6.32(s,1H),5.69(dd,J=47.7,3.6Hz,1H),5.41(dd,J=15.6,3.6Hz,1H),4. 28(d,J=48.9Hz,2H),3.61(s,3H),1.94(s,2H),0.62(q,J=4.7Hz,2H),0.50(t,J=5.0Hz,2H).

[0922] The preparation of Example 384 can refer to Example 78 or 249, and can also be synthesized according to the following steps:

[0923] 4-(2-Carbamoyl-5-chloro-4-(2-chloro-4-(2-fluoroacryloylamino)phenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (100 mg, 212 μmol) was dissolved in DMF (2.5 mL). [1-(Fluoromethyl)cyclobutyl]methanamine (65 mg, 556 μmol), DIPEA (548 mg, 4.24 mmol), and HATU (120 mg, 318 μmol) were then added. The reaction mixture was stirred for 10 minutes. The reaction mixture was filtered, and the residue was purified by prep-HPLC to yield the title compound (21.5 mg, 17%).

[0924] MS m / z(ESI):571.2[M+H] + .

[0925] 1 H NMR (400MHz, DMSO-d6) δ12.54(s,1H),10.20(s,1H),8.16(t,J=6.2Hz,1H),7.54(d,J=7.9Hz,1H ),7.51(d,J=1.7Hz,1H),7.45(dd,J=8.5,1.9Hz,1H),7.26(s,1H),7.04(d,J=8.3Hz,1H),6.83( dd,J=7.8,0.9Hz,1H),6.80(s,1H),6.31(s,1H),5.68(dd,J=47.7,3.7Hz,1H),5.41(dd,J=15.6 ,3.6Hz,1H),4.38(d,J=48.1Hz,2H),3.62(s,3H),3.39(s,2H),1.95(s,3H),1.88-1.76(m,6H).

[0926] The preparation of Example 387 can refer to Example 78 or 249, and can also be synthesized according to the following steps:

[0927] 4-(2-Carbamoyl-5-chloro-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid was dissolved in DMF (2 mL). 2-[1-(Aminomethyl)cyclopropyl]acetonitrile (47 mg, 318 μmol), DIPEA (55 mg, 424 μmol), and HATU (120 mg, 318 μmol) were added. The reaction mixture was stirred for 10 minutes. The reaction mixture was filtered, and the residue was purified by prep-HPLC to yield the title compound (37 mg, 30%).

[0928] MS m / z(ESI):564.2[M+H] +.

[0929] 1 H NMR (400MHz, DMSO-d6) δ12.52(s,1H),10.19(s,1H),8.21(t,J=6.0Hz,1H),7.72-7.49(m,4 H),7.48-7.42(m,1H),7.25(s,1H),7.04(d,J=8.3Hz,1H),6.83(d,J=7.9Hz,1H),6.78(s,1H ),6.32(s,1H),5.68(dd,J=47.7,3.6Hz,1H),5.41(dd,J=15.6,3.6Hz,1H),3.61(s,3H),3. 28(d,J=6.1Hz,2H),2.59(s,2H),1.94(s,3H),0.63(t,J=5.2Hz,2H),0.47(t,J=5.3Hz,2H).

[0930] The preparation of Example 389 can be prepared by referring to Example 78 or 249, or by following the steps below:

[0931] HATU (38 mg, 100 μmol) was added to a solution of 4-(2-carbamoyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-5-methyl-1H-pyrrol-3-yl)-2-methoxybenzoic acid (30 mg, 66 μmol), [1-(difluoromethyl)cyclopropyl]methanamine hydrochloride (13 mg, 80 μmol), and DIPEA (26 mg, 199 μmol) in DMF (2.5 mL). The reaction mixture was stirred for 1 hour. The reaction mixture was directly separated and purified by prep-HPLC to obtain the title compound (11.8 mg, 31%).

[0932] MS m / z(ESI):555.0[M+H] + .

[0933] 1H NMR (400MHz, DMSO-d6) δ11.52(s,1H),10.15(d,J=1.9Hz,1H),8.21(t,J=5.9Hz,1H) ,7.60(d,J=7.9Hz,1H),7.51-7.35(m,2H),7.02(d,J=8.2Hz,2H),6.85(dd,J=7.9,1 .5Hz,1H),6.75(d,J=1.5Hz,1H),6.13-5.58(m,3H),5.40(dd,J=15.6,3.6Hz,1H),3 .60(s,3H),3.45(d,J=5.9Hz,2H),2.02(s,3H),1.87(s,3H),0.70(d,J=3.3Hz,4H).

[0934] The preparation of Example 398 can be prepared by referring to Example 78 or 249, or by following the steps below:

[0935] 4-(2-Carbamoyl-5-chloro-4-(2-chloro-4-(2-fluoroacryloylamino)phenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (40 mg, 81 μmol) was dissolved in DMF (1 mL). Cyclopropylmethylamine (13 mg, 122 μmol), DIPEA (32 mg, 244 μmol), and HATU (62 mg, 163 μmol) were then added. The reaction mixture was stirred for 10 minutes. The reaction mixture was filtered, and the residue was purified by prep-HPLC to yield the title compound (11.3 mg, 25%).

[0936] MS m / z(ESI):545.2[M+H] + .

[0937] 1 H NMR (400MHz, DMSO-d6) δ12.61(s,1H),10.43(s,1H),8.14(t,J=5.8Hz,1H),7.89(d,J=2.1H z,1H),7.59(dd,J=13.5,5.2Hz,2H),7.37-7.22(m,1H),7.18(d,J=8.4Hz,1H),6.83(dd,J= 4.0,2.6Hz,2H),6.31(s,1H),5.72(dd,J=47.6,3.7Hz,1H),5.46(dd,J=15.6,3.7Hz,1H),3 .67(s,3H),3.13(t,J=6.3Hz,2H),1.07-0.92(m,1H),0.43-0.35(m,2H),0.24-0.15(m,2H).

[0938] The preparation of Example 399 can be prepared by referring to Example 78 or 249, or by following the steps below:

[0939] 4-(2-Carbamoyl-5-ethyl-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (30 mg, 64 μmol), DIPEA (24 mg, 191 μmol) and HATU (36 mg, 96 μmol) were added sequentially to DMF (1 mL) and stirred for 10 minutes. Cyclopropylmethylamine (9 mg, 127 μmol) was added and the reaction mixture was stirred for 1 hour. The mixture was filtered and the filtrate was separated and purified by prep-HPLC to obtain the title compound (20 mg, 57%).

[0940] MS m / z(ESI):519.2[M+H] + .

[0941] 1 H NMR(400MHz,DMSO-d6)δ11.28(s,1H),9.97(d,J=1.8Hz,1H),7.97-7.86(m,1H),7.41(dd,J=10.0,7.9Hz,1H), 6.87(d,J=3.0Hz,1H),6.84(s,1H),6.65(dd,J=7.9,1.5Hz,2H),6.59-6.50(m,1H),5.59-5.51(m,1H),5.23(d d,J=9.4,3.7Hz,1H),5.21-5.09(m,1H),3.40(s,3H),2.92(dd,J=7.3,5.3Hz,2H),1.80(q,J=7.0Hz,2H),1.71 (s,1H),1.63(s,3H),0.98(td,J=7.3,5.1Hz,1H),0.82(t,J=7.5Hz,3H),0.69-0.61(m,2H),0.24-0.15(m,2H).

[0942] The preparation of Example 400 can be prepared by referring to Example 78 or 249, or by following the steps below:

[0943] HATU (42 mg, 112 μmol) was added to a solution of 4-(4-amino-2-chloro-phenyl)-3-[4-(cyclopropylmethylcarbamoyl)-3-methoxy-phenyl]-5-ethyl-1H-pyrrole-2-carboxamide (35 mg, 75 μmol, prepared as described in Example 78, Step 8), 2-fluoroprop-2-enoic acid (10 mg, 112 μmol), and DIPEA (29 mg, 225 μmol) in DMF (2.5 mL). The reaction mixture was stirred for 1 hour. The reaction mixture was directly separated and purified by prep-HPLC to give the title compound (4 mg, 9.6%).

[0944] MS m / z(ESI):539.0[M+H] + .

[0945] 1 H NMR (400MHz, DMSO-d6) δ11.53(s,1H),10.39(s,1H),8.13(t,J=5.7Hz,1H),7.85(d,J=2.1 Hz,1H),7.63-7.50(m,2H),7.15(d,J=8.4Hz,2H),6.86-6.77(m,2H),6.02(s,1H),5.71(d d,J=47.7,3.7Hz,1H),5.44(dd,J=15.6,3.8Hz,1H),3.66(s,3H),3.12(t,J=6.2Hz,2H),2 .41(dt,J=18.1,7.2Hz,2H),1.04(t,J=7.5Hz,4H),0.43-0.35(m,2H),0.25-0.15(m,2H).

[0946] The preparation of Example 410 can be referred to Example 78 or 249, or it can be synthesized according to the following steps:

[0947] 2-Fluoroacrylic acid (400 mg, 4.5 mmol), triethylamine (3.05 g, 15.00 mmol, 2.1 mL) and HATU (1.70 g, 4.47 mmol) were added sequentially to DMF (10 mL) and stirred for 10 minutes. The mixture was then added to a solution of 4-(4-amino-2-methylphenyl)-5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)carbamoyl)-3-(methoxy-d3)phenyl)-1H-pyrrole-2-carboxamide (1.81 g, 3.90 mmol, prepared as described in Example 78, Step 8) in DMF (4 mL). The reaction mixture was stirred for 1 hour and filtered. The filtrate was separated and purified by prep-HPLC to obtain the title compound (600 mg, 29%).

[0948] MS m / z(ESI):546.2[M+H] + .

[0949] 1 H NMR (400MHz, DMSO-d6) δ12.45(s,1H),10.12(d,J=1.9Hz,1H),8.26(t,J=5.9Hz,1H),7.54(d,J=7. 9Hz,1H),7.44(d,J=2.2Hz,1H),7.39(dd,J=8.3,2.2Hz,1H),6.97(d,J=8.2Hz,1H),6.78(dd,J=7.9 ,1.5Hz,1H),6.71(d,J=1.5Hz,1H),5.34(dd,J=15.6,3.7Hz,1H),3.64(d,J=6.0Hz,1H),3.59(d,J= 6.0Hz,1H),1.93(q,J=6.8Hz,1H),1.87(s,3H),1.17(s,2H),0.96-0.83(m,2H),0.82-0.65(m,2H).

[0950] The preparation of Example 411 can refer to Example 78 or 249, and can also be synthesized according to the following steps:

[0951] 4-(2-Carbamoyl-5-chloro-4-(4-(2-fluoroacryloylamino)-2-methylphenyl)-1H-pyrrol-3-yl)-2-methoxybenzoic acid (50 mg, 106 μmol) was dissolved in DMF (1 mL). 2-Methylpropane-1-amine (8 mg, 106 μmol), DIPEA (41 mg, 318 μmol), and HATU (80 mg, 212 μmol) were then added. The reaction mixture was stirred for 10 minutes. The reaction mixture was filtered, and the residue was purified by prep-HPLC to yield the title compound (23.6 mg, 42%).

[0952] MS m / z(ESI):527.2[M+H] + .

[0953] 1H NMR (400MHz, DMSO-d6) δ12.51 (s, 1H), 10.19 (s, 1H), 8.05 (t, J = 5.8Hz, 1H), 7.57-7.49 ( m,2H),7.45(d,J=8.1Hz,1H),7.24(s,1H),7.04(d,J=8.3Hz,1H),6.82(d,J=7.8Hz,1H), 6.78(s,1H),6.32(s,1H),5.68(dd,J=47.6,3.6Hz,1H),5.41(dd,J=15.6,3.5Hz,1H),3. 61(s,3H),3.05(t,J=6.4Hz,2H),1.94(s,3H),1.83-1.72(m,1H),0.86(d,J=6.7Hz,6H).

[0954] Biological test evaluation

[0955] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[0956] 1. Enzyme test

[0957] Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on FGFR1-4 and FGFR2 V564F activities

[0958] 1. Experimental purpose: To test the IC of compounds on FGFR1, FGFR2, FGFR3, FGFR4 and FGFR2 V564F at the ATP Km concentration using the TR-FRET method. 50 .

[0959] 2. Experimental instruments and reagents:

[0960] 3. Experimental Methods: The inhibitory activity of compounds against FGFR1, FGFR2, FGFR3, FGFR4, and the FGFR2 V564F kinase domain fragment was determined by TR-FRET (time-resolved fluorescence resonance energy transfer). In all five kinase assays, the highest concentration tested was 1000 nM, and the compounds were diluted three-fold to a total of 11 concentrations (1000 nM to 0.017 nM). A 4× enzyme solution, a serially diluted 4× compound solution, and a 2× ATP / peptide substrate solution were prepared using kinase buffer (50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM MgCl2, 2 mM DTT, 0.01% Tween-20). 2.5 μL of enzyme solution and 2.5 μL of diluted 5× compound solution were added to a 384-well plate, followed by 5 μL of 2× ATP / Peptide substrate solution. FGFR1, FGFR2, FGFR3, and FGFR2 V564F kinases were reacted at room temperature for 60 minutes, and FGFR4 kinase was reacted at room temperature for 120 minutes. Then, 10 μL of 2× termination and detection mixture prepared with 1× LANCE detection buffer (EDTA concentration of 20 mM and Europium-anti-phosphotyrosine (PT66) concentration of 2 nM) was added to each well. After reacting at room temperature for 30 minutes, the fluorescence signal value of each well was measured using a microplate reader.

[0961] 4. Experimental data processing method:

[0962] 1) Inhibition rate (%): The raw data (665 nm / 620 nm reading ratio) were calculated using the following formula to obtain the inhibition rate: Inhibition rate (%) = [(average value of positive control wells – value of sample wells) / (average value of positive control wells – average value of negative control wells)] × 100, where positive control wells are reaction wells without compound or enzyme, and negative control wells are reaction wells without enzyme.

[0963] 2) Curve fitting: Use the log(inhibitor) vs. response--Variable slope (four parameters) function in GraphPad Prism 6 to perform fitting equation analysis on the compound concentration and the corresponding inhibition rate, fit the curve and obtain the compound IC 50 value.

[0964] The fitting calculation equation is Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)).

[0965] 5. Experimental results: IC values ​​of compounds for FGFR2, 3 and FGFR2 V564F kinase activity50 The values ​​are shown in Table 1-3 below:

[0966] Table 1

[0967] Table 2

[0968] Table 3

[0969] 6. Experimental conclusion: The compounds of the present invention have good inhibitory effects on the kinase activities of FGFR2, FGFR3 and FGFR2 V564F, and have good selectivity for FGFR1.

[0970] 2. Cell Viability Assay

[0971] 1. Experimental purpose: To evaluate the inhibitory effect of the compound on NCI-H716, SNU-16 and BaF3-FGFR2-BICC1 V564F cells through cell proliferation inhibition assay.

[0972] 2. Experimental instruments and reagents:

[0973] 2.3 Cell Source

[0974] 3. Experimental methods:

[0975] The inhibitory effects of compounds on NCI-H716, SNU-16, and BaF3 FGFR2-BICC1 V564F cell proliferation were assessed using the CellTiter-Glo assay. The highest concentration tested was 1000 nM, with three-fold dilutions across nine concentrations (1000 nM to 0.15 nM). Cells were plated at appropriate density and compounds were added the following day. After incubation for 72 hours, the cells were assayed using the CellTiter-Glo Luminescence Detection Kit.

[0976] 4. Experimental data processing method:

[0977] 1) Inhibition rate (%): Inhibition rate (%) = [(average value of positive control wells - value of sample wells) / (average value of positive control wells - average value of negative control wells)] × 100, where the positive control wells are reaction wells without compound enzyme, and the negative control wells are reaction wells without enzyme.

[0978] 2) Curve fitting: Use the log(inhibitor) vs. response--Variable slope (four parameters) function in GraphPad Prism 6 to perform fitting equation analysis on the compound concentration and the corresponding inhibition rate, fit the curve and obtain the compound IC 50 value.

[0979] The fitting calculation equation is Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)).

[0980] 5. The experimental results are shown in Table 4 below:

[0981] Table 5

[0982] Table 6

[0983] 6. Experimental conclusion:

[0984] The compounds of the present invention have significant proliferation inhibitory effects on NCI-H716, SNU-16 and BaF3 FGFR2-BICC1 V564F cells.

[0985] III. Determination of the ability of the compounds of the present invention to kill human renal cancer cell line UMUC-14

[0986] 1. Experimental purpose:

[0987] The purpose of this test case is to measure the proliferation of the human renal cancer cell line UMUC-14 to evaluate the ability of the compound to kill the cells.

[0988] 2. Experimental instruments and reagents:

[0989] 3. Experimental methods:

[0990] Prepare a cell suspension at 22222 cells / ml and add 180 μl of this suspension to each well of a 96-well plate, i.e., 4000 cells / well, for overnight culture. In a 96-well V-bottom plate, perform a 4-fold serial dilution of the 4 mM compound with DMSO; dilute each compound 40-fold in complete culture medium. Add 20 μl of the compound to the cell wells. Add TAS-120 to the negative control wells to a final concentration of 10 μM. Incubate in a 37°C, 5% CO2 cell culture incubator for 5 days. Remove 50 μl of the supernatant and add 50 μl of CTG lysis buffer (CTG, Suzhou Yingze, #ZEB-CV1). Shake and lyse the cells, and allow the signal to equilibrate. Measure the signal intensity using a microplate reader (PE, #2104-0010). Data were analyzed using GraphPad Prism 8.3.0.

[0991] 4. Experimental data processing method:

[0992] Data were analyzed using GraphPad Prism 8.3.0.

[0993] Inhibition rate (%) = [(average value of positive control wells – average value of sample wells) / (average value of positive control wells – average value of negative control wells)] × 100%, where the sample wells are cells plus different concentration gradient compound wells, the positive control wells are cells, and the negative control wells are cells plus 10 μM TAS-120.

[0994] Curve fitting: Based on the inhibition rate (%) of each concentration, the IC was obtained using the log (inhibitor) vs. response--Variable slope (four parameters) in GraphPad Prism 6.0. 50 The calculation equation is Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)).

[0995] 5. The experimental results are shown in Table 7 below:

[0996] 6. Experimental conclusion: The compounds of the present invention have a significant proliferation inhibitory effect on UMUC-14 cells.

[0997] Pharmacokinetics in Balb / C mice

[0998] 1. Study purpose: Balb / C mice were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in the plasma of mice after oral administration at a dose of 5 mg / kg.

[0999] 2. Experimental Plan

[1000] 2.1 Test drugs: Compounds of the present invention, homemade.

[1001] 2.2 Experimental animals: Balb / C mice (3 per example), male, Shanghai Bikai Laboratory Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 No. 311620400001794).

[1002] 2.3 Administration: Male Balb / C mice were fasted overnight and administered orally at a dose of 5 mg / kg in a volume of 10 mL / kg.

[1003] 2.4 Sample collection: Before and after administration of the drug, 0.04 mL of blood was collected from the mouse orbital cavity at 0, 0.5, 1, 2, 4, 6, 8, and 24 hours. The blood was placed in an EDTA-K2 tube and centrifuged at 6000 rpm for 6 min at 4°C to separate the plasma, which was then stored at -80°C.

[1004] 2.5 Sample processing:

[1005] 1) Add 100uL of acetonitrile to 20uL of plasma sample for precipitation, mix and centrifuge at 3500×g for 5-20 minutes.

[1006] 2) The supernatant solution was taken for LC / MS / MS analysis of the concentration of the test compound. LC / MS / MS analysis instrument: AB Sciex API 4000 Qtrap

[1007] 2.6 Liquid phase analysis

[1008] Liquid phase conditions: Shimadzu LC-20AD pump Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[1009] Chromatographic column: Waters X Bridge 5um C18 50X 4.6mm Mobile phase: Liquid A is 0.1% formic acid water

[1010] Solution B is methanol. Flow rate: 0.4 mL / min. Elution time: 0-4.0 minutes. The eluent is as follows:

[1011] 3. Test results and analysis

[1012] The main pharmacokinetic parameters were calculated using WinNonlin 6.1. The results of the mouse pharmacokinetic experiment are shown in Table 8 below:

[1013] E...

Claims

1. A compound represented by general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in: Ring A is a monocyclic heteroaryl group; M1 is N or CR m1 ; M2 is N or CR m2 ; L1, L2 and L3 are each independently selected from a bond, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, -(CH2) n C(O)(CR aa R bb ) n1 -、-(CH2) n C(O)NR aa (CR aa R bb ) n1 -、-(CH2) n (CR aa R bb ) n2 -、-(CR aa R bb ) n O(CH2) n1 -、-(CH2) n S(CR aa R bb ) n3 -、-(CR aa R bb ) n3 (CH2) n NR cc -、-(CH2) n NR aa (CR bb R cc ) n -、-(CH2) n NR aa C(O)-、-(CH2) n P(O) p R aa -、-(CH2) n S(O) m -、-(CH2) n S(O) m NR aa -、-C(=NR aa )NR aa -、-C(=CR bb R cc )-、-C(=S)NR aa - and -(CH2) n NR aa S(O) m -; R1 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR a 、-C(O)R a 、-SR a 、S(O)R a or S(O)2R a , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR b 、-C(O)R b 、-SR b 、S(O)R b or S(O)2R b , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkane alkyl, heterocyclic group, aryl, heteroaryl, -OR d 、-C(O)R d 、-SR d 、S(O)R d or S(O)2R d , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R5 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR e 、-C(O)R e 、-SR e 、S(O)R e or S(O)2R e , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R m1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR f 、-C(O)R f 、-SR f 、S(O)R f or S(O)2R f , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; R m2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR g 、-C(O)R g 、-SR g 、S(O)R g or S(O)2R g , the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted; Alternatively, one of R2 and one of R3 are linked to adjacent atoms to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, and the cycloalkyl, heterocyclic, aryl and heteroaryl group may optionally be further substituted; Alternatively, one R3 and one R4 are linked to adjacent atoms to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, and the cycloalkyl, heterocyclic, aryl and heteroaryl group may optionally be further substituted; R a 、R b 、R c 、R d 、R e 、R f and R g each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted; R aa 、R bb and R cc each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted; Or, R aa With R bb Together with adjacent atoms, they form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted; Or, R bb With R cc Together with adjacent atoms, they form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted; x is 0, 1, 2, 3, 4, 5, or 6; y is 0, 1, 2, 3, 4, 5, or 6; z is 0, 1, 2, 3, 4, 5, or 6; p is 0, 1, 2, or 3; m is 0, 1, 2, or 3; n, n1, n2, n3 and n4 are each independently 0, 1, 2 or 3; Preferably, when -L1-R1 is When the ring A is not pyridyl, pyrimidinyl or pyridazine; and the compound is not the following compounds:

2. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is as shown in formula (II) and formula (II-1), in, Ring A is a monocyclic heteroaryl group; L1 is selected from -(CH2) n C(O)(CR aa R bb ) n1 -、-(CH2) n C(O)NR aa (CR aa R bb ) n1 -、-(CH2) n (CR aa R bb ) n2 -or-(CR aa R bb ) n O(CH2) n1 -; R aa and R bb Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 Aryl, 5-14 membered heteroaryl, optionally further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl; Preferably, R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 Aryl, 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl; R2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; R3 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 3-8 Cycloalkyl substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -C 1-6 Alkyl-R c 、-NHR c 、-OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c ; Preferably, R3 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 3-8 Cycloalkyl substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 Aryl, 5-14 membered heteroaryl, -OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c ; R c independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1- 6 alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, hydroxyl, C 1-6 Alkyl-substituted amino, C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl are optionally substituted with hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 one or more substitutions of aryl or 5-14 membered heteroaryl; Preferably, R c independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; R4 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; R6, R7 and R8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- 6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 Aryl, 5-14 membered heteroaryl, optionally further substituted with hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl; Alternatively, one of R2 and one of R3 are connected to adjacent atoms to form C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1- 6 alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 one or more substitutions of aryl or 5-14 membered heteroaryl; Alternatively, one of R3 and one of R4 are connected to adjacent atoms to form C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 The aryl or 5-14 membered heteroaryl group may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1- 6 alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 one or more substitutions of aryl or 5-14 membered heteroaryl; x is 0, 1, 2, 3, 4, 5, or 6; y is 0, 1, 2, 3, 4, 5, or 6; z is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, or 3; n1 is 0, 1, 2 or 3; and n2 is 0, 1, 2 or 3.

3. The compound of formula (I) according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from monocyclic heteroaryl groups; The monocyclic heteroaryl group is preferably a 5-12-membered heteroaryl group; more preferably a 5-membered or 6-membered heteroaryl group; further preferably a 5-membered or 6-membered heteroaryl group containing 1-3 N, O or S atoms; The monocyclic heteroaryl group is preferably The monocyclic heteroaryl group is more preferably the following group:

4. The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is as shown in formula (III), L1 is selected from -(CH2) n C(O)(CR aa R bb ) n1 -、-(CH2) n C(O)NR aa (CR aa R bb ) n1 -、-(CH2) n (CR aa R bb ) n2 -or-(CR aa R bb ) n O(CH2) n1 -; R aa and R bb Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-6 hydroxyalkyl; R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl, 5-6 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, cyano substituted C 1-3 Alkyl, C 1-3 Alkyl-CO-, halogenated C 1-3 Alkyl, halogenated C 2-4 Alkenyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl; Preferably, R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1- 3 alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl; More preferably, R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl, 5-6 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl; R2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; R 31 、R 32 and R 33 are each independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 3-8 Cycloalkyl substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -C 1-6 Alkyl-R c 、-NHR c 、-OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c Preferably, R 31 、R 32 and R 33 are each independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, -C 1-3 Alkyl-R c 、-NHR c or -C(O)R c ; Preferably, R 31 、R 32 and R 33 are each independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 3-8 Cycloalkyl substituted C 1- 6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c Preferably, R 31 、R 32 and R 33 are each independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl or -C(O)R c ; R c independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1- 6 alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; R4 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; R6, R7 and R8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1- 6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 Aryl, 5-14 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl; x is 0, 1, 2, 3, 4, 5, or 6; z is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, or 3; n1 is 0, 1, 2 or 3; and n2 is 0, 1, 2 or 3.

5. The compound of formula (I) according to claim 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in formula (IV): in: R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6- 14 Aryl, 5-15 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 One or more substitutions of aryl, 5-14 membered heteroaryl; R2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; R 32 Selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 3-8 Cycloalkyl substituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl, -C 1-6 Alkyl-R c 、-NHR c 、-OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c ; R c independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1- 6 alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; R4 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; R6, R7, R8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1- 6 alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, deuterated C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1- 6 alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl, 5-14 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1- 3 alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl; x is 0, 1, 2, 3, 4, 5, or 6; z is 0, 1, 2, 3, 4, 5 or 6.

6. The compound according to claim 5, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in formula (V):

7. The compound according to claim 5 or 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl, 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl; R2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, Halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl or 5-10 membered heteroaryl; R 32 Selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 3-6 Cycloalkyl substituted C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, -C 1-6 Alkyl-R c 、-NHR c 、-OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c ; R c independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R4 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; R6 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1- 3 alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl, or one or more 5- to 6-membered heteroaryl groups.

8. The compound according to claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in formula (VI): in, R 11 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group; R2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-6 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group; R 32 Selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 3-6 Cycloalkyl substituted C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group; R4 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group; R6 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2- 4-Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group; q is 1, 2, 3 or 4.

9. The compound of formula (I) according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl, 5-6 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl; Preferably, R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl, 5-6 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl; More preferably, R1 is selected from C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, the C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy and C 1-3 substituted by one or more hydroxyalkyl groups; More preferably, R1 is selected from C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy and C 1-3 is substituted by one or more hydroxyalkyl groups.

10. The compound of formula (I) according to any one of claims 1 to 5 or 9, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl or 5-6 membered heteroaryl; Preferably, R3 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 3-6 Cycloalkyl substituted C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl, -OR c 、-C(O)R c 、-SR c 、S(O)R c or S(O)2R c ; Preferably, R c independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl; Preferably, R4 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl; Alternatively, one of R2 and one of R3 are connected to adjacent atoms to form C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 When aryl or 5-8 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl and 5-8 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy and C 1-3 one or more substitutions in the hydroxyalkyl group; Alternatively, one of R3 and one of R4 are connected to adjacent atoms to form C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 When aryl or 5-8 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6- 10 Aryl and 5-8 membered heteroaryl groups may be further optionally substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy and C 1-3 One or more substitutions in the hydroxyalkyl group.

11. The compound of formula (I) according to any one of claims 2 to 5, 9 or 10, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R6, R7, R8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1- 3 alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-6 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 One or more substitutions of aryl, 5-6 membered heteroaryl; Preferably, R6, R7, and R8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 Alkoxy; the C 1-3 Alkyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy or halogenated C 1-3 The alkoxy group may optionally be further substituted with hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio and C 1-3 One or more substitutions in the alkyl group.

12. The compound of general formula (I) according to claim 4, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: L1 is selected from -(CH2) n C(O)(CR aa R bb ) n1 -、-(CH2) n C(O)NR aa (CR aa R bb ) n1 -、-(CH2) n (CR aa R bb ) n2 -or-(CR aa R bb ) n O(CH2) n1 -; R aa and R bb Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, oxo, thio, C 1-3 Alkyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxy, oxo, thioxo, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or propoxy; R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, mercapto, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-6 membered heteroaryl containing 1-3 N, O or S atoms, the amino, C 1-3 alkyl Base, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1- 3 alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl groups may be further substituted with one or more of hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, mercapto, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methyl substituted with 1-3 fluorine, chlorine or bromine groups, ethyl substituted with 1-3 fluorine, chlorine or bromine groups, propyl substituted with 1-3 fluorine, chlorine or bromine groups, isopropyl substituted with 1-3 fluorine, chlorine or bromine groups, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups; Preferably, R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-10 Aryl or 5-6 membered heteroaryl containing 1-3 N, O or S atoms, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1- 3 alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl groups may be further substituted with one or more of hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methyl substituted with 1-3 fluorine, chlorine or bromine groups, ethyl substituted with 1-3 fluorine, chlorine or bromine groups, propyl substituted with 1-3 fluorine, chlorine or bromine groups, isopropyl substituted with 1-3 fluorine, chlorine or bromine groups, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups; More preferably, R1 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methyl containing 1-3 fluorine, chlorine or bromine substituted groups, ethyl containing 1-3 fluorine, chlorine or bromine substituted groups, propyl containing 1-3 fluorine, chlorine or bromine substituted groups, isopropyl containing 1-3 fluorine, chlorine or bromine substituted groups, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, The methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl ... Pentyl, cyclohexyl, phenyl, optionally further substituted with fluorine, chlorine, bromine, hydroxy, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy or propoxy; R2 is independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, C 1-3 Alkyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkoxy or C 1-3 Hydroxyalkyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, hydroxy, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, deuterated methoxy, deuterated ethoxy, deuterated propoxy, methyl substituted with 1-3 fluorine, chlorine or bromine, ethyl substituted with 1-3 fluorine, chlorine or bromine, propyl substituted with 1-3 fluorine, chlorine or bromine, isopropyl substituted with 1-3 fluorine, chlorine or bromine; R 31 、R 32 and R 33 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methyl-substituted amino, ethyl-substituted amino, propyl-substituted amino, hydroxy, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl substituted with 1-3 fluorine, chlorine or bromine, propyl substituted with 1-3 fluorine, chlorine or bromine, isopropyl substituted with 1-3 fluorine, chlorine or bromine, methoxy, ethoxy, propoxy, ethoxy substituted with 1-3 fluorine, chlorine or bromine, propoxy substituted with 1-3 fluorine, chlorine or bromine, isopropoxy substituted with 1-3 fluorine, chlorine or bromine, hydroxymethyl, hydroxyethyl, hydroxypropyl, -C 1-3 Alkyl-R c 、-NHR c or -C(O)R c Preferably, R 31 、R 32 and R 33 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, methyl-substituted amino, ethyl-substituted amino, propyl-substituted amino, hydroxy, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl substituted with 1-3 fluorine, chlorine or bromine, propyl substituted with 1-3 fluorine, chlorine or bromine, isopropyl substituted with 1-3 fluorine, chlorine or bromine, methoxy, ethoxy, propoxy, ethoxy substituted with 1-3 fluorine, chlorine or bromine, propoxy substituted with 1-3 fluorine, chlorine or bromine, isopropoxy substituted with 1-3 fluorine, chlorine or bromine, hydroxymethyl, hydroxyethyl, hydroxypropyl or -C(O)R c ; R c independently selected from hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-6 membered heteroaryl, the amino, C 1-3 Alkyl-substituted amino, hydroxy, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-6 membered heteroaryl are optionally substituted with hydrogen, deuterium, halogen, amino, C 1-3 Alkyl-substituted amino, hydroxy, cyano, nitro, oxo, thio Base, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl; preferably, R c independently selected from hydrogen, fluorine, chlorine, bromine, amino, methyl-substituted amino, ethyl-substituted amino, propyl-substituted amino, hydroxy, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl substituted with 1-3 fluorine, chlorine or bromine, propyl substituted with 1-3 fluorine, chlorine or bromine, isopropyl substituted with 1-3 fluorine, chlorine or bromine, methoxy, ethoxy, propoxy, ethoxy substituted with 1-3 fluorine, chlorine or bromine, propoxy substituted with 1-3 fluorine, chlorine or bromine, isopropoxy substituted with 1-3 fluorine, chlorine or bromine, hydroxymethyl, hydroxyethyl, hydroxypropyl, Preferably, R c independently selected from hydrogen, fluorine, chlorine, bromine, amino, methyl-substituted amino, ethyl-substituted amino, propyl-substituted amino, hydroxy, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl substituted with 1-3 fluorine, chlorine or bromine, propyl substituted with 1-3 fluorine, chlorine or bromine, isopropyl substituted with 1-3 fluorine, chlorine or bromine, methoxy, ethoxy, propoxy, ethoxy substituted with 1-3 fluorine, chlorine or bromine, propoxy substituted with 1-3 fluorine, chlorine or bromine, isopropoxy substituted with 1-3 fluorine, chlorine or bromine, hydroxymethyl, hydroxyethyl or hydroxypropyl; R4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl substituted with 1-3 fluorine, chlorine or bromine, propyl substituted with 1-3 fluorine, chlorine or bromine, isopropyl substituted with 1-3 fluorine, chlorine or bromine, methoxy, ethoxy, propoxy, ethoxy substituted with 1-3 fluorine, chlorine or bromine, propoxy substituted with 1-3 fluorine, chlorine or bromine, isopropoxy substituted with 1-3 fluorine, chlorine or bromine, hydroxymethyl, hydroxyethyl or hydroxypropyl; R6, R7, R8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1- 3 alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1- 3 alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, fluorine, chlorine, bromine, amino, methyl substituted amino, ethyl substituted amino, propyl substituted amino, hydroxy, cyano, nitro, oxo, thio, methyl, substituted with one or more of ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl substituted with 1-3 fluorine, chlorine or bromine, propyl substituted with 1-3 fluorine, chlorine or bromine, isopropyl substituted with 1-3 fluorine, chlorine or bromine, methoxy, ethoxy, propoxy, ethoxy substituted with 1-3 fluorine, chlorine or bromine, propoxy substituted with 1-3 fluorine, chlorine or bromine, isopropoxy substituted with 1-3 fluorine, chlorine or bromine, hydroxymethyl, hydroxyethyl, hydroxypropyl and 6-membered heterocyclic radicals; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, More preferably, hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, Preferably, R6, R7, and R8 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, deuterated C 1-3 Alkyl, halogenated C 1- 3 alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl may be further optionally substituted with hydrogen, deuterium, fluorine, chlorine, bromine, amino, methyl substituted amino, ethyl substituted amino, propyl substituted amino, hydroxy, cyano, nitro, oxo, thioxo, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl containing 1-3 fluorine, chlorine or bromine substituted ethyl, propyl containing 1-3 fluorine, chlorine or bromine substituted propyl, isopropyl containing 1-3 fluorine, chlorine or bromine substituted isopropyl One or more of propyl, methoxy, ethoxy, propoxy, ethoxy substituted with 1-3 fluorine, chlorine or bromine, propoxy substituted with 1-3 fluorine, chlorine or bromine, isopropoxy substituted with 1-3 fluorine, chlorine or bromine, hydroxymethyl, hydroxyethyl or hydroxypropyl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl or hydroxypropyl; u is 0, 1, 2, 3, 4, 5, or 6; v is 0, 1, 2, 3, 4, 5, or 6; w is 0, 1, 2, 3, 4, 5, or 6; x is 0, 1, 2, 3, 4, 5, or 6; z is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, or 3; n1 is 0, 1, 2 or 3; and n2 is 0, 1, 2 or 3.

13. The compound of general formula (I) according to claim 4 or 12, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: L1 is selected from -O-, -C(O)-, -C(O)NHCH2- or -C(O)NH-; R1 is selected from Preferably, R1 is selected from Preferably, R1 is selected from Preferably, R1 is selected from Preferably, R1 is selected from Preferably, L1 is selected from -O-, -C(O)NHCH2- or -C(O)NH-; R1 is selected from R2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methoxy, deuterated ethoxy, deuterated propoxy, cyano, ethoxy, difluoromethoxy; preferably, R2 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methoxy, deuterated ethoxy or deuterated propoxy; more preferably, fluorine, methoxy, -OCD3; R 31 is hydrogen, deuterium, methyl, ethyl, propyl; R 32 is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, cyano, -COCH2CH3, -COCH3, vinyl, cyclopropyl, Isopropyl, or -CD3; preferably, R 32 is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, cyano, -COCH2CH3, -COCH3, vinyl, cyclopropyl, More preferably, R 32 is hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl, methoxy, -COCH2CH3, -COCH3, vinyl, cyclopropyl, More preferably, R 32 is hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl, methoxy, vinyl or cyclopropyl; R 33 is -C(O)NH2; R4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, cyano, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, propyl, methoxy or cyclopropyl; preferably, R4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, cyano, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, propyl or methoxy; more preferably, R4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, propyl or methoxy; further preferably, R4 is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl or methoxy; R6, R7, R8 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH2OH, -CH2OCH3, -CF3, -CH2N(CH3)2, Preferably, R6, R7, R8 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH2OH, -CH2OCH3, -CF3, -CH2N(CH3)2, Preferably, R6, R7 and R8 are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl or cyano; preferably, R6 is independently selected from hydrogen, fluorine, methyl, -CH2OH, -CH2OCH3, -CF3; R7 is independently selected from hydrogen; R8 is independently selected from hydrogen, -CH2N(CH3)2 or R9 is methyl.

14. The compound according to any one of claims 1 to 13, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compounds are as follows:

15. A compound represented by formula (V) or a stereoisomer thereof, or a compound represented by formula (VII) or a stereoisomer thereof: in, R1, L1, R2, x, R 31 、R 32 、R 33 , R4, z are the same as those described in any one of claims 4, 5, 7, 9-14.

16. A method for preparing the compound represented by formula (III) according to claim 4, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The method comprises the following steps: reacting a compound represented by formula (V) with a compound represented by formula (VI) under the action of a condensing agent, Among them, R1, L1, R2, x, R 31 、R 32 、R 33 , R4, z, R6, R7, and R8 are the same as those described in any one of claims 4, 5, 7, 9-14.

17. A method for preparing the compound of formula (IV) according to claim 5, its stereoisomers or pharmaceutically acceptable salts thereof, characterized in that: The method comprises the following steps: reacting a compound represented by formula (VII) with a compound represented by formula (VI) under the action of a condensing agent, Among them, R1, R2, x, R 32 , R4, z, R6, R7, and R8 are the same as those described in any one of claims 5, 7, 9-14.

18. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 14, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

19. Use of the compound according to any one of claims 1 to 14, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18 in the preparation of a medicament for treating and / or preventing diseases associated with FGFR inhibitors, in particular in the preparation of a medicament for treating and / or preventing diseases associated with FGFR1-4 inhibitors.

20. Use of the compound according to any one of claims 1 to 14, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18 in the preparation of a medicament for treating and / or preventing cancer or achondroplasia-related diseases; preferably, the cancer is selected from colorectal cancer, bladder cancer, gastric cancer, thyroid cancer, esophageal cancer, head and neck cancer, brain cancer, glioma, glioblastoma, hepatocellular carcinoma, lung cancer, melanoma, myeloma, pancreatic cancer, renal cell carcinoma, cervical cancer, urothelial carcinoma, prostate cancer, ovarian cancer, breast cancer, leukemia or lymphoma.