TW202404957A - Heterocyclic derivative inhibitor, preparation method therefor and application thereof - Google Patents

Abstract

The present invention relates to a heterocyclic derivative inhibitor, a preparation method therefor and an application thereof. In particular, the present invention relates to a compound showed by the general formula (I), the preparation method therefor and the pharmaceutical composition containing the compound, and the use thereof as an inhibitor in the manufacture of a medicine for the treatment and/or prevention of cancer and achondroplasia-related diseases.

Description

Heterocyclic derivative inhibitors, preparation methods and applications thereof

The invention belongs to the field of biomedicine, and specifically relates to a heterocyclic derivative inhibitor and its preparation method and application.

FGFR (Fibroblast Growth Factor Receptor), a tyrosine kinase, includes four subtypes: FGFR1, FGFR2, FGFR3, and FGFR4. When FGFR binds to ligand, FGFR dimerizes and autophosphorylates, thereby activating downstream signaling pathways: RAS-RAF-MAPK, PI3K-AKT, STAT and PLCγ. FGFR-mediated signal transduction plays an important role in cell proliferation, migration, differentiation and survival.

Excessive activation caused by multiple mutations of FGFR is widely present in various tumors, and inhibiting FGFR is a potential target for the treatment of various cancers. In a study published in Clinical Cancer Research ( Clin Cancer Res; 22(1) January 1, 2016 ) in 2015, sequencing of 4853 solid tumors of various types showed that approximately 7.1% of cancers had 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 cholangiocarcinomas, 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.

FGFR inhibitors have good application prospects as drugs in the pharmaceutical industry. They are expected to become first-line therapy for cholangiocarcinoma and a new option for targeted cancer treatment regardless of cancer types. They are expected to be used for cancer patients with multiple FGFR aberrations. However, the current standard treatment for cholangiocarcinoma is chemotherapy, which has a poor prognosis and no second-line therapy. The current main problem with FGFR inhibitors is that patients develop drug resistance about 7 months after taking the drugs. In addition, drugs related to FGFR1 targets have hyperphosphatemia. Symptom toxicity.

There are currently two pan-FGFR inhibitors on the market globally. In April 2019, Johnson & Johnson's Balversa (erdafitinib, JNJ-42756493) was approved for patients with locally metastatic or metastatic bladder cancer with FGFR3 or FGFR2 point mutations. In April 2020, Incyte's Pemazyre (pemigatinib, INCB054828) was approved for patients with previously treated advanced cholangiocarcinoma with FGFR2 gene fusion or rearrangement.

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 object of the present invention is to provide novel compounds having FGFR inhibitory activity and useful as anticancer agents.

The object of the present invention is to provide a compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structure of the compound represented by general formula (I) is as follows:

in,

Ring A is a monocyclic heteroaryl group;

M ₁ is N or CR _m1 ;

M ₂ is N or CR _m2 ;

L ₁ , L ₂ and L ₃ are each independently selected from bond, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -(CH ₂ ) _n C(O) (CR _aa R _bb ) _n1 -, -(CH ₂ ) _n C(O)NR _aa (CR _aa R _bb ) _n1 -, -(CH ₂ ) _n (CR _aa R _bb ) _n2 -, -(CR _aa R _bb ) _n O(CH ₂ ) _n1 -, -(CH ₂ ) _n S(CR _aa R _bb ) _n3 -, -(CR _aa R _bb ) _n3 (CH ₂ ) _n NR _cc -, -(CH ₂ ) _n NR _aa (CR _bb R _cc ) _n -, -(CH ₂ ) _n NR _aa C(O)-, -(CH ₂ ) _n P(O) _p R _aa -, -(CH ₂ ) _n S(O) _m -, -(CH ₂ ) _n S(O) _m NR _aa -, -C(=NR _aa )NR _aa -, -C(=CR _bb R _cc )-, -C(=S)NR _aa -and -(CH ₂ ) _n NR _aa S(O) _m -;

R ₁ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, side oxy, 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 ) ₂ R _a , the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and the heteroaryl group may be further substituted if desired;

R ₂ is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxygen, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy group, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR _b , -C(O)R _b , -SR _b , S(O)R _b or S (O) ₂ R _b , the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkyloxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, Aryl and heteroaryl groups may optionally be further substituted;

R ₃ is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxygen, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy group, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR _c , -C(O)R _c , -SR _c , S(O)R _c or S (O) ₂ R _c , the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkyloxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, Aryl and heteroaryl groups may optionally be further substituted;

R ₄ is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxygen, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy base, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR _d , -C(O)R _d , -SR _d , S(O)R _d or S (O) ₂ R _d , the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkyloxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, Aryl and heteroaryl groups may optionally be further substituted;

R ₅ is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxygen, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy group, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR _e , -C(O)R _e , -SR _e , S(O)R _e or S (O) ₂ R _e , the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkyloxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, Aryl and heteroaryl groups may optionally be further substituted;

R _m1 is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, side oxy, 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 ) ₂ R _f , the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and the heteroaryl group may be further substituted if desired;

R _m2 is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, side oxy, 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 ) ₂ R _g , the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and the heteroaryl group may be further substituted if desired;

Alternatively, one of R ₂ and one of R ₃ are connected to adjacent atoms to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, and the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optional Land can be further displaced;

Alternatively, one of R ₃ and one of R ₄ are connected to adjacent atoms to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, and the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optional Land can be further displaced;

R _a , R _b , R _c , R _d , Re , _{R f} and R _g are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl , pendant oxygen group, thio group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, the amino group, alkyl group base, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and The heteroaryl group may be further substituted if desired;

R _aa , R _bb and R _cc are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy group, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy A group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group may be further substituted as necessary;

Alternatively, R _aa and R _bb form a cycloalkyl, heterocyclyl, aryl or heteroaryl group with adjacent atoms, and the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted if necessary. ;

Alternatively, R _bb and R _cc form a cycloalkyl, heterocyclyl, aryl or heteroaryl group with adjacent atoms, and the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted if necessary. ;

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.

In certain embodiments of the invention, the compound is represented by Formula (II), Formula (II-1), Formula (II-2) or Formula (II-3),

in,

Ring A is a heteroaryl group, and the heteroaryl group is a monocyclic heteroaryl group or a polycyclic heteroaryl group;

L ₁ is selected from -(CH ₂ ) _n C(O)(CR _aa R _bb ) _n1 -, -(CH ₂ ) _n C(O)NR _aa (CR _aa R _bb ) _n1 -, -(CH ₂ ) _n (CR _aa R _bb ) _n2 -or-(CR _aa R _bb ) _n O(CH ₂ ) _n1 -;

R _aa and R _bb are each independently selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-6 alkyl group, C _2-6 alkenyl group, C _{2- 6} alkynyl, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, _{halo C 1-6 alkoxy, C 1-6 hydroxyalkyl ,} C _3-8 Cycloalkyl, 3-12-membered heterocyclyl, C _6-14- membered aryl or 5-14-membered heteroaryl;

R ₁ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, mercapto, cyano, nitro, side oxy, thio, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl _, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl , 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterium Substitute C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, _halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3 -12-membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group, optionally further substituted by hydrogen, deuterium, halogen, amino group, hydroxyl group, mercapto group, cyano group, nitro group, side oxygen group , thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 hydroxyalkyl group, One or more substitutions among C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, and 5-6 membered heteroaryl;

Preferably, R ₁ is selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 Alkynyl _, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 ring Alkyl, 3-12-membered heterocyclyl, C _6-14 aryl or 5-14-membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl _, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl , 3-12-membered heterocyclic group, C _6-14- membered aryl group, 5-14-membered heteroaryl group, optionally can be further substituted by hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, side oxygen group, Thio group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 hydroxyalkyl, C One or more substitutions among _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, and 5-6 membered heteroaryl;

R ₂ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, deuterated C _1-6 alkyl, halo C 1-6 alkyl _, C _1-6 alkoxy, halo C _1-6 alkoxy, deuterated C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

R ₃ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, side oxy, 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, halo C _1-6 alkyl, C _1-6 alkyl Oxygen, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, 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) ₂ R _c ; preferably , R ₃ is independently selected from hydrogen, deuterium, halogen, amine group, C _1-6 alkyl substituted amine group, hydroxyl, cyano group, nitro group, side oxy group, thio group, C _1-6 alkyl group, C _3-8 cycloalkyl substituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 Alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl Base, -OR _c , -C(O)R _c , -SR _c , S(O)R _c or S(O) ₂ R _c ;

R _c is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 Hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, the amino group, hydroxyl group, C _1-6 alkyl substituted amine Base, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl are optionally hydrogenated , deuterium, halogen, amino group, C _1-6 alkyl substituted amino group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-6 alkyl group, C _2-6 alkenyl group, C _{2 -6} alkynyl, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, _{C 3-} One or more substitutions in _8- cycloalkyl, 3-12-membered heterocyclyl, C _6-14- membered aryl or 5-14-membered heteroaryl;

Preferably, R _c is independently selected from hydrogen, deuterium, halogen, amine group, C _1-6 alkyl substituted amine group, hydroxyl, cyano group, nitro group, side oxy group, thio group, C _1-6 alkyl group Base, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

R ₄ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, _{C 3- 8-} cycloalkyl, 3-12-membered heterocyclyl, C _6-14- membered aryl or 5-14-membered heteroaryl;

R ₆ , R ₇ and R ₈ are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl _, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl , 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterium Substitute C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, _halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3 -12-membered heterocyclic group, C _6-14 aryl group, 5-14-membered heteroaryl group, optionally optionally further substituted by hydrogen, deuterium, halogen, amino group, C _1-3 alkyl group, hydroxyl group, cyano group Base, nitro, side oxygen group, thio group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, One or more substitutions among C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, and 5-6 membered heteroaryl;

Alternatively, one of R ₂ and one of R ₃ are connected to adjacent atoms to form a C _3-8 cycloalkyl group, a 3-12 membered heterocyclyl group, a C _6-14 membered aryl group or a 5-14 membered heteroaryl group, which C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl may be further optionally replaced by hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, Nitro group, side oxygen group, thio group, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, deuterated C _1-6 alkyl group, halo C _1-6 alkyl group, C _{1 -6} alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered One or more substitutions in the heteroaryl group;

Or, one of R ₃ and one of R ₄ are connected to adjacent atoms to form a C _3-8 cycloalkyl group, a 3-12 membered heterocyclyl group, a C _6-14 aryl group or a 5-14 membered heteroaryl group, which C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl may be further optionally replaced by hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, Nitro group, side oxygen group, thio group, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, deuterated C _1-6 alkyl group, halo C _1-6 alkyl group, C _{1 -6} alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered One or more substitutions in the heteroaryl group;

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.

In certain embodiments of the invention,

Ring A is selected from monocyclic heteroaryl or polycyclic heteroaryl;

The monocyclic heteroaryl group is preferably a 5-12-membered heteroaryl group; more preferably a 5-membered or 6-membered heteroaryl group; further preferably, it is selected from a 5-membered or 6-membered heteroaryl group containing 1-3 N, O or S atoms. base;

、

、

、

、

、

、

或

； The preferred monocyclic heteroaryl group is

,

,

,

,

,

,

or

;

、

、

、

、

、

、

或

。 The monocyclic heteroaryl group is more preferably the following group:

,

,

,

,

,

,

or

.

In certain embodiments of the invention, the compound is such as 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)

； Ring B is independently a 5-10-membered heterocyclyl group, preferably a nitrogen-containing 5-10-membered heterocyclyl group, more preferably a 5-7-membered heterocyclyl group containing one nitrogen atom, and further preferably

;

； 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

;

L ₁ is selected from -(CH ₂ ) _n C(O)(CR _aa R _bb ) _n1 -, -(CH ₂ ) _n C(O)NR _aa (CR _aa R _bb ) _n1 -, -(CH ₂ ) _n (CR _aa R _bb ) _n2 -or-(CR _aa R _bb ) _n O(CH ₂ ) _n1 -;

L ₄ is selected from -(CH ₂ ) _n C(O)(CR _aa R _bb ) _n1 -, -(CH ₂ ) _n C(O)NR _aa (CR _aa R _bb ) _n1 -, -(CH ₂ ) _n (CR _aa R _bb ) _n2 - or -(CR _aa R _bb ) _n O(CH ₂ ) _n1 -, preferably -C(O)-;

R _aa and R _bb are each independently selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _{2- 4} alkynyl, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, _{halo C 1-3 alkoxy} , C _1-6 hydroxyalkyl;

R ₁ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, mercapto, cyano, nitro, side oxy, thio, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , Deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, _{C 1-3 hydroxyalkyl} , C _3-6 cycloalkyl , 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl, the amino group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterium Substitute C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, _halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3 -8-membered heterocyclic group, C _6-10 aryl group, 5-6 membered heteroaryl group can be further optionally substituted by hydrogen, deuterium, halogen, amino group, hydroxyl group, mercapto group, cyano group, nitro group, side oxygen group, Thio group, 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-, halo C _1-3 alkyl, halo C _2-4 alkenyl, C _{1-3 alkoxy, halo C 1-3 alkoxy} , C _1-3 hydroxyalkyl, C _3-6 ring One or more substitutions among alkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl;

Preferably, R ₁ is selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, mercapto group, cyano group, nitro group, side oxy group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _{2 -4} alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _{3- 6-} cycloalkyl, 3-8-membered heterocyclyl, C _6-10 aryl or 5-6-membered heteroaryl, the amino group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 Alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 ring Alkyl group, 3-8 membered heterocyclic group, C _6-10 aryl group, 5-6 membered heteroaryl group can be further optionally replaced by hydrogen, deuterium, halogen, amino group, hydroxyl group, mercapto group, cyano group, nitro group, Side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 alkyl group Oxygen group, halo C _1-3 alkoxy group, C _1-3 hydroxyalkyl group, C _3-6 cycloalkyl group, 3-8 membered heterocyclyl group, C _6-10 aryl group, 5-6 membered heteroaryl group one or more substitutions in;

More preferably, R ₁ is selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 Alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 ring Alkyl group, 3-8 membered heterocyclyl group, C _6-10 aryl group or 5-6 membered heteroaryl group, the amino group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group , Deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, _{C 1-3 hydroxyalkyl} , C _3-6 cycloalkyl , 3-8 membered heterocyclic group, C _6-10 aryl group, 5-6 membered heteroaryl group can be further optionally replaced by hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, side oxygen group, Thio group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo One of C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl, or multiple substitutions;

R ₂ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, deuterated C _1-6 alkyl, halo C 1-6 alkyl _, C _1-6 alkoxy, halo C _1-6 alkoxy, deuterated C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

R ₃₁ , R ₃₂ and R ₃₃ are each independently selected from hydrogen, deuterium, halogen, amine group, C _1-6 alkyl substituted amine group, hydroxyl group, cyano group, nitro group, pendant oxy group, thio group, 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, halo C _1-6 alkyl base, C _1-6 alkoxy group, halo C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _3-8 cycloalkyl group, 3-12 membered heterocyclyl group, C _6-14 aryl group, 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) ₂ R _c ; Preferably, R ₃₁ , R ₃₂ and R ₃₃ are each independently selected from hydrogen, deuterium, halogen, amino group, C _1-3 alkyl substituted amino group, hydroxyl, cyano group, nitro group, side Oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 alkoxy group base, halo C _1-3 alkoxy group, C _1-3 hydroxyalkyl group, -C _1-3 alkyl group -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 group, C _1-6 alkyl substituted amino group, hydroxyl, cyano group, nitro group, pendant oxygen group, sulfur group Base, 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, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _{6- 14} aryl, 5-14 membered heteroaryl, -OR _c , -C(O)R _c , -SR _c , S(O)R _c or S(O) ₂ R _c ; preferably, R ₃₁ , R ₃₂ and R ₃₃ are each independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, side oxy, thio, C _1-3 alkyl base, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl or -C(O)R _c ;

R _c is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 Hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

R ₄ , R ₁₀ , R ₁₁ and R ₁₂ are each independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, _{halo C 1-6 alkoxy, C 1-6 hydroxyalkyl ,} C _3-8 Cycloalkyl, 3-12-membered heterocyclyl, C _6-14 aryl or 5-14-membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkyne base _, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl A group, a 3-12-membered heterocyclic group, a C _6-14 aryl group, a 5-14-membered heteroaryl group, an amino group that may be further substituted by hydrogen, deuterium, halogen, amino group, C _1-3 alkyl group, Hydroxy, cyano, nitro, side oxy, thio, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 One or more substitutions among alkyl, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl;

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.

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

in,

R ₁ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, mercapto, cyano, nitro, side oxy, thio, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl _, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl , 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterium Substitute C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, _halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3 -12-membered heterocyclic group, C _6-14 aryl group, 5-15 membered heteroaryl group can be further optionally replaced by hydrogen, deuterium, halogen, amino group, hydroxyl group, mercapto group, cyano group, nitro group, side oxygen group, Thio group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo One of C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl, or multiple substitutions;

R ₂ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, deuterated C _1-6 alkyl, halo C 1-6 alkyl _, C _1-6 alkoxy, halo C _1-6 alkoxy, deuterated C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

R ₃₂ is selected from hydrogen, deuterium, halogen, amine group, C _1-6 alkyl substituted amine group, hydroxyl, cyano group, nitro group, side oxy group, thio group, C _1-6 alkyl group, C _3-8 Cycloalkyl-substituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy , Halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, 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) ₂ R _c ;

R _c is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 Hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl;

R ₄ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, _{C 3- 8-} cycloalkyl, 3-12-membered heterocyclyl, C _6-14- membered aryl or 5-14-membered heteroaryl;

R ₆ , R ₇ , R ₈ are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl _, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl , 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterium Substitute C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, _halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3 -12-membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group, optionally optionally further substituted by hydrogen, deuterium, halogen, amino group, C _1-3 alkyl group, hydroxyl group, cyanide group group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, One or more substitutions among C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, and 5-6 membered heteroaryl;

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

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

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

In certain embodiments of the invention, _R1 is selected from hydrogen, deuterium, halogen, amine, hydroxyl, thiol, cyano, nitro, pendant oxy, thio, C _1-3 alkyl, C _{2- 4} alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyl Alkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, the amino group, C _1-3 alkyl, C _2-4 alkene base, C _2-4 alkynyl _, deuterated C _{1-3 alkyl, halo C 1-3} alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl , C _3-6 cycloalkyl, 3-8 membered heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group can be further optionally replaced by hydrogen, deuterium, halogen, amino group, hydroxyl group, mercapto group, Cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group , C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5 - One or more substitutions in the 6-membered heteroaryl group;

R ₂ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl _{, C 1-3 alkoxy, halo C 1-3 alkoxy, deuterated C 1-3 alkoxy , C 1-3} hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl;

R ₃₂ is selected from hydrogen, deuterium, halogen, amine group, C _1-3 alkyl substituted amine group, hydroxyl, cyano group, nitro group, side oxy group, thio group, C _1-3 alkyl group, C _3-6 Cycloalkyl-substituted C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy , Halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, 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) ₂ R _c ;

R _c is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-3 alkyl, C _{2 -4} alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 Hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl;

R ₄ is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _{3- 6-} cycloalkyl, 3-8-membered heterocyclyl, C _6-10- membered aryl or 5-10-membered heteroaryl;

R ₆ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl , Halo C _1-3 alkyl, C _1-3 alkoxy, Halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; the amino group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _{6 -10} aryl group, 5-10 membered heteroaryl group, optionally further substituted by hydrogen, deuterium, halogen, amino group, C _1-3 alkyl group, hydroxyl group, cyano group, nitro group, side oxygen group, Thio group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 hydroxyalkyl, C One or more substitutions of _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl.

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

in,

R ₁₁ is selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, mercapto group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group , Deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, _{C 1-3 hydroxyalkyl} , C _3-6 cycloalkyl Or 3-8 membered heterocyclyl;

R ₂ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl, deuterated C _1-3 alkyl, halo C 1-3 alkyl _, C _1-3 alkoxy, halo C _1-3 alkoxy, deuterated C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl or 3-8 membered heterocyclyl;

R ₃₂ is selected from hydrogen, deuterium, halogen, amine group, C _1-3 alkyl substituted amine group, hydroxyl, cyano group, nitro group, side oxy group, thio group, C _1-3 alkyl group, C _3-6 Cycloalkyl-substituted C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy , halogen C _1-3 alkoxy group, C _1-3 hydroxyalkyl group, C _3-6 cycloalkyl group or 3-8 membered heterocyclyl group;

R ₄ is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _{3- 6-} cycloalkyl or 3-8-membered heterocyclyl;

R ₆ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl , halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl or 3-8 membered heterocyclyl;

q is 1, 2, 3 or 4.

In certain embodiments of the invention, _R1 is selected from hydrogen, deuterium, halogen, amine, hydroxyl, thiol, cyano, nitro, pendant oxy, thio, C _1-3 alkyl, C _{2- 4} alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyl Alkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl, the amino group, C _1-3 alkyl, C _2-4 alkene base, C _2-4 alkynyl _, deuterated C _{1-3 alkyl, halo C 1-3} alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl , C _3-6 cycloalkyl, 3-8 membered heterocyclic group, C _6-10 aryl group, 5-6 membered heteroaryl group can be further optionally replaced by hydrogen, deuterium, halogen, amino group, hydroxyl group, mercapto group, Cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group , C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5 - One or more substitutions in the 6-membered heteroaryl group.

In certain embodiments of the invention, _R1 is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-3 alkyl, C _2-4 alkene base, C _2-4 alkynyl, deuterated C _{1-3 alkyl, halo C 1-3} alkyl, C _1-3 alkoxy, halo _{C 1-3 alkoxy} , C _1-3 hydroxyalkyl , C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl, the amino group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C 1-3 alkyl _, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _{A 3-6} cycloalkyl group, a 3-8 membered heterocyclyl group, a C _6-10 aryl group, and a 5-6 membered heteroaryl group may be further substituted by hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, or nitrogen group if necessary. group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _{1- 3} alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered hetero One or more substitutions in the aryl group.

In certain embodiments of the invention, R ₁ 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 heterocyclyl, 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 heterocyclyl, C _6-10 aryl and 5-6 membered heteroaryl may be further substituted by hydrogen, deuterium, halogen, amino group, hydroxyl group if necessary. , cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group Substituted with one or more of C _1-3 alkoxy group, halo C _1-3 alkoxy group and C _1-3 hydroxyalkyl group.

In certain embodiments of the invention, R ₁ is selected from C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl, the C _3-6 Cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-6 membered heteroaryl may be further optionally flanked by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, Oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 alkoxy group Substituted with one or more of halogen C _1-3 alkoxy group and C _1-3 hydroxyalkyl group.

、

、

、

、

In certain embodiments of the invention, _R1 is selected from

,

,

,

,

、

、

、

、

In certain embodiments of the invention, _R1 is selected from

,

,

,

,

或環丁基，該

或環丁基視需要地可以進一步被氫或甲基取代。在本發明的某些實施方案中，L₁為-O-、-C(O)NHCH₂-或-C(O)NH-。 In certain embodiments of the invention, _R1 is selected from

or cyclobutyl, the

Or the cyclobutyl group may be further substituted by hydrogen or methyl if necessary. In certain embodiments of the invention, L ₁ is -O-, -C(O)NHCH ₂ -, or -C(O)NH-.

In certain embodiments of the invention, L ₁ is -O- or -C(O)NHCH ₂ -.

In certain embodiments of the invention, _R2 is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl , C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl.

In certain embodiments of the invention, _R2 is independently selected from hydrogen, fluorine, methoxy, or deuterated methoxy.

In certain embodiments of the invention, _R2 is independently selected from hydrogen, fluorine, or methoxy.

In certain embodiments of the invention, _L2 is a bond.

In certain embodiments of the invention, R ₃ is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, pendant oxy, 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, halo C _{1 -3} alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 Aryl group, 5-6 membered heteroaryl group, -OR _c , -C(O)R _c , -SR _c , S(O)R _c or S(O) ₂ R _c .

In certain embodiments of the invention, _Rc is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl , C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl.

。 In certain embodiments of the invention, _R3 is independently selected from hydrogen, methyl, -C(O) _NH2 , ethyl, vinyl, ethynyl, cyclopropyl, trifluoromethyl, methoxy , amine group, side oxygen group, cyclopropyl-methyl-, -NHCH ₃ , -NH-tert-butyl or

.

。 In certain embodiments of the invention, R ₃ is independently selected from methyl, -C(O)NH ₂ , ethyl, ethynyl, cyclopropyl, trifluoromethyl, methoxy, amine, pendant Oxy, cyclopropyl-methyl-, -NHCH ₃ or

.

In certain embodiments of the invention, R ₄ is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl , C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl.

In certain embodiments of the invention, _R4 is independently selected from hydrogen, fluoro, methyl, or methoxy.

In certain embodiments of the invention, _R4 is independently selected from hydrogen, fluorine, and methyl.

In certain embodiments of the invention, R ₁₀ is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl , C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl.

In certain embodiments of the invention, R ₁₁ is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl , C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl.

In certain embodiments of the invention, R ₁₂ is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl , C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl.

In certain embodiments of the invention, _L3 is a bond.

In certain embodiments of the invention, one of R ₂ and one of R ₃ are connected to adjacent atoms to form a C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5 -8-membered heteroaryl, the C _3-8 cycloalkyl, 3-8-membered heterocyclyl, C _6-10 aryl and 5-8-membered heteroaryl may be further substituted by hydrogen, deuterium, halogen if necessary. , amino group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo Substitution with one or more of C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy and C _1-3 hydroxyalkyl.

In certain embodiments of the invention, one of R ₃ and one of R ₄ are connected to adjacent atoms to form a C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5 -8-membered heteroaryl, the C _3-8 cycloalkyl, 3-8-membered heterocyclyl, C _6-10 aryl and 5-8-membered heteroaryl may be further substituted by hydrogen, deuterium, halogen if necessary. , amino group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo Substitution with one or more of C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy and C _1-3 hydroxyalkyl.

或

。 In certain embodiments of the invention, one of R ₃ and one of R ₄ are connected to adjacent atoms to form

or

.

In certain embodiments of the invention, R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _{1 -3} hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl; the amino group, C _1-3 alkyl, C _{2 -4} alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 Hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl may be further substituted by hydrogen, deuterium, halogen, amine group, C _1-3 alkyl substituted amino group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _{1 -3} alkyl, halo C _1-3 alkyl, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl One or more substitutions in the base.

In certain embodiments of the invention, R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-3 alkyl, Deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy or halo C _1-3 alkoxy; the C _1-3 alkyl, deuterated C _1-3 alkyl , halo C _1-3 alkyl group, C _1-3 alkoxy group or halo C _1-3 alkoxy group, optionally optionally an amino group substituted by hydrogen, deuterium, halogen, amino group, C _1-3 alkyl group , hydroxyl, cyano, nitro, side oxy, thio and C _1-3 alkyl, one or more substitutions.

In certain embodiments of the invention, R ₃ is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocycle group, C _6-14 aryl group, 5-14 membered heteroaryl group, -OR _c , -C(O)R c , -SR _c , S(O) _{R c or} S(O) ₂ R _c , the amine Base, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{3 -8} cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group can be further substituted by hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group as needed , side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 One or more substitutions among hydroxyalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl; Preferably, R ₃ is independently selected from hydrogen, deuterium, halogen, amine group, C _1-3 alkyl substituted amine group, hydroxyl, cyano group, nitro group, side oxy group, thio group, C _1-3 alkyl group base, C _3-6 cycloalkyl substituted C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 hydroxyalkyl group, 3-8 membered heterocyclyl group, -OR _c or -C(O)R _c .

In certain embodiments of the invention, R ₃₁ is hydrogen, deuterium, C _1-3 alkyl.

In certain embodiments of the invention, R ₃₂ is C _1-3 alkyl, C _2-4 alkenyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy base, halo C _1-3 alkoxy group, C _1-3 hydroxyalkyl group.

In certain embodiments of the invention, R ₃₃ is -C(O)R _c .

In certain embodiments of the invention, _Rc is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocycle group, C _6-14 aryl or 5-14 membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl , halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl as needed Can be further substituted by hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated group C _1-3 alkyl, halo C _1-3 alkyl, C 1-3 hydroxyalkyl, C _1-3 alkoxy, halo _{C 1-3 alkoxy} , C _3-6 cycloalkyl, 3- One or more substitutions among 8-membered heterocyclyl, C _6-10 aryl, and 5-6-membered heteroaryl.

In certain embodiments of the invention, one of R ₃ and one of R ₄ are connected to adjacent atoms to form a C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5 -14-membered heteroaryl group, the C _3-8- membered cycloalkyl group, 3-12-membered heterocyclyl group, C _6-14- membered aryl group and 5-14-membered heteroaryl group can be further substituted by hydrogen, deuterium, halogen, Amino group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl _, C _1-3 hydroxyalkyl, C 1-3 alkoxy, halo C _1-3 alkoxy, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6- One or more of ₁₀ aryl groups and 5-6 membered heteroaryl groups are substituted.

In certain embodiments of the invention, _R1 is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocycle group, C _6-14 aryl group, 5-14 membered heteroaryl group, -OR _a , -C(O)R _a , -SR _a , S(O)R _a or S(O) ₂ R _a , the amine Base, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{3 -8} cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group can be further substituted by hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group as needed , side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 One or more substitutions among hydroxyalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl; Preferably, R ₁ is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 hydroxyalkyl, -OR _a or -C(O)R _a .

In certain embodiments of the invention, R _a is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocycle group, C _6-14 aryl or 5-14 membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl , halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl as needed Can be further substituted by hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated group C _1-3 alkyl, halo C _1-3 alkyl, C 1-3 hydroxyalkyl, C _1-3 alkoxy, halo _{C 1-3 alkoxy} , C _3-6 cycloalkyl, 3- One or more substitutions among 8-membered heterocyclyl, C _6-10 aryl, and 5-6-membered heteroaryl.

In certain embodiments of the invention, Ring B is C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; preferably, Ring B It is C _3-6 cycloalkyl or 5-6 membered heteroaryl.

或環丁基。 In certain embodiments of the invention, Ring B is

Or cyclobutyl.

In certain embodiments of the invention, R ₈ is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocycle base, C _6-14 aryl group, 5-14 membered heteroaryl group, -OR _h , -C(O)R _h , -SR _h , S(O)R _h or S(O) ₂ R _h , the amine Base, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{3 -8} cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group can be further substituted by hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group as needed , side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 One or more substitutions among hydroxyalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl; Preferably, R ₈ is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 hydroxyalkyl, -OR _h or -C(O)R _h .

In certain embodiments of the invention, _Rh is independently selected from hydrogen, deuterium, halogen, amine, hydroxy, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocycle group, C _6-14 aryl or 5-14 membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl , halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl as needed Can be further substituted by hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated group C _1-3 alkyl, halo C _1-3 alkyl, C 1-3 hydroxyalkyl, C _1-3 alkoxy, halo _{C 1-3 alkoxy} , C _3-6 cycloalkyl, 3- One or more substitutions among 8-membered heterocyclyl, C _6-10 aryl, and 5-6-membered heteroaryl.

In certain embodiments of the invention, _R8 is independently hydrogen or methyl.

In certain embodiments of the invention, L ₁ is selected from the group consisting of bonds, -(CH ₂ ) _n C(O)(CR _aa R _bb ) _n1 -, -(CH ₂ ) _n C(O)NR _aa (CR _aa R _bb ) _n1 -, -(CH ₂ ) _n (CR _aa R _bb ) _n2 -, -(CR _aa R _bb ) _n O(CH ₂ ) _n1 -, -(CH ₂ ) _n O(CR _aa R _bb ) _n1 -, -(CR _aa R _bb ) _n3 (CH ₂ ) _n NR _cc -, -(CH ₂ ) _n NR _aa (CR _bb R _cc ) _n -, -(CH ₂ ) _n NR _aa C(O)- .

In certain embodiments of the invention, R _aa , R _bb and R _cc are each independently selected from hydrogen, deuterium, halogen, amine, hydroxy, cyano, nitro, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyl Alkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, the amino group, C _1-6 alkyl, C _2-6 alkene Base, C _2-6 alkynyl group, deuterated C _1-6 alkyl group, halo C 1-6 alkyl group, C _1-6 alkoxy group, halo _{C 1-6 alkoxy} group, C _1-6 hydroxyalkyl group , C _3-8 cycloalkyl, 3-12-membered heterocyclyl, C _6-14 -membered aryl and 5-14-membered heteroaryl may be further substituted by hydrogen, deuterium, halogen, amine, hydroxyl or cyano as needed. , nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 hydroxyalkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 One or more substitutions in the heteroaryl group.

In certain embodiments of the invention, L ₁ is -O- or -C(O)NHCH ₂ -.

In certain embodiments of the invention, _R2 is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocycle base, C _6-14 aryl group, 5-14 membered heteroaryl group, -OR _b , -C(O)R b , -SR _b , S(O)R _{b or} S(O) ₂ R _b , the amine Base, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{3 -8} cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group can be further substituted by hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group as needed , side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 One or more substitutions among hydroxyalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl; Preferably, R ₂ is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 hydroxyalkyl, -OR _b or -C(O)R _b .

In certain embodiments of the invention, R _b is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocycle group, C _6-14 aryl or 5-14 membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl , halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl as needed Can be further substituted by hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated group C _1-3 alkyl, halo C _1-3 alkyl, C 1-3 hydroxyalkyl, C _1-3 alkoxy, halo _{C 1-3 alkoxy} , C _3-6 cycloalkyl, 3- One or more substitutions among 8-membered heterocyclyl, C _6-10 aryl, and 5-6-membered heteroaryl.

In certain embodiments of the invention, _R2 is independently hydrogen, fluoro, or methoxy.

In certain embodiments of the invention, _R2 is independently hydrogen, fluoro, methoxy, or deuterated methoxy.

In certain embodiments of the invention, _R6 is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocycle group, C _6-14 aryl group, 5-14 membered heteroaryl group, -OR _f , -C(O)R _f , -SR _f , S(O)R _f or S(O) ₂ R _f , the amine Base, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{3 -8} cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group can be further substituted by hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group as needed , side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 One or more substitutions among hydroxyalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl; Preferably, R ₆ is independently selected from hydrogen, deuterium, halogen, amine group, C _1-3 alkyl substituted amine group, hydroxyl, cyano group, nitro group, side oxy group, thio group, C _1-3 alkyl group base, C _3-6 cycloalkyl substituted C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 hydroxyalkyl, 3-8 membered heterocyclyl, -OR _f or -C(O)R _f .

In certain embodiments of the invention, _Rf is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocycle group, C _6-14 aryl or 5-14 membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl , halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl as needed Can be further substituted by hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated group C _1-3 alkyl, halo C _1-3 alkyl, C 1-3 hydroxyalkyl, C _1-3 alkoxy, halo _{C 1-3 alkoxy} , C _3-6 cycloalkyl, 3- One or more substitutions among 8-membered heterocyclyl, C _6-10 aryl, and 5-6-membered heteroaryl.

In certain embodiments of the invention, _R6 is hydrogen, fluorine or methyl, preferably fluorine.

In certain embodiments of the invention, _R6 is hydrogen or fluorine.

In certain embodiments of the invention, R ₇ is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocycle base, C _6-14 aryl group, 5-14 membered heteroaryl group, -OR _g , -C(O)R _g , -SR _g , S(O)R _g or S(O) ₂ R _g , the amine Base, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{3 -8} cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group can be further substituted by hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group as needed , side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 One or more substitutions among hydroxyalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl; Preferably, R ₇ is independently selected from hydrogen, deuterium, halogen, amine group, C _1-3 alkyl substituted amine group, hydroxyl, cyano group, nitro group, side oxy group, thio group, C _1-3 alkyl group base, C _3-6 cycloalkyl substituted C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 hydroxyalkyl, 3-8 membered heterocyclyl, -OR _g or -C(O)R _g .

In certain embodiments of the invention, R _g is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocycle group, C _6-14 aryl or 5-14 membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl , halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl as needed Can be further substituted by hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated group C _1-3 alkyl, halo C _1-3 alkyl, C 1-3 hydroxyalkyl, C _1-3 alkoxy, halo _{C 1-3 alkoxy} , C _3-6 cycloalkyl, 3- One or more substitutions among 8-membered heterocyclyl, C _6-10 aryl, and 5-6-membered heteroaryl.

In certain embodiments of the invention, _R7 is hydrogen or fluorine.

In certain embodiments of the invention, _L3 is a bond.

In certain embodiments of the invention, R ₄ is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocycle base, C _6-14 aryl group, 5-14 membered heteroaryl group, -OR _d , -C(O)R d , -SR _{d ,} S(O)R _d or S(O) ₂ R _d , the amine Base, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{3 -8} cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group can be further substituted by hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group as needed , side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 One or more substitutions among hydroxyalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-6 membered heteroaryl; Preferably, R ₄ is independently selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxy group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _{2 -3} alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 hydroxyalkyl.

In certain embodiments of the invention, R _d is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocycle group, C _6-14 aryl or 5-14 membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl , halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl as needed Can be further substituted by hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated group C _1-3 alkyl, halo C _1-3 alkyl, C 1-3 hydroxyalkyl, C _1-3 alkoxy, halo _{C 1-3 alkoxy} , C _3-6 cycloalkyl, 3- One or more substitutions among 8-membered heterocyclyl, C _6-10 aryl and 5-6-membered heteroaryl.

In certain embodiments of the invention, _R4 is independently selected from hydrogen, fluoro, methyl, or methoxy.

In certain embodiments of the invention, _R4 is independently selected from hydrogen, fluorine, and methyl. In certain embodiments of the invention, _R5 is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocycle group, C _6-14 aryl group, 5-14 membered heteroaryl group, -OR _e , -C(O)R _e , -SR _e , S(O)R _e or S(O) ₂ R _e , the amine Base, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 hydroxyalkyl, C _{3 -8} cycloalkyl group, 3-12 membered heterocyclyl group, C _6-14 aryl group, 5-14 membered heteroaryl group may be further substituted by hydrogen, deuterium, halogen, amino group, C _1-3 alkyl group if necessary Amino group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl, C _1-3 hydroxyalkyl, C _1-3 alkoxy, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-6 membered One or more substitutions in the heteroaryl group; preferably, R ₅ is independently selected from C _2-6 alkenyl or C _2-6 alkynyl, and the C _2-6 alkenyl and C _2-6 alkynyl groups are regarded as Amino group optionally substituted by hydrogen, deuterium, halogen, amine group, C _1-3 alkyl group, hydroxyl group, cyano group, nitro group, C _1-3 alkyl group, C _2-3 alkenyl group, C _2-3 alkyne Substituted with one or more of a deuterated C _1-3 alkyl group, a halo C _1-3 alkyl group and a C _1-3 hydroxyalkyl group.

、

、

、

、

、

、

或

。 In certain embodiments of the invention, _R5 is vinyl,

,

,

,

,

,

,

or

.

In certain embodiments of the invention, L ₁ is selected from -(CH ₂ ) _n C(O)(CR _aa R _bb ) _n1 -, -(CH ₂ ) _n C(O)NR _aa (CR _aa R _bb ) _n1 -, -(CH ₂ ) _n (CR _aa R _bb ) _n2 - or -(CR _aa R _bb ) _n O(CH ₂ ) _n1 -;

R _aa and R _bb are each independently selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, side oxygen group, thio group, C _1-3 alkyl group, deuterated C _1-3 alkyl group, and halo C _1-3 alkyl group. , C _1-3 alkoxy, halo C _1-3 alkoxy; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, side oxygen, thio, methyl, ethyl, propyl , isopropyl, methoxy, ethoxy or propoxy;

R ₁ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, mercapto, cyano, nitro, side oxy, thio, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , Deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, _{C 1-3 hydroxyalkyl} , C _3-6 cycloalkyl , a 3-6-membered heterocyclyl group containing 1-3 N, O or S atoms, a C _6-10 aryl group or a 5-6-membered heteroaryl group containing 1-3 N, O or S atoms, the amine Base, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy group, C _1-3 hydroxyalkyl group, C _3-6 cycloalkyl group, 3-8 membered heterocyclyl group, C _6-10 aryl group, 5-6 membered heteroaryl group can be further selected as needed. By hydrogen, deuterium, fluorine, chlorine, bromine, amino group, hydroxyl group, mercapto group, cyano group, nitro group, side oxygen group, thio group, 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 substitutions , containing 1-3 fluorine, chlorine or bromine substituted ethyl groups, containing 1-3 fluorine, chlorine or bromine substituted propyl groups, containing 1-3 fluorine, chlorine or bromine substituted isopropyl groups, methoxy groups , one or more substitutions in ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

Preferably, R ₁ is selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 Alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 ring Alkyl, 3-6 membered heterocyclyl 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 group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 alkoxy group, Halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl as needed It can further be hydrogen, deuterium, fluorine, chlorine, bromine, amino group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, methyl group, ethyl group, propyl group, isopropyl group, vinyl group, propenyl group, Allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methyl containing 1-3 fluorine, chlorine or bromine substitutions , containing 1-3 fluorine, chlorine or bromine substituted ethyl groups, containing 1-3 fluorine, chlorine or bromine substituted propyl groups, containing 1-3 fluorine, chlorine or bromine substituted isopropyl groups, methoxy groups , one or more substitutions in ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

或

，其中該甲基、乙基、丙基、異丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、氘代甲基、氘代乙基、氘代丙基、氘代異丙基、甲氧基、乙氧基、丙氧基、羥甲基、羥乙基、羥丙基、環丙基、環丁基、環戊基、環己基、苯基、

、

、

、

、

、

或

視需要地進一步被氟、氯、溴、羥基、甲基、乙基、丙基、異丙基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、炔丙基、甲氧基、乙氧基或丙氧基取代； More preferably, R ₁ is selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, methyl group, ethyl group, propyl group, isopropyl group, vinyl group, propenyl group , allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methyl containing 1-3 fluorine, chlorine or bromine substitutions base, ethyl group containing 1-3 fluorine, chlorine or bromine substitutions, propyl group containing 1-3 fluorine, chlorine or bromine substitutions, isopropyl group containing 1-3 fluorine, chlorine or bromine substitutions, methoxy base, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

, wherein the methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl base, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,

,

,

,

,

,

or

Optionally further substituted by fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy , ethoxy or propoxy substitution;

R ₂ is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, C _1-3 alkyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl base, C _1-3 alkoxy group, halogen C _1-3 alkoxy group, deuterated C _1-3 alkoxy group or C _1-3 hydroxyalkyl group; preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl base, ethyl, propyl, isopropyl, hydroxyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, deuterated methyl Oxy group, deuterated ethoxy group, deuterated propoxy group, methyl group containing 1-3 fluorine, chlorine or bromine substitutions, ethyl group containing 1-3 fluorine, chlorine or bromine substitutions, Fluorine, chlorine or bromine substituted propyl, containing 1-3 fluorine, chlorine or bromine substituted isopropyl;

R ₃₁ , R ₃₂ and R ₃₃ are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amine, methyl-substituted amine, ethyl-substituted amine, propyl-substituted amine, hydroxyl, cyanide Base, nitro, side oxy, thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl base, deuterated propyl group, ethyl group containing 1-3 fluorine, chlorine or bromine substitutions, propyl group containing 1-3 fluorine, chlorine or bromine substitutions, isopropyl group containing 1-3 fluorine, chlorine or bromine substitutions. Propyl, methoxy, ethoxy, propoxy, ethoxy group containing 1-3 fluorine, chlorine or bromine substitutions, propoxy group containing 1-3 fluorine, chlorine or bromine substitutions, 3 fluorine, chlorine or bromine substituted isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, -C _1-3 alkyl -R _c , -NHR _c or -C(O)R _c ; more Preferably, R ₃₁ , R ₃₂ and R ₃₃ are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amine, methyl-substituted amine, ethyl-substituted amine, propyl-substituted amine, Hydroxy, cyano, nitro, side oxy, thio, 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, 1-3 fluorine, chlorine or bromine Substituted isopropyl, methoxy, ethoxy, propoxy, ethoxy substituted with 1-3 fluorine, chlorine or bromine, propoxy substituted with 1-3 fluorine, chlorine or bromine, Containing 1-3 fluorine, chlorine or bromine substituted isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl or -C(O)R _c ;

、

、

、

、

、

、

或

； R _c is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-3 alkyl, C _{2 -4} alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 Hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl, the amino group, C _1-3 alkyl substituted amino group, Hydroxy, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-6 membered heteroaryl are optionally hydrogenated , deuterium, halogen, amino group, C _1-3 alkyl substituted amino group, hydroxyl, cyano group, nitro group, pendant oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _{2 -4} alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3- One or more substitutions in _6- cycloalkyl, 3-8-membered heterocyclyl, C _6-10 aryl or 5-6-membered heteroaryl; preferably, R _c is independently selected from hydrogen, fluorine, chlorine , bromine, amino, methyl-substituted amino, ethyl-substituted amino, propyl-substituted amino, hydroxyl, cyano, nitro, pendant oxy, thio, methyl, ethyl, propyl , vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl containing 1-3 fluorine, chlorine or bromine substitutions Base, propyl group containing 1-3 fluorine, chlorine or bromine substitutes, isopropyl group containing 1-3 fluorine, chlorine or bromine substitutes, methoxy, ethoxy, propoxy group, containing 1-3 Fluorine, chlorine or bromine substituted ethoxy, 1-3 fluorine, chlorine or bromine substituted propoxy, 1 to 3 fluorine, chlorine or bromine substituted isopropoxy, hydroxymethyl, hydroxyethyl base, hydroxypropyl,

,

,

,

,

,

,

or

;

Preferably, R _c is independently selected from hydrogen, fluorine, chlorine, bromine, amine, methyl-substituted amine, ethyl-substituted amine, propyl-substituted amine, hydroxyl, cyano, nitro, Side oxy group, thio group, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl base, ethyl group containing 1-3 fluorine, chlorine or bromine substitutions, propyl group containing 1-3 fluorine, chlorine or bromine substitutions, isopropyl group containing 1-3 fluorine, chlorine or bromine substitutions, methoxy base, ethoxy, propoxy, containing 1-3 fluorine, chlorine or bromine substituted ethoxy, containing 1-3 fluorine, chlorine or bromine substituted propoxy, containing 1-3 fluorine, chlorine or bromo-substituted isopropoxy, hydroxymethyl, hydroxyethyl or hydroxypropyl;

R ₄ , R ₁₀ , R ₁₁ and R ₁₂ are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl _, C _2-4 alkynyl, deuterated C _{1-3 alkyl, halo C 1-3} alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino group, hydroxyl group, cyano group , nitro, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl containing 1-3 fluorine, chlorine or bromine substitutions, containing 1- 3 propyl groups substituted by fluorine, chlorine or bromine, isopropyl group containing 1-3 fluorine, chlorine or bromine substitutes, methoxy, ethoxy, propoxy group, containing 1-3 fluorine, chlorine or bromine Substituted ethoxy, propoxy containing 1-3 fluorine, chlorine or bromine substitutions, isopropoxy containing 1-3 fluorine, chlorine or bromine substitutions, hydroxymethyl, hydroxyethyl or hydroxypropyl ;

、

、

；更佳氫、氘、氟、氯、溴、胺基、羥基、氰基、硝基、甲基、乙基、丙基、異丙基、甲氧基、乙氧基、丙氧基、羥甲基、羥乙基、羥丙基、

或

； R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _{2- 4} alkynyl, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, _{halo C 1-3 alkoxy, C 1-3 hydroxyalkyl ,} C _3-6 Cycloalkyl, 3-8 membered heterocyclyl, C _6-16 aryl or 5-10 membered heteroaryl; the amino group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkyne base _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl group, 3-8 membered heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group, optionally optionally further substituted by hydrogen, deuterium, fluorine, chlorine, bromine, amino group, methyl group, Ethyl-substituted amino, propyl-substituted amino, hydroxyl, cyano, nitro, pendant oxy, thio, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl base, deuterated propyl group, ethyl group containing 1-3 fluorine, chlorine or bromine substitutions, propyl group containing 1-3 fluorine, chlorine or bromine substitutions, isopropyl group containing 1-3 fluorine, chlorine or bromine substitutions. Propyl, methoxy, ethoxy, propoxy, ethoxy group containing 1-3 fluorine, chlorine or bromine substitutions, propoxy group containing 1-3 fluorine, chlorine or bromine substitutions, One or more of 3 fluorine, chlorine or bromine substituted isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl and 6-membered heterocyclyl groups; preferably hydrogen, deuterium, fluorine, chlorine, bromine , amino, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl,

,

,

; Better hydrogen, deuterium, fluorine, chlorine, bromine, amine, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, hydroxyl Methyl, hydroxyethyl, hydroxypropyl,

or

;

Preferably, R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl _, C _2-4 alkynyl, deuterated C _{1-3 alkyl, halo C 1-3} alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; the amino group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, _{halo C 1-3 alkoxy, C 1-3 hydroxyalkyl ,} C _{3 -6} cycloalkyl group, 3-8 membered heterocyclyl group, C _6-10 aryl group, 5-10 membered heteroaryl group may be further substituted by hydrogen, deuterium, fluorine, chlorine, bromine, amino group, or methyl group if necessary. Amino group, ethyl substituted amino group, propyl substituted amino group, hydroxyl group, cyano group, nitro group, pendant oxygen group, thio group, methyl group, ethyl group, propyl group, isopropyl group, deuterated methyl group , Deuterated ethyl, deuterated propyl, containing 1-3 fluorine, chlorine or bromine substituted ethyl, containing 1-3 fluorine, chlorine or bromine substituted propyl, containing 1-3 fluorine, chlorine or bromine substituted Bromo-substituted isopropyl, methoxy, ethoxy, propoxy, containing 1-3 fluorine, chlorine or bromine-substituted ethoxy, containing 1-3 fluorine, chlorine or bromine-substituted propoxy , containing 1-3 fluorine, chlorine or bromine substituted isopropoxy, hydroxymethyl, hydroxyethyl or hydroxypropyl substituted by one or more; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amine radical, 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.

In certain preferred embodiments of the invention, L ₁ is selected from -O-, -C(O)-, -C(O)NHCH ₂ - or -C(O)NH-.

、

、

、

In certain preferred embodiments of the invention, _R1 is selected from

,

,

,

In certain preferred embodiments of the invention, R ₂ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propyl Oxygen, deuterated methoxy, deuterated ethoxy, deuterated propoxy, cyano, ethoxy, difluoromethoxy.

In certain preferred embodiments of the invention, R ₃₁ is hydrogen, deuterium, methyl, ethyl, propyl.

、

、

、

、

、

、

、

、

、

、

、

、異丙基、

、

、

或-CD₃。 In certain preferred embodiments of the invention, R ₃₂ is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, cyano, -COCH ₂ CH ₃ , -COCH ₃ , vinyl, cyclopropyl,

,

,

,

,

,

,

,

,

,

,

,

,isopropyl,

,

,

or -CD ₃ .

In certain preferred embodiments of the invention, R ₃₃ is -C(O)NH ₂ .

In certain preferred embodiments of the invention, R ₄ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, cyano, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl Fluoromethyl, ethyl, propyl, methoxy or cyclopropyl.

In certain preferred embodiments of the invention, R ₄ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, cyano, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl Fluoromethyl, ethyl, propyl or methoxy.

In certain preferred embodiments of the invention, R ₁₀ is independently selected from hydrogen, deuterium, fluorine, chlorine or bromine.

In certain preferred embodiments of the invention, R ₁₁ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine or hydroxyl.

In certain preferred embodiments of the invention, R ₁₂ is independently selected from hydrogen or cyano.

、

；較佳地，R₆、R₇、R₈和R₉各自獨立地選自氫、氘、甲基、乙基、氟、氯、溴、三氟甲基、氰基、-CH₂OH、-CH₂OCH₃、-CF₃、-CH₂N(CH₃)₂、

；較佳地，R₆、R₇和R₈各自獨立地選自氫、氘、甲基、乙基、氟、氯、溴、三氟甲基或氰基。 In certain preferred embodiments of the invention, R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyanide Base, -CH ₂ OH, -CH ₂ OCH ₃ , -CF ₃ , -CH ₂ N(CH ₃ ) ₂ ,

,

; Preferably, R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH ₂ OH, -CH ₂ OCH ₃ , -CF ₃ , -CH ₂ N(CH ₃ ) ₂ ,

; Preferably, R ₆ , R ₇ and R ₈ are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl or cyano.

In certain preferred embodiments of the invention, R ₆ is independently selected from hydrogen, fluorine, methyl, -CH ₂ OH, -CH ₂ OCH ₃ , -CF ₃ .

In certain preferred embodiments of the invention, _R7 is independently selected from hydrogen.

。 In certain preferred embodiments of the invention, R ₈ is independently selected from hydrogen, -CH ₂ N(CH ₃ ) ₂ or

.

In certain preferred embodiments of the invention, R ₉ is methyl.

In certain preferred embodiments of the invention,

L ₁ is selected from -O-, -C(O)-, -C(O)NHCH ₂ - or -C(O)NH-;

、

、

、

、

、

、

、

、

R ₁ is selected from

,

,

,

,

,

,

,

,

R ₂ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methoxy, deuterated ethyl Oxygen or deuterated propoxy; preferably fluorine, methoxy, -OCD ₃ ;

R ₃₁ is hydrogen, deuterium, methyl, ethyl, propyl;

、

、

、

、

、

、

、

、

、

、

或

；較佳地，R₃₂為氫、氘、甲基、乙基、丙基、三氟甲基、甲氧基、-COCH₂CH₃、-COCH₃、乙烯基、環丙基

、

、

、

、

、

、

、

或

；更佳地，R₃₂為氫、氘、甲基、乙基、丙基、三氟甲基、甲氧基、乙烯基或環丙基； R ₃₂ is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, cyano, -COCH ₂ CH ₃ , -COCH ₃ , vinyl, cyclopropyl ,

,

,

,

,

,

,

,

,

,

,

or

; Preferably, R ₃₂ is hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl, methoxy, -COCH ₂ CH ₃ , -COCH ₃ , vinyl, cyclopropyl

,

,

,

,

,

,

,

or

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

R ₃₃ is -C(O)NH ₂ ;

R ₄ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, cyano, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, propyl, methoxy group or cyclopropyl; preferably, R ₄ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethanol group, propyl or methoxy; more preferably, R ₄ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl or methoxy;

R ₁₀ is independently selected from hydrogen, deuterium, fluorine, chlorine or bromine;

R ₁₁ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine or hydroxyl;

R ₁₂ is independently selected from hydrogen or cyano;

、

；較佳地，R₆、R₇、R₈和R₉各自獨立地選自氫、氘、甲基、乙基、氟、氯、溴、三氟甲基、氰基、-CH₂OH、-CH₂OCH₃、-CF₃、-CH₂N(CH₃)₂、

；較佳地，R₆、R₇、R₈和R₉各自獨立地選自氫、氘、甲基、乙基、氟、氯、溴、三氟甲基、氰基、-CH₂OH、-CH₂OCH₃、-CF₃、-CH₂N(CH₃)₂。 R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH ₂ OH, -CH ₂ OCH ₃ , -CF ₃ , -CH ₂ N(CH ₃ ) ₂ ,

,

; Preferably, R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH ₂ OH, -CH ₂ OCH ₃ , -CF ₃ , -CH ₂ N(CH ₃ ) ₂ ,

; Preferably, R ₆ , R ₇ , R ₈ and R ₉ are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH ₂ OH, -CH ₂ OCH ₃ , -CF ₃ , -CH ₂ N(CH ₃ ) ₂ .

；R₉為甲基。 In certain preferred embodiments of the invention, R ₆ is independently selected from hydrogen, fluorine, methyl, -CH ₂ OH, -CH ₂ OCH ₃ , -CF ₃ ; R ₇ is independently selected from hydrogen; R ₈ Independently selected from hydrogen, -CH ₂ N(CH ₃ ) ₂ or

; R ₉ is methyl.

In certain preferred embodiments of the invention,

L ₁ is selected from -O-, -C(O)-, -C(O)NHCH ₂ - or -C(O)NH-;

、

、

、

、

、

、

、

、

R ₁ is selected from

,

,

,

,

,

,

,

,

R ₂ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methoxy, deuterated ethyl Oxygen or deuterated propoxy;

R ₃₁ is hydrogen, deuterium, methyl, ethyl, propyl;

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

R ₃₃ is -C(O)NH ₂ ;

R ₄ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl or methoxy;

R ₆ , R ₇ and R ₈ are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl or cyano.

In certain preferred embodiments of the invention,

L ₁ is selected from -O-, -C(O)NHCH ₂ - or -C(O)NH-;

、

、

、

、

、

、

、

、

R ₁ is selected from

,

,

,

,

,

,

,

,

R ₂ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methoxy, deuterated ethyl Oxygen or deuterated propoxy;

R ₃₁ is hydrogen, deuterium, methyl, ethyl, propyl;

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

R ₃₃ is -C(O)NH ₂ ;

R ₄ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl or methoxy;

R ₆ , R ₇ and R ₈ are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl or cyano.

The present invention also provides a method for preparing the compound represented by formula (III), its stereoisomer or its pharmaceutically acceptable salt as described above, which includes the following steps: the compound represented by formula (V) and The compound represented by formula (VI) can be reacted under the action of a condensing agent,

Among them, R ₁ , L ₁ , R ₂ , x, R ₃₁ , R ₃₂ , R ₃₃ , R ₄ , z, R ₆ , R ₇ and R ₈ are the same as mentioned above.

The present invention also provides a method for preparing the compound represented by formula (IV), its stereoisomer or its pharmaceutically acceptable salt as described above, which includes the following steps: the compound represented by formula (VII) and The compound represented by formula (VI) can be reacted under the action of a condensing agent,

Among them, R ₁ , R ₂ , x, R ₃₂ , R ₄ , z, R ₆ , R ₇ and R ₈ are the same as mentioned above.

The present invention also provides a compound represented by formula (V) or its stereoisomer, or a compound represented by formula (VII) or its stereoisomer:

Among them, R ₁ , L ₁ , R ₂ , x, R ₃₁ , R ₃₂ , R ₃₃ , R ₄ and z are the same as mentioned above.

The present invention further relates to a pharmaceutical composition, which includes a therapeutically effective dose of the compound of general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients. form agent.

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

In certain embodiments of the present invention, the pharmaceutical composition is selected from tablets, capsules, liquid preparations or injections. Preferably, it also contains a filler, and optionally a disintegrant, or further contains a flow aid. One or more of the agents or lubricants.

In certain embodiments of the invention, the pharmaceutical composition is an immediate release formulation or a sustained release formulation.

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

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

In certain embodiments of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, can be formulated into a liquid or solid preparation, such as syrup, suspension, emulsion, tablet, capsule , powder, granules, or lozenges.

The present invention further relates to the compound of general formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition in the preparation of FGFR1-4 inhibitor drugs.

In certain embodiments of the invention, the FGFR1-4 inhibitor is an FGFR2/3 inhibitor.

On the other hand, the object of the present invention is to provide a compound containing the compound described in general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the preparation of treatment and/or prevention of cancer and Used in medicines for bone dysplasia and other related diseases.

The present invention also relates to a method for treating and/or preventing related diseases such as cancer and achondroplasia. On the other hand, the object of the present invention is to provide a compound containing the compound described in the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for the treatment and/or prevention of cancer and cartilage development. Used in adverse diseases and other related diseases.

In the above technical solution, 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.

After structural optimization of each general formula compound, its stereoisomer or its pharmaceutically acceptable salt according to the present invention, the mother core is modified into a single ring structure, which not only improves the FGFR2 enzyme level inhibitory activity, but also has FGFR3 enzyme and Inhibits activity at the cellular level while maintaining selectivity for FGFR1.

Detailed description of the invention

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

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms alkyl group having 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-di Methylpentyl, 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 isomers thereof. More preferred are low carbon atoms containing 1 to 6 carbon atoms grade alkyl, 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-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Key et al. 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 Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ring Alkoxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, side oxygen group, carboxyl group or carboxylate group, the preferred methyl group, ethyl group, isopropyl group and tert-butyl group in the present invention , haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxyl-substituted alkyl.

The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" refers to -CH ₂ -, "ethylene" refers to -(CH ₂ ) ₂ - , "(ethylene)propylene" refers to -(CH ₂ ) ₃ -, "(ethylene)butyl" refers to -(CH ₂ ) ₄ -, etc.

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, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl etc. Alkenyl may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, and alkylthio. , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and preferably 3 to 12 carbon atoms. 8 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkyl Thio group, heterocycloalkylthio group, side oxygen group, carboxyl group or carboxylate group.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2), 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 contains 1-3 nitrogen atoms. The 8-membered heterocyclyl group, if necessary, is substituted by 1-2 oxygen atoms, sulfur atoms, and side oxygen groups, including nitrogen-containing monocyclic heterocyclyl groups, nitrogen-containing spiroheterocyclyl groups, or nitrogen-containing fused heterocyclic groups.

Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrole base, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazacycloheptyl, pyranyl, etc., preferably pyrrolidinyl, Morpholinyl, piperidinyl, azepanyl, 1,4-diazepanyl and piperazinyl. Polycyclic heterocyclyl groups include spirocyclic, fused-cyclic and bridged-cyclic heterocyclyl groups; the involved spirocyclic, fused-cyclic and bridged-cyclic heterocyclyl groups are connected to other groups through single bonds as needed, or by Any two or more atoms on the ring are further connected to other cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups. Non-limiting examples of monocyclic heterocyclyl groups include:

The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:

和

等。

and

wait.

The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkyl Thio group, heterocycloalkylthio group, side oxygen group, carboxyl group or carboxylate group.

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 members, e.g. phenyl and naphthyl. Better phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered hetero Alkyl group, preferably benzo 5-6 membered heteroaryl group, benzo 3-6 membered cycloalkyl group and benzo 3-6 membered heteroalkyl group, wherein the heterocyclyl group is A heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, and sulfur atoms; or a three-membered nitrogen-containing fused ring containing a benzene ring.

The ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

和

等。

and

wait.

The aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkylthio. , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio group, carboxyl group or carboxylate group.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably a monocyclic heteroaryl group, and the monocyclic heteroaryl group has 5 to 12 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazole base, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidine base or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl. The heteroaryl group can be a polycyclic heteroaryl group. The polycyclic heteroaryl group is a monocyclic heteroaryl group that is fused to an aryl, heteroaryl, heterocyclyl or cycloalkyl ring and connected to the parent structure. The polycyclic heteroaryl group formed may be bicyclic, tricyclic or more. Non-limiting examples include:

和

等。

and

wait.

The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkyl Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkyl Thio group, heterocycloalkylthio group, carboxyl group or carboxylate group.

"Haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.

"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

"Hydroxyalkyl" refers to an alkyl group substituted by hydroxyl, wherein alkyl is as defined above.

"Alkenyl" refers to an alkenyl group, also known as an alkenyl group, wherein the alkenyl group can be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino , halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio , carboxyl or carboxylate group.

"Alkynyl" refers to (CH≡C-), where the alkynyl group may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen , mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl Or carboxylate group.

Different terms such as "X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" all express the same Meaning, it means that X can be any one or more of A, B, and C.

The hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by a deuterium atom.

"As appropriate" or "as appropriate" means that the subsequently described event or circumstances may but need not occur, and that description includes instances where the event or circumstances do or do not occur. For example, "a heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but need not be present, and this description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .

"Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted by a corresponding number of substituents. It goes without saying, take Substituents are only in their possible chemical positions, and one of ordinary skill in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amine or hydroxyl group with a free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, together with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.

"Pharmaceutically acceptable salts" or "pharmaceutically acceptable salts" refer to salts of the compounds of the present invention. Such salts are safe and effective when used in mammals, and have due biological activity.

The invention will be further described below with reference to examples, but these examples do not limit the scope of the invention.

Example

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm) units. NMR was measured using a Bruker AVANCE-400 nuclear magnetic instrument. The measurement solvents were deuterated dimethyl styrene (DMSO- d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ). The internal standard was tetrahydrofuran. Methylsilane (TMS).

Agilent 1200 Infinity Series mass spectrometer was used for LC-MS measurement. The HPLC measurement used Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150×4.6mm chromatography column) and Waters 2695-2996 high-pressure liquid chromatograph (Gimini C ₁₈ 150×4.6mm chromatography column).

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.

The starting materials in the embodiments of the present invention are known and can be purchased on the market, or can be synthesized using or according to methods known in the art.

Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature unit is degrees Celsius.

Example 1

4-(4-Acrylamide phenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)pendoxy)phenyl)-5-methyl-1H- Pyrrole-2-methamide

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

Dissolve methyl 5-methyl-1H-pyrrole-2-carboxylate (5.06g, 36.36mmol) in dichloromethane (100mL), cool the reaction solution to 0°C in an ice-water bath, and add N-bromine under stirring Succinimide (6.86g, 38.55mmol), the reaction solution was stirred for 40 minutes at 0°C. Add 2N aqueous sodium hydroxide solution (70mL) under stirring at 0°C, stir for 2 minutes, let stand and separate into layers, and use diluent to separate the water phase. Extract with methyl chloride, combine the organic phases, add anhydrous sodium sulfate to dry, filter, and concentrate under reduced pressure. The residue is directly used in the next reaction.

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

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

Dissolve methyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (7.93g, 36.37mmol) in acetonitrile (50mL), and add 4-dimethylaminopyridine (444.31mg, 3.64mmol) ), add tert-butoxycarbonyl tert-butyl carbonate (8.73g, 40.01mmol) with stirring at room temperature, stir the reaction mixture at room temperature for 5 hours, concentrate under reduced pressure to remove the solvent, and disperse the residue in dichloro in methane, washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography to obtain the target compound (10.67g, 92%).

MS m/z (ESI): 318.0,320.0[M+H] ⁺ .

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

1-(Tertiary-butyl)2-methyl 4-bromo-5-methyl-1H-pyrrole-1,2-dicarboxylate (10.67g, 33.54mmol), 4-nitrobenzeneboronic acid ( 11.20g, 67.07mmol), Pd(PPh ₃ ) ₄ (3.87g, 3.35mmol) and anhydrous sodium carbonate (35.55g, 335.36mmol) were dispersed in a mixed solvent of DMF (100mL) and water (20mL). The reaction solution was Under nitrogen protection, the temperature was raised to 90°C and the reaction was stirred for 4 hours, and then the temperature was raised to 110°C and the reaction was stirred for 12 hours. The solvent was 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 slurried with ethyl acetate to obtain the target compound (5.6 g, 64%).

MS m/z (ESI): 261.1[M+H] ⁺ .

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

Dissolve methyl 5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate (2.85g, 10.95mmol) in DMF (40mL), and add N- Bromosuccinimide (2.05g, 11.50mmol), the reaction solution was stirred at room temperature for 1 hour, and the reaction solution was directly used in the next reaction.

MS m/z (ESI): 339.0,341.0[M+H] ⁺ .

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

Add 4-dimethylaminopyridine (268mg, 2.19mmol) and tert-butoxycarbonyl tert-butyl carbonate (5.98g, 27.38mmol) to the reaction solution in the previous step, and stir the reaction mixture at room temperature for 3 hour, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was treated with saturated chlorine Wash with sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is separated by silica gel column chromatography to obtain the target compound (3.75 g, two-step yield 78%).

MS m/z (ESI): 439.0,441.0[M+H] ⁺ .

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

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

MS m/z (ESI): 463.1,465.1[M+H] ⁺ .

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

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

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

Step 8: 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)side oxy)phenyl)-5-methyl-4-(4-nitrophenyl)-1H -Preparation of pyrrole-2-methamide

3-(3-Fluoro-4-((4-methylpyrimidin-2-yl)sideoxy)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole- 2-Carboxylic acid (564mg, 1.26mmol), diisopropylethylamine (488mg, 3.77mmol, 657.24μL), HOBt (340mg, 2.52mmol) and EDCI (482mg, 2.52mmol, hydrochloride) were added to the dihydrate in sequence. in methyl chloride (50 mL), stir and react at room temperature for 16 hours, concentrate under reduced pressure to remove the solvent, disperse the residue in a saturated ammonium chloride solution, beat, filter, collect the filter residue, wash the filter residue with water, collect the filter residue, and dry under reduced pressure , the target compound (562.76mg, 100%) was obtained.

MS m/z (ESI): 448.1[M+H] ⁺ .

Step 9: 4-(4-aminophenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)side oxy)phenyl)-5-methyl-1H -Preparation of pyrrole-2-methamide

3-(3-Fluoro-4-((4-methylpyrimidin-2-yl)sideoxy)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole- 2-Formamide (563 mg, 1.26 mmol) was dissolved in a mixed solvent of dioxane (30 mL) and ethanol (30 mL), and iron powder (7.02 g, 125.78 mmol) and ammonium chloride (3.36 g, 62.89 mmol) were added in sequence. ) solution in water (20 mL), the reaction solution was heated to 50°C under nitrogen protection and stirred for 1 hour, concentrated under reduced pressure to remove the solvent, the residue was dispersed in water, extracted with dichloromethane, the dichloromethane layers were combined, and treated with saturated chlorine Wash with sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is separated by silica gel column chromatography to obtain the target compound (338 mg, 64%).

MS m/z (ESI): 418.2[M+H] ⁺ .

Step 10: 4-(4-acrylamide phenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)side oxy)phenyl)-5-methyl Preparation of base-1H-pyrrole-2-methamide

4-(4-Aminophenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)sideoxy)phenyl)-5-methyl-1H-pyrrole- 2-Formamide (60 mg, 143.73 μmol) was dissolved in DMF (5 mL), cooled to 0°C in an ice-water bath, and triethylamine (15 mg, 143.73 μmol, 20.05 μL) and acrylic chloride (13 mg, 143.73 μmol), the reaction mixture was stirred for 30 minutes at 0°C, and the reaction solution was directly subjected to ODS-Flash column chromatography to obtain the target compound (21.2 mg, 28%).

MS m/z (ESI): 472.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.52 (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).

Example 2

3-(3-fluoro-4-((4-methylpyrimidin-2-yl)pendoxy)phenyl)-4-(4-methacryloylamidophenyl)-5-methyl- 1H-pyrrole-2-methamide

4-(4-Aminophenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)sideoxy)phenyl)-5-methyl-1H-pyrrole- 2-Formamide (60 mg, 143.73 μmol) was dissolved in DMF (5 mL), cooled to 0°C in an ice-water bath, and triethylamine (73 mg, 718.67 μmol, 100.24 μL) and 2-methacrylamide were added in sequence under stirring. Chlorine (15 mg, 143.73 μmol), the reaction mixture was stirred and reacted at 0°C for 30 minutes, and the reaction solution was directly subjected to ODS-Flash column chromatography to obtain the target compound (22.2 mg, 29%).

MS m/z (ESI): 486.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.52(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).

Example 3

3-(3-fluoro-4-(4-methylpyrimidin-2-yl)pendoxy-phenyl)-4-(4-(2-fluoroprop-2-enamide)phenyl)- 5-Methyl-1H-pyrrole-2-methamide

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 was Stir the reaction at room temperature for 10 minutes, then add 4-(4-aminophenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl) side oxy-phenyl)-5 -Methyl-1H-pyrrole-2-methamide (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 target compound (21 mg, 35%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.53 (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 =47.7,3.6Hz,1H),5.40(dd, J =15.6,3.6Hz,1H),2.41(s,3H),2.22(s,3H).

MS m/z (ESI): 490.2[M+H] ⁺ .

Example 4

3-(3-fluoro-4-((4-methylpyrimidin-2-yl)pendoxy)phenyl)-5-methyl-4-(4-(2-(trifluoromethyl)acrylamide) (Amino)phenyl)-1H-pyrrole-2-methamide

4-(4-Aminophenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-5-methyl-1H-pyrrole-2 -Formamide (50 mg, 119.78 μmol) and 2-(trifluoromethyl)prop-2-enoic acid (50 mg, 359.34 μmol) were dissolved in DMF (3 mL), and EDCI (69 mg, 359.34) was added in sequence while stirring at room temperature. μmol, hydrochloride) and 4-dimethylaminopyridine (3 mg, 23.96 μmol). 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 %).

MS m/z (ESI): 540.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.53(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).

Example 5

4-(4-(2-Chloroacrylamide)phenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)sideoxy)phenyl)-5- Methyl-1H-pyrrole-2-methamide

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

MS m/z (ESI): 506.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.53 (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).

Example 10

3-(3-fluoro-4-((4-methylpyrimidin-2-yl)pendoxy)phenyl)-4-(2-fluoro-4-methacryloylaminophenyl)-5 -Methyl-1H-pyrrole-2-methamide

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

Dissolve methyl 5-methyl-1H-pyrrole-2-carboxylate (5.06g, 36.36mmol) in dichloromethane (100mL), cool to 0°C in an ice-water bath, and add N-bromine in batches under stirring Succinimide (6.80g, 38.18mmol), the reaction solution continued to stir at 0°C for 1 hour, then N-iodosuccinimide (9.00g, 40.00mmol) was added in batches, the reaction solution continued to stir at 0 Stir the reaction at ℃ for 30 minutes, then remove the ice water bath, transfer to room temperature and stir the reaction for 30 minutes, add 4-dimethylaminopyridine (4.44g, 36.36mmol) and tert-butoxycarbonyl tert-butyl in sequence. base carbonate (23.81g, 109.09mmol), the reaction mixture was stirred at room temperature for 2 hours, the reaction mixture was washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. After concentration, the residue was separated by silica gel column chromatography to obtain the title compound (11.6 g, 72%).

MS m/z (ESI): 444.0,446.0[M+H] ⁺ .

Step 2: Methyl 4-bromo-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-5-methyl-1H-pyrrole-2-carboxy Preparation of acid esters

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

MS m/z (ESI): 420.1[M+H] ⁺ .

Step 3: 4-Bromo-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-5-methyl-1H-pyrrole-2-carboxylic acid Preparation

Methyl 4-bromo-3-(3-fluoro-4-(4-methylpyrimidin-2-yl) pendant 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. React for 1 hour, concentrate under reduced pressure to remove the solvent, disperse the residue in water, add acetic acid to adjust the pH to acidity, extract with dichloromethane, combine the dichloromethane extracts, wash with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, and filter. , concentrated, and the residue was directly used in the next reaction.

MS m/z (ESI): 406.1[M+H] ⁺ .

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

Dissolve 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.05g, 4.43mmol) in dichloro In methane (20 mL), cool to 0°C in an ice-water bath, and add diisopropylethylamine (859 mg, 6.64 mmol, 1.16 mL) and 2-methylprop-2-enyl chloride (556 mg, 5.31 mL) in sequence under stirring. mmol), the resulting reaction solution was continued to stir for 30 minutes at 0°C. The reaction solution was diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered , concentrated, and the residue was separated by silica gel column chromatography to obtain the target compound (1.2g, 89%).

MS m/z (ESI): 306.2[M+H] ⁺ .

Step 5: 3-Butyl 4-bromo-2-aminomethane-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-5- Preparation of methyl-pyrrole-1-carboxylate

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 chlorine were added in sequence with stirring at room temperature. Ammonium chloride (452 mg, 8.45 mmol) 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, concentrated, and the residue was dissolved in acetonitrile ( 50 mL), add tert-butoxycarbonyl tert-butyl carbonate (1.11g, 5.07mmol) and 4-dimethylaminopyridine (207mg, 1.69mmol) in sequence while stirring at room temperature, and the resulting reaction liquid chamber The reaction was carried out with warm stirring for 2 hours, and the solvent was concentrated 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 separated by silica gel column chromatography to obtain the target compound. (390mg, 46%).

MS m/z (ESI): 505.1,507.1[M+H] ⁺ .

Step 6: 4-(2-fluoro-4-(2-methylprop-2-enamide)phenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl) ) Preparation of pendant oxy-phenyl)-5-methyl-1H-pyrrole-2-methamide

3-Butyl 4-bromo-2-aminoformyl-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-5-methyl- Pyrrole-1-carboxylate (130 mg, 257.25 μmol), N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborole- 2-yl)phenyl)-2-methyl-prop-2-enamide (157 mg, 514.51 μmol) and Pd(dppf)Cl ₂ (38 mg, 51.45 μmol) were added to DMF (10 mL), and the reaction solution was Under nitrogen protection, a solution of potassium carbonate (107 mg, 771.76 μmol) in water (1 mL) was added with stirring at room temperature. The reaction solution was replaced with nitrogen in sequence, transferred to an oil bath, heated to 100°C, and stirred for 2 hours. The solvent was concentrated under reduced pressure to remove the solvent. 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 separated by preparative TLC and prep-HPLC to obtain the target compound (0.9 mg, 1%).

MS m/z (ESI): 504.2[M+H] ⁺ .

Example 12

3-(3-fluoro-4-((4-methylpyrimidin-2-yl)pendoxy)phenyl)-4-(4-methacrylamide-2-methylphenyl)- 5-Methyl-1H-pyrrole-2-methamide

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

Add O1-tert-butyl O2-methyl 4-bromo-5-methyl-pyrrole-1,2-dicarboxylate (6.05g, 19.02mmol), 4,4,5,5-tetramethyl -2-(2-Methyl-4-nitro-phenyl)-1,3,2-dioxaborolane (7.50g, 28.52mmol) and tetrakis(triphenylphosphine)palladium (2.20 g, 1.90mmol) was added to DMF (100mL), and sodium carbonate (20.15g, 190.15 mmol) in water (20 mL), the resulting reaction solution was heated to 90°C under nitrogen protection and stirred for 16 hours. Filtered through diatomaceous earth, and the filter residue was washed with ethyl acetate. The filtrate was collected, washed with saturated sodium chloride aqueous solution, and anhydrous sulfuric acid was used. Dried over sodium, filtered, and concentrated, the residue was separated by silica gel column chromatography to obtain the target compound (4.22 g, 81%).

MS m/z (ESI): 275.1[M+H] ⁺ .

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

Dissolve methyl 5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrole-2-carboxylate (4.22g, 15.39mmol) in DMF (30mL). Add N-bromosuccinimide (2.79g, 15.69mmol) in batches with stirring at room temperature. The resulting reaction solution continues to stir and react at room temperature for 1 hour. To the reaction solution, tert-butoxycarbonyl tert. -Butyl carbonate (6.72g, 30.77mmol) and 4-dimethylaminopyridine (1.88g, 15.39mmol). The resulting reaction solution was continued to stir at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and saturated. Wash with sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is separated by silica gel column chromatography to obtain the target compound (3.65g, 52%).

MS m/z (ESI): 453.1[M+H] ⁺ .

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

O1-tert-butyl O2-methyl 3-bromo-5-methyl-4-(2-methyl-4-nitro-phenyl)pyrrole-1,2-dicarboxylate (1g, 2.21mmol), 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-4 -Methyl-pyrimidine (1.09g, 3.31mmol) and Pd(dppf)Cl ₂ (323mg, 441.23μmol) were dispersed in DMF (15mL). The reaction solution was protected with nitrogen, and potassium carbonate (914mg, 6.62) was added with stirring at room temperature. mmol) in water (1.5 mL), the reaction solution was replaced once with nitrogen, 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 target compound (922 mg, 88%).

MS m/z (ESI): 477.2[M+H] ⁺ .

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

3-(3-Fluoro-4-(4-methylpyrimidin-2-yl) pendant oxy-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl) -1H-pyrrole-2-carboxylate (922mg, 1.94mmol) was dissolved in a mixed solvent of methanol (25mL) and tetrahydrofuran (25mL), and sodium hydroxide (774mg, 19.35mmol) in water (15mL) was added under stirring. solution, the resulting reaction solution was transferred to 50°C and stirred for 4 hours, concentrated under reduced pressure to remove the organic solvent, the residue was diluted with water, and acetic acid was added under stirring conditions to adjust the pH. to neutrality, add ethyl acetate for extraction, wash the organic phase with saturated sodium chloride aqueous solution and saturated sodium bicarbonate aqueous solution, dry over anhydrous sodium sulfate, filter, shrink, and the residue is used directly for the next reaction.

MS m/z (ESI): 463.1[M+H] ⁺ .

Step 5: 4-(4-amino-2-methyl-phenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-5 -Preparation of methyl-1H-pyrrole-2-methamide

3-(3-Fluoro-4-(4-methylpyrimidin-2-yl) pendant oxy-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl) -1H-pyrrole-2-carboxylic acid (894mg, 1.93mmol) was dissolved in DMF (15mL), and diisopropylethylamine (749mg, 5.80mmol, 1.01mL) and HOBt (522mg, 3.87mmol), EDCI (741mg, 3.87mmol, hydrochloride) and ammonium chloride (517mg, 9.67mmol). The resulting reaction solution was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and mixed with saturated sodium bicarbonate and saturated chlorine. Wash with sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is dissolved in a mixed solvent of dioxane (25 mL) and ethanol (25 mL), and iron powder (5.40 g, 96.66 mmol) and ammonium chloride ( 3.10g, 58.00mmol) water (20mL) solution, the reaction solution was protected with nitrogen, the temperature was raised to 50°C and stirred for 2 hours, concentrated under reduced pressure to remove the solvent, the residue was dissolved in dichloromethane, diatomaceous earth was filtered, and the filter residue was filtered with dichloromethane. Wash with methyl chloride, collect the filtrate, wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, and concentrate. The residue is separated by silica gel column chromatography to obtain the target compound (465 mg, 56%).

MS m/z (ESI): 432.2[M+H] ⁺ .

Step 6: 3-(3-fluoro-4-((4-methylpyrimidin-2-yl)side oxy)phenyl)-4-(4-methacrylamide-2-methyl Preparation of phenyl)-5-methyl-1H-pyrrole-2-methamide

4-(4-Amino-2-methyl-phenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-5-methyl -1H-pyrrole-2-methamide (100 mg, 231.77 μmol) was dissolved in dry DMF (5 mL), cooled to 0°C in an ice-water bath, and diisopropylethylamine (45 mg, 347.66 μmol) was added in sequence under stirring. ) and 2-methylprop-2-enyl chloride (27 mg, 254.95 μmol). The resulting 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 target compound (23 mg, 17 %).

MS m/z (ESI): 500.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.46 (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),5.76(s,1H),5.47(s,1H),2.39(s,3H),2.02(s,3H),1.93(s,3H),1.88 (s,3H).

Example 13

3-(3-fluoro-4-((4-methylpyrimidin-2-yl)pendoxy)phenyl)-4-(4-(2-fluoroacrylamide)-2-methylbenzene methyl)-5-methyl-1H-pyrrole-2-methamide

Dissolve 2-fluoroprop-2-enoic acid (63 mg, 695.31 μmol) in dry DMF (5 mL), and add EDCI (133 mg, 695.31 μmol, hydrochloride), HOBt (31 mg, 231.77 μmol) and 4-Dimethylaminopyridine (14 mg, 115.89 μmol), the resulting reaction solution was stirred at room temperature for a few minutes, and 4-(4-amino-2-methyl-phenyl)-3-(3-fluoro-4) was added -(4-methylpyrimidin-2-yl)side oxy-phenyl)-5-methyl-1H-pyrrole-2-methamide (100 mg, 231.77 μmol), the resulting reaction mixture was continued to stir at room temperature. 2 hours, dilute with ethyl acetate, wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, and concentrate. The residue is separated by prep-HPLC to obtain the target compound (6.5 mg, 6%).

MS m/z (ESI): 504.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.50(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).

Example 14

4-(4-(2-Chloroacrylamide)-2-methylphenyl)-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)pendoxy)benzene methyl)-5-methyl-1H-pyrrole-2-methamide

Dissolve 2-chloroprop-2-enoic acid (49 mg, 463.54 μmol) in DMF (5 mL), and add dicyclohexylcarbodiimide (96 mg, 463.54 μmol) and diisopropylethyl in sequence while stirring at room temperature. Amine (60 mg, 463.54 μmol), stir the reaction solution at room temperature for a few minutes, then add 4-(4-amino-2-methyl-phenyl)-3-(3-fluoro-4-(4-methylpyrimidine) -2-yl) pendant oxy-phenyl)-5-methyl-1H-pyrrole-2-carboxamide (100 mg, 231.77 μmol), the resulting reaction solution was continued to stir at room temperature for 12 hours, and the reaction solution was added with acetic acid Dilute with ethyl ester, wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, and concentrate. The residue is separated by preparative TLC and prep-HPLC in sequence to obtain the target compound (26.5 mg, 22%).

MS m/z (ESI): 520.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.49(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),7.04(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).

Example 15

5-ethyl-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)sideoxy)phenyl)-4-(4-(2-fluoroacrylamide)benzene base)-1H-pyrrole-2-methamide

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

Methyl 4-bromo-1H-pyrrole-2-carboxylate (7.7g, 37.74mmol) and tert-butoxycarbonyl tert-butyl carbonate (10.71g, 49.06mmol) were dissolved in acetonitrile (50 mL ), add 4-dimethylaminopyridine (4.61g, 37.74mmol), stir the reaction solution at room temperature under nitrogen protection for 2 hours, concentrate under reduced pressure to remove the solvent, and the residue is separated by silica gel column chromatography to obtain the target compound. (11.1g,97%).

MS m/z (ESI): 304.1,306.1[M+H] ⁺ .

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

Combine O1-tert-butyl O2-methyl 4-bromopyrrole-1,2-dicarboxylate (7.8g, 25.65mmol), 4-nitrobenzeneboronic acid (8.56g, 51.29mmol), tetrakis(tris) Phenylphosphine) palladium (2.96g, 2.56mmol) and anhydrous sodium carbonate (27.19g, 256.46mmol) were added to DMF (100 mL) and water (20 mL), replace the reaction solution with nitrogen, raise the temperature to 90°C and stir for 3 hours, then raise the temperature to 110°C and stir for 3 hours, concentrate under reduced pressure to remove the solvent, and dissolve the residue in ethyl acetate. in, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was slurried with ethyl acetate to obtain the target compound (4.65g, 74%).

MS m/z (ESI): 247.1[M+H] ⁺ .

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

Dissolve methyl 4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate (2.77g, 11.23mmol) in DMF (35mL), cool to 0°C in an ice-water bath, and mix in batches under stirring conditions Add N-bromosuccinimide (2g, 11.23mmol), remove the ice water bath, transfer the reaction solution to room temperature and stir for 4 hours, add N-iodosuccinimide (2.53g, 11.23mmol), and the reaction solution Stir the reaction at room temperature for 2 hours. Add 4-dimethylaminopyridine (1.37g, 11.23mmol) and tert-butoxycarbonyl tert-butyl carbonate (9.8g, 44.91mmol) respectively. The reaction solution is room temperature. The reaction was stirred for 24 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 target compound (5.5g, 89%).

MS m/z (ESI): 551.1,553.1[M+H] ⁺ .

Step 4: Methyl 5-bromo-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-4-(4-nitrophenyl)-1H -Preparation of pyrrole-2-carboxylate

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

MS m/z (ESI): 527.1,529.1[M+H] ⁺ .

Step 5: Methyl 3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-4-(4-nitrophenyl)-5-vinyl- Preparation of 1H-pyrrole-2-carboxylate

Methyl 5-bromo-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)pendoxy-phenyl)-4-(4-nitrophenyl)-1H-pyrrole- 2-carboxylate (1g, 1.90mmol), potassium vinylfluoroborate (1.26g, 9.48mmol), Pd(dppf)Cl ₂ (277mg, 379.29μmol) and tetrabutylammonium bromide (122mg, 379.29μmol) Add to dioxane (15 mL), add anhydrous potassium carbonate (785 mg, 5.69 mmol) and water (3 mL), replace the resulting reaction solution with nitrogen, transfer to a microwave synthesizer, heat to 100°C, stir and react for 4 hours, and concentrate under reduced pressure The solvent was removed, and 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 separated by silica gel column chromatography to obtain the target compound (355 mg, 39%).

MS m/z (ESI): 475.2[M+H] ⁺ .

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

Methyl 3-(3-fluoro-4-(4-methylpyrimidin-2-yl) pendant oxy-phenyl)-4-(4-nitrophenyl)-5-vinyl-1H-pyrrole -2-Carboxylate (355 mg, 748.25 μmol) was dissolved in methanol (5 mL). 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 70°C oil. The reaction was heated in a bath for 5 hours, concentrated under reduced pressure to remove the organic solvent, the residue was diluted with water, 2N hydrochloric acid aqueous solution was added to adjust to pH=5, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue used directly for the next reaction.

MS m/z (ESI): 461.1[M+H] ⁺ .

Step 7: 3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-4-(4-nitrophenyl)-5-vinyl-1H- Preparation of pyrrole-2-methamide

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

MS m/z (ESI): 460.2[M+H] ⁺ .

Step 8: 4-(4-aminophenyl)-5-ethyl-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-1H- Preparation of pyrrole-2-methamide

3-(3-Fluoro-4-(4-methylpyrimidin-2-yl) pendant oxy-phenyl)-4-(4-nitrophenyl)-5-vinyl-1H-pyrrole-2 -Formamide (775 mg, 1.69 mmol) was dissolved in a mixed solvent of ethanol (15 mL), ethyl acetate (10 mL) and dichloromethane (5 mL), palladium/carbon (200 mg) was added, and the reaction solution was replaced with hydrogen, and 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 column chromatography to obtain the title compound (244 mg, 34%).

MS m/z (ESI): 432.2[M+H] ⁺ .

Step 9: 5-ethyl-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-4-(4-(2-fluoropropan-2- Preparation of enamide)phenyl)-1H-pyrrole-2-carboxamide

Dissolve 2-fluoroprop-2-enoic acid (38 mg, 417.19 μmol) in DMF (3 mL), and add EDCI (80 mg, 417.19 μmol, hydrochloride) and 4-dimethylaminopyridine ( 5mg, 41.72μmol), the resulting reaction solution was stirred at room temperature for a few minutes and then 4-(4-aminophenyl)-5-ethyl-3-(3-fluoro-4-(4-methylpyrimidine-2- (1H-pyrrole-2-carboxamide (60 mg, 139.06 μmol)), and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, and then treated with saturated sodium bicarbonate aqueous solution. Wash with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is separated by prep-HPLC to obtain the target compound (2.7 mg, 4%).

MS m/z (ESI): 504.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.44(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 =11.9,1.4Hz,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).

Example 16

4-(4-(2-Chloroacrylamide)phenyl)-5-ethyl-3-(3-fluoro-4-((4-methylpyrimidin-2-yl)pendoxy)benzene base)-1H-pyrrole-2-methamide

Dissolve 2-chloroprop-2-enoic acid (91 mg, 852.92 μmol) in DMF (5 mL), and add dicyclohexylcarbodiimide (176 mg, 852.92 μmol) and diisopropylethyl in sequence while stirring at room temperature. Amine (110 mg, 852.92 μmol, 148.56 μL), the resulting reaction solution was stirred at room temperature for a few minutes, and 4-(4-aminophenyl)-5-ethyl-3-(3-fluoro-4-(4-methyl) was added (pyrimidin-2-yl) pendant oxy-phenyl)-1H-pyrrole-2-carboxamide (184 mg, 426.46 μmol), the resulting reaction solution was stirred at room temperature for 2 hours, filtered, and the filtrate was collected and washed with ethyl acetate. Dilute, wash with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is sequentially separated by preparative TLC and prep-HPLC to obtain the target compound (33 mg, 15%).

MS m/z (ESI): 520.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.44(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).

Example 17

3-(3-fluoro-4-(4-methylpyrimidin-2-yl)oxy-phenyl)-4-(4-(prop-2-enamide)phenyl)-5-ethylene Base-1H-pyrrole-2-methamide

Step 1: 4-(4-Aminophenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-5-vinyl-1H- Preparation of pyrrole-2-methamide

3-(3-Fluoro-4-(4-methylpyrimidin-2-yl) pendant oxy-phenyl)-4-(4-nitrophenyl)-5-vinyl-1H-pyrrole-2 -Formamide (343 mg, 746.58 μmol) was dissolved in a mixed solution of dioxane (10 mL) and ethanol (10 mL). Iron powder (1.25 g, 22.40 mmol) and ammonium chloride (599.13 mg) were added in sequence while stirring at room temperature. , 11.20 mmol) in water (10 mL), the reaction solution was protected with nitrogen, transferred to a 50°C oil bath, heated and stirred for 1 hour, 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 sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography to obtain the target compound (113 mg, 35%).

MS m/z (ESI): 430.2[M+H] ⁺ .

Step 2: 3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-4-(4-(prop-2-enamide)phenyl) -Preparation of 5-vinyl-1H-pyrrole-2-methamide

4-(4-Aminophenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-5-vinyl-1H-pyrrole-2 -Formamide (37 mg, 86.16 μmol) was dissolved in DMF (3 mL), cooled to 0°C in an ice-water bath, and triethylamine (44 mg, 430.79 μmol, 60.08 μL) and acrylic chloride (8 mg, 86.16 μL) were added in sequence under stirring. μmol), the reaction mixture was continued to stir at 0°C for 1 hour, and the reaction solution was directly separated by ODS-Flash column chromatography to obtain the target compound (13.1 mg, 29%).

MS m/z (ESI): 484.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.65 (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),5.86(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).

Example 18

3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-4-(4-(2-methylprop-2-enamide)phenyl) -5-Vinyl-1H-pyrrole-2-methamide

4-(4-Aminophenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-5-vinyl-1H-pyrrole-2 -Formamide (37 mg, 86.16 μmol) was dissolved in DMF (3 mL), cooled to 0°C in an ice-water bath, and triethylamine (44 mg, 430.79 μmol, 60.08 μL) and 2-methacrylamide chloride were added in sequence under stirring. (9 mg, 86.16 μmol), the reaction mixture continued to stir and react at 0°C for 1 hour, and the reaction liquid was directly separated by ODS-Flash chromatography to obtain the target compound (10.8 mg, 23%).

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.63 (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 =17.9Hz,1H),5.79(s,1H),5.49(s,1H),5.14(d, J = 12.0Hz,1H),2.41(s,3H),1.93(s,3H).

MS m/z (ESI): 498.2[M+H] ⁺ .

Example 19

3-(3-fluoro-4-(4-methylpyrimidin-2-yl)pendoxy-phenyl)-4-(4-(2-fluoroprop-2-enamide)phenyl)- 5-Vinyl-1H-pyrrole-2-methamide

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. Stir the reaction at room temperature for 10 minutes, then add 4-(4-aminophenyl)-3-(3-fluoro-4-(4-methylpyrimidin-2-yl)side oxy-phenyl)-5- In a solution of vinyl-1H-pyrrole-2-methamide (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 target compound. (12.4 mg, 28.7%).

MS m/z (ESI): 502.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.63(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 =17.6Hz,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).

Example 28

4-(4-Acrylamide phenyl)-3-(4-((cyclobutylmethyl)aminoformamide)phenyl)-5-methyl-1H-pyrrole-2-methamide

Step 1: Preparation of N-(cyclobutylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenamide

Dissolve 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1g, 4.03mmol) in dichloromethane (20mL) medium, add 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) in sequence under stirring at room temperature. Add cyclobutylmethylamine (412mg, 4.84mmol) after a few minutes of warm stirring reaction. The resulting reaction solution is stirred at room temperature for 2 hours. The reaction solution is diluted with methylene chloride, washed with saturated sodium chloride aqueous solution and saturated ammonium chloride aqueous solution, and anhydrous. Dry over sodium sulfate, filter and concentrate, and the residue is separated by silica gel column chromatography to obtain the target compound (1g, 79%).

MS m/z (ESI): 316.2[M+H] ⁺ .

Step 2: Methyl 3-(4-(cyclobutylmethylaminoformyl)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate Preparation

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

MS m/z (ESI): 448.2[M+H] ⁺ .

Step 3: Preparation of 3-(4-(cyclobutylmethylaminoformyl)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylic acid

Methyl 3-(4-(cyclobutylmethylaminoformyl)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylate (1.42g, 3.17mmol) was dissolved in a mixed solvent of tetrahydrofuran (10mL) and methanol (10mL). A solution of sodium hydroxide (381mg, 9.52mmol) in water (10mL) was added with stirring at room temperature. The resulting reaction solution was transferred to 90°C and stirred for reaction 8 hours, concentrate under reduced pressure to remove the organic solvent, dilute the residue with water, add acetic acid to adjust the pH to acidity, filter the precipitate, dry under reduced pressure, wash with a small amount of ethyl acetate, collect the solid obtained, and dry under reduced pressure to obtain the target compound (1.02g, 74%).

MS m/z (ESI): 434.2[M+H] ⁺ .

Step 4: Preparation of 4-(4-aminophenyl)-3-(4-(cyclobutylmethylaminoformamide)phenyl)-5-methyl-1H-pyrrole-2-formamide

3-(4-(Cyclobutylmethylaminoformyl)phenyl)-5-methyl-4-(4-nitrophenyl)-1H-pyrrole-2-carboxylic acid (1.02g, 2.35mmol) Dissolve in DMF (15 mL), add diisopropylethylamine (911 mg, 7.05 mmol), HOBt (636 mg, 4.7 mmol), EDCI (901 mg, 4.7 mmol, hydrochloride) and chloride in sequence while stirring at room temperature. Ammonium (629 mg, 11.75 mmol), the resulting 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 a solution of iron powder (6.58 g, 117.5 mmol) and ammonium chloride (3.77 g, 70.5 mmol) in water (10 mL) was added successively to obtain The reaction solution was transferred to 90°C and heated for 2 hours, filtered through diatomaceous earth, and the filter residue was washed with ethyl acetate. The filtrate was collected and dried under reduced pressure. The residue was dissolved in methylene chloride and treated with saturated sodium bicarbonate aqueous solution and saturated sodium chloride. The aqueous solution was washed, dried over anhydrous sodium sulfate, filtered, and shrunk. The residue was separated by silica gel column chromatography to obtain the target compound (947 mg, 100%).

MS m/z (ESI): 403.2[M+H] ⁺ .

Step 5: 3-(4-(cyclobutylmethylaminoformamide)phenyl)-5-methyl-4-(4-(prop-2-enylamide)phenyl)-1H-pyrrole- Preparation of 2-formamide

4-(4-Aminophenyl)-3-(4-(cyclobutylmethylaminoformamide)phenyl)-5-methyl-1H-pyrrole-2-formamide (100 mg, 248.45 μmol) Dissolve in DMF (2 mL), add diisopropylethylamine (32 mg, 248.45 μmol) and acryl chloride (33.73 mg, 372.68 μmol) in sequence while stirring at room temperature. The resulting reaction solution is stirred at room temperature for 30 minutes and filtered. , the obtained filtrate was separated by prep-HPLC to obtain the target compound (31.3 mg, 27.6%).

MS m/z (ESI): 457.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.52 (s, 1H), 10.03 (s, 1H), 8.41 (t, J =5.6Hz, 1H), 7.73 (d, J =8.1Hz, 2H), 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 =17.0,10.1Hz,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).

Example 29

3-(4-((cyclobutylmethyl)aminoformamide)phenyl)-4-(4-methacrylamidephenyl)-5-methyl-1H-pyrrole-2-methamide

4-(4-Aminophenyl)-3-(4-(cyclobutylmethylaminoformamide)phenyl)-5-methyl-1H-pyrrole-2-formamide (100 mg, 248.45 μmol) Dissolve in DMF (2 mL), add diisopropylethylamine (32 mg, 248.45 μmol) and 2-methylprop-2-enyl chloride (26 mg, 248.45 μmol) in sequence while stirring at room temperature, and the resulting reaction liquid chamber The reaction was carried out with warm stirring for 30 minutes, and then filtered. The obtained filtrate was separated by prep-HPLC to obtain the target compound (33.6 mg, 27%).

MS m/z (ESI): 471.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.53 (s, 1H), 9.67 (s, 1H), 8.41 (t, J =5.6Hz, 1H), 7.73 (d, J =8.1Hz, 2H), 7.47(d, J =8.5Hz,2H),7.22(d, J =8.1Hz,2H),6.89(d, J =8.5Hz,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).

Example 30

3-(4-((cyclobutylmethyl)aminoformamide)phenyl)-4-(4-(2-fluoroacrylamide)phenyl)-5-methyl-1H-pyrrole-2- Formamide

Dissolve 2-fluoroprop-2-enoic acid (67 mg, 745.36 μmol) in DMF (2 mL), and add EDCI (95 mg, 496.91 μmol, hydrochloride) and 4-dimethylaminopyridine ( 15 mg, 124.23 μmol), the resulting reaction solution was stirred at room temperature for 5 minutes, and 4-(4-aminophenyl)-3-(4-(cyclobutylmethylaminoformyl)phenyl)-5-methyl was added -1H-pyrrole-2-methamide (100 mg, 248.45 μmol), the resulting reaction solution was continued to stir at room temperature for 30 minutes, filtered, and the filtrate was separated by prep-HPLC to obtain the target compound (9.1 mg, 7%).

MS m/z (ESI): 475.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.55 (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).

Example 31

4-(4-(2-Chloroacrylamide)phenyl)-3-(4-((cyclobutylmethyl)aminoformamide)phenyl)-5-methyl-1H-pyrrole-2- Formamide

Dissolve 2-chloroprop-2-enoic acid (159 mg, 1.49 mmol) in DMF (6 mL), and add EDCI (286 mg, 1.49 mmol, hydrochloride) and 4-dimethylaminopyridine ( 61 mg, 496.91 μmol), the resulting reaction solution was stirred for a few minutes at room temperature, and 4-(4-aminophenyl)-3-(4-(cyclobutylmethylaminoformyl)phenyl)-5-methyl was added -1H-pyrrole-2-carboxamide (200 mg, 496.91 μmol), the resulting 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, and filtered. After concentration, the residue was separated by preparative TLC and prep-HPLC to obtain the target compound (2.4 mg, 1%).

MS m/z (ESI): 491.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.54 (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),6.36(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).

Example 32

4-(4-Acrylamide-2-methylphenyl)-3-(4-((cyclobutylmethyl)aminoformyl)-3-methoxyphenyl)-5-methyl-1H -pyrrole-2-methamide

Step 1: Preparation of 4-bromo-N-(cyclobutylmethyl)-2-methoxy-phenamide

Dissolve 4-bromo-2-methoxy-benzoic acid (5g, 21.64mmol) in DMF (20mL), and add diisopropylethylamine (5.59g, 43.28mmol, 7.54mL) in sequence while stirring at room temperature. , HOBt (585mg, 4.33mmol) and EDCI (5.39g, 28.13mmol, hydrochloride), the resulting reaction solution was stirred at room temperature for a few minutes, cyclobutylmethylamine hydrochloride (3.16g, 25.97mmol) was added, and the resulting reaction solution was continued Stir the reaction at room temperature for 30 minutes. The reaction solution is diluted with ethyl acetate, washed successively 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 residue. The target compound (6.45g, 100%) was used directly in the next reaction without further purification.

MS m/z (ESI): 298.0,300.0[M+H] ⁺ .

Step 2: N-(cyclobutylmethyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) Preparation of Benzamide

4-Bromo-N-(cyclobutylmethyl)-2-methoxy-phenylamide (6.45g, 21.64mmol), 4,4,5,5-tetramethyl-2-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (6.59g, 25.97mmol), and Pd( dppf)Cl ₂ (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 with dry nitrogen. The temperature was raised to 100°C and stirred for 20 hours. The reaction was concentrated under reduced pressure and removed. Solvent, and the residue was separated by silica gel column chromatography to obtain the target compound (7.47g, 100%).

MS m/z (ESI): 346.2[M+H] ⁺ .

Step 3: Methyl 3-(4-(cyclobutylmethylaminoformamide)-3-methoxy-phenyl)-5-methyl-4-(2-methyl-4-nitro-benzene Preparation of 1H-pyrrole-2-carboxylate

1-(tert-butyl)2-methyl3-bromo-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-1,2-dicarboxylic acid Ester (1g, 2.28mmol), N-(cyclobutylmethyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)phenamide (1.18g, 3.41mmol) and Pd(dppf)Cl ₂ (332.84mg, 455.31μmol) were dissolved in DMF (15mL), and potassium carbonate (942.50mg, 6.83mmol) was added under nitrogen protection. water (2.5 mL) solution, the resulting reaction liquid was replaced with nitrogen, and the reaction liquid was heated to 90°C under nitrogen protection and stirred for 1 hour. The reaction liquid was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. , filtered, concentrated, and the residue was separated by silica gel column chromatography to obtain the target compound (980 mg, 88%).

MS m/z (ESI): 492.2[M+H] ⁺ .

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

Methyl 3-(4-(cyclobutylmethylaminoformate)-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), and sodium hydroxide (797.50 mg, 19.94 mmol) in water (15 mL) was added with stirring at room temperature. ) solution, transfer the reaction solution to an oil bath, heat to 50°C and stir for 16 hours. Concentrate under reduced pressure to remove the organic solvent. Dilute the residue with water. Add acetic acid to adjust the pH to neutral while stirring at room temperature. Add ethyl acetate for extraction. Organic phase dependence. It was 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 directly used in the next reaction.

MS m/z (ESI): 478.2[M+H] ⁺ .

Step 5: 4-(4-amino-2-methyl-phenyl)-3-(4-(cyclobutylmethylaminoformamide)-3-methoxy-phenyl)-5-methyl -Preparation of 1H-pyrrole-2-methamide

3-(4-(Cyclobutylmethylaminoformate)-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) and diisopropyl ethyl were added in sequence while stirring at room temperature. amine (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). The resulting reaction solution was stirred at room temperature for 1 hour. The reaction solution was Dilute with ethyl acetate, wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, and concentrate. The residue is dissolved in a mixed solvent of dioxane (25 mL) and ethanol (25 mL). Iron powder ( 5.57g, 99.68mmol) and ammonium chloride (3.20g, 59.81mmol) in water (20mL), the resulting reaction liquid was protected with nitrogen, heated to 50°C and stirred for 1 hour, concentrated under reduced pressure to remove the solvent, and the residue was dispersed in In water, add saturated sodium bicarbonate aqueous solution to adjust the pH to alkaline, extract with ethyl acetate, wash the organic phase with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, and concentrate, and the residue is separated by silica gel column chromatography to obtain the target Compound (890mg, 99%).

MS m/z (ESI): 447.2[M+H] ⁺ .

Step 6: 3-(4-(cyclobutylmethylaminoformate)-3-methoxy-phenyl)-5-methyl-4-(2-methyl-4-(prop-2-ene) Preparation of amide)phenyl)-1H-pyrrole-2-methamide

4-(4-Amino-2-methyl-phenyl)-3-(4-(cyclobutylmethylaminoformate)-3-methoxy-phenyl)-5-methyl-1H- Pyrrole-2-methamide (100 mg, 223.94 μmol) was dissolved in dry DMF (5 mL), cooled to 0°C in an ice-water bath, and diisopropylethylamine (43.41 mg, 335.92 μmol, 58.51 μL) was added in sequence under stirring. ) and acrylic chloride (22.30 mg, 246.34 μmol). The resulting 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 target compound (28 mg, 23%).

MS m/z (ESI): 501.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.49 (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).

Example 33

3-(4-((cyclobutylmethyl)aminoformamide)-3-methoxyphenyl)-4-(4-methacrylamide-2-methylphenyl)-5-methyl -1H-pyrrole-2-methamide

4-(4-Amino-2-methyl-phenyl)-3-(4-(cyclobutylmethylaminoformate)-3-methoxy-phenyl)-5-methyl-1H- Pyrrole-2-methamide (100 mg, 223.94 μmol) was dissolved in dry DMF (5 mL), cooled to 0°C in an ice-water bath, and diisopropylethylamine (44 mg, 335.92 μmol) and 2- Methylprop-2-enyl chloride (26 mg, 246.34 μmol), the resulting reaction 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 target compound (27 mg, 22%).

MS m/z (ESI): 515.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.50(s,1H),9.62(s,1H),8.02(t, J =5.8Hz,1H),7.56(d, J =7.9Hz,1H), 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,1H), 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).

Example 34

3-(4-((cyclobutylmethyl)aminoformamide)-3-methoxyphenyl)-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-5 -Methyl-1H-pyrrole-2-methamide

Dissolve 2-fluoroprop-2-enoic acid (61 mg, 671.83 μmol) in dry DMF (5 mL), and add EDCI (129 mg, 671.83 μmol, hydrochloride), HOBt (30 mg, 223.94 μmol) and 4-Dimethylaminopyridine (14 mg, 111.97 μmol), the resulting reaction solution was stirred at room temperature for a few minutes, and 4-(4-amino-2-methyl-phenyl)-3-(4-(cyclobutylmethyl) was added amine group Formamide)-3-methoxy-phenyl)-5-methyl-1H-pyrrole-2-formamide (100 mg, 223.94 μmol), the resulting reaction mixture was stirred at room temperature for 2 hours, and ethyl acetate was added It was diluted with ester, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by prep-HPLC to obtain the target compound (15.2 mg, 13%).

MS m/z (ESI): 519.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.51(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), 2.02(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) .

Example 35

4-(4-(2-Chloroacrylamide)-2-methylphenyl)-3-(4-((cyclobutylmethyl)aminoformamide)-3-methoxyphenyl)-5 -Methyl-1H-pyrrole-2-methamide

Dissolve 2-chloroacrylic acid (48 mg, 447.89 μmol) in dry tetrahydrofuran (1 mL), and add dicyclohexylcarbodiimide (46 mg, 223.94 μmol) and diisopropylethyl ethyl in sequence. amine (29 mg, 223.94 μmol, 39.01 μL), the resulting reaction solution was stirred at room temperature for 10 minutes, and then added to 4-(4-amino-2-methyl-phenyl)-3-(4-(cyclobutylmethyl) Aminoformamide)-3-methoxy-phenyl)-5-methyl-1H-pyrrole-2-formamide (100 mg, 223.94 μmol) in DMF (5 mL), the resulting reaction solution was stirred at room temperature React for 12 hours, filter, and dilute the reaction solution with ethyl acetate, wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, and concentrate. The residue is separated by preparative TLC and prep-HPLC to obtain the target compound (6.6 mg, 5% ).

MS m/z (ESI): 535.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.51(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).

Example 52

Step 1: Preparation of ethyl-2-(4-bromo-3-methoxy-benzyl)-3-(dimethylamino)prop-2-enoate

Disperse 4-bromo-3-methoxybenzoic acid (20g, 86.56mmol) in dry dichloromethane (150mL). The reaction solution is protected with dry nitrogen, cooled to 0°C in an ice-water bath, and N, N are added under stirring conditions. -Dimethylformamide (1mL), cool for a few minutes and then add oxalic acid chloride (19.78g, 155.82mmol) dropwise. After the dropwise addition is completed, the reaction solution is transferred to room temperature and stirred for 16 hours. Concentrate under reduced pressure. The solvent was removed, and the residue was dispersed in dry toluene (150 mL), protected by dry nitrogen, and ethyl-3-(dimethylamino)prop-2-enoate (14.87g, 103.88mmol) was added while stirring at room temperature. ) and triethylamine (26.28g, 259.69mmol, 36.22mL), the resulting reaction solution was stirred at room temperature for a few minutes, then transferred to an oil bath, heated to 110°C, stirred for 4 hours, concentrated under reduced pressure to remove the solvent, and the residue was dissolved in ethyl acetate The ester 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 (24.60 g, 80%).

MS m/z (ESI): 356.2[M+H] ⁺ .

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

Dissolve ethyl-2-(4-bromo-3-methoxy-benzyl)-3-(dimethylamino)prop-2-enoate (24.60g, 69.06mmol) in methanol (250mL) , add hydroxylamine hydrochloride (4.80g, 69.06mmol) under stirring at room temperature, and the resulting reaction solution is stirred and reacted at room temperature for 16 hours. Concentrate under reduced pressure to remove part of the solvent, add an equal amount of water, beat the mixture, and filter. The filter residue is washed with water and collected. The filter residue was dried under reduced pressure to obtain the title compound (16.40 g, 73%).

MS m/z (ESI): 326.0[M+H] ⁺ .

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

The mixture of ethyl 5-(4-bromo-3-methoxy-phenyl)isoxazole-4-carboxylate (1.76g, 5.40mmol) and tert-butanol (480mg, 6.48mmol) was cooled to -20°C, add perchloric acid (2.71g, 26.98mmol) under stirring conditions, transfer the reaction solution to room temperature and stir for 16 hours. The reaction solution is diluted with ice water, extracted with dichloromethane, and the dichloromethane layers are combined. Dry over anhydrous sodium sulfate, filter, and concentrate, and the residue is directly used in the next reaction.

MS m/z (ESI): 382.1,384.1[M] ⁺ .

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

5-(4-Bromo-3-methoxyphenyl)-2-tert-butyl-4-ethoxyformylisoxazole perchlorate (2.07g, 5.40mmol) and 2-methyl 4-Nitrophenylhydrazine (903 mg, 5.40 mmol) was dispersed in ethanol (40 mL). The reaction solution was protected with dry nitrogen. The temperature was raised to 100°C and the reaction was stirred for 2 hours. The solvent was concentrated under reduced pressure and the residue was dissolved in methyl in tertiary butyl ether, washed with saturated aqueous ammonium chloride solution, 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 (1.25g ,44%).

MS m/z (ESI): 531.2[M+H] ⁺ .

Step 5: 5-(4-bromo-3-methoxy-phenyl)-3-(tert-butylamino)-1-(2-methyl-4-nitro-phenyl)pyridine Preparation of azole-4-carboxylic acid

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

MS m/z (ESI): 503.2[M+H] ⁺ .

Step 6: 5-(4-bromo-3-methoxy-phenyl)-3-(tert-butylamino)-1-(2-methyl-4-nitro-phenyl)pyridine Preparation of azole-4-methamide

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

MS m/z (ESI): 502.2[M+H] ⁺ .

Step 7: 1-(4-amino-2-methyl-phenyl)-3-(tert-butylamino)-5-(4-(isobutylaminoformamide)-3- Preparation of methoxy-phenyl)pyrazole-4-methamide

Take dry microwave reaction tube A and add 5-(4-bromo-3-methoxy-phenyl)-3-(tert-butylamino)-1-(2-methyl-4-nitro-benzene) methyl)pyrazole-4-carboxamide (502mg, 999μmol), 2-methyl-1-propylamine (219mg, 3.00mmol), Pd(dppf)Cl ₂ (730mg, 999μmol), triethylamine (202mg, 2.00 mmol, 279 μL) and dioxane (10 mL), and the reaction solution is sealed; take another microwave reaction tube B, add molybdenum hexacarbonyl (2.64g, 9.99 mmol) and dioxane (10 mL), seal it, and microwave reaction tubes A and B Connect them with a double-ended needle, and the reaction system is protected by dry nitrogen. Add DBU (4.56g, 29.98mmol, 4.5mL) into microwave reaction tube B. The reaction solution is transferred to 90°C, heated and stirred for 4 hours, and then cooled to room temperature. Take the compound in the microwave reaction tube A, concentrate it under reduced pressure, and separate it through a silica column to obtain the title compound (235 mg, 48%).

MS m/z (ESI): 493.3[M+H] ⁺ .

Step 8: 3-amino-1-(4-amino-2-methyl-phenyl)-5-(4-(isobutylaminoformyl)-3-methoxy-phenyl) Preparation of pyrazole-4-methamide

1-(4-Amino-2-methyl-phenyl)-3-(tert-butylamino)-5-(4-(isobutylaminoformamide)-3-methoxy -Phenyl)pyrazole-4-carboxamide (235 mg, 477 μmol) was dissolved in trifluoromethanesulfonic acid (3 mL), and the reaction was stirred at room temperature for 4 hours. The reaction solution was added to ice water to quench, and amine water was added to adjust The pH was adjusted to alkaline, and the aqueous solution was extracted several times with ethyl acetate. 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%).

MS m/z (ESI): 437.3[M+H] ⁺ .

Step 9: 3-amino-1-(4-(2-fluoroprop-2-enamide)-2-methyl-phenyl)-5-(4-(isobutylaminoformamide) Preparation of )-3-methoxy-phenyl)pyrazole-4-carboxamide

Dissolve 2-fluoroacrylic acid (9.7mg, 108μmol) in N,N-dimethylformamide (3mL), and add N,N,N ' , N' -tetramethyl-O- in sequence while stirring at room temperature. (7-Azabenzotriazol-1-yl)urea hexafluorophosphate (47 mg, 108 μmol) and triethylamine (11 mg, 108 μmol, 15 μL). The resulting reaction solution was stirred at room temperature for a few minutes and then added to 3-amine. Base-1-(4-amino-2-methyl-phenyl)-5-(4-(isobutylaminoformate)-3-methoxy-phenyl)pyrazole-4-formate In amine (47 mg, 108 μmol), the resulting reaction solution was stirred at room temperature for 30 minutes, filtered, and the filtrate was separated by prep-HPLC to obtain the title compound (7.5 mg, 13%).

MS m/z (ESI): 509.3[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.29(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,3H),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).

Example 67

Methyl 4-(2-aminoformyl-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-5-methyl-1 H -pyrrol-3-yl) -2-Methoxybenzoate

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

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

MS m/z (ESI): 473.1[M+H] ⁺ .

Step 2: 3-Bromo-1-(4-methoxybenzyl)-5-methyl-4-(2-methyl-4-nitrophenyl) -1H -pyrrole-2-carboxylic acid Preparation

Methyl 3-bromo-1-(4-methoxybenzyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate (2.81 g, 5.94mmol) was dissolved in a mixed solution of tetrahydrofuran (20mL) and methanol (40mL). A solution of sodium hydroxide (712mg, 17.81mmol) in water (20mL) was added with stirring at room temperature. The resulting reaction solution was heated to 50°C and stirred. React for 18 hours, concentrate under reduced pressure to remove the organic solvent, dilute the residue with water, adjust the pH to acidity with dilute hydrochloric acid, extract with ethyl acetate, combine the ethyl acetate layers, wash with saturated sodium chloride aqueous solution, and dry over anhydrous sodium sulfate. Filter, concentrate, and the residue is directly used in the next reaction.

MS m/z (ESI): 459.2[M+H] ⁺ .

Step 3: 3-Bromo-1-(4-methoxybenzyl)-5-methyl-4-(2-methyl-4-nitrophenyl) -1H -pyrrole-2-methamide Preparation

3-Bromo-1-(4-methoxybenzyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylic acid (2.73g, 5.94 mmol) was dissolved in N,N-dimethylformamide (30 mL), While stirring at room temperature, add diisopropylethylamine (2.30g, 17.83mmol, 3.11mL), 1-hydroxybenzotriazole (803mg, 5.94mmol), 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (3.42g, 17.83mmol) and ammonium chloride (1.59g, 29.72mmol) were stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate. Wash with saturated aqueous ammonium chloride solution and saturated aqueous 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 (1.68 g, 62%).

MS m/z (ESI): 458.1[M+H] ⁺ .

Step 4: Methyl 4-(2-aminoformyl)-1-(4-methoxybenzyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1 H - Preparation of -pyrrole-3-yl)-2-methoxybenzoate

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

MS m/z (ESI): 544.2[M+H] ⁺ .

Step 5: Methyl 4-(4-(4-amino-2-methylphenyl)-2-aminoformate-1-(4-methoxybenzyl)-5-methyl-1 H - Preparation of -pyrrole-3-yl)-2-methoxybenzoate

Methyl 4-(2-aminoformyl)-1-(4-methoxybenzyl)-5-methyl-4-(2-methyl-4-nitrophenyl)-1 H -pyrrole- 3-yl)-2-methoxybenzoate (732mg, 1.35mmol) was dissolved in a mixed solvent of tetrahydrofuran (60mL) and methanol (30mL), palladium/carbon (200mg) was added, and the resulting reaction solution was added in the presence of hydrogen The reaction was stirred at high temperature for 16 hours, filtered through diatomaceous earth, and the residue was directly used in the next reaction.

MS m/z (ESI): 514.2[M+H] ⁺ .

Step 6: Methyl 4-(4-(4-amino-2-methylphenyl)-2-aminoformyl-5-methyl- 1H -pyrrol-3-yl)-2-methyl Preparation of oxybenzoates

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

MS m/z (ESI): 394.2[M+H] ⁺ .

Step 7: Methyl 4-(2-aminoformyl-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-5-methyl- 1H -pyrrole- Preparation of 3-yl)-2-methoxybenzoate

Dissolve 2-fluoroacrylic acid (243mg, 2.70mmol) in N,N-dimethylformamide (10mL), add HATU (1.02g, 2.70mmol) and triethylamine (410mg, 4.05 mmol, 565 μL), stir the reaction solution at room temperature for a few minutes, and add methyl 4-(4-(4-amino-2-methylphenyl)-2-aminoformyl-5-methyl- 1H -Pyrrol-3-yl)-2-methoxybenzoate (531mg, 1.35mmol), the resulting reaction solution was continued to stir at room temperature for 30 minutes, the reaction solution was diluted with ethyl acetate, and supersaturated was added in sequence Wash with aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate. 15 mg of crude product from the residue is used to prepare 6 mg of pure product of the title compound.

MS m/z (ESI): 466.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.54(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).

Example 68

3-(4-((cyclopropylmethyl)aminoformamide)-3-methoxyphenyl)-4-(4-(2-fluoropropenylmethylamino)-2-methylphenyl) -5-Methyl- 1H -pyrrole-2-methamide

Step 1: 4-(2-Aminoformyl-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-5-methyl- 1H -pyrrole-3- Preparation of methyl)-2-methoxybenzoic acid

Methyl 4-(2-aminoformyl-4-(4-(2-fluoroprop-2-enamide)-2-methyl-phenyl)-5-methyl-1 H -pyrrole -3-yl)-2-methoxy-benzoate (628 mg, 1.35 mmol) was dissolved in tetrahydrofuran (30 mL), and lithium hydroxide monohydrate (283 mg, 6.75 mmol) in water (283 mg, 6.75 mmol) was added with stirring at room temperature. 10 mL) solution, the resulting 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%).

MS m/z (ESI): 452.2[M+H] ⁺ .

Step 2: 3-(4-((cyclopropylmethyl)aminoformamide)-3-methoxyphenyl)-4-(4-(2-fluoroacrylamide)-2-methyl Preparation of phenyl)-5-methyl- 1H -pyrrole-2-methamide

4-(2-Aminoformyl-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-5-methyl-1 H -pyrrol-3-yl)- 2-Methoxybenzoic acid (25 mg, 55 μmol) and cyclopropylmethylamine (8 mg, 111 μmol) were dissolved in N,N-dimethylformamide (3 mL), and triethylamine ( 171 mg, 166 μmol, 23 μL) and HATU (42 mg, 111 μmol). The resulting reaction 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%).

MS m/z (ESI): 505.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.52(s,1H),10.16(s,1H),8.12(t, J =5.7Hz,1H),7.61(d, J =7.9Hz,1H), 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 =6.2Hz,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).

Example 78

4-(4-(2-fluoroprop-2-enamide)-2-methyl-phenyl)-3-(4-(isobutylaminoformamide)-3-(methoxy- d ₃ ) phenyl)-5-methyl-1H-pyrrole-2-methamide

Step 1: Preparation of methyl 4-bromo-2-(methoxy- d ₃ ) benzoate

Methyl 4-bromo-2-hydroxybenzoate (2.00g, 8.66mmol), deuterated methyl iodide (1.51g, 10.39mmol) and cesium carbonate (5.62g, 17.32mmol) were added to DMF (20mL) , stirred for 14 hours, the reaction solution was diluted with saturated sodium chloride aqueous solution, and extracted with ethyl acetate. Take, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is separated by silica gel column chromatography to obtain crude product (2.10 g, 98%).

MS m/z (ESI): 248.1,250.1[M+H] ⁺ .

Step 2: Methyl 2-(methoxy- d ₃ )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Preparation of benzoate esters

Methyl 4-bromo-2-(methoxy- d3 ) benzoate (2.10g, 8.35mmol) _, 4,4,5,5-tetramethyl-2-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.79g, 11mmol), Pd(dppf)Cl _2. Dichloromethane complex (0.68g, 0.84mmol) and anhydrous potassium acetate (1.64g, 16.7mmol) were added to dioxane (30mL). The reaction solution was heated to 90°C, stirred for 14 hours, and concentrated under reduced pressure. The solvent was removed, and the residue was dispersed in 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 (2.30 g, 92%).

MS m/z (ESI): 296.2[M+H] ⁺ .

Step 3: Methyl 3-(methoxy- d ₃ )-4-(methoxycarbonyl)phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl) Preparation of -1H -pyrrole-2-carboxylate

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

MS m/z (ESI): 442.2[M+H] ⁺ .

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

Methyl 3-(methoxy- d ₃ )-4-(methoxycarbonyl)phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1 H -Pyrrole-2-carboxylate (859 mg, 1.95 mmol) was dissolved in tetrahydrofuran (15 mL). 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 Stir the reaction at 30°C for 8 hours, concentrate under reduced pressure to remove the organic solvent, dilute the residue with water, adjust the pH to weak acidity with 1N hydrochloric acid aqueous solution, extract the aqueous solution with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate, and use the residue directly Next reaction.

MS m/z (ESI): 428.2[M+H] ⁺ .

Step 5: Methyl 3-(4-(isobutylaminomethane)-3-(methoxy- d ₃ )phenyl)-5-methyl-4-(2-methyl-4- Preparation of nitro-phenyl) -1H -pyrrole-2-carboxylate

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

MS m/z (ESI): 483.3[M+H] ⁺ .

Step 6: 3-(4-(isobutylaminoformamide)-3-(methoxy- d ₃ )phenyl)-5-methyl-4-(2-methyl-4-nitro) Preparation of -phenyl) -1H -pyrrole-2-carboxylic acid

Methyl 3-(4-(isobutylaminoformate)-3-(methoxy- d ₃ )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), and sodium hydroxide (46 mg, 1.15 mmol) was added with stirring at room temperature. water (10mL) solution, the resulting reaction solution was heated to 50°C and stirred for 16 hours, concentrated under reduced pressure to remove the organic solvent, the residue was dispersed in ethyl acetate, 1N hydrochloric acid aqueous solution was added to adjust the pH to acidic, and the ethyl acetate layer was saturated Wash with sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, and concentrate, and the residue will be used directly for the next reaction.

MS m/z (ESI): 469.2[M+H] ⁺ .

Step 7: 3-(4-(isobutylaminoformamide)-3-(methoxy- d ₃ )phenyl)-5-methyl-4-(2-methyl-4-nitro) Preparation of -phenyl) -1H -pyrrole-2-methamide

3-(4-(isobutylaminoformyl)-3-(methoxy- d ₃ )phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl )-1 H -pyrrole-2-carboxylic acid (537mg, 1.15mmol) was dissolved in N,N-dimethylformamide (20mL), and ammonium chloride (613mg, 11.46mmol) was added in sequence while stirring at room temperature. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.10g, 5.73mmol), 1-hydroxybenzotriazole (155mg, 1.15mmol) and triethylamine ( 580 mg, 5.73 mmol, 799 μL), and the resulting 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, concentrated, and the residue The material was directly used in the next reaction.

MS m/z (ESI): 468.2[M+H] ⁺ .

Step 8: 4-(4-amino-2-methyl-phenyl)-3-(4-(isobutylaminoformamide)-3-(methoxy- d ₃ )phenyl)- Preparation of 5-methyl- 1H -pyrrole-2-methamide

3-(4-(isobutylaminoformyl)-3-(methoxy- d ₃ )phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl )-1 H -pyrrole-2-methamide (536 mg, 1.15 mmol) was dissolved in methanol (30 mL), and palladium/carbon (200 mg, 1.65 mmol) was added under nitrogen protection. The reaction system was replaced with hydrogen and transferred to room temperature. The reaction was stirred for 2 hours, filtered through diatomaceous earth, 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%).

MS m/z (ESI): 438.2[M+H] ⁺ .

Step 9: 4-(4-(2-fluoroprop-2-enamide)-2-methyl-phenyl)-3-(4-(isobutylaminoformamide)-3-( Preparation of methoxy- d3 )phenyl)-5 _- methyl- 1H -pyrrole-2-methamide

Dissolve 2-fluoroacrylic acid (82 mg, 906.19 μmol) in N,N-dimethylformamide (5 mL), and add N,N,N ' , N' -tetramethyl-O- in sequence while stirring at room temperature. (7-Azabenzotriazol-1-yl)urea hexafluorophosphate (342 mg, 906 μmol) and triethylamine (212 mg, 2.09 mmol, 292 μL), the resulting reaction solution was stirred at room temperature for a few minutes, and then added to 4- (4-Amino-2-methyl-phenyl)-3-(4-(isobutylaminoformate)-3-(methoxy- d ₃ )phenyl)-5-methyl-1H -pyrrole-2-methamide (305 mg, 697 μmol), the resulting reaction solution was stirred at room temperature for 20 minutes, filtered, and the filtrate was separated by prep-HPLC to obtain the title compound (220 mg, 61%).

MS m/z (ESI): 510.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.51(s,1H),10.15(d, J =0.9Hz,1H),8.04(t, J =5.9Hz,1H),7.55(d, J =7.9 Hz,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).

Example 90

3-(4-((cyclopropylmethyl)aminoformamide)-3-fluorophenyl)-4-(4-(2-fluoropropenylmethylamino)-2-methylphenyl)- 5-Methyl- 1H -pyrrole-2-methamide

Step 1: tertiary-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate Preparation

3-Butyl 4-bromo-2-fluoro-benzoate (25g, 90.87mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl (32.31g, 127.22mmol), Pd(dppf)Cl ₂ Methyl chloride complex (2.22g, 2.73mmol) and anhydrous potassium acetate (26.72g, 272.61mmol) were added to dioxane (200mL). The resulting reaction solution was protected with dry nitrogen, heated to 95°C and stirred for 18 hours. Cool to room temperature, filter through diatomaceous earth, wash the filter residue with ethyl acetate, and concentrate the filtrate obtained under reduced pressure. The crude product obtained is separated by silica gel column chromatography to obtain the title compound (29g, 99%).

MS m/z (ESI): 323.2[M+H] ⁺ .

Step 2: O1-tert-butylO2-methyl3-(4-tert-butoxycarbonyl-3-fluoro-phenyl)-5-methyl-4-(2-methyl-4 - Preparation of -nitro-phenyl)pyrrole-1,2-dicarboxylate

O1-tert-butyl O2-methyl 3-bromo-5-methyl-4-(2-methyl-4-nitro-phenyl)pyrrole-1,2-dicarboxylate (1.60g ,3.53mmol), tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate ( 2.27g, 7.06mmol), Pd(dppf)Cl ₂ (516mg, 706μmol) was dissolved in N,N-dimethylformamide (16mL), and anhydrous potassium carbonate (1.46g, 10.59mmol) was added under nitrogen protection. water (1.6mL) solution, the reaction solution was replaced once with nitrogen, transferred to 90°C and stirred for 1 hour, filtered with diatomaceous earth, and the filter residue was washed with ethyl acetate. The filtrate was collected, diluted with ethyl acetate, and the organic phase was treated with saturated chlorine Wash with sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is separated by silica gel column chromatography to obtain the title compound (2.01g).

MS m/z (ESI): 469.2[M+H] ⁺ .

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

O1-tert-butylO2-methyl3-(4-tert-butoxycarbonyl-3-fluoro-phenyl)-5-methyl-4-(2-methyl-4-nitro -Phenyl)pyrrole-1,2-dicarboxylate (2.01g, 3.54mmol) was dissolved in dioxane (30mL), and a solution of sodium hydroxide (707mg, 17.68mmol) in water (10mL) was added. The resulting reaction The liquid was heated to 50°C and stirred for 48 hours, concentrated under reduced pressure to remove the organic solvent, the residue was diluted with water, acetic acid was added to adjust the pH to weak acidity, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. Filter, concentrate, and the residue is directly used in the next reaction.

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

Step 4: tertiary-butyl 4-(2-aminoformyl-5-methyl-4-(2-methyl-4-nitro-phenyl) -1H -pyrrole-3-yl) -2-Fluoro-benzoate

3-(4-tert-butoxycarbonyl-3-fluoro-phenyl)-5-methyl-4-(2-methyl-4-nitro-phenyl)-1 H -pyrrole-2 -Carboxylic acid (1.61g, 3.54mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.39g, 17.70mmol) and 1-hydroxybenzotriazole (2.39g, 17.70mmol) was dissolved in N,N-dimethylformamide (20mL), and diisopropylethylamine (1.37g, 10.62mmol, 1.85mL) and chlorine were added in sequence while stirring at room temperature. Ammonium (947 mg, 17.70 mmol), the resulting reaction solution was stirred at room temperature for 2 hours. 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 separated by silica gel column chromatography to obtain the title compound (1.61 g, 100%).

MS m/z (ESI): 454.2[M+H] ⁺ .

Step 5: tertiary-butyl 4-(4-(4-amino-2-methyl-phenyl)-2-aminoformyl-5-methyl- 1H -pyrrole-3-yl) Preparation of -2-fluoro-benzoate

tert-Butyl 4-(2-aminoformyl-5-methyl-4-(2-methyl-4-nitro-phenyl)-1H-pyrrol-3-yl)-2-fluoro -Dissolve benzoate (1.61g, 3.55mmol) in methanol (20mL), add palladium/carbon (200mg), replace the resulting reaction solution with hydrogen, stir and react at room temperature for 2 hours in the presence of hydrogen, filter, and collect the filtrate , concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain the title compound (572 mg, 38%).

MS m/z (ESI): 424.2[M+H] ⁺ .

Step 6: tertiary-butyl 4-(2-aminoformyl-4-(4-(2-fluoroprop-2-enylamide)-2-methyl-phenyl)-5-methyl Preparation of 1H -pyrrol-3-yl)-2-fluoro-benzoate

2-Fluoroacrylic acid (365 mg, 4.05 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (777 mg, 4.05 mmol), 1-hydroxybenzotriazole (183mg, 1.35mmol) was dissolved in N,N-dimethylformamide (10mL), and 4-dimethylamine was added with stirring at room temperature. pyridine (83 mg, 676 μmol), the resulting reaction solution was stirred at room temperature for a few minutes, and tert-butyl 4-(4-(4-amino-2-methyl-phenyl)-2-aminomethyl was added Benzyl-5-methyl-1H-pyrrol-3-yl)-2-fluoro-benzoate (572 mg, 1.35 mmol), the resulting reaction mixture was continued to stir at room temperature for 1 hour, and the reaction solution was diluted with ethyl acetate. It was diluted with ester, 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%).

MS m/z (ESI): 496.2[M+H] ⁺ .

Step 7: 4-(2-Aminoformyl-4-(4-(2-fluoroprop-2-enylamide)-2-methyl-phenyl)-5-methyl-1 H - Preparation of pyrrol-3-yl)-2-fluoro-benzoic acid

tertiary-Butyl 4-(2-aminoformyl-4-(4-(2-fluoroprop-2-enylamide)-2-methyl-phenyl)-5-methyl-1 H -pyrrol-3-yl)-2-fluoro-benzoate (297 mg, 599 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) was added with stirring at room temperature, and the resulting reaction solution was stirred at room temperature. The reaction was carried out for 2 hours, the solvent was concentrated under reduced pressure, and the residue was directly used in the next reaction.

MS m/z (ESI): 440.1[M+H] ⁺ .

Step 8: 3-(4-((cyclopropylmethyl)aminoformamide)-3-fluorophenyl)-4-(4-(2-fluoroacrylamide)-2-methyl Preparation of phenyl)-5-methyl- 1H -pyrrole-2-methamide

4-(2-Aminoformyl-4-(4-(2-fluoroprop-2-enamide)-2-methyl-phenyl)-5-methyl-1H-pyrrole-3- methyl)-2-fluoro-benzoic acid (66 mg, 150 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 451 μmol), 1-hydroxybenzo Dissolve triazole (20 mg, 150 μmol) in DMF (3 mL), add diisopropylethylamine (97 mg, 751 μmol, 131 μL) and cyclopropylmethylamine (32 mg, 451 μmol) in sequence while stirring at room temperature, and the resulting reaction solution The reaction 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%).

MS m/z (ESI): 493.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.53(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) ,3.09(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).

Example 108

4-(4-(2-Fluoroacrylamide)-2-methylphenyl)-3-(4-(((1-fluorocyclopropyl)methyl)aminoformamide)-3- Methoxyphenyl)-5-methyl-1H-pyrrole-2-methamide

4-(4-(2-Fluoroacrylamide)-2-methylphenyl)-3-(4-(((1-fluorocyclopropyl)methyl)aminoformamide)-3- For the preparation of methoxyphenyl)-5-methyl-1H-pyrrole-2-methamide, refer to Example 13 or 68.

It can also be synthesized as follows:

4-(2-Aminoformyl-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-5-methyl-1 H -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) and DIPEA (28 mg, 221 μmol) and DIPEA (28 mg, 221 μmol) were added in sequence with stirring at medium temperature. HATU (25 mg, 66 μmol), the reaction solution was stirred for 30 minutes, filtered, and the filtrate was separated by prep-HPLC to obtain the target compound (11 mg, 47%).

MS m/z (ESI): 523.2[M+H] ⁺ .

¹ H NMR(400MHz, DMSO- d ₆ ) δ 11.53(s,1H),10.16(d, J =1.8Hz,1H),8.32(t, J =5.9Hz,1H),7.62(d, J =7.9 Hz,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).

Example 109

4-(4-(2-fluoroacrylamide)-2-methylphenyl)-3-(4-((2-fluoropropyl)aminoformamide)-3-methoxyphenyl) -5-Methyl-1H-pyrrole-2-methamide

4-(4-(2-Fluoroacrylamide)-2-methylphenyl)-3-(4-((2-fluoropropyl)aminomethyl)-3-methoxyphenyl )-5-Methyl-1H-pyrrole-2-methamide is prepared with reference to Example 13 or 68.

You can also refer to the following operations to synthesize:

HATU (25 mg, 66 μmol) was added to 4-(2-aminoformamide-4-(4-(2-fluoropropenylamide)-2-methylphenyl)-5-methyl-1H- Pyrrol-3-yl)-2-methoxybenzoic acid (20 mg, 44.30 μmol), 2-fluoropropan-1-amine hydrochloride (5.5 mg, 49 μmol) and DIPEA (29 mg, 222 μmol) in DMF (4.3 mL ) solution, the reaction solution was stirred for 1 hour and then separated and purified by prep-HPLC to obtain the title compound (10.1 mg, 44%).

MS m/z (ESI): 511.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.52(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).

The following Examples 109-1 and 109-2 are prepared with reference to Example 13 or 68

Example 111

3-(4-(((2,2-difluorocyclopropyl)methyl)aminoformamide)-3-methoxyphenyl)-4-(4-(2-fluoropropenylamide) -2-methylphenyl)-5-methyl-1H-pyrrole-2-methamide

3-(4-(((2,2-difluorocyclopropyl)methyl)aminoformamide)-3-methoxyphenyl)-4-(4-(2-fluoropropenylamide) For the preparation of -2-methylphenyl)-5-methyl-1H-pyrrole-2-carboxamide, refer to Example 13 or 68.

You can also refer to the following operations to synthesize:

HATU (44 mg, 116 μmol) was added to 4-(2-aminoformamide-4-(4-(2-fluoropropenylamide)-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), and the reaction solution was stirred for 1 hour. The reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (18 mg, 42%).

MS m/z (ESI): 541.2[M+H] ⁺ .

¹ H NMR(400MHz, DMSO- d ₆ ) δ 11.53(s,1H),10.17(d, J =1.8Hz,1H),8.31(t, J =5.8Hz,1H),7.62(d, J =7.9 Hz,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).

The following Examples 111-1 and 111-2 are prepared with reference to Example 13 or 68

Example 157

4-(4-(but-2-ynylamide)-2-methylphenyl)-3-(4-(isobutylaminoformamide)-3-methoxyphenyl)-5-methyl Base-1H-pyrrole-2-methamide

4-(4-(but-2-ynylamide)-2-methylphenyl)-3-(4-(isobutylaminoformamide)-3-methoxyphenyl)-5-methyl The preparation of base-1H-pyrrole-2-methamide is referred to Example 13 or 78.

You can also refer to the following operations to synthesize:

HATU (26 mg, 69 μmol) was added to 4-(4-amino-2-methyl-phenyl)-3-[4-(isobutylaminoformamide)-3-methoxy-phenyl] -5-Methyl-1H-pyrrole-2-carboxamide (20 mg, 46 μmol, preparation refers to step 8 of Example 78), butan-2-ynoic acid (3.9 mg, 46 μmol) and DIPEA (17.8 mg, 138 μmol) of DMF (2.5 ml) solution, and the reaction solution was stirred for 2 hours. The reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (9.1 mg, 39%).

MS m/z (ESI): 501.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.50 (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).

Example 159

(E)-4-(4-(4-(dimethylamino)but-2-enamide)-2-methylphenyl)-3-(4-(isobutylaminoformamide) -3-methoxyphenyl)-5-methyl-1H-pyrrole-2-methamide

(E)-4-(4-(4-(dimethylamino)but-2-enamide)-2-methylphenyl)-3-(4-(isobutylaminoformamide) For the preparation of -3-methoxyphenyl)-5-methyl-1H-pyrrole-2-methamide, refer to Example 13 or 78.

You can also refer to the following operations to synthesize:

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

MS m/z (ESI): 546.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.50 (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),6.76-6.64(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).

Example 164

5-Ethyl-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-3-(4-(isobutylaminoformamide)-3-methoxyphenyl )-1H-pyrrole-2-methamide

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

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

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

MS m/z (ESI): 261.1[M+H] ⁺ .

Step 2: 1-(tert-butyl)2-methyl5-bromo-3-iodo-4-(2-methyl-4-nitrophenyl)pyrrole-1,2-dicarboxylate Preparation

Dissolve methyl 4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate (2.5g, 9.61mmol) in DMF (35mL), cool to 0°C in an ice-water bath, Add N-bromosuccinimide (1.71g, 9.61mmol) in batches under stirring conditions, remove the ice water bath, transfer the reaction solution to room temperature and stir for 4 hours, add N-iodosuccinimide (2.16g, 9.61mmol), the reaction solution was stirred at room temperature for 2 hours, and 4-dimethylaminopyridine (1.41g, 11.53mmol) and tert-butoxycarbonyl tert-butyl carbonate (4.15g, 19.21mmol) were added respectively. ), the reaction solution was stirred at room temperature for 24 hours, the reaction solution was diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by silica gel column chromatography to obtain the target compound (2.0g ,37%).

MS m/z (ESI): 565.1,567.1[M+H] ⁺ .

Step 3: Methyl 5-bromo-3-(4-(isobutylaminoformyl)-3-methoxyphenyl)-4-(2-methyl-4-nitro-phenyl) Preparation of -1H -pyrrole-2-carboxylate

1-(tert-butyl)2-methyl5-bromo-3-iodo-4-(2-methyl-4-nitrophenyl)pyrrole-1,2-dicarboxylate (1.0g ,1.77mmol), N-isobutyl-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Amide (0.65g, 1.95mmol) and Pd(dppf)Cl ₂ (129mg, 177μmol) were dissolved in dioxane (30mL). The reaction solution was protected with nitrogen. Anhydrous potassium carbonate (0.73g, 5.31) was added under stirring at room temperature. mmol) in water (5 mL), the reaction solution was replaced with nitrogen, transferred to an oil bath, heated to 90°C and stirred for 16 hours, concentrated under reduced pressure to remove the solvent, the residue was dissolved in dichloromethane, and the organic phase was treated with saturated sodium chloride aqueous solution Wash, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is separated by silica gel column chromatography to obtain the target compound (600 mg, 63%).

MS m/z (ESI): 544.1,546.1[M+H] ⁺ .

Step 4: Methyl 3-(4-(isobutylaminoformyl)-3-methoxyphenyl)-4-(2-methyl-4-nitro-phenyl)-5-ethylene Preparation of base- 1H -pyrrole-2-carboxylate

Methyl 5-bromo-3-(4-(isobutylaminoformyl)-3-methoxy-phenyl)-4-(2-methyl-4-nitro-phenyl)-1 H -pyrrole-2-carboxylate (400mg, 734.76μmol), potassium vinylfluoroborate (197mg, 1.47mmol), Pd(dppf)Cl ₂ (54mg, 73.48μmol) and tetrabutylammonium bromide (23mg, 73.48 μmol) was added to dioxane (15 mL), anhydrous potassium carbonate (304 mg, 2.20 mmol) and water (3 mL) were added. The resulting reaction liquid was replaced with nitrogen, transferred to a microwave synthesizer, heated to 100°C, stirred for 4 hours, and reduced to The solvent was removed by concentrating under pressure, and 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 separated by silica gel column chromatography to obtain the target compound (250 mg, 69%).

MS m/z (ESI): 492.2[M+H] ⁺ .

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

Methyl 3-(4-(isobutylaminoformyl)-3-methoxyphenyl)-4-(2-methyl-4-nitro-phenyl)-5-vinyl-1 H -pyrrole-2-carboxylate (400 mg, 813.78 μmol) was dissolved in methanol (5 mL). 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 Heat the reaction in an oil bath at 70°C for 5 hours, concentrate under reduced pressure to remove the organic solvent, dilute the residue with water, add 2N hydrochloric acid aqueous solution to adjust to pH=5, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate. , the residue was directly used in the next reaction.

MS m/z (ESI): 478.2[M+H] ⁺ .

Step 6: 3-(4-(isobutylaminoformyl)-3-methoxy-phenyl)-4-(2-methyl-4-nitro-phenyl)-5-vinyl- Preparation of 1H-pyrrole-2-methamide

3-(4-(isobutylaminoformyl)-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), and HOBt (201.91 mg, 1.49 mmol) and triethylamine (227 mg, 2.24mmol, 312.63μL), EDCI (287mg, 1.49mmol, hydrochloride) and ammonium chloride (200mg, 3.74mmol). The reaction solution continued to stir at room temperature for 2 hours. The solvent was concentrated under reduced pressure to remove the residue. Dissolve in ethyl acetate, wash with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, filter, and concentrate. The residue is directly used in the next reaction.

MS m/z (ESI): 477.2[M+H] ⁺ .

Step 7: 4-(4-amino-2-methyl-phenyl)-5-ethyl-3-(4-(isobutylaminoformyl)-3-methoxy-phenyl)- Preparation of 1H-pyrrole-formamide

3-(4-(isobutylaminoformyl)-3-methoxyphenyl)-4-(2-methyl-4-nitrophenyl)-5-vinyl-1H-pyrrole-2 -Formamide (170 mg, 356.75 μmol) was dissolved in a mixed solvent of ethanol (15 mL), ethyl acetate (10 mL) and dichloromethane (5 mL), palladium/carbon (50 mg) was added, and the reaction solution was replaced with hydrogen, and 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 (130 mg, 81%).

MS m/z (ESI): 449.2[M+H] ⁺ .

Step 8: 5-ethyl-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-3-(4-(isobutylaminoformamide)-3- Preparation of methoxyphenyl)-1H-pyrrole-2-methamide

Add 2-fluoroacrylic acid (16 mg, 179.67 μmol), triethylamine (61 mg, 598.90 μmol, 83.53 μL) and HATU (68 mg, 179.67 μmol) to DMF (1 mL) in sequence, and stir the reaction solution at room temperature for 10 minutes. Add to 4-(4-amino-2-methyl-phenyl)-5-ethyl-3-(4-(isobutylaminoformyl)-3-methoxy-phenyl)-1H- In a solution of pyrrole-2-methamide (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%).

MS m/z (ESI): 521.2[M+H] ⁺ .

¹ H NMR(400MHz, DMSO- d ₆ ) δ 11.45(s,1H),10.14(d, J =1.9Hz,1H),8.03(t, J =5.9Hz,1H),7.55(d, J =7.9 Hz,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 =3.2 Hz,3H),1.02(t, J =7.5Hz,3H),0.86(d, J =6.7Hz,6H).

Example 167

5-ethyl-3-(4-((2-fluoro-2-methylpropyl)aminoformyl)-3-methoxyphenyl)-4-(4-(2-fluoropropenylamine) methyl)-2-methylphenyl)-1H-pyrrole-2-methamide

5-ethyl-3-(4-((2-fluoro-2-methylpropyl)aminoformyl)-3-methoxyphenyl)-4-(4-(2-fluoropropenylamine) For the preparation of methyl)-2-methylphenyl)-1H-pyrrole-2-methamide, refer to Example 13 or 164.

You can also refer to the following operations to synthesize:

DIPEA (33 mg, 257 μmol) was added to 4-(4-amino-2-methyl-phenyl)-5-ethyl-3-[4-[(2-fluoro-2-methyl-propyl) Aminomethyl]-3-methoxy-phenyl]-1H-pyrrole-2-methamide (40 mg, 86 μmol, preparation refers to the seventh step of Example 164), 2-fluoroprop-2-enoic acid (9.3 mg, 103 μmol) and HATU (48.9 mg, 129 μmol) in DMF (3 mL) solution, the reaction solution was stirred for 1 hour. The reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (19.7 mg, 42%).

MS m/z (ESI): 539.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.47(s,1H),10.16(d, J =1.9Hz,1H),8.16(t, J =6.2Hz,1H),7.60(d, J =7.9 Hz,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 =1.5 Hz,1H ),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),3.50-3.43(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).

Example 169

5-ethyl-4-(4-(2-fluoropropenyl)-2-methylphenyl)-3-(4-((1-fluorocyclopropyl)methyl)aminomethyl (Method)-3-methoxyphenyl)-1H-pyrrole-2-methamide

5-ethyl-4-(4-(2-fluoropropenyl)-2-methylphenyl)-3-(4-((1-fluorocyclopropyl)methyl)aminomethyl For the preparation of acyl)-3-methoxyphenyl)-1H-pyrrole-2-methamide, refer to Example 13 or 164.

You can also refer to the following operations to synthesize:

Add 2-fluoroacrylic acid (80 mg, 895 μmol), triethylamine (305 mg, 3.00 mmol, 420 μL) and HATU (340 mg, 895 μmol) to DMF (2 mL) in sequence, stir the reaction solution for 10 minutes, and add 4-( 4-Amino-2-methylphenyl)-5-ethyl-3-(4-(((1-fluorocyclopropyl)methyl)aminoformyl)-3-methoxyphenyl)- 1H-pyrrole-2-methamide (362mg, 780 μmol) in DMF (4 mL), stirred for 1 hour, filtered, and the filtrate was separated by prep-HPLC to obtain the title compound (250 mg, 60%).

MS m/z (ESI): 537.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.47(s,1H),10.16(d, J =1.9Hz,1H),8.33(t, J =5.9Hz,1H),7.62(d, J =8.0 Hz,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).

Example 170

5-ethyl-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-3-(4-(((1-(fluoromethyl)cyclopropyl)methyl) )Aminoformamide)-3-methoxyphenyl)-1H-pyrrole-2-formamide

5-ethyl-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-3-(4-(((1-(fluoromethyl)cyclopropyl)methyl) )Aminoformamide)-3-methoxyphenyl)-1H-pyrrole-2-formamide is prepared with reference to Example 13 or 164.

You can also refer to the following operations to synthesize:

4-(2-Aminoformyl-5-ethyl-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-1H-pyrrol-3-yl)-2 - Methoxybenzoic acid (30 mg, 64.5 μmol, refer to the first step of preparation in Example 68) was dissolved in DMF (1 mL), HATU (29 mg, 77 μmol) and DIPEA (42 mg, 322 μmol) were added under stirring, and the reaction solution continued to stir. 30 minutes. (1-(Fluoromethyl)cyclopropyl)methanamine hydrochloride (8.0 mg, 77 μmol) was added to the reaction solution, and the reaction solution was stirred for 1 hour. The reaction solution was separated and purified by reverse-phase column chromatography to obtain the title compound (8.0 mg, 23%).

MS m/z (ESI): 551.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.41(s,1H),10.09(d, J =1.9Hz,1H),8.11(t, J =5.7Hz,1H),7.50(d, J =7.9 Hz,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) .

Example 190

4-(4-Acrylamide-2-methylphenyl)-3-(3-methoxy-4-(3-methylbutylamino)phenyl)-5-methyl-1H -pyrrole-2-methamide

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

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

MS m/z (ESI): 286.2[M+H] ⁺ .

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

[1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (64 mg, 88.71 μmol) was added to N-(4-bromo-2-methoxyphenyl)-3-methylbutanol A solution of amide (600 mg, 2.10 mmol), pinacol diborate (692 mg, 2.73 mmol), and potassium acetate (261 mg, 2.66 mmol) in 1'4-dioxane (20 mL) was heated to React at 90°C for 16 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was dried, filtered, and concentrated. The residue was separated by column chromatography to obtain the target compound (600 mg, 86%).

MS m/z (ESI): 334.3[M+H] ⁺ .

Step 3: Methyl 3-(3-methoxy-4-(3-methylbutylamino)phenyl)-5-methyl-4-(2-methyl-4-nitrophenyl) )-1H-pyrrole-2-carboxylic acid ester preparation

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

MS m/z (ESI): 480.2[M+H] ⁺ .

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

Sodium hydroxide (359 mg, 8.97 mmol) was added to methyl 3-(3-methoxy-4-(3-methylbutylamino)phenyl)-5-methyl-4-(2-methyl (4-nitrophenyl)-1H-pyrrole-2-carboxylic acid A solution of ester (430 mg, 896.72 μmol) in THF (3 mL), water (1 mL) and methanol (3 mL) was heated to 50°C and stirred for 16 hours. Spin the reaction solution to dryness and then pour it into water. Adjust the pH to 5 with 2N hydrochloric acid. Extract with ethyl acetate. Dry the organic phase and spin it to dryness to obtain the target compound (230 mg, 55%).

MS m/z (ESI): 466.1[M+H] ⁺ .

Step 5: 3-(3-methoxy-4-(3-methylbutylamino)phenyl)-5-methyl-4-(2-methyl-4-nitrophenyl)- Preparation of 1H-pyrrole-2-methamide

DIPEA (191 mg, 1.48 mmol) was added to 3-(3-methoxy-4-(3-methylbutylamino)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- In a solution of dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (189 mg, 988.19 μmol) in DMF (5 mL), the reaction solution was stirred at room temperature for 16 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was washed with brine, dried, filtered, and concentrated to obtain the target compound (120 mg, 52%).

MS m/z (ESI): 465.1[M+H] ⁺ .

Step 6: 4-(4-amino-2-methylphenyl)-3-(3-methoxy-4-(3-methylbutylamino)phenyl)-5-methyl- Preparation of 1H-pyrrole-2-methamide

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

MS m/z (ESI): 435.2[M+H] ⁺ .

Step 7: 4-(4-propylamino-2-methylphenyl)-3-(3-methoxy-4-(3-methylbutylamino)phenyl)-5- Preparation of methyl-1H-pyrrole-2-methamide

Acrylyl chloride (4.50 mg, 49.71 μmol) was added to 4-(4-amino-2-methylphenyl)-3-(3-methoxy-4-(3-methylbutylamino) 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 solution was Stir at room temperature for 1 hour. The reaction solution was concentrated and prepared by prep-HPLC to obtain the target compound (3.7 mg, 18%).

MS m/z (ESI): 489.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.48(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).

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

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:

For the preparation of Examples 227, 228, 229, and 230, please refer to Example 159.

For the preparation of Examples 259 and 260, reference may also be made to Example 164.

For the preparation of Examples 325 and 328-330, reference may also be made to Example 108.

The preparation of Example 231 refers to Example 78, and can also be synthesized according to the following steps.

Add 2-fluoroacrylic acid (8mg, 89.5μmol), triethylamine (61mg, 300μmol) and HATU (34mg, 89.5μmol) to DMF (2mL) in sequence, stir the reaction solution for 10 minutes, add 4-(4 -Amino-2-methylphenyl)-5-cyclopropyl-3-(4-((2-fluoro-2-methylpropyl)aminoformyl)-3-methoxyphenyl)- In a solution of 1H-pyrrole-2-methamide (37 mg, 78 μmol, refer to step 8 of Example 78 for preparation) in DMF (4 mL), the reaction solution was stirred and reacted for 1 hour, filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound. (20mg, 47%).

MS m/z (ESI): 551.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.54(s,1H),10.17(d, J =1.9Hz,1H),8.18(t, J =6.2Hz,1H),7.61(d, J =8.0 Hz,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,1H),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).

The preparation of Example 234 refers to Example 78, and can also be synthesized according to the following steps.

Step 1: Methyl 5-cyano-3-(4-((2-fluoro-2-methylpropyl)aminoformate)-3-methoxyphenyl)-4-(2-methyl Preparation of -4-nitrophenyl)-1H-pyrrole-2-carboxylate

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

MS m/z (ESI): 509.2[M+H] ⁺ .

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

Methyl 5-cyano-3-(4-((2-fluoro-2-methylpropyl)aminoformate)-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, concentrated under reduced pressure to remove the organic solvent, the residue was diluted with water, added with 2N hydrochloric acid aqueous solution to adjust to pH=5, extracted with ethyl acetate, combined organic phases, and treated with anhydrous sodium sulfate Dry, filter and concentrate, and the residue is directly used in the next reaction.

MS m/z (ESI): 495.2[M+H] ⁺ .

Step 3: 5-cyano-3-(4-((2-fluoro-2-methylpropyl)aminoformate)-3-methoxyphenyl)-4-(2-methyl-4 Preparation of -nitrophenyl)-1H-pyrrole-2-methamide

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

MS m/z (ESI): 494.2[M+H] ⁺ .

Step 4: 4-(4-Amino-2-methylphenyl)-5-cyano-3-(4-((2-fluoro-2-methylpropyl)aminoformamide)-3 Preparation of -methoxyphenyl)-1H-pyrrole-2-methamide

5-cyano-3-(4-((2-fluoro-2-methylpropyl)aminoformate)-3-methoxyphenyl)-4-(2-methyl-4-nitro Phenyl)-1H-pyrrole-2-methamide (162 mg, 330 μmol) was added to a mixed solvent (9 mL) of ethanol and water (V/V = 5:1), and iron powder (130 mg, 2.19 mol) and Ammonium chloride (120 mg, 2.19 mol), 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 separated by silica gel column chromatography to obtain the title compound (50 mg, 33%).

MS m/z (ESI): 464.2[M+H] ⁺ .

Step 5: 5-cyano-3-(4-((2-fluoro-2-methylpropyl)aminoformate)-3-methoxyphenyl)-4-(4-(2-fluoro) Preparation of acrylamino)-2-methylphenyl)-1H-pyrrole-2-carboxamide

Add 2-fluoroacrylic acid (16 mg, 180 μmol), triethylamine (61 mg, 599 μmol) and HATU (68 mg, 180 μmol) to DMF (1 mL) in sequence, stir for 10 minutes, and add 4-(4-amino- 2-Methylphenyl)-5-cyano-3-(4-((2-fluoro-2-methylpropyl)aminoformyl)-3-methoxyphenyl)-1H-pyrrole-2 -In a solution of formamide (50 mg, 108 μmol) in DMF (2 mL), the reaction solution was stirred and reacted for 1 hour, filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (10 mg, 16%).

MS m/z (ESI): 536.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.14(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).

The preparation of Example 244 refers to Example 78, and can also be synthesized according to the following steps.

Add 2-fluoroacrylic acid (400mg, 4.47mmol), triethylamine (3.05g, 15.00mmol, 2.1mL) and HATU (1.70g, 4.47mmol) to DMF (10mL) in sequence, and stir the reaction solution for 10 minutes. Add to 4-(4-amino-2-methylphenyl)-5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)aminoformamide)-3-(methane In a solution of oxy-d3)phenyl)-1H-pyrrole-2-carboxamide (1.77g, 3.90mmol, prepared according to the eighth step of Example 78) in DMF (4mL), the reaction solution was stirred for 1 hour and filtered. , the filtrate was separated and purified by prep-HPLC to obtain the title compound (1.43g, 70%).

MS m/z (ESI): 526.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.52(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 =7.9,1.4Hz,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,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).

The preparation of Example 245 refers to Example 78, and can also be synthesized according to the following steps.

Add 2-fluoroacrylic acid (8mg, 89.5μmol), triethylamine (61mg, 300μmol) and HATU (34mg, 89.5μmol) to DMF (2mL) in sequence, stir the reaction solution for 10 minutes, add 4-(4 -Amino-2-methylphenyl)-3-(4-(((1-fluorocyclopropyl)methyl)aminoformyl)-3-methoxyphenyl)-5-(methoxy Methyl)-1H-pyrrole-2-methamide (37 mg, 78 μmol, preparation refers to the eighth step of Example 78) in DMF (4 mL), the reaction solution was stirred for 1 hour, filtered, and the filtrate was separated by prep-HPLC The title compound (4.2 mg, 10%) was purified.

MS m/z (ESI): 553.2[M+H] ⁺ .

The preparation of Example 247 refers to Example 78, and can also be synthesized according to the following steps.

Add 2-fluoroacrylic acid (8mg, 89.5μmol), triethylamine (61mg, 300μmol) and HATU (34mg, 89.5μmol) to DMF (2mL) in sequence, stir the reaction solution for 10 minutes, add 4-(4 -Amino-2-methylphenyl)-3-(4-(((1-fluorocyclopropyl)methyl)aminoformyl)-3-methoxyphenyl)-1H-pyrrole-2- In a solution of formamide (34 mg, 78 μmol, prepared according to step 8 of Example 78) in DMF (4 mL), the reaction solution was stirred and reacted for 1 hour, filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (10 mg, 25%). .

MS m/z (ESI): 509.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.52(s,1H),10.15(s,1H),8.18(t, J =5.8Hz,1H),7.78(d, J =7.9Hz,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 =7.9,1.4Hz,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).

Example 249

5-Chloro-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-3-(4-(((1-fluorocyclopropyl)methyl)aminoformamide) )-3-methoxyphenyl)-1H-pyrrole-2-methamide

The preparation of Example 249 refers to Example 78, and can also be synthesized according to the following steps:

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

Dissolve methyl 4-(2-methyl-4-nitrophenyl)-1H-pyrrole-2-carboxylate (0.5g, 1.92mmol) in DMF (10mL), and add it in batches under ice-water bath conditions N-chlorosuccinimide (256mg, 1.92mmol), then the reaction solution was stirred at 50°C for 4 hours, cooled to room temperature, N-iodosuccinimide (0.43g, 1.92mmol) was added, and the reaction The 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.

MS m/z (ESI): 421.0[M+H] ⁺ .

Step 2: 1-(tert-butyl)2-methyl5-chloro-3-iodo-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-1,2-di Preparation of carboxylic acid esters

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

MS m/z (ESI): 521.0[M+H] ⁺ .

Step 3: Methyl 5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)aminoformamide)-3-methoxyphenyl)-4-(2-methyl- Preparation of 4-nitrophenyl)-1H-pyrrole-2-carboxylate

1-(tert-butyl)2-methyl5-chloro-3-iodo-4-(2-methyl-4-nitrophenyl)-1H-pyrrole-1,2-dicarboxylate (900mg, 1.72mmol), N-((1-fluorocyclopropyl)methyl)-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-di Oxaboropent-2-yl) benzamide (0.72g, 2.06mmol), Pd(dppf)Cl ₂ (125mg, 172μmol) were dissolved in DMF (18mL), and anhydrous potassium phosphate (0.73g) was added under nitrogen protection. 3.44 mmol) in water (3 mL). The reaction solution was replaced with nitrogen and transferred to an oil bath. It was heated to 85°C and stirred for 2 hours. Dissolve in DCM. The organic phase was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and filtered. , concentrated, and the residue was separated by silica gel column chromatography to obtain the target compound (600 mg, 67%).

MS m/z (ESI): 516.1[M+H] ⁺ .

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

Methyl 5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)aminoformate)-3-methoxyphenyl)-4-(2-methyl-4-nitro phenyl)-1H-pyrrole-2-carboxylate (600 mg, 1.16 mmol) 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. Concentrate under reduced pressure to remove organic matter. Solvent, the residue was acidified with hydrochloric acid, extracted with ethyl acetate, the organic phases were combined, and condensed under reduced pressure, and the crude product was directly used in the next reaction.

MS m/z (ESI): 502.1[M+H] ⁺ .

Step 5: 5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)aminoformate)-3-methoxyphenyl)-4-(2-methyl-4- Preparation of nitrophenyl)-1H-pyrrole-2-methamide

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

MS m/z (ESI): 501.1[M+H] ⁺ .

Step 6: 4-(4-amino-2-methylphenyl)-5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)aminoformamide)-3- Preparation of methoxyphenyl)-1H-pyrrole-2-methamide

5-Chloro-3-(4-(((1-fluorocyclopropyl)methyl)aminoformate)-3-methoxyphenyl)-4-(2-methyl-4-nitrobenzene (200 mg, 0.40 mmol) was dissolved in a mixed solvent of dioxane (10 mL) and ethanol (10 mL), and iron powder (224 mg, 4.0 mmol) and ammonium chloride were added in sequence. (220mg, 4.0mmol) in water (5mL), the reaction solution was heated to 60°C under nitrogen protection and stirred for 2 hours, concentrated under reduced pressure to remove the solvent, the residue was dispersed in water, extracted with DCM, the DCM layers were combined, and treated with saturated chlorine Wash with sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, and concentrate. The residue is separated by silica gel column chromatography to obtain the target compound (100 mg, 53%).

MS m/z (ESI): 471.2[M+H] ⁺

Step 7: 5-chloro-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-3-(4-(((1-fluorocyclopropyl)methyl) Preparation of aminoformamide)-3-methoxyphenyl)-1H-pyrrole-2-formamide

Add 2-fluoroacrylic acid (16 mg, 179.67 μmol), triethylamine (61 mg, 598.90 μmol, 83.53 μL) and HATU (68 mg, 179.67 μmol) to DMF (1 mL) in sequence, and stir the reaction solution at room temperature for 10 minutes. Add to 4-(4-amino-2-methyl-phenyl)-3-(4-(isobutylaminoformate)-3-methoxy-phenyl)-5-ethyl-1H- In a solution of pyrrole-2-methamide (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%).

MS m/z (ESI): 543.2[M+H] ⁺ .

¹ H NMR(400MHz, DMSO- d ₆ ) δ 12.45(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),3.64(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),0.96-0.83 (m,2H),0.82-0.65(m,2H).

The preparation of Example 261 refers to Example 78, and can also be synthesized according to the following steps.

HATU (50.14 mg, 132.91 μmol) was added to 4-(2-aminoformamide-4-(4-(2-fluoroacrylamide)-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), and the reaction solution was stirred for 1 hour. The reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (19.6 mg, 38.55%).

MS m/z (ESI): 573.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.51(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).

The preparation of Example 270 refers to Example 78, and can also be synthesized according to the following steps.

HATU (50.14 mg, 132.91 μmol) was added to 4-(2-aminoformamide-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-5-methyl- 1H-pyrrole-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), and the reaction solution was stirred for 1 hour. The reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (20.1 mg, 42.02%).

MS m/z (ESI): 537.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.52(s,1H),10.14(s,1H),8.18(d, J =6.2Hz,1H),7.63(d, J =8.0Hz,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 =1.5Hz,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).

The preparation of Example 273 refers to Example 78, and can also be synthesized according to the following steps.

HATU (50.14 mg, 132.91 μmol) was added to 4-(2-aminoformamide-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-5-methyl- 1H-pyrrole-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 solution was stirred for 1 hour. The reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (26.3 mg, 55.38%).

MS m/z (ESI): 530.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.52(s,1H),10.15(d, J =1.8Hz,1H),8.40(t, J =6.2Hz,1H),7.58(d, J =7.9 Hz,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 =15.6,3.6Hz,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).

The preparation of Example 274 refers to Example 78, and can also be synthesized according to the following steps.

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

MS m/z (ESI): 535.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.46 (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).

The preparation of Example 276 refers to Example 78, and can also be synthesized according to the following steps.

HATU (107 mg, 283 μmol) was added to 4-(4-amino-2-chloro-phenyl)-3-[4-[(1-fluorocyclopropyl)methylaminoformamide]-3-methyl Oxy-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) solution, the reaction solution was stirred for 1 hour. The reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (23 mg, 22%).

MS m/z (ESI): 523.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.61(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).

The preparation of Example 277 refers to Example 78, and can also be synthesized according to the following steps.

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

MS m/z (ESI): 550.0[M+H] ⁺ .

The preparation of Example 279 refers to Example 78, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(2-chloro-4-(2-fluoroacrylamide)phenyl)-1H-pyrrol-3-yl)-2-methyl Oxybenzoic acid (25 mg, 51 μmol, prepared with reference to Example 68 First Step) Dissolve in DMF (1 mL), then add (1-fluorocyclopropyl)methylamine (10 mg, 76 μmol), DIPEA (20 mg, 152 μmol) and HATU (38 mg, 102 μmol), and stir the reaction solution for 10 minutes. After the reaction solution was filtered, the residue was separated and purified by prep-HPLC to obtain the title compound (7.8 mg, 27%).

MS m/z (ESI): 563.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 12.61(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).

The preparation of Example 280 refers to Example 78, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(2-chloro-4-methacryloylaminophenyl)-1H-pyrrol-3-yl)-2-methoxybenzene Formic acid (25 mg, 51 μmol, refer to the first step of preparation in Example 68) was dissolved in DMF (1 mL), and then 1-(aminomethyl)cyclopropanecarbonitrile (11 mg, 76 μmol), DIPEA (20 mg, 152 μmol) and HATU (38 mg, 102 μmol), the reaction solution was stirred for 10 minutes. After the reaction solution was filtered, the residue was separated and purified by prep-HPLC to obtain the title compound (9.8 mg, 33%).

MS m/z (ESI): 570.2[M+H] ⁺ .

1H NMR (400MHz, DMSO- d ₆ ) δ 12.62(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 =7.7Hz,2H),6.36(s,1H),5.72(dd, J =47.6,3.7Hz, 1H),5.45(dd, J =15.5,3.7Hz,1H),3.67(s,3H),3.42(d, J =6.1Hz,2H),1.20-1.13(m,2H),1.12-1.05(m ,2H).

The preparation of Example 282 refers to Example 78, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-1H-pyrrol-3-yl)-2- Methoxybenzoic acid (30 mg, 64 μmol, refer to the first step of Example 68 for preparation), DIPEA (24 mg, 191 μmol) and HATU (36 mg, 96 μmol) were added to DMF (1 mL) in sequence, 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 to stir for 1 hour, then filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (16 mg, 45 %).

MS m/z (ESI): 550.2[M+H] ⁺ .

¹ H NMR(400MHz, DMSO- d ₆ ) δ 12.45(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 ,3H),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).

The preparation of Example 283 refers to Example 78, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(2-fluoro-4-(2-fluoroacrylamide)phenyl)-1H-pyrrol-3-yl)-2-methyl Oxybenzoic acid (50 mg, 105 μmol, preparation refers to the first step of Example 68) was dissolved in DMF (1 mL), HATU (55.5 mg, 147 μmol) and DIPEA (68 mg, 525 μmol) were added under stirring, and the reaction solution was stirred for 30 minutes. 1-(Aminomethyl)cyclopropane-1-carbonitrile hydrochloride (20 mg, 152 μmol) was added to the reaction solution, and stirring was continued for 1 hour. The reaction solution was separated and purified by reverse-phase chromatography column to obtain the title compound (12.8 mg, 22%).

MS m/z (ESI): 554.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 12.65(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).

The preparation of Example 284 refers to Example 78, and can also be synthesized according to the following steps.

Add 2-fluoroacrylic acid (8mg, 89.5μmol), triethylamine (61mg, 300μmol) and HATU (34mg, 89.5μmol) to DMF (2mL) in sequence, stir and react for 10 minutes, add 4-(4-amine methyl-2-chlorophenyl)-5-ethyl-3-(4-(((1-fluorocyclopropyl)methyl)aminoformyl)-3-methoxyphenyl)-1H-pyrrole- In a solution of 2-formamide (37 mg, 78 μmol, refer to step 8 of Example 78) in DMF (4 mL), the reaction solution was stirred and reacted for 1 hour, filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (25 mg, 60 %).

MS m/z (ESI): 557.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.36 (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),3.43(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).

The preparation of Example 287 refers to Example 78, and can also be synthesized according to the following steps.

Add 2-fluoroacrylic acid (8mg, 89.5μmol), triethylamine (61mg, 300μmol) and HATU (34mg, 89.5μmol) to DMF (2mL) in sequence, stir and react for 10 minutes, add 4-(4-amine methyl-2-chlorophenyl)-5-ethyl-3-(4-(((1-fluorocyclopropyl)methyl)aminoformyl)-3-methoxyphenyl)-1H-pyrrole- In a solution of 2-formamide (36 mg, 78 μmol, refer to step 8 of Example 78) in DMF (4 mL), the reaction solution was stirred and reacted for 1 hour, filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (24 mg, 57 %).

MS m/z (ESI): 541.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO -d ₆ ) δ 11.59(s,1H),10.42(s,1H),8.36(t, J =5.9Hz,1H),7.63(d, J =7.9Hz,1H), 7.57(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),2.45(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),

The preparation of Example 352 refers to Example 78, and can also be synthesized according to the following steps.

HATU (87 mg, 231 μmol) was added to 4-(4-amino-2-fluoro-phenyl)-3-[4-[(1-fluorocyclopropyl)methylaminoformamide]-3-methyl Oxy-phenyl]-5-methyl-1H-pyrrole-2-carboxamide (70 mg, 154 μmol, preparation refers to step 8 of Example 78), 2-fluoroprop-2-enoic acid (21 mg, 231 μmol) and DIPEA (60 mg, 462 μmol) in DMF (2 mL), and the reaction solution was stirred for 1 hour. The reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (13.5 mg, 15%).

MS m/z (ESI): 527.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.65 (s, 1H), 10.40 (s, 1H), 8.36 (t, J =5.9Hz, 1H), 7.69-7.55 (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).

The preparation of Example 354 refers to Example 78, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-1H-pyrrol-3-yl)-2- Methoxybenzoic acid (30 mg, 64 μmol, preparation refers to the first step of Example 68), DIPEA (24 mg, 191 μmol) and HATU (36 mg, 96 μmol) were added to DMF (1 mL) in sequence, and the reaction was stirred for 10 minutes. 2-Fluoro-2-methylpropan-1-amine hydrochloride (17 mg, 127 μmol) was added to the reaction solution. The reaction solution was stirred for 1 hour and filtered. The filtrate was separated and purified by prep-HPLC to obtain the title compound (19 mg, 54 %).

MS m/z (ESI): 545.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.13(s,1H),8.11(t, J =6.2Hz,1H),7.52(d, J =7.9Hz,1H),7.44(d, J =2.1 Hz,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).

The preparation of Example 355 refers to Example 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(2-chloro-4-(2-fluoroacrylamide)phenyl)-1H-pyrrol-3-yl)-2-methyl Oxybenzoic acid (25 mg, 51 μmol, preparation refers to the first step of Example 68) was dissolved in DMF (1 mL), and then 2-fluoro-2-methyl-propan-1-amine (10 mg, 77 μmol), DIPEA ( 20 mg, 152 μmol) and HATU (38 mg, 102 μmol), the reaction solution was stirred and reacted for 10 minutes. The reaction solution was filtered and the residue was separated and purified by prep-HPLC to obtain the title compound (9.3 mg, 32%).

MS m/z (ESI): 565.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 12.59(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).

The preparation of Example 364 refers to Example 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-5-methyl-1H-pyrrol-3-yl)-2 -Methoxybenzoic acid (30mg, 67μmol), DIPEA (26mg, 200 μmol) and HATU (38 mg, 100 μmol) were added to DMF (1 mL) in sequence, stirred for 10 minutes, and 3-amino-2,2-dimethylpropionitrile (12 mg, 127 μmol) was added to the reaction solution. The reaction was stirred for 1 hour, filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (15 mg, 42%).

MS m/z (ESI): 532.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 12.18(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).

For the preparation of Example 365, refer to Example 78 or 249. It can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(4-(2-fluoroacrylamide)-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, stirred for 10 minutes, and 3-amino-2 was added to the reaction solution. 2-Dimethylpropionitrile (12mg, 127μmol), reaction solution The reaction was stirred for 1 hour, filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (13 mg, 37%).

MS m/z (ESI): 552.2[M+H] ⁺ .

¹ H NMR(400MHz, DMSO- d ₆ ) δ 12.45(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),3.64(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),

The preparation of Example 366 refers to Example 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(2-chloro-4-(2-fluoroacrylamide)phenyl)-1H-pyrrol-3-yl)-2-methyl Oxybenzoic acid (25 mg, 51 μmol) was dissolved in DMF (1 mL), and 3-amino-2,2-dimethyl-propionitrile (10 mg, 76 μmol), DIPEA (20 mg, 152 μmol) and HATU (38 mg, 102 μmol), the reaction solution was stirred for 10 minutes. The reaction solution was filtered and the residue was separated and purified by prep-HPLC to obtain the title compound (8.2 mg, 28%).

MS m/z (ESI): 572.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 12.62(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).

The preparation of Example 367 refers to Example 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(2-fluoro-4-(2-fluoroacrylamide)phenyl)-1H-pyrrol-3-yl)-2-methyl Oxybenzoic acid (50 mg, 105 μmol, preparation refers to the first step of Example 68) was dissolved in DMF (1 mL), DIPEA (68 mg, 525 μmol) and HATU (52 mg, 137 μmol) were added under stirring, and stirring was continued for 30 minutes. 3-Amino-2,2-dimethylpropionitrile (21 mg, 210 μmol) was added. The reaction solution was continued to stir for 1 hour. The reaction solution was separated and purified by reverse-phase column chromatography to obtain the title compound (11.3 mg, 19%).

MS m/z (ESI): 556.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.46 (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 =47.6,3.8Hz,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).

The preparation of Example 368 refers to Example 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(2-fluoro-4-(2-fluoroacrylamide)phenyl)-1H-pyrrol-3-yl)-2-methyl Oxybenzoic 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, and stirred for 30 minutes. Subsequently, 2-methylpropane-1-amine (8 mg, 105 μmol) was added, and the reaction solution was stirred for 1 hour. The reaction solution was separated by reverse-phase column chromatography to obtain the title compound (12.8 mg, 23%).

MS m/z (ESI): 531.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.46 (s, 1H), 8.23 (s, 1H), 8.08 (t, J =5.9Hz, 1H), 7.64-7.46 (m, 2H), 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).

The preparation of Example 369 refers to Example 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(2-fluoro-4-(2-fluoroacrylamide)phenyl)-1H-pyrrol-3-yl)-2-methyl Oxybenzoic acid (600mg, 1.26mmol) was dissolved in DMF (10mL), and HATU (618mg, 1.64mmol) and DIPEA (815mg, 6.30 mmol), the reaction solution was stirred for 30 minutes. 2-Fluoro-2-methylpropan-1-amine hydrochloride (161 mg, 1.77 mmol) was added and stirring was continued for 1 hour. The reaction solution was diluted with ethyl acetate, and the organic phase was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by reverse-phase column chromatography to obtain the title compound (167.2 mg, 24% ).

MS m/z (ESI): 549.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 12.63(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 =1.5Hz,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).

The preparation of Example 372 refers to Example 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(2-fluoro-4-(2-fluoroacrylamide)phenyl)-1H-pyrrol-3-yl)-2-methyl Oxybenzoic acid (1g, 2.1mmol) was dissolved in DMF (20mL), HATU (1.03g, 2.73mmol) and DIPEA (1.36g, 10.5mmol) were added with stirring, and the reaction solution was stirred for 30 minutes. (1-Fluorocyclopropyl)methanamine hydrochloride (262 mg, 2.94 mmol) was added, and stirring was continued for 1 hour. The reaction solution was diluted with ethyl acetate, and the organic phase was treated with saturated aqueous ammonium chloride solution and Wash with saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, filter, concentrate, and be separated and purified by reverse-phase column chromatography to obtain the title compound (320.4 mg, 28%).

MS m/z (ESI): 547.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 12.56 (s, 1H), 10.38 (s, 1H), 8.30 (t, J =5.9Hz, 1H), 7.59-7.49 (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).

The preparation of Example 373 refers to Example 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(2-fluoro-4-(2-fluoroacrylamide)phenyl)-1H-pyrrol-3-yl)-2-methyl Oxybenzoic 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, and the reaction solution was stirred for 30 minutes. 1-(1-(Aminomethyl)cyclopropyl)ethane-1-one hydrochloride (18 mg, 158 μmol) was added, and then the reaction solution was stirred at room temperature for 1 hour. The reaction solution was separated and purified by reverse-phase column chromatography to obtain the title compound (9.4 mg, 16%).

MS m/z (ESI): 571.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 12.66 (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 =15.4,3.8Hz,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).

The preparation of Example 374 refers to Example 78 or 249, and can also be synthesized according to the following steps.

HATU (48 mg, 126 μmol) was added to 4-(2-aminoformamide-4-(4-(2-fluoropropenylamide)-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), and the reaction solution was stirred for 1 hour. The reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (18.5 mg, 40%).

MS m/z (ESI): 547.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.53 (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).

The preparation of Example 375 refers to Example 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(4-(2-fluoroacrylamide)-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, stirred and reacted for 10 minutes, then cyclopropylmethylamine (9 mg, 127 μmol) was added. , the reaction solution was stirred for 1 hour, filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (18 mg, 51%).

MS m/z (ESI): 525.2[M+H] ⁺ .

¹ H NMR(400MHz, DMSO- d ₆ ) δ 12.45(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),3.64(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).

The preparation of Example 376 refers to Example 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(4-(2-fluoroacrylamide)-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, stirred for 10 minutes, and 2,2-difluoropropan-1-amine was added. (12 mg, 127 μmol), the reaction solution was stirred for 1 hour, filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (16 mg, 45%).

MS m/z (ESI): 549.1[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.20 (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).

The preparation of Example 381 refers to Example 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-1H-pyrrol-3-yl)-2- Methoxybenzoic acid (50 mg, 106 μmol) was dissolved in DMF (2 mL), add [1-(difluoromethyl)cyclopropyl]methylamine (25 mg, 159 μmol), DIPEA (28 mg, 212 μmol) and HATU (60 mg, 159 μmol), and stir the reaction solution for 10 minutes. The reaction solution was filtered and the residue was separated and purified by prep-HPLC to obtain the title compound (14 mg, 22%).

MS m/z (ESI): 575.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 12.55(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 =8.3Hz,1H),6.84(d, J =7.9Hz,1H ),6.79(s,1H),6.37(s,1H),6.01-5.57(m,2H),5.41(dd, 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).

The preparation of Example 383 refers to Example 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-1H-pyrrol-3-yl)-2- Methoxybenzoic acid (25 mg, 53 μmol) was dissolved in DMF (1 mL), and [1-(fluoromethyl)cyclopropyl]methanamine (9 mg, 64 μmol), DIPEA (14 mg, 106 μmol) and HATU (30 mg, 80 μmol), the reaction solution was stirred for 10 minutes. The reaction solution was filtered and the residue was separated and purified by prep-HPLC to obtain the title compound (8 mg, 27%).

MS m/z (ESI): 557.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 12.51(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,1H),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).

The preparation of Example 384 refers to Example 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(2-chloro-4-(2-fluoroacrylamide)phenyl)-1H-pyrrol-3-yl)-2-methyl Oxybenzoic acid (100 mg, 212 μmol) was dissolved in DMF (2.5 mL), and then [1-(fluoromethyl)cyclobutyl]methanamine (65 mg, 556 μmol), DIPEA (548 mg, 4.24 mmol) and HATU ( 120 mg, 318 μmol), the reaction solution was stirred for 10 minutes. The reaction solution was filtered and the residue was separated and purified by prep-HPLC to obtain the title compound (21.5 mg, 17%).

MS m/z (ESI): 571.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 12.54(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).

The preparation of Example 387 refers to Example 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-1H-pyrrol-3-yl)-2- Methoxybenzoic acid was dissolved in DMF (2mL), and 2-[1-(aminomethyl)cyclopropyl]acetonitrile (47mg, 318μmol), DIPEA (55mg, 424μmol) and HATU (120mg, 318μmol) were added ), the reaction solution was stirred for 10 minutes. The reaction solution was filtered and the residue was separated and purified by prep-HPLC to obtain the title compound (37 mg, 30%).

MS m/z (ESI): 564.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 12.52(s,1H),10.19(s,1H),8.21(t, J =6.0Hz,1H),7.72-7.49(m,4H),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).

The preparation of Example 389 refers to Example 78 or 249, and can also be synthesized according to the following steps.

HATU (38 mg, 100 μmol) was added to 4-(2-aminoformamide-4-(4-(2-fluoropropenylamide)-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) of DMF (2.5 mL) solution, and the reaction solution was stirred for 1 hour. The reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (11.8 mg, 31%).

MS m/z (ESI): 555.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.52(s,1H),10.15(d, J =1.9Hz,1H),8.21(t, J =5.9Hz,1H),7.60(d, J =7.9 Hz,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).

The preparation of Example 398 refers to Example 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(2-chloro-4-(2-fluoroacrylamide)phenyl)-1H-pyrrol-3-yl)-2-methyl Oxybenzoic acid (40 mg, 81 μmol) was dissolved in DMF (1 mL), then cyclopropylmethylamine (13 mg, 122 μmol), DIPEA (32 mg, 244 μmol) and HATU (62 mg, 163 μmol), the reaction solution was stirred for 10 minutes. The reaction solution was filtered and the residue was separated and purified by prep-HPLC to obtain the title compound (11.3 mg, 25%).

MS m/z (ESI): 545.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 12.61(s,1H),10.43(s,1H),8.14(t, J =5.8Hz,1H),7.89(d, J =2.1Hz,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).

The preparation of Embodiment 399 refers to Embodiment 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-ethyl-4-(4-(2-fluoroacrylamide)-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, stirred for 10 minutes, and then added cyclopropylmethylamine (9 mg, 127 μmol) , the reaction solution was stirred for 1 hour, filtered, and the filtrate was separated and purified by prep-HPLC to obtain the title compound (20 mg, 57%).

MS m/z (ESI): 519.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.28(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 =3.0 Hz,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(dd, 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).

The preparation of Embodiment 400 refers to Embodiment 78 or 249, and can also be synthesized according to the following steps.

HATU (42 mg, 112 μmol) was added to 4-(4-amino-2-chloro-phenyl)-3-[4-(cyclopropylmethylaminoformamide)-3-methoxy-phenyl ]-5-ethyl-1H-pyrrole-2-carboxamide (35 mg, 75 μmol, preparation refers to step 8 of Example 78), 2-fluoroprop-2-enoic acid (10 mg, 112 μmol) and DIPEA (29 mg, 225 μmol) in DMF (2.5 mL), and the reaction solution was stirred for 1 hour. The reaction solution was directly separated and purified by prep-HPLC to obtain the title compound (4 mg, 9.6%).

MS m/z (ESI): 539.0[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.53(s,1H),10.39(s,1H),8.13(t, J =5.7Hz,1H),7.85(d, J =2.1Hz,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(dd, 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).

The preparation of Example 410 refers to Example 78 or 249, and can also be synthesized according to the following steps.

Add 2-fluoroacrylic acid (400mg, 4.5mmol), triethylamine (3.05g, 15.00mmol, 2.1mL) and HATU (1.70g, 4.47mmol) to DMF (10mL) in sequence, stir for 10 minutes, and add 4-(4-Amino-2-methylphenyl)-5-chloro-3-(4-(((1-fluorocyclopropyl)methyl)aminoformamide)-3-(methoxy -d3) Phenyl)-1H-pyrrole-2-carboxamide (1.81g, 3.90mmol, for preparation, refer to the eighth step of Example 78) in DMF (4mL), the reaction solution was stirred for 1 hour, filtered, and the filtrate The title compound (600 mg, 29%) was obtained through prep-HPLC separation and purification.

MS m/z (ESI): 546.2[M+H] ⁺ .

¹ H NMR(400MHz, DMSO- d ₆ ) δ 12.45(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),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) .

The preparation of Example 411 refers to Example 78 or 249, and can also be synthesized according to the following steps.

4-(2-Aminoformyl-5-chloro-4-(4-(2-fluoroacrylamide)-2-methylphenyl)-1H-pyrrol-3-yl)-2- Methoxybenzoic acid (50 mg, 106 μmol) was dissolved in DMF (1 mL), then 2-methylpropan-1-amine (8 mg, 106 μmol), DIPEA (41 mg, 318 μmol) and HATU (80 mg, 212 μmol) were added, and the reaction The liquid was stirred and reacted for 10 minutes. The reaction solution was filtered and the residue was separated and purified by prep-HPLC to obtain the title compound (23.6 mg, 42%).

MS m/z (ESI): 527.2[M+H] ⁺ .

¹ H NMR (400MHz, DMSO- d ₆ ) δ 12.51(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).

Biological test evaluation

The invention will be further described and explained below in conjunction with test examples, but these examples are not meant to limit the scope of the invention.

1. Test enzymology experiments

Test Example 1. Determination of the inhibitory effect of the compounds of the present invention on the activity of FGFR1-4 and FGFR2 V564F

1. Experimental purpose: Use the TR-FRET method to test the IC ₅₀ of compounds on FGFR1, FGFR2, FGFR3, FGFR4 and FGFR2 V564F at the ATP Km concentration.

2. Experimental instruments and reagents:

3. Experimental method: The inhibitory activity of compounds against FGFR1, FGFR2, FGFR3, FGFR4 and FGFR2 V564F kinase region fragment was detected by TR-FRET (time-resolved fluorescence resonance energy transfer) method. Among the five kinase tests, the compound detected the highest The concentration is 1000nM, 3-fold dilution, a total of 11 concentrations (1000nM-0.017nM). Use kinase buffer (50mM HEPES pH 7.5, 1mM EGTA, 10mM MgCl2, 2mM DTT, 0.01% Tween-20) to prepare 4× enzyme solution, gradient dilution of 4× compound solution, 2× ATP/Peptide substrate solution. Add 2.5 μL enzyme solution and 2.5 μL diluted 5× compound solution to the 384-well plate, then add 5 μL 2× ATP/Peptide substrate solution, FGFR1, FGFR2, FGFR3 and FGFR2 V564F kinase react at room temperature for 60 minutes, FGFR4 kinase After reacting at room temperature for 120 minutes, add 10 μL of 2× stop and detection mixture prepared with 1×LANCE detection buffer with a concentration of 20mM EDTA and 2nM Europium-anti-phosphotyrosine (PT66). After reacting at room temperature for 30 minutes, use Use a microplate reader to measure the fluorescence signal value of each plate well.

4. Experimental data processing method:

1) Inhibition rate (%): Calculate the original data (665nm/620nm reading ratio) according to 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)] Add enzyme to the reaction well.

2) Curve fitting: Use log(inhibitor) vs.response--Variable slope(four parameters) in GraphPad Prism 6 to perform fitting equation analysis on the compound concentration and corresponding inhibition rate, fit the curve and obtain the compound IC ₅₀ value.

The fitting calculation equation is Y=Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)* HillSlope)).

5. Experimental results: The IC ₅₀ values of the compounds for FGFR2, 3 and FGFR2 V564F kinase activities are shown in Table 1-3 below:

6. Experimental conclusion: The compounds of the present invention have good inhibitory effects on FGFR2, FGFR3 and FGFR2 V564F kinase activities, and have good selectivity for FGFR1.

2. Cell viability experiment

1. Experimental purpose: To evaluate the inhibitory effect of compounds on the proliferation of NCI-H716, SNU-16 and BaF3-FGFR2-BICC1 V564F cells through cell proliferation inhibition experiments.

2. Experimental instruments and reagents:

2.3 Cell source

3.Experimental method:

The CellTiter-Glo method was used to detect the compound's inhibitory effect on the proliferation of NCI-H716, SNU-16 and BaF3 FGFR2-BICC1 V564F cells. The highest concentration of the compound tested was 1000nM, 3-fold dilution, a total of 9 concentrations (1000nM-0.15nM ). After the cells were plated at an appropriate density, compounds were added the next day and incubated for 72 hours before detection using the CellTiter-Glo Luminescebt detection kit.

4. Experimental data processing method:

1) Inhibition rate (%): Inhibition rate % = [(average value of positive control wells - sample well value)/(average value of positive control wells - average value of negative control wells)] × 100, where the positive control wells are enzymes without compounds Reaction wells, negative control wells are reaction wells without enzyme.

2) Curve fitting: Use log(inhibitor) vs.response--Variable slope(four parameters) in GraphPad Prism 6 to perform fitting equation analysis on the compound concentration and corresponding inhibition rate, fit the curve and obtain the compound IC ₅₀ value.

The fitting calculation equation is Y=Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)* HillSlope)).

5. The experimental results are shown in Table 4 below:

6.Experimental conclusion:

The compounds of the present invention have significant proliferation inhibitory effects on NCI-H716, SNU-16 and BaF3 FGFR2-BICC1 V564F cells.

3. Determination of the ability of the compound of the present invention to kill human renal cancer cell line UMUC-14

1. Experimental purpose:

The purpose of this test example is to measure the proliferation of human renal cancer cell line UMUC-14 to evaluate the ability of compounds to kill this cell.

2. Experimental instruments and reagents:

3. Experimental methods:

Prepare a cell suspension of 22,222 cells/ml, add 180 μl of cell suspension to each well in a 96-well plate, that is, 4,000 cells/well, and culture overnight. In a 96-well V-bottom plate, 4mM compounds were diluted 4-fold with DMSO; compounds in each well were diluted 40-fold with complete medium. Add 20 μl of compound to the cell wells. Add TAS-120 to the negative control wells to a final concentration of 10uM. Incubate for 5 days in a 37°C, 5% _CO2 cell culture incubator. Remove 50ul of supernatant, add 50ul of CTG lysis solution (CTG, Suzhou Yingze, #ZEB-CV1), shake for lysis, and let stand to balance the signal. The signal intensity was measured using a microplate reader (PE, #2104-0010). Data were analyzed using GraphPad Prism 8.3.0.

4. Experimental data processing method:

Data were analyzed using GraphPad Prism 8.3.0.

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 sample wells are cells plus different concentration gradient compound wells, and the positive control wells For cells, add 10uM TAS-120 to the negative control well for cells.

Curve fitting: According to the inhibition rate (%) of each concentration, use log(inhibitor) vs. response--Variable slope (four parameters) in GraphPad Prism 6.0 to perform curve fitting to obtain the IC ₅₀ value. The calculation equation is Y=Bottom+( Top-Bottom)/(1+10^ ((LogIC ₅₀ -X)*HillSlope)).

5. The experimental results are shown in Table 7 below:

6. Experimental conclusion: The compounds of the present invention have significant inhibitory effect on the proliferation of UMUC-14 cells.

4. Determination of pharmacokinetics in Balb/C mice

1. Research purpose: Using Balb/C mice as test animals, 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.

2.Test plan

2.1 Test drugs: Compounds of the present invention, homemade.

2.2 Experimental animals: Balb/C Mouse (3 animals/example), male, Shanghai Bikai Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 N0.311620400001794).

2.3 Administration: Balb/C mice, male; p.o. after fasting overnight, the dose is 5 mg/kg, and the administration volume is 10 mL/kg.

2.4 Sample collection: Before and after administration of mice, 0.04mL of blood was collected from the orbit at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours, and placed in an EDTA-K ₂ test tube at 4°C 6000rpm. Centrifuge for 6 minutes to separate plasma and store at -80°C.

2.5 Sample processing:

1) Add 100uL acetonitrile to 20uL of plasma sample to precipitate, mix and centrifuge at 3500×g for 5 to 20 minutes.

2) Take the treated supernatant solution and perform LC/MS/MS analysis of the concentration of the compound to be tested. LC/MS/MS analysis instrument: AB Sciex API 4000 Qtrap

2.6 Liquid phase analysis

Liquid phase conditions: Shimadzu LC-20AD pump Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

Chromatography column: Waters X Bridge 5um C18 50

3. Test results and analysis

The main parameters of pharmacokinetics were calculated using WinNonlin 6.1. The results of mouse drug metabolism experiments are shown in Table 8 below:

Experimental conclusion: The compound of the present invention shows good drug metabolism properties.

5. Determination of pharmacokinetics in rats

1. Experimental purpose: SD rats were used as test animals to study the pharmacokinetic behavior of the compound of the present invention in the rat body (plasma) when administered orally at a dose of 100 mg/kg.

2. Experimental plan

2.1. Test drugs: compounds of the examples of the present invention, homemade.

2.2. Experimental animals: 3 SD rats in each group, male, Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 N0.311620400001794).

2.3. Drug preparation: PO, 10%solutol HS15-0.5%CMC-Na, dissolve with ultrasound, and prepare into a clear solution or uniform suspension.

2.4. Dosing schedule: 3 SD rats in each group, male; after fasting overnight, they were administered p.o., the dose was 100 mg/kg, and the administration volume was 10 mL/kg.

2.5. Sample collection: After oral administration to rats, at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours; collect 0.2 mL of blood from the jugular vein, place it in an EDTA-K ₂ test tube, and centrifuge at 6000 rpm for 6 minutes at 4°C. The plasma was separated and stored at -80°C.

2.6. Sample processing:

1) Add 100uL acetonitrile to 20uL of plasma sample to precipitate, mix and centrifuge at 3500×g for 5 to 20 minutes.

2) Take the treated supernatant solution and conduct LC/MS/MS analysis of the concentration of the compound to be tested. LC/MS/MS analysis instrument: AB Sciex API 4000.

2.7. Liquid phase analysis:

●Liquid phase conditions: Shimadzu LC-20AD pump

●Chromatography column: Waters Xbridge C18 5μm, 4.6 X 50mm Mobile phase: Liquid A is 0.1% formic acid aqueous solution, Liquid B is methanol

●Flow rate: 1.0mL/min Elution time: 0-4.0 minutes, the elution solution is as follows:

3. The experimental results and data processing are shown in Table 9 below:

4. Experimental conclusion:

The compounds of the present invention exhibit good drug metabolism properties.

6. In vivo pharmacodynamic study of compounds in subcutaneous xenograft tumor model of human renal cancer cell line UMUC-14 nude mice

1.1 Experimental purpose: To evaluate the in vivo efficacy of the compound in the human renal cancer cell line UMUC-14 nude mouse subcutaneous transplant tumor model.

1.2 Experimental instruments and reagents

1.2.1 Instruments

1.2.2 Reagents

1.3 Experimental operation and data processing

1.3.1 Animals: Nu/nu Mice, ♀, 6 weeks, purchased from Beijing Viton Lever

1.3.2 Cell culture and cell suspension preparation

a, Take out a UMUC-14 cell line from the cell bank, resuscitate the cells with MEM medium (1% MEM NEAA+1X L-Glutamine+10% FBS), and place the resuscitated cells in a cell culture flask (marked on the wall of the flask Cell type, date, cultivator's name, etc.) were placed in a CO ₂ incubator (the incubator temperature is 37°C, and the CO ₂ concentration is 5%).

b. Passage every three days. After passage, the cells continue to be cultured in a CO ₂ incubator. This process is repeated until the cell number meets the in vivo drug efficacy requirements.

c. Collect the cells in the exponential growth phase and count them with a fully automatic cell counter. According to the counting results, resuspend the cells in 1:1 PBS and Matrigel to 2.5×10 ⁷ cells/mL and place them in an ice box for later use.

1.3.3 Cell seeding

a, Before inoculation, nude mice were marked with disposable ear tags for rats and mice;

b. Mix the cell suspension evenly during inoculation, use a 1mL syringe to draw 0.1-1mL of cell suspension, eliminate air bubbles, and then place the syringe on an ice pack for later use;

c, Use 75% alcohol cotton ball to disinfect the right side of the nude mouse’s back near the armpit (inoculation site)

d. Inoculate the experimental nude mice in sequence (0.2mL cell suspension is inoculated into each mouse). After inoculation, the wound was disinfected with alcohol and returned to the breeding cage for follow-up observation.

1.3.4 Tumor measurement, grouping and administration of tumor-bearing mice

a. According to the tumor growth, measure the tumor and calculate the tumor size on the 14th to 16th day after vaccination;

Tumor volume calculation: Tumor volume (mm ³ ) = length (mm) × width (mm) × width (mm)/2

b, According to the body weight and tumor size of tumor-bearing mice, random grouping method is used to divide the groups into groups;

c. According to the grouping results, start administering the test drug (administration method: oral administration; administration volume: 10mL/kg; administration frequency: 1 time/day or 2 times/day; administration period: 2-3 weeks; Solvent: 10%Solutol HS15/0.5%CMC-Na).

d. After starting to administer the test drug, measure and weigh the tumor twice a week.

e, The animals were euthanized after the experiment.

f. Use Excel and other software to process data. Calculation of compound tumor inhibition rate TGI (%): When the tumor does not regress, TGI (%) = [1-(average tumor volume at the end of administration in a treatment group - average tumor volume at the beginning of administration in this treatment group)/( The average tumor volume in the solvent control group at the end of treatment - the average tumor volume in the solvent control group at the beginning of treatment)] × 100%. When the tumor regresses, TGI (%) = [1-(average tumor volume at the end of administration in a certain treatment group - average tumor volume at the beginning of administration in this treatment group)/average tumor volume at the beginning of administration in this treatment group] × 100%.

1.4 The experimental results are shown in Table 10 below:

1.5 Experimental conclusion: The compounds of the present invention exhibit excellent tumor inhibitory effects in the model.

Claims (20)

A compound represented by general formula (I), its stereoisomer or its pharmaceutically acceptable salt,

in, Ring A is a monocyclic heteroaryl group; M ₁ is N or CR _m1 ; M ₂ is N or CR _m2 ; L ₁ , L ₂ and L ₃ are each independently selected from bond, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -(CH ₂ ) _n C(O) (CR _aa R _bb ) _n1 -, -(CH ₂ ) _n C(O)NR _aa (CR _aa R _bb ) _n1 -, -(CH ₂ ) _n (CR _aa R _bb ) _n2 -, -(CR _aa R _bb ) _n O(CH ₂ ) _n1 -, -(CH ₂ ) _n S(CR _aa R _bb ) _n3 -, -(CR _aa R _bb ) _n3 (CH ₂ ) _n NR _cc -, -(CH ₂ ) _n NR _aa (CR _bb R _cc ) _n -, -(CH ₂ ) _n NR _aa C(O)-, -(CH ₂ ) _n P(O) _p R _aa -, -(CH ₂ ) _n S(O) _m -, -(CH ₂ ) _n S(O) _m NR _aa -, -C(=NR _aa )NR _aa -, -C(=CR _bb R _cc )-, -C(=S)NR _aa -and -(CH ₂ ) _n NR _aa S(O) _m -; R ₁ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, side oxy, 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 ) ₂ R _a , the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and the heteroaryl group may be further substituted if desired; R ₂ is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxygen, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy group, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR _b , -C(O)R _b , -SR _b , S(O)R _b or S (O) ₂ R _b , the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkyloxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, Aryl and heteroaryl groups may optionally be further substituted; R ₃ is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxygen, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy group, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR _c , -C(O)R _c , -SR _c , S(O)R _c or S (O) ₂ R _c , the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkyloxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, Aryl and heteroaryl groups may optionally be further substituted; R ₄ is independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, pendant oxygen, thio, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy base, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR _d , -C(O)R _d , -SR _d , S(O)R _d or S (O) ₂ R _d , the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkyloxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, Aryl and heteroaryl groups may optionally be further substituted; R ₅ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, side oxy, 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 ) ₂ R _e , the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and the heteroaryl group may be further substituted if desired; R _m1 is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, side oxy, 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 ) ₂ R _f , the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and the heteroaryl group may be further substituted if desired; R _m2 is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, side oxy, 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 ) ₂ R _g , the amino group, alkyl group, alkenyl group, alkynyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and the heteroaryl group may be further substituted if desired; Alternatively, one of R ₂ and one of R ₃ are connected to adjacent atoms to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, and the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optional Land can be further displaced; Alternatively, one of R ₃ and one of R ₄ are connected to adjacent atoms to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, and the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optional. Land can be further displaced; R _a , R _b , R _c , R _d , Re , _{R f} and R _g are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl , pendant oxygen group, thio group, deuterated alkyl group, haloalkyl group, hydroxyalkyl group, alkoxy group, haloalkoxy group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group, the amino group, alkyl group base, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and The heteroaryl group may be further substituted if desired; R _aa , R _bb and R _cc are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy group, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the amino group, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy A group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group may be further substituted as necessary; Alternatively, R _aa and R _bb form a cycloalkyl, heterocyclyl, aryl or heteroaryl group with adjacent atoms, and the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted if necessary. ; Alternatively, R _bb and R _cc form a cycloalkyl, heterocyclyl, aryl or heteroaryl group with adjacent atoms, and the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted if necessary. ; 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 -L ₁ -R ₁ is

When , the ring A is not pyridyl, pyrimidinyl or pyridazine; and the compound is not the following compound:

The compound described in claim 1, its stereoisomer or its pharmaceutically acceptable salt, wherein the compound is represented by formula (II) or formula (II-1),

in, Ring A is a monocyclic heteroaryl group; L ₁ is selected from -(CH ₂ ) _n C(O)(CR _aa R _bb ) _n1 -, -(CH ₂ ) _n C(O)NR _aa (CR _aa R _bb ) _n1 -, -(CH ₂ ) _n (CR _aa R _bb ) _n2 -or-(CR _aa R _bb ) _n O(CH ₂ ) _n1 -; R _aa and R _bb are each independently selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-6 alkyl group, C _2-6 alkenyl group, C _{2- 6} alkynyl, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, _{halo C 1-6 alkoxy, C 1-6 hydroxyalkyl ,} C _3-8 Cycloalkyl, 3-12-membered heterocyclyl, C _6-14- membered aryl or 5-14-membered heteroaryl; R ₁ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, mercapto, cyano, nitro, side oxy, thio, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl _, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl , 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterium Substitute C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, _halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3 -12-membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group, optionally further substituted by hydrogen, deuterium, halogen, amino group, hydroxyl group, mercapto group, cyano group, nitro group, side oxygen group , thio group, C _1-3 alkyl group, C _2-4 alkenyl group _, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 hydroxyalkyl group, One or more substitutions among C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, and 5-6 membered heteroaryl; Preferably, R ₁ is selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 Alkynyl _, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 ring Alkyl, 3-12-membered heterocyclyl, C _6-14 aryl or 5-14-membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl _, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl , 3-12-membered heterocyclic group, C _6-14- membered aryl group, 5-14-membered heteroaryl group, optionally further hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, side oxygen group , thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 hydroxyalkyl group, One or more substitutions among C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, and 5-6 membered heteroaryl; R ₂ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, deuterated C _1-6 alkyl, halo C 1-6 alkyl _, C _1-6 alkoxy, halo C _1-6 alkoxy, deuterated C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; R ₃ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, side oxy, 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, halo C _1-6 alkyl, C _1-6 alkyl Oxygen, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, 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) ₂ R _c ; preferably , R ₃ is independently selected from hydrogen, deuterium, halogen, amine group, C _1-6 alkyl substituted amine group, hydroxyl, cyano group, nitro group, side oxy group, thio group, C _1-6 alkyl group, C _3-8 cycloalkyl substituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 Alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl Base, -OR _c , -C(O)R _c , -SR _c , S(O)R _c or S(O) ₂ R _c ; R _c is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 Hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, the amino group, hydroxyl group, C _1-6 alkyl substituted amine Base, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl and 5-14 membered heteroaryl are optionally hydrogenated , deuterium, halogen, amino group, C _1-6 alkyl substituted amino group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-6 alkyl group, C _2-6 alkenyl group, C _{2 -6} alkynyl, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, _{C 3-} One or more substitutions in _8- cycloalkyl, 3-12-membered heterocyclyl, C _6-14- membered aryl or 5-14-membered heteroaryl; Preferably, R _c is independently selected from hydrogen, deuterium, halogen, amine group, C _1-6 alkyl substituted amine group, hydroxyl, cyano group, nitro group, side oxy group, thio group, C _1-6 alkyl group Base, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; R ₄ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, _{C 3- 8-} cycloalkyl, 3-12-membered heterocyclyl, C _6-14- membered aryl or 5-14-membered heteroaryl; R ₆ , R ₇ and R ₈ are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl _, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl , 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterium Substitute C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, _halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3 -12-membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group, optionally optionally an amino group, hydroxyl group which may be further substituted by hydrogen, deuterium, halogen, amino group, C _1-3 alkyl group, Cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group , one or more substitutions among C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl; Alternatively, one of R ₂ and one of R ₃ are connected to adjacent atoms to form a C _3-8 cycloalkyl group, a 3-12 membered heterocyclyl group, a C _6-14 membered aryl group or a 5-14 membered heteroaryl group, which C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl may be further optionally replaced by hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, Nitro group, side oxygen group, thio group, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, deuterated C _1-6 alkyl group, halo C _1-6 alkyl group, C _{1 -6} alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered One or more substitutions in the heteroaryl group; Or, one of R ₃ and one of R ₄ are connected to adjacent atoms to form a C _3-8 cycloalkyl group, a 3-12 membered heterocyclyl group, a C _6-14 aryl group or a 5-14 membered heteroaryl group, which C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl may be further optionally replaced by hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, Nitro group, side oxygen group, thio group, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, deuterated C _1-6 alkyl group, halo C _1-6 alkyl group, C _{1 -6} alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered One or more substitutions in the heteroaryl group; 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. The compound described in claim 1 or 2, its stereoisomer or its pharmaceutically acceptable salt, wherein, Ring A is selected from monocyclic heteroaryl; The monocyclic heteroaryl group is preferably a 5-12-membered heteroaryl group; more preferably a 5-membered or 6-membered heteroaryl group; further preferably, it is selected from a 5-membered or 6-membered heteroaryl group containing 1-3 N, O or S atoms. base; The preferred monocyclic heteroaryl group is

,

,

,

,

,

,

or

; The monocyclic heteroaryl group is more preferably the following group:

The compound described in claim 1, its stereoisomer or its pharmaceutically acceptable salt, wherein the compound is represented by formula (III),

L ₁ is selected from -(CH ₂ ) _n C(O)(CR _aa R _bb ) _n1 -, -(CH ₂ ) _n C(O)NR _aa (CR _aa R _bb ) _n1 -, -(CH ₂ ) _n (CR _aa R _bb ) _n2 -or-(CR _aa R _bb ) _n O(CH ₂ ) _n1 -; R _aa and R _bb are each independently selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _{2- 4} alkynyl, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, _{halo C 1-3 alkoxy} , C _1-6 hydroxyalkyl; R ₁ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, mercapto, cyano, nitro, side oxy, thio, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , Deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, _{C 1-3 hydroxyalkyl} , C _3-6 cycloalkyl , 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl, the amino group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterium Substitute C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, _halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3 -8-membered heterocyclic group, C _6-10 aryl group, 5-6 membered heteroaryl group can be further optionally substituted by hydrogen, deuterium, halogen, amino group, hydroxyl group, mercapto group, cyano group, nitro group, side oxygen group, Thio group, 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-, halo C _1-3 alkyl, halo C _2-4 alkenyl, C _{1-3 alkoxy, halo C 1-3 alkoxy} , C _1-3 hydroxyalkyl, C _3-6 ring One or more substitutions among alkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl; Preferably, R ₁ is selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, mercapto group, cyano group, nitro group, side oxy group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _{2 -4} alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _{3- 6-} cycloalkyl, 3-8-membered heterocyclyl, C _6-10 aryl or 5-6-membered heteroaryl, the amino group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 Alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 ring Alkyl group, 3-8 membered heterocyclic group, C _6-10 aryl group, 5-6 membered heteroaryl group can be further optionally replaced by hydrogen, deuterium, halogen, amino group, hydroxyl group, mercapto group, cyano group, nitro group, Side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 alkyl group Oxygen group, halo C _1-3 alkoxy group, C _1-3 hydroxyalkyl group, C _3-6 cycloalkyl group, 3-8 membered heterocyclyl group, C _6-10 aryl group, 5-6 membered heteroaryl group one or more substitutions in; More preferably, R ₁ is selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 Alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 ring Alkyl group, 3-8 membered heterocyclyl group, C _6-10 aryl group or 5-6 membered heteroaryl group, the amino group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group , Deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, _{C 1-3 hydroxyalkyl} , C _3-6 cycloalkyl , 3-8 membered heterocyclic group, C _6-10 aryl group, 5-6 membered heteroaryl group can be further optionally replaced by hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, side oxygen group, Thio group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo One of C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl, or multiple substitutions; R ₂ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, deuterated C _1-6 alkyl, halo C 1-6 alkyl _, C _1-6 alkoxy, halo C _1-6 alkoxy, deuterated C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; R ₃₁ , R ₃₂ and R ₃₃ are each independently selected from hydrogen, deuterium, halogen, amine group, C _1-6 alkyl substituted amine group, hydroxyl group, cyano group, nitro group, pendant oxy group, thio group, 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, halo C _1-6 alkyl base, C _1-6 alkoxy group, halo C _1-6 alkoxy group, C _1-6 hydroxyalkyl group, C _3-8 cycloalkyl group, 3-12 membered heterocyclyl group, C _6-14 aryl group, 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) ₂ R _c ; Preferably, R ₃₁ , R ₃₂ and R ₃₃ are each independently selected from hydrogen, deuterium, halogen, amino group, C _1-3 alkyl substituted amino group, hydroxyl, cyano group, nitro group, side Oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 alkoxy group base, halo C _1-3 alkoxy group, C _1-3 hydroxyalkyl group, -C _1-3 alkyl group -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 group, C _1-6 alkyl substituted amino group, hydroxyl, cyano group, nitro group, pendant oxygen group, sulfur group Base, 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, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _{6- 14} aryl, 5-14 membered heteroaryl, -OR _c , -C(O)R _c , -SR _c , S(O)R _c or S(O) ₂ R _c ; preferably, R ₃₁ , R ₃₂ and R ₃₃ are each independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, side oxy, thio, C _1-3 alkyl base, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl or -C(O)R _c ; R _c is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 Hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; R ₄ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, _{C 3- 8-} cycloalkyl, 3-12-membered heterocyclyl, C _6-14- membered aryl or 5-14-membered heteroaryl; R ₆ , R ₇ and R ₈ are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl _, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl , 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterium Substitute C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, _halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3 -12-membered heterocyclic group, C _6-14 aryl group, 5-14-membered heteroaryl group, optionally optionally further substituted by hydrogen, deuterium, halogen, amino group, C _1-3 alkyl group, hydroxyl group, cyano group Base, nitro, side oxygen group, thio group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, One or more substitutions among C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, and 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. The compound described in claim 4, its stereoisomer or its pharmaceutically acceptable salt, wherein the compound is represented by formula (IV):

in, R ₁ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, mercapto, cyano, nitro, side oxy, thio, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl _, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl , 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl, the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterium Substitute C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, _halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3 -12-membered heterocyclic group, C _6-14 aryl group, 5-15 membered heteroaryl group can be further optionally replaced by hydrogen, deuterium, halogen, amino group, hydroxyl group, mercapto group, cyano group, nitro group, side oxygen group, Thio group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo One of C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl, or multiple substitutions; R ₂ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, deuterated C _1-6 alkyl, halo C 1-6 alkyl _, C _1-6 alkoxy, halo C _1-6 alkoxy, deuterated C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; R ₃₂ is selected from hydrogen, deuterium, halogen, amine group, C _1-6 alkyl substituted amine group, hydroxyl, cyano group, nitro group, side oxy group, thio group, C _1-6 alkyl group, C _3-8 Cycloalkyl-substituted C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy , Halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, 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) ₂ R _c ; R _c is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, deuterated C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 Hydroxyalkyl, C _3-8 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; R ₄ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _{2 -6} alkynyl, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, _{C 3- 8-} cycloalkyl, 3-12-membered heterocyclyl, C _6-14- membered aryl or 5-14-membered heteroaryl; R ₆ , R ₇ , R ₈ are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl _, deuterated C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl , 3-12 membered heterocyclyl, C _6-14 aryl or 5-14 membered heteroaryl; the amino group, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, deuterium Substitute C _1-6 alkyl, halo C 1-6 alkyl, C _1-6 alkoxy, _halo C _1-6 alkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3 -12-membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group, optionally optionally further substituted by hydrogen, deuterium, halogen, amino group, C _1-3 alkyl group, hydroxyl group, cyanide group Base, nitro, side oxygen group, thio group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, One or more substitutions among C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, and 5-6 membered heteroaryl; x is 0, 1, 2, 3, 4, 5 or 6; z is 0, 1, 2, 3, 4, 5 or 6. The compound described in claim 5, its stereoisomer or its pharmaceutically acceptable salt, wherein the compound is represented by formula (V):

The compound described in claim 5 or 6, its stereoisomer or its pharmaceutically acceptable salt, wherein, R ₁ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, mercapto, cyano, nitro, side oxy, thio, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , Deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, _{C 1-3 hydroxyalkyl} , C _3-6 cycloalkyl , 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl, the amino group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterium Substitute C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, _halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3 -8-membered heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group can be further optionally replaced by hydrogen, deuterium, halogen, amino group, hydroxyl group, mercapto group, cyano group, nitro group, side oxygen group, Thio group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo One of C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl, or multiple substitutions; R ₂ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl, deuterated C _1-3 alkyl, halo C 1-3 alkyl _, C _1-3 alkoxy, halo C _1-3 alkoxy, deuterated C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; R ₃₂ is selected from hydrogen, deuterium, halogen, amine group, C _1-3 alkyl substituted amine group, hydroxyl, cyano group, nitro group, side oxy group, thio group, C _1-3 alkyl group, C _3-6 Cycloalkyl-substituted C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy , Halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, 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) ₂ R _c ; R _c is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-3 alkyl, C _{2 -4} alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 Hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; R ₄ is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _{3- 6-} cycloalkyl, 3-8-membered heterocyclyl, C _6-10- membered aryl or 5-10-membered heteroaryl; R ₆ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl , Halo C _1-3 alkyl, C _1-3 alkoxy, Halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; the amino group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _{6 -10} aryl group, 5-10 membered heteroaryl group may optionally be further substituted by hydrogen, deuterium, halogen, amino group, C _1-3 alkyl group, hydroxyl group, cyano group, nitro group, side oxygen group, Thio group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 hydroxyalkyl, C One or more substitutions of _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl. The compound described in claim 6, its stereoisomer or its pharmaceutically acceptable salt, wherein the compound is represented by formula (VI):

in, R ₁₁ is selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, mercapto group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group , Deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, _{C 1-3 hydroxyalkyl} , C _3-6 cycloalkyl Or 3-8 membered heterocyclyl; R ₂ is independently selected from hydrogen, deuterium, halogen, amine, C _1-6 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl, deuterated C _1-3 alkyl, halo C 1-3 alkyl _, C _1-3 alkoxy, halo C _1-3 alkoxy, deuterated C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl or 3-8 membered heterocyclyl; R ₃₂ is selected from hydrogen, deuterium, halogen, amine group, C _1-3 alkyl substituted amine group, hydroxyl, cyano group, nitro group, side oxy group, thio group, C _1-3 alkyl group, C _3-6 Cycloalkyl-substituted C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo _{C 1-3 alkyl} , C _1-3 alkoxy , halogen C _1-3 alkoxy group, C _1-3 hydroxyalkyl group, C _3-6 cycloalkyl group or 3-8 membered heterocyclyl group; R ₄ is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _{3- 6-} cycloalkyl or 3-8-membered heterocyclyl; R ₆ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl , halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl or 3-8 membered heterocyclyl; q is 1, 2, 3 or 4. The compound according to any one of claims 1 to 5, its stereoisomer or its pharmaceutically acceptable salt, wherein, R ₁ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, mercapto, cyano, nitro, side oxy, thio, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , Deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, _{C 1-3 hydroxyalkyl} , C _3-6 cycloalkyl , 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl, the amino group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterium Substitute C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, _halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3 -8-membered heterocyclic group, C _6-10 aryl group, 5-6 membered heteroaryl group can be further optionally substituted by hydrogen, deuterium, halogen, amino group, hydroxyl group, mercapto group, cyano group, nitro group, side oxygen group, Thio group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo One of C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl, or multiple substitutions; Preferably, R ₁ is selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 Alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 ring Alkyl group, 3-8 membered heterocyclyl group, C _6-10 aryl group or 5-6 membered heteroaryl group, the amino group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group , Deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, _{C 1-3 hydroxyalkyl} , C _3-6 cycloalkyl , 3-8 membered heterocyclic group, C _6-10 aryl group, 5-6 membered heteroaryl group can be further optionally replaced by hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, side oxygen group, Thio group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo One of C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl, or multiple substitutions; More preferably, R ₁ 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 hetero Ring group, C _6-10 aryl group or 5-6 membered heteroaryl group, the C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, C _1-3 alkoxy group, C _{3 -6} cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-6 membered heteroaryl may be further substituted by hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro if necessary , side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 Substituted with one or more of alkoxy, halo C _1-3 alkoxy and C _1-3 hydroxyalkyl; Further preferably, R ₁ is selected from C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl, and the C _3-6 cycloalkyl, 3- 8-membered heterocyclic group, C _6-10 aryl group and 5-6 membered heteroaryl group can be further optionally replaced by hydrogen, deuterium, halogen, amino group, hydroxyl group, cyano group, nitro group, side oxy group, thio group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1- Substituted with one or more of ₃ alkoxy and C _1-3 hydroxyalkyl. The compound as described in any one of claims 1 to 5 or 9, its stereoisomer or its pharmaceutically acceptable salt, wherein, R ₂ is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl, deuterated C _1-3 alkyl, halo C 1-3 alkyl _, C _1-3 alkoxy, halo C _1-3 alkoxy, deuterated C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl; Preferably, R ₃ is independently selected from hydrogen, deuterium, halogen, amine group, C _1-3 alkyl substituted amine group, hydroxyl, cyano group, nitro group, side oxy group, thio group, C _1-3 alkyl group base, C _3-6 cycloalkyl substituted C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 Member heteroaryl, -OR _c , -C(O)R _c , -SR _c , S(O)R _c or S(O) ₂ R _c ; Preferably, R _c is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkene base, C _2-4 alkynyl _, deuterated C _{1-3 alkyl, halo C 1-3} alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl , C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl; Preferably, R ₄ is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkene base, C _2-4 alkynyl _, deuterated C _{1-3 alkyl, halo C 1-3} alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl , C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl; Or, when one of R ₂ and one of R ₃ are connected with adjacent atoms to form a C _3-8 cycloalkyl group, a 3-8 membered heterocyclyl group, a C _6-10 aryl group or a 5-8 membered heteroaryl group, The C _3-8 cycloalkyl group, 3-8 membered heterocyclyl group, C _6-10 aryl group and 5-8 membered heteroaryl group may be further substituted by hydrogen, deuterium, halogen, amine group, hydroxyl group or cyano group if necessary. , nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C One or more substitutions among _1-3 alkoxy, halo C _1-3 alkoxy and C _1-3 hydroxyalkyl; Or, when one of R ₃ and one of R ₄ are connected with adjacent atoms to form a C _3-8 cycloalkyl group, a 3-8 membered heterocyclyl group, a C _6-10 aryl group or a 5-8 membered heteroaryl group, The C _3-8 cycloalkyl group, 3-8 membered heterocyclyl group, C _6-10 aryl group and 5-8 membered heteroaryl group may be further substituted by hydrogen, deuterium, halogen, amine group, hydroxyl group or cyano group if necessary. , nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C Substituted with one or more of _1-3 alkoxy, halo C _1-3 alkoxy and C _1-3 hydroxyalkyl. The compound as described in any one of claims 2 to 5, 9 or 10, its stereoisomer or its pharmaceutically acceptable salt, wherein, R ₆ , R ₇ , R ₈ are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , Deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, _{C 1-3 hydroxyalkyl} , C _3-6 cycloalkyl , 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl; the amino group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterium Substitute C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, _halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3 -8-membered heterocyclic group, C _6-10 aryl group, 5-6 membered heteroaryl group, optionally optionally further substituted by hydrogen, deuterium, halogen, amino group, C _1-3 alkyl group, hydroxyl group, cyanide group Base, nitro, side oxygen group, thio group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, One or more substitutions among C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, and 5-6 membered heteroaryl; Preferably, R ₆ , R ₇ , and R ₈ are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-3 alkyl, deuterated C _1-3 alkyl, Halo C _1-3 alkyl, C _1-3 alkoxy or halo C _1-3 alkoxy; the C _1-3 alkyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy or halo C _1-3 alkoxy may optionally be further substituted by hydrogen, deuterium, halogen, amine, C _1-3 alkyl, hydroxy, cyano, nitro, One or more of the pendant oxy group, thio group and C _1-3 alkyl group are substituted. The compound described in claim 4, its stereoisomer or its pharmaceutically acceptable salt, wherein, L ₁ is selected from -(CH ₂ ) _n C(O)(CR _aa R _bb ) _n1 -, -(CH ₂ ) _n C(O)NR _aa (CR _aa R _bb ) _n1 -, -(CH ₂ ) _n (CR _aa R _bb ) _n2 -or-(CR _aa R _bb ) _n O(CH ₂ ) _n1 -; R _aa and R _bb are each independently selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, side oxygen group, thio group, C _1-3 alkyl group, deuterated C _1-3 alkyl group, and halo C _1-3 alkyl group. , C _1-3 alkoxy, halo C _1-3 alkoxy; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino, hydroxyl, side oxygen, thio, methyl, ethyl, propyl , isopropyl, methoxy, ethoxy or propoxy; R ₁ is selected from hydrogen, deuterium, halogen, amine, hydroxyl, mercapto, cyano, nitro, side oxy, thio, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , Deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, _{C 1-3 hydroxyalkyl} , C _3-6 cycloalkyl , a 3-6-membered heterocyclyl group containing 1-3 N, O or S atoms, a C _6-10 aryl group or a 5-6-membered heteroaryl group containing 1-3 N, O or S atoms, the amine Base, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy group, C _1-3 hydroxyalkyl group, C _3-6 cycloalkyl group, 3-8 membered heterocyclyl group, C _6-10 aryl group, 5-6 membered heteroaryl group can be further selected as needed. By hydrogen, deuterium, fluorine, chlorine, bromine, amino group, hydroxyl group, mercapto group, cyano group, nitro group, side oxygen group, thio group, 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 substitutions , containing 1-3 fluorine, chlorine or bromine substituted ethyl groups, containing 1-3 fluorine, chlorine or bromine substituted propyl groups, containing 1-3 fluorine, chlorine or bromine substituted isopropyl groups, methoxy groups , one or more substitutions in ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Preferably, R ₁ is selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 Alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 ring Alkyl group, 3-6 membered heterocyclyl group containing 1-3 N, O or S atoms, C _6-10 aryl group or 5-6 membered heteroaryl group containing 1-3 N, O or S atoms, The amino group, C _1-3 alkyl group, C _2-4 alkenyl group, C _2-4 alkynyl group, deuterated C _1-3 alkyl group, halo C _1-3 alkyl group, C _1-3 alkoxy group, Halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl as needed Can be further hydrogen, deuterium, fluorine, chlorine, bromine, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, methyl group, ethyl group, propyl group, isopropyl group, vinyl group, propenyl group, Allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methyl containing 1-3 fluorine, chlorine or bromine substitutions , containing 1-3 fluorine, chlorine or bromine substituted ethyl groups, containing 1-3 fluorine, chlorine or bromine substituted propyl groups, containing 1-3 fluorine, chlorine or bromine substituted isopropyl groups, methoxy groups , one or more substitutions in ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; More preferably, R ₁ is selected from hydrogen, deuterium, halogen, amine group, hydroxyl group, cyano group, nitro group, side oxygen group, thio group, methyl group, ethyl group, propyl group, isopropyl group, vinyl group, propenyl group , allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methyl containing 1-3 fluorine, chlorine or bromine substitutions base, ethyl group containing 1-3 fluorine, chlorine or bromine substitutions, propyl group containing 1-3 fluorine, chlorine or bromine substitutions, isopropyl group containing 1-3 fluorine, chlorine or bromine substitutions, methoxy base, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

or

, wherein the methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl base, deuterated isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,

,

,

,

,

,

or

Optionally further substituted by fluorine, chlorine, bromine, hydroxyl, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy , ethoxy or propoxy substitution; R ₂ is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, C _1-3 alkyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl base, C _1-3 alkoxy group, halogen C _1-3 alkoxy group, deuterated C _1-3 alkoxy group or C _1-3 hydroxyalkyl group; preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl base, ethyl, propyl, isopropyl, hydroxyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, methoxy, ethoxy, propoxy, deuterated methyl Oxy group, deuterated ethoxy group, deuterated propoxy group, methyl group containing 1-3 fluorine, chlorine or bromine substitutions, ethyl group containing 1-3 fluorine, chlorine or bromine substitutions, Fluorine, chlorine or bromine substituted propyl, containing 1-3 fluorine, chlorine or bromine substituted isopropyl; R ₃₁ , R ₃₂ and R ₃₃ are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amine, methyl-substituted amine, ethyl-substituted amine, propyl-substituted amine, hydroxyl, cyanide Base, nitro, side oxy, thio, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl base, deuterated propyl group, ethyl group containing 1-3 fluorine, chlorine or bromine substitutions, propyl group containing 1-3 fluorine, chlorine or bromine substitutions, isopropyl group containing 1-3 fluorine, chlorine or bromine substitutions. Propyl, methoxy, ethoxy, propoxy, ethoxy group containing 1-3 fluorine, chlorine or bromine substitutions, propoxy group containing 1-3 fluorine, chlorine or bromine substitutions, 3 fluorine, chlorine or bromine substituted isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, -C _1-3 alkyl -R _c , -NHR _c or -C(O)R _c ; more Preferably, R ₃₁ , R ₃₂ and R ₃₃ are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amine, methyl-substituted amine, ethyl-substituted amine, propyl-substituted amine, Hydroxy, cyano, nitro, side oxy, thio, 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, 1-3 fluorine, chlorine or bromine Substituted isopropyl, methoxy, ethoxy, propoxy, ethoxy substituted with 1-3 fluorine, chlorine or bromine, propoxy substituted with 1-3 fluorine, chlorine or bromine, Containing 1-3 fluorine, chlorine or bromine substituted isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl or -C(O)R _c ; R _c is independently selected from hydrogen, deuterium, halogen, amine, C _1-3 alkyl substituted amine, hydroxyl, cyano, nitro, pendant oxy, thio, C _1-3 alkyl, C _{2 -4} alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 Hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl or 5-6 membered heteroaryl, the amino group, C _1-3 alkyl substituted amino group, Hydroxy, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C _1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3-8 membered heterocyclyl, C _6-10 aryl and 5-6 membered heteroaryl are optionally hydrogenated , deuterium, halogen, amino group, C _1-3 alkyl substituted amino group, hydroxyl, cyano group, nitro group, pendant oxygen group, thio group, C _1-3 alkyl group, C _2-4 alkenyl group, C _{2 -4} alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3- One or more substitutions in _6- cycloalkyl, 3-8-membered heterocyclyl, C _6-10 aryl or 5-6-membered heteroaryl; preferably, R _c is independently selected from hydrogen, fluorine, chlorine , bromine, amino, methyl-substituted amino, ethyl-substituted amino, propyl-substituted amino, hydroxyl, cyano, nitro, pendant oxy, thio, methyl, ethyl, propyl , vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl, ethyl containing 1-3 fluorine, chlorine or bromine substitutions Base, propyl group containing 1-3 fluorine, chlorine or bromine substitutes, isopropyl group containing 1-3 fluorine, chlorine or bromine substitutes, methoxy, ethoxy, propoxy group, containing 1-3 Fluorine, chlorine or bromine substituted ethoxy, 1-3 fluorine, chlorine or bromine substituted propoxy, 1 to 3 fluorine, chlorine or bromine substituted isopropoxy, hydroxymethyl, hydroxyethyl base, hydroxypropyl,

,

,

,

,

,

,

or

; Preferably, R _c is independently selected from hydrogen, fluorine, chlorine, bromine, amine, methyl-substituted amine, ethyl-substituted amine, propyl-substituted amine, hydroxyl, cyano, nitro, Side oxy group, thio group, methyl, ethyl, propyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, deuterated methyl, deuterated ethyl, deuterated propyl base, ethyl group containing 1-3 fluorine, chlorine or bromine substitutions, propyl group containing 1-3 fluorine, chlorine or bromine substitutions, isopropyl group containing 1-3 fluorine, chlorine or bromine substitutions, methoxy base, ethoxy, propoxy, containing 1-3 fluorine, chlorine or bromine substituted ethoxy, containing 1-3 fluorine, chlorine or bromine substituted propoxy, containing 1-3 fluorine, chlorine or bromo-substituted isopropoxy, hydroxymethyl, hydroxyethyl or hydroxypropyl; R ₄ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, amine, hydroxy, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, _{C 1-3 hydroxyalkyl} , C _3-6 cycloalkyl, 3- 6-membered heterocyclyl, 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 containing 1-3 fluorine, chlorine or bromine substitutions, propyl containing 1-3 fluorine, chlorine or bromine substitutions Base, isopropyl group containing 1-3 fluorine, chlorine or bromine substituted, methoxy, ethoxy, propoxy group, ethoxy group containing 1-3 fluorine, chlorine or bromine substituted, containing 1-3 A propoxy group substituted by fluorine, chlorine or bromine, an isopropoxy group containing 1-3 fluorine, chlorine or bromine substitutes, hydroxymethyl, hydroxyethyl or hydroxypropyl; R ₆ , R ₇ , R ₈ are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , Deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, _{C 1-3 hydroxyalkyl} , C _3-6 cycloalkyl , 3-8 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl; the amino group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, deuterium Substitute C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, _halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 cycloalkyl, 3 -8-membered heterocyclic group, C _6-10 aryl group, 5-10 membered heteroaryl group may be further substituted by hydrogen, deuterium, fluorine, chlorine, bromine, amino group, methyl-substituted amino group, or ethyl group if necessary Amino group, propyl-substituted amine group, hydroxyl, cyano group, nitro group, pendant oxygen group, thio group, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterium Propyl group, ethyl group containing 1-3 fluorine, chlorine or bromine substitutions, propyl group containing 1-3 fluorine, chlorine or bromine substitutions, isopropyl group containing 1-3 fluorine, chlorine or bromine substitutions, Methoxy, ethoxy, propoxy, containing 1-3 fluorine, chlorine or bromine substituted ethoxy, containing 1-3 fluorine, chlorine or bromine substituted propoxy, containing 1-3 fluorine , one or more substituted isopropoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl and 6-membered heterocyclyl substituted by chlorine or bromine; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amino group , hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl,

,

,

; Better hydrogen, deuterium, fluorine, chlorine, bromine, amine, hydroxyl, cyano, nitro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, hydroxyl Methyl, hydroxyethyl, hydroxypropyl,

or

; Preferably, R ₆ , R ₇ , and R ₈ are each independently selected from hydrogen, deuterium, halogen, amine, hydroxyl, cyano, nitro, C _1-3 alkyl, C _2-4 alkenyl, C _{2 -4} alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _{3- 6-} cycloalkyl, 3-8-membered heterocyclyl, C _6-10 aryl or 5-10-membered heteroaryl; the amino group, C _1-3 alkyl, C _2-4 alkenyl, C _2-4 Alkynyl _, deuterated C _1-3 alkyl, halo C 1-3 alkyl, C _1-3 alkoxy, halo C _1-3 alkoxy, C _1-3 hydroxyalkyl, C _3-6 ring Alkyl group, 3-8 membered heterocyclyl group, C _6-10 aryl group, 5-10 membered heteroaryl group, optionally an amino group which may be further substituted by hydrogen, deuterium, fluorine, chlorine, bromine, amino group, or methyl group , Ethyl-substituted amino, propyl-substituted amino, hydroxyl, cyano, nitro, pendant oxy, thio, methyl, ethyl, propyl, isopropyl, deuterated methyl, deuterated Ethyl, deuterated propyl, ethyl containing 1-3 fluorine, chlorine or bromine substitutions, propyl containing 1-3 fluorine, chlorine or bromine substitutions, 1-3 fluorine, chlorine or bromine substitutions Isopropyl, methoxy, ethoxy, propoxy, containing 1-3 fluorine, chlorine or bromine substituted ethoxy, containing 1-3 fluorine, chlorine or bromine substituted propoxy, containing 1 - One or more of 3 fluorine, chlorine or bromine substituted isopropoxy, hydroxymethyl, hydroxyethyl or hydroxypropyl groups; preferably hydrogen, deuterium, fluorine, chlorine, bromine, amine, 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. The compound as described in claim 4 or 12, its stereoisomer or its pharmaceutically acceptable salt, wherein, L ₁ is selected from -O-, -C(O)-, -C(O)NHCH ₂ - or -C(O)NH-; R ₁ is selected from

,

,

,

,

,

,

,

,

Preferably, R ₁ is selected from

,

,

,

,

,

,

,

or

; Preferably, R ₁ is selected from

,

,

,

,

,

,

,

,

,

or

; Preferably, R ₁ is selected from

,

,

,

,

,

,

,

or

; Preferably, R ₁ is selected from

,

,

Preferably, L ₁ is selected from -O-, -C(O)NHCH ₂ - or -C(O)NH-; R ₁ is selected from

,

,

,

,

,

,

,

,

R ₂ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methoxy, deuterated ethyl Oxygen, deuterated propoxy, cyano, ethoxy, difluoromethoxy; preferably, R ₂ 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, -OCD ₃ ; R ₃₁ is hydrogen, deuterium, methyl, ethyl, propyl; R ₃₂ is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, cyano, -COCH ₂ CH ₃ , -COCH ₃ , vinyl, cyclopropyl ,

,

,

,

,isopropyl,

,

,

Or -CD ₃ ; preferably, R ₃₂ is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, trifluoromethyl, methoxy, cyano, -COCH ₂ CH ₃ , - COCH ₃ , vinyl, cyclopropyl,

,

,

,

,

,

,

,

,

,

,

or

;More preferably, R ₃₂ is hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl, methoxy, -COCH ₂ CH ₃ , -COCH ₃ , vinyl, cyclopropyl,

,

,

,

,

,

,

,

or

; Further preferably, R ₃₂ is hydrogen, deuterium, methyl, ethyl, propyl, trifluoromethyl, methoxy, vinyl or cyclopropyl; R ₃₃ is -C(O)NH ₂ ; R ₄ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, cyano, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl, propyl, methoxy group or cyclopropyl; preferably, R ₄ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, cyano, deuterated methyl, monofluoromethyl, difluoromethyl, trifluoromethyl group, ethyl, propyl or methoxy; more preferably, R ₄ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, deuterated methyl, monofluoromethyl, difluoromethyl, Trifluoromethyl, ethyl, propyl or methoxy; further preferably, R ₄ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl or methoxy; R ₆ , R ₇ , and R ₈ are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH ₂ OH, -CH ₂ OCH ₃ , -CF ₃ , -CH ₂ N(CH ₃ ) ₂ ,

,

; Preferably, R ₆ , R ₇ , and R ₈ are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, cyano, -CH ₂ OH, -CH ₂ OCH ₃ , -CF ₃ , -CH ₂ N(CH ₃ ) ₂ ,

; Preferably, R ₆ , R ₇ and R ₈ are each independently selected from hydrogen, deuterium, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl or cyano; preferably, R ₆ is independently selected Selected from hydrogen, fluorine, methyl, -CH ₂ OH, -CH ₂ OCH ₃ , -CF ₃ ; R ₇ is independently selected from hydrogen; R ₈ is independently selected from hydrogen, -CH ₂ N(CH ₃ ) ₂ or

; R ₉ is methyl. The compound described in any one of claims 1 to 13, its stereoisomer or its pharmaceutically acceptable salt, wherein the compound is as follows:

A compound represented by formula (V) or its stereoisomer, or a compound represented by formula (VII) or its stereoisomer:

Among them, R ₁ , L ₁ , R ₂ , x, R ₃₁ , R ₃₂ , R ₃₃ , R ₄ and z are the same as described in any one of claims 4, 5, 7, 9 to 14. A method for preparing the compound described in claim 4, its stereoisomer or its pharmaceutically acceptable salt, characterized in that it includes the following steps: a compound represented by formula (V) and a compound represented by formula (VI) The compound can react under the action of condensing agent,

Among them, R ₁ , L ₁ , R ₂ , x, R ₃₁ , R ₃₂ , R ₃₃ , R ₄ , z, R ₆ , R ₇ and R ₈ are the same as any one of claim items 4, 5, 7, 9 to 14. mentioned in the item. A method for preparing the compound described in claim 5, its stereoisomer or its pharmaceutically acceptable salt, characterized in that it includes the following steps: a compound represented by formula (VII) and a compound represented by formula (VI) The compound can react under the action of condensing agent,

Among them, R ₁ , R ₂ , x, R ₃₂ , R ₄ , z, R ₆ , R ₇ and R ₈ are the same as those described in any one of claims 5, 7, 9 to 14. A pharmaceutical composition comprising a therapeutically effective dose of a compound as described in any one of claims 1 to 14, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or Excipients. A compound as described in any one of claims 1 to 14, its stereoisomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 18 in relation to the preparation of treatment and/or prevention of FGFR inhibitors The use in medicines for diseases, especially the use in preparing medicines for treating and/or preventing diseases related to FGFR1-4 inhibitors. A compound as described in any one of claims 1 to 14, a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 18 in the preparation, treatment and/or prevention of cancer or cartilage development Use in medicines for incompletely 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 cancer, prostate cancer, ovarian cancer, breast cancer, leukemia, or lymphoma.