WO2025124429A1 - Aromatic amine compound, and pharmaceutical composition and use thereof - Google Patents

Abstract

Provided in the present application are an aromatic amine compound, and a pharmaceutical composition and the use thereof. The aromatic amine compound comprises a compound as represented by formula (I) or an enantiomer, diastereoisomer, pharmaceutically acceptable salt, prodrug, isotope derivative, solvate, stereoisomer and tritiated compound: (I). The aromatic amine compound of the present application can inhibit the activity of YES1 protein, inhibit the transcription of related genes, and inhibit cell growth by means of binding to the YES1 protein, so that the compound can be used for treating YES1 protein-related diseases or conditions, such as cancer.

Description

Aromatic amine compound and pharmaceutical composition and application thereof

This application claims the priority of the following prior applications: the Chinese invention patent application with patent application number 202311694800.3 filed with the State Intellectual Property Office of China on December 11, 2023, and the invention name “Aromatic amine compounds, pharmaceutical compositions thereof, and applications thereof”; and the Chinese invention patent application with patent application number 202411463789.4 filed with the State Intellectual Property Office of China on October 18, 2024, and the invention name “Aromatic amine compounds, pharmaceutical compositions thereof, and applications thereof”. The full texts of the above two prior applications are incorporated into this application by reference.

Technical Field

The present invention relates to the field of medical technology, and in particular to an aromatic amine compound and a pharmaceutical composition and application thereof.

Background Art

Protein kinase is an important enzyme that catalyzes the phosphorylation process of proteins. It can regulate the activity of proteins through phosphorylation, and can also amplify signals and cause cellular responses through the step-by-step phosphorylation of proteins. Protein kinase plays a key regulatory role in life processes, and abnormalities in protein kinases often lead to the occurrence of malignant diseases such as cancer. Dysregulation of protein kinase function, such as through functional acquisition genetic mutations, gene amplification, autonomous activation, and activation of chromosomal rearrangements, is closely related to cancer development and progression, and is involved in cancer cell transformation, growth, proliferation, and survival.

At present, protein kinases have been considered as important targets for the development of molecular targeted therapy. Src family kinases (SFKs) are a class of non-receptor protein tyrosine kinases. Src family kinases are a class of membrane-bound proteins, including about nine members, namely: Src, Fyn, YES1, Lck, Lyn, Hck, Fgr and Blk. Src protein is a non-receptor tyrosine kinase that can be activated by multiple signal transduction pathways. The activated Src kinase activates the corresponding target protein by phosphorylating the tyrosine residues, thereby activating the corresponding signaling pathways, including MAPK, STAT, PI3K/AKT and EGFR, etc. Abnormally activated Src protein is associated with many tumors, and its activity is closely related to the development of tumors. Inhibiting the activity of Src family kinase members in tumor tissues is likely to be an effective means of treating cancer. Currently reported Src kinase family inhibitors include dasatinib and bosutinib. However, due to the poor selectivity of these inhibitors, they have not shown sufficient effects as Src family kinase inhibitors in clinical practice. Therefore, more selective and effective Src family kinase inhibitors are clinically needed.

Summary of the invention

The present invention provides an aromatic amine compound, which can bind to the YES1 protein with high selectivity, thereby inhibiting the activity of the YES1 protein and the transcription of related genes, and is further used for treating diseases or conditions related to the YES1 protein, such as cancer.

In a first aspect, the embodiments of the present application provide an aromatic amine compound, or an enantiomer, a diastereomer, a pharmaceutically acceptable salt, a prodrug, an isotopic derivative, or a solvate of the aromatic amine compound, wherein the aromatic amine compound includes a compound represented by formula (I):

In formula (I):

X ₁ , X ₂ and X ₃ are each independently selected from CH or N, wherein X ₁ , X ₂ and X ₃ are not N at the same time;

Ring Cy is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl;

n is 1 to 4, 1 to 4 R _1s are the same or different; R ₁ is selected from C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, 4-10 membered heterocyclyl or 3-10 membered cycloalkyl which is mono- or poly-substituted _by R 4; R ₄ substituents are selected from hydrogen, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ hydroxyalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkoxy, di(C ₁ -C ₁₀ alkyl)amino, C ₁ -C ₁₀ alkylsulfonyl or 5-10 membered heterocyclyl;

_R2 is selected from _C1 - _C10 alkoxy-CO-N(R6)-, C1 _{- C10 alkyl-SO2-N(R6)-, C1-C10 alkyl - CO} -N( _R6 )-, _C3 - _C10 cycloalkyl-CO-N( _R6 )-, _{C3 - C10} cycloalkyloxy-CO-N( _R6 )-, _{C3 - C10} cycloalkyl-( _C1 - _C10 )alkylene-CO-N( _R6 )-, _C1 - _C10 alkoxy _- CO-( _C1 - _C10 )alkylene, 5-10 membered heteroaryl-( _C1 - _C10 )alkylene, 5-10 membered heterocyclyl-(C1- _C10 )alkylene, 5-10 membered heteroaryl-N( _R6 )-, ₆ )-, C ₆ -C ₁₀ aryl-(C ₁ -C ₁₀ ) alkyloxy or 4-10 membered heterocyclyl-O-CO-N(R ₆ )-; R ₅ is selected from hydrogen, halogen, cyano, C ₁ -C ₁₀ alkyl, halogenated C ₁ -C ₁₀ alkyl or oxy; R ₆ is selected from hydrogen, C ₁ -C ₁₀ alkyl;

m is 1 to 4, 1 to 4 R ₃ are the same or different; R ₃ is selected from hydrogen, halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkyl or C ₁ -C ₁₀ haloalkoxy.

In a second aspect, an embodiment of the present application provides a pharmaceutical composition, which includes the aromatic amine compound represented by formula (I) described in the first aspect, any one of the enantiomers, diastereomers, pharmaceutically acceptable salts, solvates, stereoisomers, tritiated products and pharmaceutically acceptable carriers of the aromatic amine compound represented by formula (I).

In a third aspect, an embodiment of the present application provides the use of the pharmaceutical composition described in the second aspect in a drug for treating diseases related to YES1 amplification or YES1 overexpression.

DETAILED DESCRIPTION

In order to better illustrate the present application and facilitate understanding of the technical solution of the present application, the present application is further described in detail below. It should be clear that the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

The definitions of specific functional groups and chemical terms are described in more detail below. The abbreviations used herein have their conventional meanings in the chemical and biological fields. Chemical structures and chemical formulas described herein are constructed according to standard chemical valence rules known in the chemical field.

When a range of values is listed, it is intended to include every number within the range. For example, " _C1 - _C10 alkyl" is intended to include _C1 , _C2 , _C3 , _C4 , _C5 , _C6 , _C7 , _C8 , _C9 , _C10 , _C1 - _C6 , _C1 - _C5 , C1- _C4 , _C1 - _C3 , _C1 - _C2 , _C2 - _C6 , _C2 -C5, _C2 - _C4 , _C2 - _C3 , _C3 - _C6 , _C3 - _C5 , _C3 - _C4 , _C4 - _C6 , _C4 - _C5 , and _{C5 - C6} alkyl _.

The substituents listed in this application are The ligation sites are indicated.

The term "alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 10 carbon atoms. In some embodiments, the alkyl group has 1 to 6 carbon atoms. In some embodiments, the alkyl group has 1 to 5 carbon atoms. In some embodiments, the alkyl group has 1 to 4 carbon atoms. In some embodiments, the alkyl group has 1 to 3 carbon atoms. In some embodiments, the alkyl group has 1 to 2 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl, and n-hexyl.

Unless otherwise specified, the term "alkylene" means a divalent group derived from a straight chain _or branched alkyl group, such as but not limited to _-CH2- , _-CH2CH2- , _{-CH2CH2CH2- , -CH2CH2CH2CH2- ;} the above definition of alkylene applies to the "alkylene" in _heterocyclyl -alkylene, cycloalkyl-alkylene and _{the like} groups mentioned herein.

"Cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms. In some embodiments, cycloalkyl has 3 to 6 ring carbon atoms. In some embodiments, cycloalkyl has 5 to 10 ring carbon atoms. Cycloalkyl includes but is not limited to cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctyl, cyclooctenyl, cubic alkyl, bicyclo [1.1.1] pentyl, bicyclo [2.2.2] octyl, bicyclo [2.1.1] hexyl, bicyclo [3.1.1] heptyl, cyclononyl, cyclononenyl, cyclodecyl, cyclodecenyl, octahydro-1H-indenyl, decahydronaphthyl, spiral [4.5] decyl and the like. In certain embodiments, a cycloalkyl group is a single ring (a "monocyclic cycloalkyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic ring system (a "bicyclic cycloalkyl") and may be saturated or may be partially unsaturated.

"Heterocyclyl" or "heterocycle" refers to a 3-10 membered non-aromatic ring system radical having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from N, O, S. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom if valence permits. The heterocyclyl group may be a monocyclic ring ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. The heterocyclyl bicyclic ring system may include one or more heteroatoms in one or both rings. In some embodiments, the heterocyclyl group is a 3-8 membered non-aromatic ring system having ring carbon atoms and 1-3 ring heteroatoms, wherein each heteroatom is independently selected from N, O and S. In some embodiments, the heterocyclyl group is a 3-6 membered non-aromatic ring system having ring carbon atoms and 1-2 ring heteroatoms, wherein each heteroatom is independently selected from N, O and S. In some embodiments, the heterocyclyl group is a 4-6 membered non-aromatic ring system having ring carbon atoms and 1-2 ring heteroatoms, wherein each heteroatom is independently selected from N and O.

Examples of heterocyclic groups include, but are not limited to, aziridine, oxirane, thiirane; azetidinyl, oxetanyl, and thietanyl; tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione; dioxolanyl, oxathiolane, dithiolane, and oxazolidin-2-one; triazolinyl, oxadiazolinyl, and thiadiazolinyl; piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl; piperazinyl, morpholinyl, dithianyl, dioxanyl; triazinyl; azepanyl, oxepanyl and thiepanyl; azocanyl, oxepanyl and thiocanyl; indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl and the like; tetrahydroquinolinyl, tetrahydroisoquinolinyl and the like. Preferred examples of heterocyclic groups include oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinyl, piperidinyl, tetrahydro-2H-pyranyl, 1,2,5,6-tetrahydropyridinyl, pyranyl, 3,6-dihydro-2H-pyranyl, 2,5-dihydro-1H-pyrrolyl, 1,2-dihydropyridinyl, 1,6-dihydropyridazinyl. The heterocyclic group may be further oxo-substituted, for example, to form 2-oxo-1,2-dihydropyridinyl, 6-oxo-1,6-dihydropyridazinyl, and the like.

"Aryl" refers to a monocyclic or polycyclic aromatic ring system having 6-10 ring carbon atoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C10 aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). Aryl groups may be described, for example, as _C6 - _C10 membered aryl groups, where the term "membered" refers to the non-hydrogen ring atoms within the moiety. Aryl moieties include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Aryl groups may be optionally substituted, independently at each occurrence, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents.

"Heteroaryl" refers to a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-8 membered heteroaryl"). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-6 membered heteroaryl"). In some embodiments, 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of heteroaryl can independently be optionally substituted, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted with one or more substituents (“substituted heteroaryl”).

Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, and thienyl; imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl; triazolyl, oxadiazolyl, and thiadiazolyl; tetrazolyl; pyridinyl; pyridazinyl, pyrimidinyl, and pyrazinyl; triazinyl and tetrazinyl; azacycloheptatrienyl, oxepinyl, and thiepigenyl; indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl; naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

or "heteroaryl" refers to any monocyclic, bicyclic, or tricyclic heteroaromatic system containing 5 to 20 ring atoms (5-20 members) and wherein at least one ring atom is a heteroatom selected from O, N, Si, and S. In some embodiments, the heteroaryl contains 5 to 14 ring atoms (5-14 members) and wherein 1 to 5 ring atoms are heteroatoms selected from O, N, and S. In some embodiments, the heteroaryl contains 5 to 10 ring atoms (5-10 members) and wherein 1 to 3 ring heteroatoms are heteroatoms selected from O, N, and S. In other embodiments, the heteroaryl is a 5-20 membered, 5-15 membered, 5-12 membered, 5-11 membered, 5-10 membered, 5-9 membered, 5-8 membered, 5-7 membered, or 5-6 membered heteroaryl and wherein 1-5, 1-3, or 1-2 ring atoms are heteroatoms selected from O, N, and S. In other embodiments, the heteroaryl group is a 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered heteroaryl group, and wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from O, N, and S.

In one embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups in which one or more of the ring heteroatoms is nitrogen, sulfur or oxygen. Examples include, but are not limited to, pyrrolyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl (e.g., 1,2,4-triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl), tetrazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, thiadiazinyl, azecinyl, and the like.

In another embodiment, heteroaryl includes 8-10 membered bicyclic heteroaryl, preferably 9-10 membered bicyclic heteroaryl, wherein one or more ring heteroatoms are nitrogen, sulfur or oxygen. In some cases, bicyclic heteroaryl can be an overall aromatic system, or a partial aromatic system (i.e., one ring is an aromatic system, and the other ring is a non-aromatic system). Examples include, but are not limited to, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzopyranyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzotriazolyl, naphthyridinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, cinnolinyl, quinolinyl, isoquinolinyl, quinazolinyl, oxazolopyridinyl, isoxazolopyridinyl, pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolotriazinyl, triazolopyridinyl, triazolopyrimidinyl, imidazothiazolyl, triazolopyridinyl, triazolopyrimidinyl, and the like; or 4,5,6,7-tetrahydropyrazolo[1,5-a] pyridyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, imidazolinyl, dihydroindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzopyranyl, dihydropyridooxazinyl, dihydrobenzodioxinyl (e.g., 2,3-dihydrobenzo[b][1,4]dioxinyl), benzodioxolyl (e.g., benzo[d][1,3]dioxol), dihydrobenzoxazinyl (e.g., 3,4-dihydro-2H-benzo[b][1,4]oxazine), tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydroimidazo[4,5-c]pyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, and the like.

The term "halogen" means F, Cl, Br or I.

The term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo-C ₁ -C ₆ alkyl" or "C ₁ -C ₆ haloalkyl" includes but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and the like.

The term "alkoxy" means alkyl-O-, wherein alkyl is as defined herein. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, and the like.

The term "cycloalkyloxy" or "cycloalkoxy" means cycloalkyl-O-, wherein cycloalkyl is as defined herein.

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

The term "alkylacyl" means alkyl-C(O)-, wherein alkyl is as defined herein. Alkylacyl includes, but is not limited to, acetyl, propionyl or butyryl, and the like.

The term "acyl" means -C(O)-.

The term "oxo" means =O, or the term "oxy" alone also means =O. When "oxy" is combined with other groups to form a group, such as "5-10 membered heteroaryloxy", "4-10 membered heterocyclyloxy" or "C ₃ -C ₁₀ cycloalkyloxy", the "oxy" therein means -O-.

The term "C ₁ -C ₁₀ hydroxyalkyl" means that 1, 2, 3 _{, 4, 5, 6 or more H on the C 1 -C 10 alkyl group is} substituted by OH, wherein the C _{1 -C 10 alkyl group has the above-mentioned definition. The C 1} -C ₁₀ hydroxyalkyl group is preferably a C ₁ -C ₆ hydroxyalkyl group. Examples thereof include hydroxymethyl, hydroxyethyl or hydroxypropyl.

The term "C ₁ -C ₁₀ haloalkoxy" means -OC ₁ -C ₁₀ haloalkyl, wherein the C ₁ -C ₁₀ haloalkyl is as defined herein.

The term "di(C ₁ -C ₁₀ alkyl)amine" or "disubstituted (C ₁ -C ₁₀ alkyl)amine" means -N(C ₁ -C ₁₀ alkyl) ₂ , wherein the C ₁ -C ₁₀ alkyl is as defined herein.

The term "mono(C ₁ -C ₁₀ alkyl)amine" refers to -NHC ₁ -C ₁₀ alkyl, wherein the C ₁ -C ₁₀ alkyl is as defined herein.

The term "C ₁ -C ₁₀ alkylsulfonyl" means -SO ₂ -C ₁ -C ₁₀ alkyl, wherein the C ₁ -C ₁₀ alkyl is as defined herein.

The term "C ₁ -C ₁₀ alkylsulfinyl" means -SO-C ₁ -C ₁₀ alkyl, wherein the C ₁ -C ₁₀ alkyl is as defined herein.

The term "di(C ₁ -C ₆ alkyl)aminoacyl" refers to -CO-N(C ₁ -C ₆ alkyl) ₂ , wherein the C ₁ -C ₆ alkyl is as defined herein.

The term "(C ₁ -C ₆ alkyl)aminoacyl" refers to -CO-NHC ₁ -C ₆ alkyl, wherein the C ₁ -C ₆ alkyl is as defined herein.

Unless otherwise indicated, "mono- or poly-substituted" means that the group can be unsubstituted or substituted with one or more (e.g., 0, 1, 2, 3, 4, or 5 or more) of the substituents listed for the group, wherein the substituents can be the same or different. In one embodiment, the optionally substituted group has 1 substituent. In another embodiment, the optionally substituted group has 2 substituents. In another embodiment, the optionally substituted group has 3 substituents. In another embodiment, the optionally substituted group has 4 substituents. In another embodiment, the optionally substituted group has 5 substituents.

It should be understood that "polysubstituted" in "monosubstituted, disubstituted or polysubstituted" means that the number of substituents is greater than disubstituted (2 substituents) (eg, the number of substituents is 3, 4, 5, 6 or more).

When a group is defined as "substituted or unsubstituted", the substitution means "mono- or poly-substitution".

The present application provides an aromatic amine compound, or an enantiomer, a diastereomer, a pharmaceutically acceptable salt, a prodrug, an isotope derivative, or a solvate of the aromatic amine compound. The aromatic amine compound includes a compound represented by formula (I):

In formula (I):

X ₁ , X ₂ and X ₃ are each independently selected from CH or N, wherein X ₁ , X ₂ and X ₃ are not N at the same time;

Ring Cy is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl;

n is 1 to 4, 1 to 4 R _1s are the same or different; R ₁ is selected from C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, 4-10 membered heterocyclyl or 3-10 membered cycloalkyl which is mono- or poly-substituted _by R 4; R ₄ substituents are selected from hydrogen, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ hydroxyalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkoxy, disubstituted (C ₁ -C ₁₀ alkyl)amino, C ₁ -C ₁₀ alkylsulfonyl or 5-10 membered heterocyclyl;

_R2 is selected from _C1 - _C10 alkoxy-CO-N(R6)-, C1 _{- C10 alkyl-SO2-N(R6)-, C1-C10 alkyl - CO} -N( _R6 )-, _C3 - _C10 cycloalkyl-CO-N( _R6 )-, _{C3 - C10} cycloalkyloxy-CO-N( _R6 )-, _{C3 - C10} cycloalkyl-( _C1 - _C10 )alkylene-CO-N( _R6 )-, _C1 - _C10 alkoxy _- CO-( _C1 - _C10 )alkylene, 5-10 membered heteroaryl-( _C1 - _C10 )alkylene, 5-10 membered heterocyclyl-( _C1 - _C10 )alkylene-5-10 membered heteroaryl-N(R6)-, ₆ )-, C ₆ -C ₁₀ aryl-(C ₁ -C ₁₀ ) alkyleneoxy or 4-10 membered heterocyclyl-O-CO-N(R ₆ )-; R ₅ is selected from hydrogen, halogen, cyano, C ₁ -C ₁₀ alkyl, halogenated C ₁ -C ₁₀ alkyl or oxy; R ₆ is selected from hydrogen, C ₁ -C ₁₀ alkyl;

m is 1 to 4, 1 to 4 R ₃ are the same or different; R ₃ is selected from hydrogen, halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkyl or C ₁ -C ₁₀ haloalkoxy.

In some embodiments, _X1 is selected from CH, and _X2 and _X3 are selected from N.

In some embodiments, _X1 and _X2 are selected from CH, and _X3 is selected from N.

In some embodiments, _X1 and _X3 are selected from CH, and _X2 is selected from N.

In some embodiments, _X2 is selected from CH, and _X1 and _X3 are selected from N.

In some embodiments, in the compound represented by formula (I), ring Cy is selected from 5-10 membered heteroaryl or C ₃ -C ₁₀ cycloalkyl. The 5-10 membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S.

Preferably, the ring Cy is selected from a 5-6 membered heteroaryl group, more preferably a 5 membered heteroaryl group, wherein the heteroaryl group contains 1-3 heteroatoms selected from N, O, and S, preferably contains 1-2 heteroatoms selected from N, O, and S.

Preferably, the ring Cy is selected from C ₃ -C ₆ cycloalkyl; more preferably, the ring Cy is selected from C ₃ -C ₄ cycloalkyl.

As examples of cyclic Cy groups, the cyclic Cy group is selected from pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl or cyclopropyl.

In some embodiments, in the compound represented by formula (I), ring Cy is selected from 5-10 membered heteroaryl, 3-10 membered heterocyclic group, C ₃ -C ₁₀ cycloalkyl, wherein the 5-10 membered heteroaryl or 3-10 membered heterocyclic group contains 1-3 heteroatoms selected from N, O, and S.

In some embodiments, ring Cy is selected from 8-10 membered bicyclic heteroaryl, preferably 9-10 membered bicyclic heteroaryl, more preferably partially aromatic 9-10 membered bicyclic heteroaryl, wherein the heteroaryl contains 1-3 heteroatoms selected from N, O, S, preferably 1-2 heteroatoms selected from N, O, S.

As an example of a bicyclic heteroaryl ring, the Cy ring is selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl. Preferably, it is selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl.

In some embodiments, ring Cy is selected from a 3-10 membered heterocyclic group, preferably a 4-6 membered heterocyclic group; wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O, and S, preferably contains 1-2 heteroatoms selected from N, O, and S.

As an example of a heterocyclic group, the Cy group is selected from oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydro-2H-pyranyl, 1,2,5,6-tetrahydropyridinyl, pyranyl, 3,6-dihydro-2H-pyranyl, 2,5-dihydro-1H-pyrrolyl, 1,2-dihydropyridinyl, 1,6-dihydropyridazinyl. Preferably, the cyclic Cy group is selected from oxetan-3-yl, azetidin-1-yl, tetrahydrofuran-3-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-3-yl, piperidin-4-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, 1,2,5,6-tetrahydropyridin-3-yl, pyran-4-yl, 3,6-dihydro-2H-pyran-4-yl, 2,5-dihydro-1H-pyrrol-3-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,6-dihydropyridazin-4-yl.

In some embodiments, in the compound represented by formula (I), n(R ₁ )-ring Cy- is selected from the following groups:

In some embodiments, in the compound represented by formula (I), n(R ₁ )-ring Cy- is selected from the following groups:

In some embodiments, R ₁ can be substituted on the carbon atom to which the above-mentioned cyclic Cy group is attached or on the ring atom which is not attached.

In some embodiments, when the ring Cy group is a 5-10 membered heteroaryl group or a 3-10 membered heterocyclyl group, R ₁ may be substituted on a heteroatom of the 5-10 membered heteroaryl group or the 3-10 membered heterocyclyl group.

In some embodiments, when R ₁ is not H, the number n of R ₁ is 1 or 2.

In some embodiments, in the compound represented by the general formula (I), the number n of R ₁ is 1 to 4, wherein 1 to 4 R ₁ are the same or different, wherein each R ₁ is independently selected from the following groups which are optionally substituted or polysubstituted by R ₄ : C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, 4-10 membered heterocyclic group or 3-10 membered cycloalkyl, wherein the heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S.

Preferably, each R ₁ is independently selected from the following groups which are optionally substituted or polysubstituted by R ₄ : C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, 4-6 membered heterocyclyl or 3-6 membered cycloalkyl, wherein the 4-6 membered heterocyclyl contains 1-2 heteroatoms selected from N, O and S.

More preferably, each R ₁ is independently selected from the following groups which are optionally substituted or polysubstituted by R ₄ : C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, 4-6 membered heterocyclyl or 3-4 membered cycloalkyl, wherein the 4-6 membered heterocyclyl contains 1-2 heteroatoms selected from N, O and S.

Further preferably, each R ₁ is independently selected from the following groups which are optionally monosubstituted, disubstituted, or trisubstituted by R ₄ : C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, 4-6 membered heterocyclyl or 3-4 membered cycloalkyl, wherein the heterocyclyl contains 1-2 heteroatoms selected from N, O, S.

As an example of an _R group, the _R group is selected from the following groups which are optionally _{monosubstituted} , disubstituted, or trisubstituted by R: N,N-dimethylaminoethyl, N,N-dimethylaminomethyl, cyclopropyl, cyclobutyl, methyl, difluoromethyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxyethyl, hydroxyethyl, methylsulfonylethyl, cyanoethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or piperidinyl.

In other embodiments, in the compound represented by the general formula (I), the number n of R ₁ is 1 to 4, and 1 to 4 R ₁ are the same or different, wherein each R ₁ is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, oxo, or the following groups which are optionally substituted or polysubstituted by R ₄ : C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkylacyl, C ₁ -C ₁₀ alkylsulfonyl, 4-10 membered heterocyclic group or 3-10 membered cycloalkyl, wherein the 4-10 membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O, and S.

Preferably, each R ₁ is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, oxo, or the following groups which are optionally substituted or polysubstituted by R ₄ : C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylacyl, C ₁ -C ₆ alkylsulfonyl, 4-6 membered heterocyclyl or 3-6 membered cycloalkyl, wherein the 4-6 membered heterocyclyl contains 1-2 heteroatoms selected from N, O, S.

More preferably, each R ₁ is independently selected from hydrogen, halogen, hydroxy, cyano, amino, oxo, or the following groups which are optionally substituted or polysubstituted by R ₄ : C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylacyl, C ₁ -C ₄ alkylsulfonyl, 4-6 membered heterocyclyl or 3-4 membered cycloalkyl, wherein the 4-6 membered heterocyclyl contains 1-2 heteroatoms selected from N, O, S.

Further preferably, each R ₁ is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, oxo, or the following groups which are optionally monosubstituted, disubstituted, or trisubstituted by R ₄ : C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylacyl, C ₁ -C ₃ alkylsulfonyl, 4-6 membered heterocyclyl or 3-4 membered cycloalkyl, wherein the 4-6 membered heterocyclyl contains 1-2 heteroatoms selected from N, O, and S.

As examples of _R groups, _R groups are selected from hydrogen, halogen, hydroxy, cyano, amino, oxo, N,N-dimethylaminoethyl, N,N-dimethylaminomethyl, N,N-dimethylaminoacylmethyl, N,N-dimethylaminomethylacyl, N,N-dimethylaminoethylacyl, methyl, difluoromethyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxyethyl, hydroxyethyl, methylsulfonylethyl, cyanoethyl, 2-hydroxy-propyl, 2-hydroxy-2-methylpropyl, methylsulfonyl, ethylsulfonyl, acetyl, propionyl, or the following groups optionally substituted, disubstituted, or trisubstituted by _R : cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, 4-methylpiperazinyl.

In some embodiments, in the compound represented by the general formula (I), _R4 is independently selected from hydrogen, hydroxyl, halogen, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 hydroxyalkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkoxy, di( _C1 - _C6 alkyl)amine, _C1 - _C6 alkylsulfonyl or 5-6 membered heterocyclic group.

Preferably, _R4 is independently selected from hydrogen, hydroxyl, halogen, _C1 - _C3 alkyl, _C1 - _C3 haloalkyl, _C1 - _C3 hydroxyalkyl, _C1 -C3 alkoxy, _C1 - _C3 haloalkoxy, di( _C1 - _{C3 alkyl} )amino, _C1 - _C3 alkylsulfonyl or 5-6 membered heterocyclyl.

As examples of R ₄ groups, the R ₄ group is selected from: hydrogen, hydroxy, halogen, methyl, ethyl, propyl, isopropyl, hydroxyethyl, oxetane, dimethylamino, methoxy or mesyl.

In some embodiments, in the compound represented by the general formula (I), _R4 is independently selected from hydrogen, hydroxyl, halogen, cyano, amino, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _{C1 - C6} hydroxyalkyl, C1- _C6 alkoxy, _C1 - _C6 haloalkoxy, di( _C1 - _C6 alkyl)amino, ( _C1 - _C6 alkyl)aminoacyl, di( _C1 - _C6 alkyl)aminoacyl, _C1 - _C6 alkylsulfonyl or 4-6 membered heterocyclic group.

Preferably, _R4 is independently selected from hydrogen, hydroxyl, halogen, cyano, amino, _C1 - _C3 alkyl, _C1 - _C3 haloalkyl, _C1 - _C3 hydroxyalkyl, _C1 - _C3 alkoxy, _C1 - _C3 haloalkoxy, di( _C1 - _C3 alkyl)amino, ( _C1 - _C3 alkyl)aminoacyl, di( _C1 - _C3 alkyl)aminoacyl, _C1 - _C3 alkylsulfonyl or 5-6 membered heterocyclyl.

As an example, the R ₄ group is selected from: hydrogen, hydroxy, halogen, cyano, amino, methyl, ethyl, propyl, isopropyl, hydroxyethyl, oxetane, dimethylamino, methylaminoacyl, dimethylaminoacyl, methoxy or methylsulfonyl.

In some embodiments, in the compound represented by the general formula (I), R ₃ is selected from hydrogen, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl or C ₁ -C ₆ haloalkoxy.

Preferably, R ₃ is selected from hydrogen, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ haloalkyl or C ₁ -C ₃ haloalkoxy.

More preferably, R ₃ is selected from hydrogen, halogen, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl or C ₁ -C ₂ haloalkoxy.

Particularly preferably, R ₃ is selected from hydrogen, halogen, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl or C ₁ -C ₂ haloalkoxy, and R ₃ is located in the ortho position to R ₂ .

In some embodiments, m is 1.

As an example of the R ₃ group, R ₃ is selected from: halogen, methyl, ethyl, methoxy, ethoxy, halomethoxy, haloethoxy, halomethyl or haloethyl; and R ₃ is located in the ortho position to R ₂ .

In some embodiments, in the compound represented by the general formula (I), R ₂ is selected from _{C 1} -C ₁₀ alkoxy-CO-N(R ₆ )-, C ₁ -C ₁₀ alkyl-SO ₂ -N(R ₆ )-, C ₁ -C ₁₀ alkyl-CO-N(R ₆ )-, C ₃ -C ₁₀ cycloalkyl-CO-N(R ₆ )-, C ₃ -C ₁₀ cycloalkyloxy-CO-N(R ₆ )-, C ₃ -C ₁₀ cycloalkyl-(C ₁ -C ₁₀ )alkylene-CO-N(R ₆ )-, C ₁ -C ₁₀ alkoxy-CO-(C ₁ -C ₁₀ )alkylene, 5-10 membered heteroaryl-(C ₁ -C ₁₀ )alkylene, 5-10 membered heterocyclyl-(C ₁ -C ₁₀ )alkylene, 5-10 membered heteroaryl-N(R ₆ )-, C ₆ -C ₁₀ aryl-(C ₁ -C ₁₀ )alkyleneoxy or 4-10 membered heterocyclyl-O-CO-N(R ₆ )-; wherein the heteroaryl contains 1-3 heteroatoms selected from N, O and S.

R ₅ is selected from hydrogen, halogen, cyano, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl or oxy;

R ₆ is selected from hydrogen or C ₁ -C ₆ alkyl;

Preferably, _R2 is selected from _C1 - _C6 alkoxy-CO-N(R6)-, _C1 - _C6 alkyl-SO2- _N ( _R6 )-, C1-C6 alkyl-CO-N _{( R6} )-, _C3 - _C6 cycloalkyl-CO-N( _R6 )-, _{C3 - C6 cycloalkyloxy} -CO-N( _{R6 )} -, _C3 - _C6 cycloalkyl-( _C1 - _C6 )alkylene-CO-N( _R6 )-, _C1 - _C6 alkoxy-CO-( _C1 - _C6 )alkylene, 5-6-membered heteroaryl-(C1- _{C6)alkylene, 5-6-membered heterocyclyl-(C1-C6 ) alkylene ,} 5-6-membered heteroaryl-N( _R6 )-, _C6 -C ₁₀ aryl-(C ₁ -C ₆ )alkyleneoxy- or 4-6 membered heterocyclic-O-CO-N(R ₆ )-; wherein the heteroaryl contains 1-3 heteroatoms selected from N, O and S.

More preferably, R ₂ is selected from C ₁ -C ₄ alkoxy-CO-N(R ₆ )-, C ₁ -C ₄ alkyl-SO ₂ -N(R ₆ )- _, C ₁ -C ₄ alkyl-CO-N(R ₆ )-, C ₃ -C ₄ cycloalkyl-CO-N(R ₆ )-, C ₃ -C ₅ cycloalkyloxy-CO-N(R ₆ )-, C ₃ -C ₄ cycloalkyl-(C ₁ -C ₃ )alkylene-CO-N(R ₆ )-, C ₁ -C ₄ alkoxy-CO-(C ₁ -C ₃ )alkylene, 5-6 membered heteroaryl-(C ₁ -C ₃ )alkylene, 5-6 membered heterocyclyl-(C ₁ -C ₃ )alkylene, 5-6 membered heteroaryl-N(R ₆ )-, C ₆ -C ₁₀ aryl-(C ₁ -C ₃ ) alkyleneoxy- or 4-6 membered heterocyclyl-O-CO-N(R ₆ )-; wherein the heteroaryl contains 1-3 heteroatoms selected from N, O, and S; and R ₆ is independently selected from H and C ₁ -C ₃ alkyl.

Further preferably, R ₂ is selected from C ₁ -C ₄ alkoxy-CO-N(R ₆ )-, C ₁ -C ₄ alkyl-SO ₂ -N(R ₆ )- _, C ₁ -C ₄ alkyl-CO-N(R ₆ )-, C ₃ -C ₄ cycloalkyl-CO-N(R ₆ )-, C ₃ -C ₅ cycloalkoxy-CO-N(R ₆ )-, C ₃ -C ₄ cycloalkyl-(C ₁ -C ₂ )alkylene-CO-N(R ₆ )-, C ₁ -C ₄ alkoxy-CO-(C ₁ -C ₂ )alkylene, 5-6 membered heteroaryl-(C ₁ -C ₂ )alkylene, 5-6 membered heterocyclyl-(C ₁ -C ₂ )alkylene, 5-6 membered heteroaryl-N(R ₆ )-, C ₆ -C ₁₀ aryl-(C ₁ -C ₂ ) alkyleneoxy- or 4-6 membered heterocyclic-O-CO-N(R ₆ )-; wherein the heteroaryl contains 1-3 heteroatoms selected from N, O and S.

R ₅ is selected from hydrogen, halogen, cyano, C ₁ -C ₃ alkyl, halogenated C ₁ -C ₃ alkyl or oxy.

_R6 is selected from hydrogen or methyl.

Particularly preferably, R ₂ is selected from C ₁ -C ₄ alkoxy-CO-N(R ₆ )-, C ₁ -C ₄ alkyl-SO ₂ -N(R ₆ )- _, C ₁ -C ₄ alkyl-CO-N(R ₆ )-, C ₃ -C ₄ cycloalkyl-CO-N(R ₆ )-, C ₃ -C ₅ cycloalkoxy-CO-N(R ₆ )-, C ₃ -C ₄ cycloalkyl-(C ₁ )alkylene-CO-N(R ₆ )-, C ₁ -C ₄ alkoxy-CO-(C ₁ )alkylene, 5-6 membered heteroaryl-(C ₁ )alkylene, 5-6 membered heterocyclyl-(C ₁ )alkylene, 5-6 membered heteroaryl-N(R ₆ )-, benzyloxy- or 4-6 membered heterocyclyl-O-CO-N(R ₆ )-; wherein the heteroaryl is selected from pyrazolyl, isoxazole, triazolyl, oxazolyl, oxadiazole, thiazole, isothiazole or thiadiazole, and the heterocyclyl is selected from pyrrolidinyl, tetrahydrofuran or azetidine.

_R5 is selected from hydrogen, halogen, cyano, methyl, ethyl, trifluoromethyl, trifluoroethyl or oxy.

_R6 is selected from hydrogen or methyl.

As an example of the _R2 group, _R2 is selected from: tert-butyl-O-CO-NH-, tert-butyl-O-CO-methylene-, ethylsulfonylamino, tert-butylacylamino, benzyloxy, cyclopropylacylamino, cyclopropylmethylacylamino,

In some embodiments, the _R2 group and the benzene ring to which it is connected together form a benzo C3 _{- C4} cycloalkyl or a benzo 3-4 membered heterocyclic group, for example, the _R2 group and the benzene ring to which it is connected together form

In some embodiments, the aromatic amine compound of the present application is a compound represented by formula (II), an enantiomer, a diastereomer, a pharmaceutically acceptable salt, a prodrug, an isotopic derivative, or a solvate of the aromatic amine compound, wherein X ₁ , X ₂ , X ₃ , R ₁ , R ₂ , R ₃ , and m in formula (II) are as defined in general formula (I);

In some embodiments, the aromatic amine compound of the present application is a compound represented by formula (III), an enantiomer, a diastereomer, a pharmaceutically acceptable salt, a prodrug, an isotope derivative, or a solvate of the aromatic amine compound, wherein the definitions of X ₁ , X ₂ , X ₃ , R ₁ , R ₂ , and R ₃ in formula (III) are as defined in general formula (I);

In some embodiments, the aromatic amine compound of the present application is a compound represented by formula (IV), an enantiomer, a diastereomer, a pharmaceutically acceptable salt, a prodrug, an isotopic derivative, or a solvate of the aromatic amine compound, wherein the definitions of X ₁ , X ₂ , X ₃ , R ₁ , R ₂ , and R ₃ in formula (IV) are as defined in general formula (I);

In some embodiments, the aromatic amine compound of the present application is a compound represented by formula (V), an enantiomer, a diastereomer, a pharmaceutically acceptable salt, a prodrug, an isotope derivative, or a solvate of the aromatic amine compound:

Wherein, in formula (V), X ₁ , X ₂ , X ₃ , R ₂ , R ₃ and m are as defined in general formula (I);

R ₁₁ is selected from H, hydroxyl, halogen, cyano, amino, or the following groups which are optionally monosubstituted, disubstituted or polysubstituted by R ₂₁ : C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkylacyl, C ₁ -C ₁₀ alkylsulfonyl, C ₁ -C ₁₀ alkylsulfinyl, mono(C ₁ -C ₁₀ alkyl)amino, di(C ₁ -C ₁₀ alkyl)amino, di(C ₁ -C ₁₀ alkyl)aminoacyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C ₃ -C ₁₀ cycloalkyl, 5-10 membered heteroaryloxy, 4-10 membered heterocyclyloxy or C ₃ -C ₁₀ cycloalkyloxy. Wherein the heteroaryl or heterocyclyl contains 1 to 3 heteroatoms selected from N, O and S;

_R21 are the same or different and are independently selected from hydrogen, hydroxy, halogen, cyano, amino, _C1 - _C10 alkyl, _C1 - _C10 haloalkyl, _C1 - _C10 hydroxyalkyl, _C1 - _C10 alkoxy, _C1 - _C10 haloalkoxy, mono( _C1 - _C10 alkyl)amino, di( _C1 - _C10 alkyl)amino, ( _C1 - _C10 alkyl)aminoacyl, di( _C1 - _C10 alkyl)aminoacyl, _C1 - _C10 alkylsulfonyl or 5-10 membered heterocyclyl;

p is an integer selected from 1 to 4, and may be an integer selected from 1, 2, 3, and 4.

In some embodiments, R ₁₁ is selected from H, hydroxyl, halogen, cyano, amino, or the following groups which are optionally monosubstituted, disubstituted or polysubstituted by R ₂₁ : C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl acyl, C ₁ -C ₆ alkyl sulfonyl, C ₁ -C ₆ alkyl sulfinyl, mono(C ₁ -C ₆ alkyl)amino, di(C ₁ -C ₆ alkyl)amino, di(C ₁ -C ₆ alkyl)aminoacyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, C ₃ -C ₆ cycloalkyl, 5-6 membered heteroaryloxy, 4-6 membered heterocyclyloxy, or C ₃ -C ₆ cycloalkyloxy. Wherein, the heteroaryl or heterocyclyl contains 1-2 heteroatoms selected from N, O, and S.

Preferably, R ₁₁ is selected from the following groups which are optionally monosubstituted, disubstituted or polysubstituted by R ₂₁ : C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl acyl, C ₁ -C ₆ alkyl sulfonyl, C ₁ -C ₆ alkyl sulfinyl, mono(C ₁ -C ₆ alkyl)amino, di(C ₁ -C ₆ alkyl)amino, di(C ₁ -C ₆ alkyl)aminoacyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, C ₃ -C ₆ cycloalkyl, 5-6 membered heteroaryloxy, 4-6 membered heterocyclyloxy, or C ₃ -C ₆ cycloalkyloxy. Wherein, the heteroaryl or heterocyclyl contains 1-2 heteroatoms selected from N, O, and S.

As an example, the R ₁₁ group is selected from hydrogen, halogen, hydroxy, cyano, amino, methoxy, ethoxy, dimethylamino, N,N-methylethylamino, methylsulfonyl, azetidine, pyrrolyl, piperidine, piperazinyl, 4-methylpiperazin-1-yl, 4-isopropylpiperazin-1-yl,

In some embodiments, _R21 is the same or different and is independently selected from hydrogen, hydroxyl, halogen, cyano, amino, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 hydroxyalkyl, _C1 - _{C6 alkoxy, C1-C6 haloalkoxy ,} mono( _C1 - _C6 alkyl)amino, di(C1- _C6 alkyl)amino, ( _C1 -C6 alkyl)aminoacyl, di( _C1 - _{C6 alkyl} )aminoacyl, _C1 - _{C6 alkylsulfonyl} , or 5-6 membered heterocyclyl.

Preferably, _R21 are the same or different and are independently selected from hydrogen, hydroxyl, halogen, cyano, amino, _C1 - _C3 alkyl, _C1 - _C3 haloalkyl, _C1 - _C3 hydroxyalkyl, _C1 - _C3 alkoxy, _C1 - _C3 haloalkoxy, mono( _C1 - _C3 alkyl)amino, di(C1-C3 alkyl)amino, ( _C1 - _{C3 alkyl)aminoacyl, di(C1-C3 alkyl ) aminoacyl} , _C1 - _C3 alkylsulfonyl or 5-6 membered heterocyclyl.

As an example, the _R21 group is selected from: hydrogen, hydroxy, halogen, cyano, amino, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, oxetane, dimethylamino, methylaminoacyl, dimethylaminoacyl, methoxy or methylsulfonyl.

As an example, the aromatic amine compound of the present application is selected from any one of the compounds shown in Table 1 below:

Table 1. Aromatic amine compounds

The present application also provides a pharmaceutical composition, comprising as an active ingredient a compound represented by any one of the general formulas (I)-(V) or any one of its enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs, isotope derivatives, solvates, stereoisomers, tritiated products, and a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present application can be used to prepare drugs for treating diseases related to YES1 amplification or YES1 overexpression.

In addition to the above-mentioned active ingredients of the compound, the pharmaceutical composition disclosed in the present application may also contain one or more auxiliary materials, including fillers, excipients, disintegrants, binders and wetting agents. Depending on the administration method, the composition of the present application may contain 10% to 90% by weight of the compound represented by the above formula (I).

The pharmaceutical composition of the present application is in the form of an oral preparation or an injection, wherein the oral preparation may be a capsule, tablet, etc., and the injection may be an intravenous injection, an intramuscular injection, or a subcutaneous injection, etc., and the present application does not limit this.

The present application also provides the use of any compound represented by general formula (I)-(V) or any one of its enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs, isotope derivatives, solvates, stereoisomers, tritiated products in the preparation of drugs for preventing and treating diseases related to YES1 amplification or YES1 overexpression.

The present application also provides a method for preventing and treating diseases associated with YES1 amplification or YES1 overexpression, for example, by administering a therapeutically effective amount and/or a preventively effective amount of a compound of formula (I)-(V) or the above-mentioned pharmaceutical composition to a patient in need, so as to prevent and treat diseases associated with YES1 amplification or YES1 overexpression.

In the present application, the disease associated with YES1 amplification or YES1 overexpression can be selected from cancer, and the cancer includes at least one of acute myeloid leukemia, chloroma, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, B-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, myelodysplastic syndrome, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, reproductive tract cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, uterine cancer, gestational trophoblastic disease, gastric cancer, bile duct cancer, gallbladder cancer, small intestine cancer, esophageal cancer, oropharyngeal cancer, hypopharyngeal cancer, eye cancer, neural cancer, head and neck cancer, melanoma, plasmacytoma, endocrine gland tumors, neuroendocrine cancer, brain tumor, bone cancer and sarcoma.

The present application also provides a method for synthesizing compounds represented by general formula (I)-(IV), wherein the method is selected from one of the following:

Solution 1:

wherein ring Cy, X ₁ , X ₂ , X ₃ , R ₁ , R ₂ , R ₃ , m and n are as defined in general formulae (I) to (IV); P ₁ is selected from Cl, Br, I or trifluoromethanesulfonyl OTf; two R's are the same or different, and any R' is independently selected from OH, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy or two R's together with the B atom to which they are attached form a 5-6 membered heterocyclic group additionally containing two O atoms, and the 5-6 membered heterocyclic group is optionally mono- or poly-substituted by C ₁ -C ₁₀ alkyl.

Intermediate Z-1 and intermediate Z-2 are subjected to coupling reaction to obtain the compound represented by general formula (I) of the present application or a salt thereof. The coupling reaction is a cross-coupling reaction such as Suzuki coupling reaction, for example, in the presence of a metal catalyst such as palladium or nickel, a ligand or a base is optionally added to react. Among them, the catalyst is selected from Pd(dppf)Cl ₂ , Pd ₂ (dba) ₃ , Pd(PPh ₃ ) ₄ or Pd(OAc) ₂ , etc.; the ligand is selected from triphenylphosphine, tri(o-tolyl)phosphine and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) BINAP, etc.; the base is selected from sodium carbonate, cesium carbonate, potassium carbonate, sodium hydroxide, cesium fluoride, potassium fluoride or potassium phosphate, etc.

Option 2:

Wherein, ring Cy, X ₁ , X ₂ , X ₃ , R ₁ , R ₂ , R ₃ , m, n, P ₁ , and R′ are as defined in Scheme 1.

Intermediate Z-3 and intermediate Z-4 are subjected to coupling reaction to obtain the compound represented by general formula (I) of the present application or a salt thereof. The coupling reaction is a cross-coupling reaction such as Suzuki coupling reaction, for example, in the presence of a metal catalyst such as palladium or nickel, a ligand or a base is optionally added to carry out the reaction. Among them, the catalyst is selected from Pd(dppf)Cl ₂ , Pd ₂ (dba) ₃ , Pd(PPh ₃ ) ₄ or Pd(OAc) ₂ , etc.; the ligand is selected from triphenylphosphine, tri(o-tolyl)phosphine and BINAP, etc.; the base is selected from sodium carbonate, cesium carbonate, potassium carbonate, sodium hydroxide, cesium fluoride, potassium fluoride, potassium phosphate, etc.

The present invention also provides a method for preparing a compound represented by formula (V) or its enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs, isotope derivatives, solvates, stereoisomers, and tritiated products, comprising reacting intermediate V-1 with intermediate V-2 to obtain a compound represented by general formula (V) of the present application:

Wherein, X ₁ , X ₂ , X ₃ , R ₂ , R ₃ , m, and p are as defined in Formula (V);

L is a leaving group (eg, halogen).

Beneficial Effects

The compounds provided in the present application can inhibit the activity of YES1 protein, inhibit the transcription of related genes, and inhibit cell growth by binding to YES1 protein, thereby being used to treat YES1 protein-related diseases or conditions, such as cancer.

Preparation Example

1. Preparation of intermediates

Intermediate A1:

Step 1: Dissolve 7-bromopyrrolo[2,1-f][1,2,4]triazine-4-amine (400 mg) and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl)ethane-1-ol (670 mg) in a mixture of 1,4-dioxane and water (10 mL, v/v = 5/2) at room temperature, and add Pd(dppf)Cl ₂ (140 mg) and potassium carbonate (777 mg). After the nitrogen is fully replaced in the above mixture, heat to 100°C and continue stirring for 2 hours until the reaction is complete. After the reaction is completed, the reaction is cooled to room temperature, and ethyl acetate and water are added. The above mixture is fully stirred and separated. The organic phase is washed with water and brine, and then dried over anhydrous sodium sulfate. After concentration, a crude product was obtained, which was purified by column chromatography to give Intermediate 1 (300 mg) as an off-white solid. LCMS (ES, m/z): 245.0 [M+H] ⁺ .

Step 2: At room temperature, the intermediate 1 (280 mg) obtained in step 1 was dissolved in glacial acetic acid (10 mL), and NIS (250 mg) was added in batches. After the addition, the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was removed. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate aqueous solution, water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate A1 (230 mg) as an off-white solid. LCMS (ES, m/z): 370.7 [M+H] ⁺ .

Intermediate A2:

Step 1: At room temperature, 7-bromopyrrolo[2,1-f][1,2,4]triazine-4-amine (400 mg) and N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethane-1-amine (750 mg) were dissolved in a mixture of 1,4-dioxane and water (10 mL, v/v = 5/2), and Pd(dppf)Cl ₂ (140 mg) and potassium carbonate (777 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and stirred for 2 hours until the reaction was complete. After the reaction was completed, the reaction was cooled to room temperature, and ethyl acetate and water were added. The above mixture was fully stirred and separated. The organic phase was washed with water and brine, and then dried over anhydrous sodium sulfate. After concentration, a crude product was obtained, which was purified by column chromatography to give Intermediate 1 (310 mg) as an off-white solid. LCMS (ES, m/z): 272.0 [M+H] ⁺ .

Step 2: At room temperature, the intermediate 1 (290 mg) obtained in step 1 was dissolved in glacial acetic acid (10 mL), and NIS (260 mg) was added in batches. After the addition, the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was removed. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate A2 (300 mg) as an off-white solid. LCMS (ES, m/z): 397.8 [M+H] ⁺ .

Intermediate A3:

Step 1: At room temperature, add Pd(dppf)Cl ₂ (1.2 g) to a mixed solution of 7-bromopyrrolo[2,1-F][1,2,4]triazine-4-amine (7 g), bis-pinacol borate (6.85 g), and potassium carbonate (9.08 g) in 1,4-dioxane and water (120 mL, v/v = 5/1). After the above mixture is fully replaced with nitrogen, the reaction solution is heated to 80°C and stirred for 16 hours until the reaction is complete. After the reaction is completed, the reaction solution is cooled to room temperature and ethyl acetate is added. The resulting mixture is washed with water and saturated brine, and the organic phase is dried over anhydrous sodium sulfate and the solvent is removed. The resulting residue is purified by column chromatography to obtain the product intermediate (6.8 g). LCMS (ES, m/z): 213.0, 215.0 [M+H] ⁺ .

Step 2: At 0 degrees, NBS (5.64 g) was added to the DMF solution (100 mL) of the intermediate 1 (6.8 g) obtained in step 1, and the reaction solution was stirred at 0 degrees for 3 hours until the reaction was complete. After the reaction was completed, the mixed solution was poured into water and extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain the product intermediate A3 (4.3 g). LCMS (ES, m/z): 293.0, 295.0 [M+H] ⁺ .

Intermediate B1:

Step 1: Add Boc anhydride (890 mg) and DMAP (25 mg) to a tert-butyl alcohol solution (5 mL) of 2-(4-bromo-2-methoxyphenyl)acetic acid (500 mg) at room temperature. Stir the mixture at room temperature overnight until the reaction is complete. After the reaction is complete, concentrate the organic phase to obtain a crude product. The crude product is purified by column chromatography to obtain intermediate 1 (450 mg) as a light brown oil. LCMS (ES, m/z): 301.0, 303.0 [M+H] ⁺ .

Step 2: At room temperature, the intermediate 1 (450 mg) obtained in step 1 and bis(boronic acid pinacol) (762 mg) were dissolved in 1,4-dioxane (5 mL), and potassium acetate (441 mg) and Pd(dppf)Cl ₂ (164 mg) were added. After the mixture was fully replaced with nitrogen, it was heated to 100°C and stirred for 2 hours until the reaction was complete. After the reaction was completed, ethyl acetate was added to the above mixture. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product intermediate 2 (900 mg) as a brown solid. The crude product was directly subjected to the next step without purification. LCMS (ES, m/z): 349.0 [M+H] ⁺ .

Step 3: At room temperature, the intermediate 2 (900 mg) obtained in step 2 and 7-bromo-5-iodopyrrole [2.1-F] [1.2.4] triazine-4-amine (350 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v = 4/1), and potassium carbonate (425 mg) and Pd (dppf) Cl ₂ (113 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 80 ° C and stirred for 2 hours. After the reaction was completed, ethyl acetate was added to the above mixture. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate B1 (450 mg) as a gray-brown solid. LCMS (ES, m/z): 433.0, 435.0 [M + H] ⁺ .

Intermediate B2:

Step 1: Dissolve 7-bromopyrrolo[2,1-f][1,2,4]triazine-4-amine (1.21 g) in DMF (15 mL) at room temperature and add acetic acid (1 mL). Add NIS (1.41 g) to the above mixture in batches, and stir the resulting mixture at room temperature overnight until the reaction is complete. After the reaction is completed, add ethyl acetate to the above mixture. Wash the resulting mixture with saturated aqueous sodium bicarbonate solution, then with water and saturated brine. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by column chromatography to obtain intermediate 1 (1.52 g) as a white solid.

Step 2: At room temperature, the intermediate 1 (820 mg) obtained in step 1 was dissolved in a mixed solution of 1,4-dioxane and water (10 mL, v/v = 4/1), and tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (845 mg), Pd(dppf)Cl ₂ (141 mg) and potassium carbonate (836 mg) were added. The above mixture was fully replaced with nitrogen and heated to 70°C until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature and ethyl acetate was added. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography to obtain intermediate B2 (1.06 g). LCMS (ES, m/z): 434.0, 436.0 [M+H] ⁺ .

II. Preparation steps of some aromatic amine compounds in this application

Embodiment 1:

Step 1: At room temperature, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine (220 mg) and intermediate B2 (310 mg) were dissolved in a mixture of 1,4-dioxane and water (3 mL, v/v = 4/1), and potassium carbonate (247 mg) and Pd(PPh ₃ ) ₄ (83 mg) were added. The above mixture was fully replaced with nitrogen and heated to 90°C and stirred for 2 hours until the reaction was complete. The above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate 1 (380 mg). LCMS (ES, m/z): 504.9 [M+H] ⁺ .

Step 2: At room temperature, the intermediate 1 (130 mg) obtained in step 1 was dissolved in a mixed solution of methanol and tetrahydrofuran (2 mL, v/v = 1/1), and tert-butyldimethylsilyl acetaldehyde (67 mg) and acetic acid (10 μL) were added. The above mixture was reacted at room temperature for 0.5 h, and sodium cyanoborohydride (49 mg) was added. The above mixture was continued to react at room temperature for 2 h until the reaction was complete. After the reaction was completed, the solvent was removed to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate 2 (80 mg) as a yellow solid. LCMS (ES, m/z): 662.9 [M+H] ⁺ .

Step 3: At room temperature, the intermediate 2 (80 mg) obtained in step 2 was dissolved in a mixed solution of tetrahydrofuran and water (2 mL, v/v = 1/1), and glacial acetic acid (1.5 mL) was added. The above mixture was reacted at room temperature overnight until the reaction was complete. After the reaction was completed, the solvent was removed to obtain a crude product. The crude product was purified by column chromatography to obtain Example 1 compound (18 mg). LCMS (ES, m/z): 549.1 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.46(s,1H),8.12(s,1H),7.99(s,2H),7.85(d,J＝8.0Hz,1H),7.11(s,1H),7.04-7.02(m,2H),4.26-4.19(m,1H) ,3.87(s,3H),3.53-3.50(m,3H),3.00-2.97(m,2H),2.45-2.42(m,2H),2.19-2.13(m,3H),2.05-1.95(m,4H),1.48(s,9H).

Embodiment 2:

At room temperature, the intermediate A1 (100 mg) was dissolved in a mixture of 1,4-dioxane and water (2.5 mL, v/v = 4/1), and tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (141 mg), Pd(PPh ₃ ) ₄ (32 mg) and potassium carbonate (112 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100° C. and the reaction was continued for 2 h until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 2 compound (30 mg). LCMS (ES, m/z): 466.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.48(s,1H),8.11(s,1H),8.00-7.99(m,2H),7.85(d,J＝8.0Hz,1H),7.12(s,1H),7.05-7. 02(m,2H),4.93(brs,3H),4.24-4.21(m,2H),3.87(s,3H),3.79-3.77(t,J＝4.0Hz,2H),1.48(s,9H).

Embodiment 3:

At room temperature, intermediate A2 (100 mg) and tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (141 mg) were dissolved in a mixture of 1,4-dioxane and water (2.5 mL, v/v = 4/1), and potassium carbonate (112 mg) and Pd(PPh ₃ ) ₄ (32 mg) were added. After nitrogen was fully replaced in the above mixture, it was heated to 100° C. and the reaction was continued for 2 h until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 3 compound (40 mg). LCMS (ES, m/z): 492.9 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.44(s,1H),8.15(s,1H),8.10(s,1H),8.00-7.99(m,2H),7.85(d,J＝8.0Hz,1H),7.12(d,J＝4.0 Hz,1H),7.04-7.02(m,2H),4.29-4.26(m,2H),3.87(s,3H),2.71-2.68(m,2H),2.19(s,6H),1.48(s,9H).

Embodiment 4:

At room temperature, intermediate B2 (150 mg) and 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (121 mg) were dissolved in a mixture of 1,4-dioxane and water (2.5 mL, v/v = 4/1), and potassium carbonate (143 mg) and Pd(dppf)Cl ₂ (25 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 4 compound (24 mg). LCMS (ES, m/z): 462.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.46(s,1H),8.09(s,1H),8.00(s,1H),7.99(s,1H),7.85(d,J＝8.0Hz,1H),7.12(d,J＝4.0Hz,1H ),7.04-7.01(m,2H),3.87(s,3H),3.84-3.80(m,1H),1.48(s,9H),1.12-1.08(m,2H),1.03-0.98(m,2H).

Embodiment 5:

At room temperature, intermediate B2 (150 mg) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (110 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v = 4/1), and potassium carbonate (143 mg) and Pd(dppf)Cl ₂ (38 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 5 compound (16 mg). LCMS (ES, m/z): 436.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.42(s,1H),8.08,(s,1H),7.99(s,1H),7.98(s,1H),7.85(d,J＝8.0Hz,1H ),7.12(d,J=4.0Hz,1H),7.05-7.02(m,2H),3.92(s,3H),3.87(s,3H),1.48(s,9H).

Example 6

At room temperature, intermediate B2 (150 mg) and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (115 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v = 4/1), and potassium carbonate (143 mg) and Pd(dppf)Cl ₂ (38 mg) were added. After nitrogen was fully replaced in the above mixture, it was heated to 100°C and reacted for 2 hours until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 6 compound (56 mg). LCMS (ES, m/z): 450.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.44(s,1H),8.12(s,1H),8.10(d,J＝0.4Hz,1H),8.02-7.99(m,2H),7.86-7.83(m,1H),7.12(d, J＝1.6Hz,1H),7.04-7.00(m,2H),4.24(q,J＝7.2Hz,2H),3.84(s,3H),1.48(s,9H),1.44(t,J＝7.2Hz,3H).

Example 7

At room temperature, intermediate B2 (150 mg) and 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (123 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v = 4/1), and potassium carbonate (143 mg) and Pd(dppf)Cl ₂ (38 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 7 compound (51 mg). LCMS (ES, m/z): 464.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.44(d,J＝0.8Hz,1H),8.12(d,J＝0.8Hz,1H),8.01-7.99(m,2H),7.86-7.83(m,1H), 7.12(d,J＝2.0Hz,1H),7.04-7.02(m,2H),4.63-4.56(m,1H),3.87(s,3H),1.48-1.46(m,15H).

Example 8

At room temperature, intermediate B2 (150 mg) and 1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (137 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v = 4/1), and potassium carbonate (143 mg) and Pd(dppf)Cl ₂ (38 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 8 compound (55 mg). LCMS (ES, m/z): 492.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.48(s,1H),8.15(s,1H),8.00-7.99(m,2H),7.84(d,J＝8.0Hz,1H),7.65-7.56(m,2H),7.12(d,J＝2.0Hz,1H),7.08-7.00 (m,2H),5.15-5.12(m,1H),4.23-4.21(m,1H),4.05-3.92(m,3H),3.86(s,3H),2.48-2.38(m,1H),2.31-2.26(m,1H),1.48(s,9H).

Example 9

At room temperature, intermediate B2 (150 mg) and 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (144 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v = 4/1), and potassium carbonate (143 mg) and Pd(dppf)Cl ₂ (38 mg) were added. After nitrogen was fully replaced in the above mixture, it was heated to 100°C and reacted for 2 hours until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 9 compound (70 mg). LCMS (ES, m/z): 506.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.39(s,1H),8.19(d,J＝8.4Hz,1H),8.02(s,2H),7.15(s,1H),7.09-7.09(m,1H),6.99(d,J＝2.0Hz,1H),6.83(s ,1H),5.56(s,2H),4.47-4.41(m,1H),4.17-4.10(m,2H),3.93(s,3H),3.61-3.53(m,2H),2.21-2.16(m,4H),1.55(s,9H).

Embodiment 10:

At room temperature, intermediate B2 (150 mg) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (110 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v = 4/1), and potassium carbonate (138 mg) and Pd(dppf)Cl ₂ (25 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 10 compound (15 mg). LCMS (ES, m/z): 436.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 8.08, (s, 1H), 7.99 (s, 1H), 7.84-7.78 (m, 2H), 7.14-7.03 (m, 4H), 3.92 (s, 3H), 3.88 (s, 3H), 1.48 (s, 9H).

Embodiment 11

Step 1: At room temperature, 4-bromo-1-(bromomethyl)-2-methoxybenzene (200 mg) was dissolved in DMF (5 mL), and 4-fluoropyrazole (93 mg) and potassium carbonate (297 mg) were added. The above mixture was stirred at room temperature overnight until the reaction was complete. After the reaction was completed, water and ethyl acetate were added to the above mixture, and the mixture was separated after sufficient stirring. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate 1 (260 mg) as a light yellow solid. LCMS (ES, m/z): 284.5 [M + H] ⁺ .

Step 2: At room temperature, the intermediate 1 (190 mg) obtained in step 1 was dissolved in 1,4-dioxane (4 mL), and bis-pinacol borate (465 mg), potassium acetate (270 mg) and Pd(dppf)Cl ₂ (32 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After the reaction was completed, the solvent was removed, ethyl acetate was added, and the mixture was fully stirred and filtered. The filtrate was concentrated, and n-hexane was added to the residue, stirred and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product intermediate 2 (270 mg) as a light yellow solid. LCMS (ES, m/z): 333.0 [M+H] ⁺ .

Step 3: At room temperature, potassium carbonate (78 mg) and Pd(PPh 3 ) 4 (44 mg) were added to a mixture of 1,4-dioxane and water (2.5 mL, v/v=4/1) of intermediate 2 (150 mg) and intermediate _A1 (100 mg) obtained in step _2. After nitrogen was fully replaced, the mixture was heated to 80°C and the reaction was continued for 2 h until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 11 compound (22 mg). LCMS (ES, m/z): 448.9 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.43(s,1H),8.10(s,1H),8.01(s,1H),7.90(d,J＝4.0Hz,1H),7.50(d,J＝4.0Hz,1H),7.15 (s,1H),7.06-7.02(m,3H),5.25(s,2H),4.92(s,1H),4.24-4.21(t,J＝4.0Hz,2H),3.89(s,3H),3.80 -3.74(m,2H).

Example 12

Step 1: At room temperature, 4-bromo-1-(bromomethyl)-2-methoxybenzene (200 mg) was dissolved in DMF (5 mL), and 4-cyanopyrazole (100 mg) and potassium carbonate (297 mg) were added. The above mixture was stirred at room temperature overnight until the reaction was complete. After the reaction was completed, water and ethyl acetate were added to the above mixture, and the mixture was separated after sufficient stirring. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate 1 (190 mg) as a light yellow solid. LCMS (ES, m/z): 291.5 [M+H] ⁺ .

Step 2: At room temperature, the intermediate 1 (260 mg) obtained in step 1 was dissolved in 1,4-dioxane (4 mL), and bis-pinacol borate (465 mg), potassium acetate (270 mg) and Pd(dppf)Cl ₂ (32 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After the reaction was completed, the solvent was removed, ethyl acetate was added, and the mixture was fully stirred and filtered. The filtrate was concentrated, and n-hexane was added to the residue, stirred and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product intermediate 2 (270 mg) as a light yellow solid. LCMS (ES, m/z): 340.2 [M+H] ⁺ .

Step 3: At room temperature, potassium carbonate (78 mg) and Pd(PPh 3 ) 4 (44 mg) were added to a mixture of 1,4-dioxane and water (2.5 mL, v/v=4/1) of intermediate 2 (150 mg) and intermediate _A1 (100 mg) obtained in step _2. After nitrogen was fully replaced, the mixture was heated to 80°C and the reaction was continued for 2 h until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 12 compound (22 mg). LCMS (ES, m/z): 456.1 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.58(s,1H),8.43(s,1H),8.10(s,1H),8.08(s,1H),8.02(s,1H),7.21-7.16(m,2H), 7.09-7.07(m,2H),5.39(s,2H),4.92(t,J＝4.0Hz,1H),4.24(t,J＝4.0Hz,2H),3.88(s,3H),3.80 -3.75(m,2H).

Example 13

Step 1: At room temperature, 4-bromo-1-(bromomethyl)-2-methoxybenzene (200 mg) was dissolved in DMF (5 mL), and pyrazole (140 mg) and potassium carbonate (297 mg) were added. The above mixture was stirred at room temperature overnight until the reaction was complete. After the reaction was completed, water and ethyl acetate were added to the above mixture, and the mixture was separated after sufficient stirring. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate 1 (180 mg) as a light yellow solid. LCMS (ES, m/z): 266.5 [M+H] ⁺ .

Step 2: At room temperature, the intermediate 1 (180 mg) obtained in step 1 was dissolved in 1,4-dioxane (4 mL), and bis-pinacol borate (340 mg), potassium acetate (180 mg) and Pd(dppf)Cl ₂ (55 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After the reaction was completed, the solvent was removed, ethyl acetate was added, and the mixture was filtered after sufficient stirring. The filtrate was concentrated, and n-hexane was added to the residue, stirred and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product intermediate 2 (240 mg) as a light yellow solid. LCMS (ES, m/z): 315.0 [M+H] ⁺ .

Step 3: At room temperature, potassium carbonate (78 mg) and Pd(PPh 3 ) 4 (44 mg) were added to a mixture of 1,4-dioxane and water (2.5 mL, v/v=4/1) of intermediate 2 (240 mg) and intermediate _A1 (100 mg) obtained in step _2. After nitrogen was fully replaced, the mixture was heated to 80°C and the reaction was continued for 2 h until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 13 compound (11 mg). LCMS (ES, m/z): 431.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.43(s,1H),8.10(s,1H),8.01(s,1H),7.78(d,J＝4.0Hz,1H),7.48(s,1H),7.15(s,1H),7.06-7.02(m,2H),6.94(d ,J＝8.0Hz,1H),6.29-6.28(m,1H),5.34(s,2H),4.93(t,J＝4.0Hz,1H),4.22(t,J＝4.0Hz,2H),3.90(s,3H),3.79-3.75(m,2H).

Embodiment 14

Step 1: At room temperature, 4-bromo-1-(bromomethyl)-2-methoxybenzene (200 mg) was dissolved in DMF (5 mL), and 4-methylpyrazole (88 mg) and potassium carbonate (297 mg) were added. The above mixture was stirred at room temperature overnight until the reaction was complete. After the reaction was completed, water and ethyl acetate were added to the above mixture, and the mixture was separated after sufficient stirring. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate 1 (190 mg) as a light yellow solid. LCMS (ES, m/z): 280.8 [M + H] ⁺ .

Step 2: At room temperature, the intermediate 1 (190 mg) obtained in step 1 was dissolved in 1,4-dioxane (4 mL), and bis-pinacol borate (350 mg), potassium acetate (200 mg) and Pd(dppf)Cl ₂ (50 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After the reaction was completed, the solvent was removed, ethyl acetate was added, and the mixture was fully stirred and filtered. The filtrate was concentrated, and n-hexane was added to the residue, stirred and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product intermediate 2 (200 mg) as a light yellow solid. LCMS (ES, m/z): 329.0 [M+H] ⁺ .

Step 3: At room temperature, potassium carbonate (78 mg) and Pd(PPh 3 ) 4 (44 mg) were added to a mixture of 1,4-dioxane and water (2.5 mL, v/v=4/1) of intermediate 2 (200 mg) and intermediate _A1 (100 mg) obtained in step _2. After nitrogen was fully replaced, the mixture was heated to 80°C and the reaction was continued for 2 h until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 14 compound (11 mg). LCMS (ES, m/z): 445.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.43(s,1H),8.10(s,1H),8.01(s,1H),7.52(s,1H),7.27(s,1H),7.14(s,1H),7.05-7.02(m,2H),6.93(d,J =8.0Hz,1H),5.25(s,2H),4.93(t,J＝4.0Hz,1H),4.22(t,J＝4.0Hz,2H),3.90(s,3H),3.79-3.75(m,2H),2.02(s,3H).

Embodiment 15

At room temperature, intermediate B2 (100 mg) and 1-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (56 mg) were dissolved in a mixture of 1,4-dioxane and water (2.5 mL, v/v = 4/1), and potassium carbonate (100 mg) and Pd(dppf)Cl ₂ (20 mg) were added. After nitrogen was fully replaced in the above mixture, it was heated to 100°C and reacted for 2 hours until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 15 compound (20 mg). LCMS (ES, m/z): 450.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.20(s,1H),8.00(d,J＝4.0Hz,2H),7.85-7.82(m,2H),7.14(d,J＝4Hz,1H),7.09(d,J＝4 Hz,1H),7.05-7.03(m,2H),4.24-4.18(m,2H),3.88(s,3H),1.48(s,9H),1.42(t,J＝7.20Hz,3H).

Example 16

At room temperature, intermediate B2 (150 mg) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl)propan-2-ol (131 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v=4/1), and potassium carbonate (138 mg) and Pd(dppf)Cl ₂ (38 mg) were added. After nitrogen was fully replaced in the above mixture, it was heated to 100° C. and the reaction was continued for 2 h until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was fully stirred and separated. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 16 compound (48 mg). LCMS (ES, m/z): 480.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.42(s,1H),8.10(s,1H),8.00(d,J＝4.4Hz,2H),7.85-7.83(m,1H),7.14-7.11(m,1H),7.05- 7.02(m,2H),4.94(d,J＝4.8Hz,1H),4.14-4.00(m,3H),3.88(s,3H),1.48(s,9H),1.07(d,J＝6.0Hz,3H).

Embodiment 17

At room temperature, intermediate B2 (150 mg) and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl)propan-2-ol (144 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v=4/1), and potassium carbonate (138 mg) and Pd(dppf)Cl ₂ (38 mg) were added. After nitrogen was fully replaced in the above mixture, it was heated to 100° C. and the reaction was continued for 2 h until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was fully stirred and separated. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 17 compound (53 mg). LCMS (ES, m/z): 494.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.43(s,1H),8.11(s,1H),8.00-7.99(m,2H),7.85-7.83(m,1H),7.65-7.53(m,2H),7.12(d ,J＝2.0Hz,1H),7.06-7.02(m,2H),4.74(s,1H),4.10(s,2H),3.87(s,3H),1.48(s,9H),1.10(s,6H).

Embodiment 18

At room temperature, intermediate B2 (450 mg) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (120 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v=4/1), and potassium carbonate (238 mg) and Pd(dppf)Cl ₂ (63 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and stirred for 2 hours until the reaction was complete. After the reaction was completed, ethyl acetate was added to the above mixture. The mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain Example 18 compound (88 mg). LCMS (ES, m/z): 435.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ (ppm): 8.01 (s, 1H), 7.80 (d, J = 2.0Hz, 1H), 7.30 (d, J = 7.6Hz, 1H), 7.12-7.03 (m, 4H), 3.92 (s, 3H), 3.83 (s, 3H), 3.55 (s, 2H), 1.42 (s, 9H).

Embodiment 19

At room temperature, intermediate B2 (150 mg) and 1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (129 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v = 4/1), and potassium carbonate (143 mg) and Pd(dppf)Cl ₂ (38 mg) were added. After nitrogen was fully replaced in the above mixture, it was heated to 100°C and reacted for 2 hours until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 19 compound (62 mg). LCMS (ES, m/z): 476.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.48(s,1H),8.15(s,1H),8.00(d,J＝4.8Hz,2H),7.85(d,J＝8.4Hz,1H),7.12(d,J＝2.0Hz,1H),7.04-7. 02(m,2H),4.98-4.89(m,1H),3.87(s,3H),2.56-2.52(m,1H),2.48-2.36(m,3H),1.86-1.76(m,2H),1.48(s,9H).

Embodiment 20

Step 1: At room temperature, dissolve 4-bromo-2-methoxyaniline (800 mg) in anhydrous dichloromethane (10 mL) and add pyridine (960 mg). After the mixture is cooled to 0°C with an ice-water bath, ethylsulfonyl chloride (770 mg) is added dropwise. After the addition is completed, the mixture is slowly warmed to room temperature and stirred continuously until the reaction is complete. After the reaction is completed, dichloromethane is added to the mixture, and the resulting mixture is washed with water and saturated brine. The organic phase is dried over anhydrous sodium sulfate and the solvent is removed. The residue is purified by column chromatography to obtain intermediate 1 (900 mg) as a light brown oil. LCMS (ES, m/z): 294.0, 296.0 [M+H] ⁺ .

Step 2: At room temperature, the intermediate 1 (900 mg) obtained in step 1 and the bis-pinacol borate (1.56 g) were dissolved in 1,4-dioxane (10 mL), and potassium acetate (950 mg) and Pd(dppf)Cl ₂ (336 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and stirred for 2 hours until the reaction was complete. After the reaction was completed, ethyl acetate was added to the above reaction solution, and the resulting mixture was washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate 2 (1.02 g) as a brown solid. LCMS (ES, m/z): 342.0 [M+H] ⁺ .

Step 3: At room temperature, potassium carbonate (1.2 g) and Pd(dppf)Cl 2 (320 mg) were added to a mixture of intermediate 2 (1.01 g) obtained in step 2 and 7-bromo-5-iodopyrrole[2.1-F][1.2.4]triazine-4-amine (500 mg) in 1,4-dioxane and water (10 mL, v/v= ₄ /1). After the mixture was fully replaced with nitrogen, it was heated to 80°C and stirred for 2 h until the reaction was complete. After the reaction was completed, the liquids were separated and the organic phase was concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate 3 (690 mg) as a brown solid. LCMS (ES, m/z): 426.0, 428.0 [M+H] ⁺ .

Step 4: At room temperature, the intermediate 3 (200 mg) obtained in step 3 and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl)ethane-1-ol (168 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v = 4/1), and potassium carbonate (195 mg) and Pd(dppf)Cl ₂ (53 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and stirred for 2 hours until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 20 compound (100 mg). LCMS (ES, m/z): 458.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.96(s,1H),8.44(s,1H),8.16(s,1H),8.11(s,1H),8.01(s,1H),7.40(d,J＝8.0Hz,1H),7.17(d,J＝1.6Hz, 1H),7.07-7.05(m,2H),4.24-4.21(m,2H),3.88(s,3H),3.79-3.77(m,2H),3.10-3.06(m,2H),1.28(t,J＝7.2Hz,3H).

Embodiment 21

Step 1: At room temperature, dissolve N-(4-bromo-2-methoxyphenyl) pivalamide (300 mg) and bis(boronic acid pinacol) (514 mg) in 1,4-dioxane (4 mL), and add potassium acetate (310 mg) and Pd(dppf)Cl ₂ (77 mg). After the above mixture is fully replaced with nitrogen, it is heated to 100°C and reacted for 2 hours until the reaction is complete. After the reaction is completed, the solvent is removed, ethyl acetate is added, and the mixture is stirred thoroughly and filtered. The filtrate is concentrated, and n-hexane is added to the residue, stirred thoroughly and filtered. The filtrate is concentrated under reduced pressure to obtain the crude product intermediate 1 (280 mg) as a light yellow solid. LCMS (ES, m/z): 333.50 [M+H] ⁺ .

Step 2: At room temperature, the intermediate 1 (260 mg) obtained in step 1 and 7-bromo-5-iodopyrrole [2.1-F] [1.2.4] triazine-4-amine (200 mg) were dissolved in a mixture of 1,4-dioxane and water (2.5 mL, v/v = 4/1), and potassium carbonate (250 mg) and Pd (PPh ₃ ) ₄ (140 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 80°C and the reaction was continued for 2 h until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate 2 (230 mg) as a light yellow solid. LCMS (ES, m/z): 414.9 [M+H] ⁺ .

Step 3: At room temperature, the intermediate 2 (100 mg) obtained in step 2 and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole (75 mg) were dissolved in a mixture of 1,4-dioxane and water (2.5 mL, v/v = 4/1), and potassium carbonate (100 mg) and Pd(dppf)Cl ₂ (35 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 21 compound (14 mg). LCMS (ES, m/z): 420.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.03(s,1H),7.87(s,1H),7.80(s,1H),7.24(s,1H),7.18-7.16(m,1H), 7.12(s,1H),7.10-7.09(d,J＝4.0Hz,1H),3.98(s,3H),3.92(s,3H),1.40(s,9H).

Embodiment 22

Step 1: At room temperature, 4-bromo-1-(bromomethyl)-2-methoxybenzene (200 mg) was dissolved in DMF (5 mL), and 3-trifluoromethylpyrazole (146 mg) and potassium carbonate (297 mg) were added. The above mixture was stirred at room temperature overnight until the reaction was complete. After the reaction was completed, water and ethyl acetate were added to the above mixture, and the mixture was separated after sufficient stirring. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate 1 (200 mg) as a light yellow solid. LCMS (ES, m/z): 334.5 [M + H] ⁺ .

Step 2: At room temperature, the intermediate 1 (200 mg) obtained in step 1 was dissolved in 1,4-dioxane (4 mL), and bis-pinacol borate (228 mg), potassium acetate (177 mg) and Pd(dppf)Cl ₂ (44 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After the reaction was completed, the solvent was removed, ethyl acetate was added, and the mixture was filtered after sufficient stirring. The filtrate was concentrated, and n-hexane was added to the residue, stirred and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product intermediate 2 (250 mg) as a light yellow solid. LCMS (ES, m/z): 383.0 [M+H] ⁺ .

Step 3: At room temperature, potassium carbonate (78 mg) and Pd(PPh 3 ) 4 (44 mg) were added to a mixture of 1,4-dioxane and water (2.5 mL, v/v=4/1) of intermediate 2 (200 mg) and intermediate _A1 (100 mg) obtained in step _2. After nitrogen was fully replaced, the mixture was heated to 80°C and the reaction was continued for 2 h until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 22 compound (30 mg). LCMS (ES, m/z): 499.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.43(s,1H),8.10(s,1H),8.02-8.00(m,2H),7.17-7.13(m,2H),7.10-7.08(m,2H),6.75-6.74(d ,J＝2.40Hz,1H),5.43(s,2H),4.92(t,J＝5.6Hz,1H),4.22(t,J＝5.6Hz,2H),3.89(s,3H),3.79-3.75(m,2H).

Embodiment 23

Step 1: At room temperature, 4-bromo-1-(bromomethyl)-2-methoxybenzene (200 mg) was dissolved in DMF (5 mL), and 4-trifluoromethylpyrazole (146 mg) and potassium carbonate (297 mg) were added. The above mixture was stirred at room temperature overnight until the reaction was complete. After the reaction was completed, water and ethyl acetate were added to the above mixture, and the mixture was separated after sufficient stirring. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate 1 (205 mg) as a light yellow solid. LCMS (ES, m/z): 334.5 [M + H] ⁺ .

Step 2: At room temperature, the intermediate 1 (205 mg) obtained in step 1 was dissolved in 1,4-dioxane (4 mL), and bis(boronic acid pinacol) (228 mg), potassium acetate (177 mg) and Pd(dppf)Cl ₂ (44 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After the reaction was completed, the solvent was removed, ethyl acetate was added, and the mixture was fully stirred and filtered. The filtrate was concentrated, and n-hexane was added to the residue, stirred and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product intermediate 2 (240 mg) as a light yellow solid. LCMS (ES, m/z): 383.0 [M+H] ⁺ .

Step 3: At room temperature, potassium carbonate (78 mg) and Pd(PPh 3 ) 4 (44 mg) were added to a mixture of 1,4-dioxane and water (2.5 mL, v/v=4/1) of intermediate 2 (240 mg) and intermediate _A1 (100 mg) obtained in step _2. After nitrogen was fully replaced, the mixture was heated to 80°C and the reaction was continued for 2 h until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 23 compound (14 mg). LCMS (ES, m/z): 499.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.43(s,1H),8.41(s,1H),8.10(s,1H),8.02(s,1H),7.92(s,1H),7.17-7.12(m,2H),7.09-7 .07(m,2H),5.40(s,2H),4.92(t,J＝5.6Hz,1H),4.22(t,J＝5.6Hz,2H),3.89(s,3H),3.79-3.75(m,2H).

Embodiment 24

At room temperature, intermediate B1 (150 mg) and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazol-1-yl)ethane-1-ol (124 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v=4/1), and potassium carbonate (143 mg) and Pd(dppf)Cl ₂ (38 mg) were added. After the mixture was fully replaced with nitrogen, it was heated to 100° C. and stirred for 2 h until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 24 compound (50 mg). LCMS (ES, m/z): 465.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.44(d,J＝0.8Hz,1H),8.12-8.11(m,1H),8.03(d,J＝4Hz,1H),7.28(d,J＝7.6Hz,1H),7.12-7.08(m,2H),7.04 -7.02(m,1H),4.93(t,J＝5.2Hz,1H),4.24(t,J＝5.6Hz,2H),3.84(s,3H),3.80-3.76(m,2H),3.54(s,2H),1.42(s,9H).

Embodiment 25

At room temperature, intermediate B2 (150 mg) and 1-isopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (123 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v = 4/1), and potassium carbonate (138 mg) and Pd(dppf)Cl ₂ (38 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 25 compound (80 mg). LCMS (ES, m/z): 464.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.00-7.99(m,2H),7.87-7.82(m,2H),7.15(d,J＝2.0Hz,1H),7.11(d,J＝2 .4Hz,1H),7.09-7.03(m,2H),4.61-4.54(m,1H),3.88(s,3H),1.48-1.46(m,15H).

Embodiment 26

At room temperature, intermediate B2 (150 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (101 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v = 4/1), and potassium carbonate (143 mg) and Pd(dppf)Cl ₂ (38 mg) were added. After the mixture was fully replaced with nitrogen, it was heated to 100°C and stirred for 2 hours until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 26 compound (35 mg). LCMS (ES, m/z): 422.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):13.05(s,1H),8.27-7.99(m,2H),7.85(d,J＝8.0Hz,1H),7.65-7.55(m,1 H),7.14-7.12(m,2H),7.08(s,1H),7.09-7.03(m,2H),3.87(s,3H),1.48(s,9H).

Embodiment 27

At room temperature, intermediate B2 (150 mg) and 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (127 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v=4/1), and potassium carbonate (143 mg) and Pd(dppf)Cl ₂ (38 mg) were added. After the mixture was fully replaced with nitrogen, it was heated to 100°C and stirred for 2 hours until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 27 compound (55 mg). LCMS (ES, m/z): 472.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.35(d,J＝2.8Hz,1H),8.05(d,J＝4.0Hz,1H),8.01(d,J＝0.8Hz,1H),7.90(d,J＝4.4Hz,1H),7.83(t,J＝64.4H z,1H),7.76(d,J＝4.8Hz,1H),7.36(d,J＝2.8Hz,1H),7.17-7.16(m,2H),7.07-7.05(m,1H),3.88(s,3H),1.48(s,9H).

Embodiment 28

At room temperature, intermediate B2 (150 mg) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (101 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v = 4/1), and potassium carbonate (143 mg) and Pd(dppf)Cl ₂ (38 mg) were added. After the mixture was fully replaced with nitrogen, it was heated to 100°C and stirred for 2 hours until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 28 compound (10 mg). LCMS (ES, m/z): 422.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):13.06(s,1H),8.00(d,J＝2.8Hz,2H),7.84(d,J＝4.84Hz,1H),7.65-7.61(m,1H), 7.12(d,J＝1.6Hz,1H),7.09-7.02(m,2H),7.04(d,J＝2.0Hz,1H),3.87(s,3H),1.48(s,9H).

Embodiment 29

Step 1: At room temperature, add Ephos Pd G ₄ (73 mg) to a tert-butanol solution (10 mL) of 4-bromo-1-iodo-2-methoxybenzene (500 mg), 1,3-oxazol-2-amine (147 mg) and potassium carbonate (440 mg). The above mixture is fully replaced with nitrogen, the reaction solution is heated to 100°C, and stirred for 16 hours until the reaction is complete. After the reaction is completed, the reaction solution is cooled to room temperature and ethyl acetate is added. The resulting mixture is washed with water and saturated brine, and the organic phase is dried over anhydrous sodium sulfate and the solvent is removed. The resulting residue is purified by column chromatography to obtain the product intermediate 1 (50 mg). LCMS (ES, m/z): 269.0, 271.0 [M+H] ⁺ .

Step 2: At room temperature, add Pd(dppf)Cl ₂ (21 mg) to a 1,4-dioxane solution (5 mL) of intermediate 1 (80 mg), bis-pinacol borate (113 mg) and potassium acetate (58 mg) obtained in step 1. After the nitrogen is fully replaced by the above mixture, the reaction solution is heated to 90°C and stirred for 16 hours until the reaction is complete. After the reaction is completed, the reaction solution is cooled to room temperature and ethyl acetate is added. The obtained mixture is washed with water and saturated brine, and the organic phase is dried over anhydrous sodium sulfate and the solvent is removed. The obtained residue is purified by column chromatography to obtain the product intermediate 2 (90 mg). LCMS (ES, m/z): 317.1 [M+H] ⁺ .

Step 3: At room temperature, add intermediate 2 (86 mg) and intermediate A3 (100 mg) obtained in step 2 to a mixed solution of Pd(dppf)Cl ₂ (24 mg) and potassium carbonate (94 mg) in 1,4-dioxane (5 mL, v/v = 10/1). After the nitrogen is fully replaced by the above mixture, the reaction solution is heated to 90°C and stirred for 16 hours until the reaction is complete. After the reaction is completed, the reaction solution is cooled to room temperature and ethyl acetate is added. The obtained mixture is washed with water and saturated brine, and the organic phase is dried over anhydrous sodium sulfate and the solvent is removed. The obtained residue is purified by reverse phase preparative chromatography to obtain Example 29 compound (8.9 mg). LCMS (ES, m/z): 403.0 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ(ppm):8.35(d,J＝8.0Hz,1H),7.93(s,1H),7.48(d,J＝2.4Hz,1H),7.31(s,1H),7.23(s,1 H),7.16(d,J＝2.4Hz,1H),7.15-7.12(m,1H),7.02-6.96(m,2H),4.00(s,3H),3.95(s,3H).

Embodiment 30

Step 1: At room temperature, diisopropylethylamine (3.18 g) and T ₃ P (5.22 g) were added to a dichloromethane solution (40 mL) of (4-bromo-2-methoxyphenyl)acetic acid (2.0 g) and methylamine hydrochloride (0.61 g). The reaction solution was stirred at room temperature for 2 h until the reaction was complete. After the reaction was completed, water was added to the reaction solution, the resulting mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate 1 (1.50 g). LCMS (ES, m/z): 258.1, 260.1 [M+H] ⁺ .

Step 2: Add Lawesson's reagent (1.17 g) to the toluene solution (20 mL) of intermediate 1 (1.50 g) obtained in step 1. Heat the above reaction solution to 100°C and continue stirring for 2 hours until the reaction is complete. After the reaction is completed, cool the reaction solution to room temperature and add sodium thiosulfate solution to the reaction solution to quench the reaction. The resulting mixture is extracted with ethyl acetate and the organic phases are combined. The organic phase is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography to obtain intermediate 2 (1.60 g). LCMS (ES, m/z): 274.0, 276.0 [M+H] ⁺ .

Step 3: Add silver benzoate (585 mg) to a dichloromethane solution (10 mL) of intermediate 1 (350 mg) and acetic hydrazide (113 mg) obtained in step 1, and finally add acetic acid (230 mg). The above mixture is stirred at room temperature for 16 h until the reaction is complete. After the reaction is completed, the filtrate is filtered and concentrated under reduced pressure. The resulting residue is purified by column chromatography to obtain intermediate 3 (700 mg). LCMS (ES, m/z): 296.0, 298.0 [M+H] ⁺ .

Step 4: At room temperature, potassium acetate (696 mg) and Pd(dppf)Cl ₂ (193 mg) were added to the 1,4-dioxane solution (15 mL) of intermediate 3 (700 mg) and bis-pinacol borate (660 mg) obtained in step 3, respectively. After the nitrogen was fully replaced by the above mixture, the reaction solution was heated to 80°C and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature and ethyl acetate was added. The obtained mixture was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The obtained residue was purified by column chromatography to obtain the product intermediate 4 (500 mg). LCMS (ES, m/z): 344.1 [M+H] ⁺ .

Step 5: At room temperature, potassium carbonate (242 mg) and Pd(dppf)Cl ₂ (47 mg) were slowly added to a mixed solution of intermediate 4 (200 mg) and intermediate A3 (171 mg) obtained in step 4 in 1,4-dioxane and water (11 mL, v/v=10/1). After the nitrogen was fully replaced by the above mixture, the reaction solution was heated to 80°C and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature and ethyl acetate was added. The obtained mixture was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The obtained residue was purified by reverse phase preparative chromatography to obtain Example 30 compound (45 mg). LCMS (ES, m/z): 430.3 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ(ppm):8.20(s,1H),7.94(s,1H),7.48(d,J＝2.0Hz,1H),7.21-7.17(m,3H),7.0 5-7.03(m,2H),4.18(s,2H),4.00(s,3H),3.89(s,3H),3.47(s,3H),2.46(s,3H).

Embodiment 31

Step 1: At room temperature, sodium tert-butoxide (1.35 g), t-BuXPhos (285 mg) and Xphos Pd G1 (247 mg) were added to a n-butanol solution (20 mL) of 4-bromo-1-iodo-2-methoxybenzene (2.10 mg) and 5-methyl-1,2-oxazol-3-amine (724 mg). The above mixture was heated to 100 ° C under N ₂ protection and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature, and water and ethyl acetate were added to the reaction solution. After the mixture was fully stirred, the liquid was separated, the filtrate was extracted with ethyl acetate, and the organic phase was combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain intermediate 1 (440 mg). LCMS (ES, m/z): 283.0, 285.0 [M+H] ⁺ .

Step 2: At room temperature, add bis-pinacol borate (161 mg) to the 1,4-dioxane solution (5 mL) of intermediate 1 (120 mg) obtained in step 1, and add potassium acetate (104 mg) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (172 mg). After the above mixture is fully replaced with nitrogen, it is heated to 90°C and stirred for 16 hours until the reaction is complete. After the reaction is completed, the reaction solution is cooled to room temperature and ethyl acetate is added. The obtained mixture is washed with water and saturated brine, and the organic phase is dried over anhydrous sodium sulfate and the solvent is removed. The obtained residue is purified by column chromatography to obtain the product Example 31 compound (50 mg). LCMS (ES, m/z): 331.1 [M+H] ⁺ .

Step 3: At room temperature, intermediate A3 (44 mg) and intermediate 2 (50 mg) obtained in step 2 were dissolved in a mixed solution of 1,4-dioxane and water (5 mL, v/v = 5/1), and K ₂ CO ₃ (42 mg) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (12 mg) were added. The above mixture was fully replaced with nitrogen and heated to 90°C and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature and ethyl acetate was added. The obtained mixture was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The obtained residue was purified by reverse phase preparative chromatography to obtain Example 31 compound (3.4 mg). LCMS (ES, m/z): 417.0 [M+H] ⁺ .

¹ H NMR(400MHz,MeOD)δ(ppm):8.1(s,1H),8.08(s,1H),7.74(s,1H),7.28(s,1H),7.22( d,J＝2.4Hz,1H),7.18-7.14(m,2H),6.04(s,1H),4.02(d,J＝1.2Hz,6H),2.38(s,3H).

Embodiment 32

Step 1: At room temperature, CDI (436 mg) was added to a dichloromethane solution (10 mL) of (4-bromo-2-methoxyphenyl)acetic acid (600 mg), and the mixture was stirred at room temperature for 30 minutes. Then prop-2-yn-1-amine (148 mg) was added, and the reaction solution was stirred for 3 hours at room temperature until the reaction was complete. After the reaction was completed, ethyl acetate was added to the reaction solution. The resulting mixture was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The resulting residue was purified by column chromatography to obtain the product intermediate 1 (630 mg). LCMS (ES, m/z): 282.1, 284.1 [M+H] ⁺ .

Step 2: At room temperature, gold chloride (31 mg) was added to a dichloromethane solution (10 mL) of the intermediate 1 (580 mg) obtained in step 1. The above reaction solution was stirred at room temperature for 16 h until the reaction was complete. After the reaction was completed, ethyl acetate was added to the reaction solution. The resulting mixture was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The resulting residue was purified by column chromatography to obtain the product intermediate 2 (60 mg). LCMS (ES, m/z): 282.1, 284.1 [M+H] ⁺ .

Step 3: At room temperature, the intermediate 2 (100 mg) obtained in step 2 and the bis-pinacol borate (134 mg) were dissolved in a 1,4-dioxane solution (5 mL), and Pd(dppf)Cl ₂ (25 mg) and potassium acetate (69 mg) were added. The above mixture was fully replaced with nitrogen, the reaction solution was heated to 90°C, and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature and ethyl acetate was added. The obtained mixture was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The obtained residue was purified by column chromatography to obtain the product intermediate (100 mg). LCMS (ES, m/z): 330.2 [M+H] ⁺ .

Step 4: At room temperature, add Pd(dppf)Cl ₂ (23 mg) to a mixed solution of intermediate A2 (94 mg), intermediate 3 (84 mg) obtained in step 3, and potassium carbonate (88 mg) in 1,4-dioxane and water (10 mL, v/v = 10/1). After the nitrogen is fully replaced by the above mixture, the reaction solution is heated to 90°C and stirred for 16 hours until the reaction is complete. After the reaction is completed, the reaction solution is cooled to room temperature and ethyl acetate is added. The obtained mixture is washed with water and saturated brine, and the organic phase is dried over anhydrous sodium sulfate and the solvent is removed. The obtained residue is purified by reverse phase preparative chromatography to obtain Example 32 compound (30 mg). LCMS (ES, m/z): 415.9 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD-d ₄ )δ(ppm):7.89(s,1H),7.49(s,1H),7.32(d,J＝7.6Hz,1H),7.29(s,1H),7.14(d,J＝2.4Hz,1 H),7.03(d,J=7.6Hz,1H),6.98(s,1H),4.12(s,2H),4.01(s,3H),3.86(s,3H),2.29(s,3H).

Embodiment 33

Step 1: At 0°C, sodium hydride (81 mg, 60%) was added in batches to the anhydrous tetrahydrofuran solution (5 mL) of the intermediate 1 (190 mg) obtained in step 1 in Example 31. After the addition was complete, the reaction solution was warmed to room temperature and stirred for 30 minutes, and then iodomethane (143 mg) was added. The above reaction solution was stirred at room temperature and continued to react for 2 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to 0°C and quenched with ice water. The mixture was extracted with ethyl acetate and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate 1 (200 mg). LCMS (ES, m/z): 297.1, 299.1 [M+H] ⁺ .

Step 2: At room temperature, add bis-pinacol borate (427 mg) to the 1,4-dioxane solution (5 mL) of intermediate 1 (200 mg) obtained in step 1, and add potassium acetate (165 mg) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (273 mg). The above mixture is heated to 90°C under nitrogen protection and stirred for 16 hours until the reaction is complete. After the reaction is completed, the reaction solution is concentrated under reduced pressure. The residue is subjected to column chromatography to obtain intermediate 2 (200 mg). LCMS (ES, m/z): 345.1 [M+H] ⁺ .

Step 3: At room temperature, add K ₂ CO 3 (96 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (28 mg) to a mixed solution of intermediate _A2 (102 mg) and intermediate 2 (120 mg) obtained in step 2 in 1,4-dioxane and water (5 mL, v/v=10/1). After the above mixture is fully replaced with nitrogen, it is heated to 100°C and stirred for 16 hours until the reaction is complete. After the reaction is completed, the reaction solution is cooled to room temperature and ethyl acetate is added. The obtained mixture is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is purified by reverse phase preparative chromatography to obtain Example 33 compound (17.5 mg). LCMS (ES, m/z): 431.3 [M+H] ⁺ .

¹ H NMR (400MHz, MeOD) δ (ppm): 7.11 (s, 1H), 6.85 (s, 1H), 6.59 (d, J = 4.0Hz, 1H), 6.39-6.37 (m ,2H),6.32-6.30(m,2H),4.74(s,1H),3.15(s,3H),3.04(s,3H),2.42(s,3H),1.44(s,3H).

Embodiment 34

Step 1: Dissolve 4-bromo-2-methoxyaniline (600 mg), cyclopropylacetic acid (466 mg) and TEA (601 mg) in DMF (6 mL) at room temperature, and add HATU (1.70 g). The reaction solution was stirred at room temperature for 4 h until the reaction was complete. After the reaction was completed, water was added to the reaction solution, the resulting mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate 1 (890 mg). LCMS (ES, m/z): 270.0, 272.0 [M+H] ⁺ .

Step 2: At room temperature, add bis-pinacol borate (940 mg) to the 1,4-dioxane solution (5 mL) of intermediate 1 (500 mg) obtained in step 1, and add potassium acetate (454 mg) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (75 mg). The above mixture is heated to 90°C under nitrogen atmosphere and stirred for 16 hours until the reaction is complete. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the residue is purified by column chromatography to obtain intermediate 2 (600 mg). LCMS (ES, m/z): 318.1 [M+H] ⁺ .

Step 3: Potassium carbonate (96 mg) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (28 mg) were added to a mixed solution (5 mL, v/v = 10/1) of 1,4-dioxane and water of intermediate A3 (102 mg) and intermediate 2 (120 mg) obtained in step 2 at room temperature. The above mixture was heated to 100°C under nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature and water was added to the reaction solution. The obtained mixture was extracted with ethyl acetate and the organic phases were combined. The obtained organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase preparative chromatography to obtain Example 34 compound (13.9 mg). LCMS (ES, m/z): 404.2 [M+H] ⁺ .

¹ HNMR (400MHz, CD ₃ OD)δ(ppm):7.28(s,1H),7.21(d,J＝8.0Hz,1H),7.09(s,1H),6.84(d,J＝2.4Hz,1H),6.36(d,J＝2.4Hz,1H),6.33(d,J＝1.6 Hz, 1H), 6.29 (s, 1H), 6.25-6.23 (m, 1H), 3.14 (d, J = 3.6Hz, 6H), 1.18-1.07 (m, 1H), 0.15-0.13 (m, 2H), 0.05-0.03 (m, 2H).

Embodiment 35

Step 1: At room temperature, 4-bromo-2-methoxyaniline (600 mg), cyclopropylacetic acid (446 mg) and triethylamine (601 mg) were dissolved in DMF (6 mL), and HATU (1.69 g) was added. The reaction solution was stirred at room temperature for 4 h until the reaction was complete. After the reaction was completed, water was added to the reaction solution, the resulting mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate 1 (890 mg). LCMS (ES, m/z): 284.0, 286.0 [M+H] ⁺ .

Step 2: At room temperature, add bis-pinacol borate (894 mg) to the 1,4-dioxane solution (5 mL) of the intermediate 1 (500 mg) obtained in step 1, and add potassium acetate (432 mg) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (71 mg). The above mixture is heated to 90°C under nitrogen atmosphere and stirred for 16 hours until the reaction is complete. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the residue is purified by column chromatography to obtain intermediate 2 (600 mg). LCMS (ES, m/z): 332.1 [M+H] ⁺ .

Step 3: Potassium carbonate (42 mg) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (12 mg) were added to a mixed solution (5 mL, v/v = 10/1) of 1,4-dioxane and water of intermediate A3 (44 mg) and intermediate 2 (50 mg) obtained in step 2 at room temperature. The above mixture was heated to 100°C under nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature and water was added to the reaction solution. The obtained mixture was extracted with ethyl acetate and the organic phases were combined. The obtained organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase preparative chromatography to obtain Example 35 compound (28.5 mg). LCMS (ES, m/z): 418.3 [M+H] ⁺ .

¹ HNMR (400MHz, CD ₃ OD)δ(ppm):8.11(d,J＝8.0Hz,1H),7.90(s,1H),7.65(d,J＝2.0Hz,1H),7.19-7.13(m,2H),7.12-7.06(m,2 H), 3.95 (d, J = 5.2Hz, 6H), 2.36 (d, J = 7.2Hz, 2H), 1.14-1.09 (m, 1H), 0.63-0.59 (m, 2H), 0.31-0.27 (m, 2H).

Embodiment 36

Step 1: At room temperature, add ethanethiocyanate (720 mg) to an acetonitrile solution (20 mL) of 4-bromo-2-methoxyaniline (1800 mg), and stir the reaction solution at room temperature for 16 h until the reaction is complete. After the reaction is completed, add dichloromethane and water to the reaction solution. Stir the mixture and separate the liquids. Wash the organic phase with water and saturated brine and dry it with anhydrous sodium sulfate. The organic phase is concentrated under reduced pressure, and the resulting residue is purified by column chromatography to obtain the product intermediate 1 (2.0 g). LCMS (ES, m/z): 275.0, 277.0 [M+H] ⁺ .

Step 2: Add iodomethane (929 mg) to the acetone solution (20 mL) of intermediate 1 obtained in step 1. Heat the reaction solution to 55°C and continue stirring for 2 h until the reaction is complete. After the reaction is completed, add ethyl acetate and water to the reaction solution. After the above mixture is fully stirred, separate the liquids, wash the organic phase with water and saturated brine and dry it with anhydrous sodium sulfate. The organic phase is concentrated under reduced pressure, and the resulting residue is purified by column chromatography to obtain the product intermediate 2 (550 mg). LCMS (ES, m/z): 289.0, 291.0 [M+H] ⁺ .

Step 3: At room temperature, add acetylhydrazine (169 mg) to the pyridine solution (7 mL) of intermediate 2 (550 mg) obtained in step 2. Heat the reaction solution to 140°C and continue stirring for 2 h until the reaction is complete. After the reaction is completed, add ethyl acetate and water to the reaction solution. After the above mixture is fully stirred, separate the liquids, wash the organic phase with water and saturated brine and dry it with anhydrous sodium sulfate. The organic phase is concentrated under reduced pressure, and the resulting residue is purified by column chromatography to obtain the product intermediate 3 (500 mg). LCMS (ES, m/z): 297.1, 299.1 [M+H] ⁺ .

Step 4: Potassium acetate (99 mg) and Pd(dppf)Cl ₂ (27 mg) were added to the 1,4-dioxane solution (10 mL) of intermediate 3 (100 mg) and bis-pinacol borate (97.0 mg) obtained in step 3 at room temperature. The mixture was fully replaced with nitrogen and heated to 90 degrees and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature and ethyl acetate was added. The obtained mixture was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The obtained residue was purified by column chromatography to obtain the product intermediate 4 (80 mg). LCMS (ES, m/z): 345.1 [M+H] ⁺ .

Step 5: Potassium carbonate (96 mg) and Pd(dppf)Cl ₂ (19 mg) were added to a mixed solution of intermediate 4 (80 mg) and intermediate A2 (68 mg) obtained in step 4 in 1,4-dioxane and water (11 mL, v/v=10:1) at room temperature. The above mixture was fully replaced with nitrogen and heated to 100 degrees and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature and ethyl acetate was added. The obtained mixture was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The obtained residue was purified by column chromatography to obtain Example 36 compound (4 mg). LCMS (ES, m/z): 431.1 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ7.98(s,1H),7.86(d,J＝7.6Hz,1H),7.47(s,2H),7.17(s,2H),7.09(d,J＝8 .4Hz,1H),7.04(s,1H),4.00(s,3H),3.96(s,3H),3.50(s,3H),2.44(s,3H).

Embodiment 37

Step 1: At 0°C, pyridine (1.57 g) was added dropwise to a dichloromethane solution (40 mL) of 4-bromo-2-methoxyaniline (2.0 g) and 4-nitrophenyl chloroformate (2.20 g). After the addition was completed, the reaction solution was slowly warmed to room temperature and stirred for 3 h until the reaction was complete. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain intermediate 1 (2.10 g). LCMS (ES, m/z): 367.0, 369.0 [M+H] ⁺ .

Step 2: At room temperature, diisopropylethylamine (317 mg) and oxacyclopentane-3-ol (144 mg) were added to the acetonitrile solution (7.0 mL) of the intermediate 1 (300 mg) obtained in step 1. The above mixture was stirred at 80 degrees for 1 hour until the reaction was complete. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by column chromatography to obtain intermediate 2 (270 mg). LCMS (ES, m/z): 316.0, 318.0 [M+H] ⁺ .

Step 3: At room temperature, potassium acetate (228 mg) and Pd(dppf)Cl ₂ (63 mg) were slowly added to the 1,4-dioxane solution (10 mL) of intermediate 2 (216 mg) and bis-pinacol borate (245 mg) obtained in step 2. The mixture was heated to 90 degrees under nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain intermediate 3 (115 mg). LCMS (ES, m/z): 364.3 [M+H] ⁺ .

Step 4: At room temperature, potassium carbonate (97.0 mg) and Pd(dppf)Cl ₂ (19.1 mg) were slowly added to a solution of intermediate 3 (85.0 mg) and intermediate A3 (68 mg) obtained in step 3 in 1,4-dioxane and water (5.5 mL, v/v = 10/1). The above mixture was heated to 90 degrees under nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature and ethyl acetate was added to the reaction solution. The obtained mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under pressure. The obtained residue was purified by reverse phase preparative chromatography to obtain Example 37 compound (21.0 mg). LCMS (ES, m/z): 450.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.58(s,1H),8.00(s,1H),7.79-7.76(m,2H),7.09(d,J＝2.0Hz,1H),7.07-7.04(m,3H),5. 26-5.23(m,1H),3.91(s,3H),3.87(s,3H),3.81-3.74(m,4H),2.22-2.13(m,1H),2.00-1.94(m,1H).

Embodiment 38

Step 1: At room temperature, add oxetane-3-ol (121 mg) and diisopropylethylamine (317 mg) to an acetonitrile solution (5.0 mL) of the intermediate 1 (300 mg) obtained in step 1 in Example 37. The above mixture was stirred at 80°C for 1 h until the reaction was completed. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain intermediate 1 (250 mg). LCMS (ES, m/z): 302.0, 304.0 [M+H] ⁺ .

Step 2: At room temperature, potassium acetate (244 mg) and Pd(dppf)Cl ₂ (67.6 mg) were slowly added to the 1,4-dioxane solution (10 mL) of intermediate 1 (250 mg) and bis-pinacol borate (231 mg) obtained in step 1. The mixture was heated to 90 degrees under nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain intermediate 2 (200 mg). LCMS (ES, m/z): 350.1 [M+H] ⁺ .

Step 3: At room temperature, potassium carbonate (262 mg) and Pd(dppf)Cl ₂ (51.6 mg) were slowly added in batches to a mixed solution (10 mL, v/v = 10/1) of 1,4-dioxane and water of intermediate 2 (200 mg) and intermediate A3 (185 mg) obtained in step 2. The above mixture was heated to 90 degrees under nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature and ethyl acetate was added to the reaction solution. The obtained mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by reverse phase preparative chromatography to obtain Example 38 compound (32.6 mg). LCMS (ES, m/z): 436.0 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ(ppm):8.20(d,J＝7.6Hz,1H),7.87(s,1H),7.51(s,1H),7.44(s,1H),7.15(s,1H),7.09(d,J＝8Hz,1H),6.98( s,1H),6.33(s,1H),5.58-5.55(m,1H),4.96(t,J＝8.0Hz,2H),4.75(t,J＝8.0Hz,2H),4.02(s,3H),3.94(s,3H).

Embodiment 39

Step 1: At 0 °C, NaN ₃ (1.4 g) was added in batches to an acetone solution (10 mL) of 1-chloro-2-propanone (1 g). The mixture was slowly warmed to room temperature and stirred at this temperature for 16 h until the reaction was complete. After the reaction was completed, ethyl acetate was added to the mixture, stirred thoroughly and filtered. The filter cake was washed with a small amount of ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain the product intermediate 1 (1 g).

Step 2: At room temperature, add 4-bromo-2-methoxyaniline (500 mg) to a mixed solution of saturated aqueous ammonium bicarbonate solution (5 mL) and dichloromethane (5 mL), stir thoroughly and then add thiophosgene (569 mg) dropwise. After the addition is complete, stir the reaction solution at 25 degrees for 16 hours until the reaction is complete. After the reaction is complete, add dichloromethane and water to the reaction solution. After the above mixture is fully stirred, separate the liquids, wash the organic phase with water and saturated brine and dry it with anhydrous sodium sulfate. The organic phase is concentrated under reduced pressure to obtain intermediate 2 (400 mg).

Step 3: At room temperature, triphenylphosphine (418 mg) was added to a dichloromethane solution (10 mL) of intermediate 2 (390 mg) obtained in step 2 and intermediate 1 (158 mg) obtained in step 1. The above mixture was stirred at 25 degrees for 16 hours until the reaction was complete. After the reaction was completed, dichloromethane and water were added to the reaction solution. After the above mixture was fully stirred, the liquid was separated, and the organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain intermediate 3 (200 mg). LCMS (ES, m/z): 282.8, 284.8 M+H] ⁺ .

Step 4: At room temperature, add Pd(dppf)Cl ₂ (25 mg) to a 1,4-dioxane solution (5 mL) of intermediate 3 (100 mg) obtained in step 3, bis-pinacol borate (134 mg) and potassium acetate (69 mg). After the nitrogen is fully replaced by the above mixture, the reaction solution is heated to 90°C and stirred for 16 hours until the reaction is complete. After the reaction is completed, the reaction solution is cooled to room temperature and ethyl acetate is added. The obtained mixture is washed with water and saturated brine, and the organic phase is dried over anhydrous sodium sulfate and the solvent is removed. The obtained residue is purified by column chromatography to obtain intermediate 4 (70 mg). LCMS (ES, m/z): 330.9 [M+H] ⁺ .

Step 5: At room temperature, add Pd(dppf)Cl ₂ (27 mg) and potassium carbonate (103 mg) to a mixed solution of intermediate A3 (110 mg) and intermediate 4 (99 mg) obtained in step 4 in 1,4-dioxane and water (5 mL, v/v = 10/1). After the nitrogen is fully replaced by the above mixture, the reaction solution is heated to 100°C and stirred for 16 hours until the reaction is complete. After the reaction is completed, the reaction solution is cooled to room temperature and ethyl acetate is added. The obtained mixture is washed with water and saturated brine, and the organic phase is dried over anhydrous sodium sulfate and the solvent is removed. The organic phase is concentrated under reduced pressure, and the obtained residue is purified by reverse phase preparative chromatography to obtain the compound (2 mg). LCMS (ES, m/z): 416.9 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ(ppm):8.00(d,J＝5.0Hz,1H),7.52-7.47(m,1H),7.39(d,J＝7.4Hz,1H),7.30(s ,1H),7.16(d,J＝2.2Hz,3H),6.17(s,1H),4.02(s,3H),3.85(s,3H),1.87(s,2H).

Embodiment 40

Step 1: Add hydroxylamine hydrochloride (922 mg) to a methanol solution (30 mL) of 2-(4-bromo-2-methoxyphenyl)acetonitrile (3.00 g) and sodium bicarbonate (1.23 g) at room temperature. Heat the reaction solution to 80°C and continue stirring for 4 hours until the reaction is complete. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and ethyl acetate is added to the residue. After sufficient stirring, filter, and concentrate the filtrate to obtain a crude intermediate 1 (3.80 g, purity: 88%). LCMS (ES, m/z): 259.0, 261.0 [M+H] ⁺ .

Step 2: At room temperature, acetic anhydride (1.5 g) was dissolved in pyridine (10 mL), and then the above solution was added dropwise to the pyridine solution (30 mL) of intermediate 1 (3.80 g) obtained in step 1 which was pre-cooled to 0°C. After the addition was completed, the above reaction solution was heated to 120°C and stirred for 4 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature and water was added to the reaction solution. The resulting mixture was extracted with ethyl acetate and the organic phases were combined. The organic phase was washed with 10% aqueous ammonium chloride solution, water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to obtain intermediate 2 (1.80 g). LCMS (ES, m/z): 282.8, 284.8 [M+H] ⁺ .

Step 3: At room temperature, add bis-pinacol borate (359 mg) to the 1,4-dioxane (3 mL) solution of intermediate 2 (200 mg) obtained in step 2, and add potassium acetate (173 mg) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (286 mg). The reaction mixture was heated to 90°C under a nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain intermediate 3 (80 mg). LCMS (ES, m/z): 331.0 [M+H] ⁺ .

Step 4: At room temperature, add intermediate A3 (71 mg) to a mixed solution of 1,4-dioxane and water (3 mL, v/v = 10/1) of intermediate 3 (80 mg) obtained in step 3, and add potassium carbonate (67 mg) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (19 mg). The above mixture is heated to 90°C under nitrogen atmosphere and stirred for 16 hours until the reaction is complete. After the reaction is completed, the reaction solution is cooled to room temperature and water and ethyl acetate are added to the reaction solution. After the above mixture is fully stirred, the liquid is separated, the aqueous phase is extracted with ethyl acetate, and the organic phases are combined. The organic phase is washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The obtained residue is purified by reverse phase preparative chromatography to obtain Example 40 compound (3.5 mg). LCMS (ES, m/z): 417.3 [M+H] ⁺ .

¹ HNMR (400MHz, CDCl ₃ )δ(ppm):7.94(s,1H),7.47(s,1H),7.31(d,J＝7.6Hz,1H),7.22(s,1H),7.15(d,J＝ 2.4Hz,1H),7.06-7.00(m,2H),4.11(s,2H),4.00(s,3H),3.86(s,3H),2.57(s,3H).

Embodiment 41

Step 1: At 0 degrees, add cyclopentyl chloroformate (80.9 mg) dropwise to a dichloromethane solution (5.0 mL) of pyridine (78 mg) and 4-bromo-2-methoxyaniline (100 mg). The reaction solution is slowly warmed to room temperature and stirred for 2 hours until the reaction is complete. After the reaction is completed, the reaction solution is concentrated under reduced pressure, and the resulting residue is purified by column chromatography to obtain intermediate 1 (150 mg). LCMS (ES, m/z): 336.1, 338.1 [M+Na] ⁺ .

Step 2: At room temperature, potassium acetate (46.8 mg) and Pd(dppf)Cl ₂ (13.0 mg) were added to a 1,4-dioxane solution (5.0 mL) of intermediate 1 (50.0 mg) and bis-pinacol borate (44.4 mg). The mixture was heated to 90 degrees under nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain intermediate 2 (57 mg). LCMS (ES, m/z): 362.1 [M+H] ⁺ .

Step 3: At room temperature, potassium carbonate (65.4 mg) and Pd(dppf)Cl ₂ (12.9 mg) were slowly added to a mixed solution (11 mL, v/v = 10/1) of 1,4-dioxane and water of intermediate 2 (57.0 mg) and intermediate A3 (46.3 mg) obtained in step 2. The above mixture was heated to 90 degrees under nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature and ethyl acetate was added. The above mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by TLC plate to obtain Example 41 compound (13.6 mg). LCMS (ES, m/z): 448.0 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ(ppm):8.20(d,J＝6.8Hz,1H),8.00(s,1H),7.47(d,J＝2.0Hz,1H),7.22(s,1H),7.18(d,J＝2.4Hz,1H)7.16(s,1H),7.10-7.09(m,1H),7 .02(d,J=1.2Hz,1H),5.73(s,2H),5.25-5.22(m,1H),4.00(s,3H),3.91(s,3H),1.95-1.88(m,2H),1.81-1.73(m,4H),1.69-1.63(m,2H).

Embodiment 42

At room temperature, intermediate B2 (150 mg) and 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (87 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v/v = 4/1), and potassium carbonate (138 mg) and Pd(dppf)Cl ₂ (25 mg) were added. After nitrogen was fully replaced in the above mixture, it was heated to 100°C and reacted for 2 h until the reaction was complete. After the reaction was completed, the above mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was separated after sufficient stirring. The organic phase was washed with water and saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain Example 42 compound (8 mg). LCMS (ES, m/z): 480.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.43(s,1H),8.12(s,1H),8.00(s,1H),7.99(s,1H),7.85(d,J＝8.0Hz,1H),7.12(d,J＝4.0Hz,1H ),7.04-7.02(m,2H),4.34(t,J＝8.0Hz,2H),3.87(s,3H),3.73(t,J＝8.0Hz,2H),3.25(s,3H),1.48(s,9H).

Embodiment 43

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine to obtain the title compound. LCMS (ES, m/z): 505.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.45(s,1H),8.30(s,1H),8.14(s,1H),8.00(s,2H),7.85(d,J＝8.0Hz,2H),7.11(s,1H),7.04-7.02(m,2H),4.3 8-4.36(m,1H),3.87(s,1H),3.19-3.16(m,2H),2.75(t,J＝12.0,2H),2.08-2.05(m,2H),1.97-1.91(m,3H),1.48(s,9H).

Embodiment 44

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 1-(oxetane-3-yl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine to obtain the title compound. LCMS (ES, m/z): 561.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.49(s,1H),8.15(d,J＝8.0Hz,2H),8.01(s,2H),7.85(d,J＝8.0Hz,1H),7.11(s,1H),7.04-7.02(m ,2H),4.77-4.44(m,6H),3.87(s,3H),3.53-3.45(m,2H),2.92-2.81(m,2H),2.15-1.96(m,4H),1.48(s,9H).

Embodiment 45

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine to obtain the title compound. LCMS (ES, m/z): 547.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.47(s,1H),8.15(d,J＝4.0Hz,2H),8.00(s,2H),7.85(d,J＝8.0Hz,1H),7.11(s,1H),7.04-7.02(m,2H),4. 36(s,2H),3.87(s,3H),3.14-3.11(m,2H),2.72-2.57(m,2H),2.24-2.05(m,4H),1.48(s,9H)1.11(d,J＝4.0Hz,6H).

Embodiment 46

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine to obtain the title compound. LCMS (ES, m/z): 519.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.48(s,1H),8.15(d,J＝4.0Hz,2H),8.00(s,2H),7.85(d,J＝8.0Hz,1H),7.11(s,1H),7.05-7.02 (m,2H),4.38(s,1H),3.87(s,3H),3.20-3.14(m,2H),2.67-2.62(m,2H),2.14-2.11(m,4H),1.48(s,9H).

Embodiment 47

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 1-(oxetane-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to obtain the title compound. LCMS (ES, m/z): 478.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.58(s,1H),8.26(s,1H),8.00(d,J＝5.2Hz,2H),7.84(d,J＝8.4Hz,1H),7.66-7.53 (m,2H),7.13-7.02(m,3H),5.74-5.67(m,1H),4.99-4.91(m,4H),3.87(s,3H),1.48(s,9H).

Embodiment 48

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole is replaced by 1-methyl-1H-pyrazole-5-boronic acid pinacol ester to obtain the title compound. LCMS (ES, m/z): 436.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.00(s,1H),7.97(s,1H),7.85(d,J＝8.4Hz,1H),7.54(d,J＝2.0Hz,1H),7.15(d,J＝ 2.0Hz,1H),7.09-7.04(m,1H),7.03(s,1H),6.69(d,J=2.0Hz,1H),3.87(s,6H),1.48(s,9H).

Embodiment 49

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole is replaced with 1,3-dimethyl-1H-pyrazole-5-boronic acid pinacol ester to obtain the title compound. LCMS (ES, m/z): 450.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.00(s,1H),7.96(s,1H),7.84(d,J＝8.4Hz,1H),7.15(d,J＝2.0Hz,1H),7.08-7. 02(m,1H),6.99(s,1H),6.48(s,1H),3.87(s,3H),3.79(s,3H),2.21(s,3H),1.48(s,9H).

Embodiment 50

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole is replaced with 1,5-dimethyl-1H-pyrazole-4-boronic acid pinacol ester to obtain the title compound. LCMS (ES, m/z): 450.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.98(s,1H),7.91(s,1H),7.82(d,J＝8.4Hz,1H),7.13(d,J＝2.0Hz,1H),7 .06-7.02(m,1H),6.77(s,1H),3.87(s,3H),3.82(s,3H),2.39(s,3H),1.48(s,9H).

Embodiment 51

The synthesis method is similar to the preparation method of Example 11, except that the intermediate 4-fluoropyrazole is replaced by 3-methylpyrazole to obtain the title compound. LCMS (ES, m/z): 445.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.43(s,1H),8.10(s,1H),8.01(s,1H),7.63(d,J＝2.0Hz,1H),7.14(d,J＝2.0Hz,1H),7.05-7.04(m,2H),6.95(d,J＝8.0 Hz, 1H), 6.05 (d, J = 2.0Hz, 1H), 5.24 (s, 2H), 4.93 (s, 1H), 4.22 (t, J = 5.6Hz, 2H), 3.89 (s, 3H), 3.77 (t, J = 5.6Hz, 2H), 2.16 (s, 3H).

Embodiment 52

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 1-(2-(methylsulfonyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to obtain the title compound. LCMS (ES, m/z): 528.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.56(s,1H),8.19(s,1H),8.00(d,J＝7.2Hz,2H),7.84(d,J＝8.0Hz,1H),7.12(d,J＝2.0Hz,1H),7. 08-7.01(m,2H),4.69-4.60(m,2H),3.87(s,3H),3.78-3.71(m,2H),2.90(s,3H),2.07(s,2H),1.48(s,9H).

Embodiment 53

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-propionitrile to obtain the title compound. LCMS (ES, m/z): 475.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.56,(s,1H),8.19(s,1H),8.01(s,1H),7.99(s,1H),7.85(d,J＝8.0Hz,1H),7.12(d,J＝2.0Hz,1H ),7.07(s,1H),7.05-7.02(m,1H),4.50(t,J＝6.4Hz,2H),3.87(s,3H),3.12(t,J＝6.48Hz,2H),1.48(s,9H).

Embodiment 54

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by cyclopropylboronic acid to obtain the title compound. LCMS (ES, m/z): 396.2 [M+H] ⁺ .

Embodiment 55

The synthesis method is similar to the preparation method of Example 11, except that the intermediate used in step 2 of the preparation method of Example 11 is replaced with 1-(benzyloxy)-4-bromo-2-methoxybenzene, and then the intermediate A1 in step 3 of the preparation method of Example 11 is replaced with intermediate A3 to obtain the title compound. LCMS (ES, m/z): 426.9 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.98(s,1H),7.52-7.46(m,3H),7.32-7.30(m,2H),7.26-7.25(m,1H),7.16( s,1H),7.15(s,1H),7.04(s,1H),6.97(s,2H),5.20(s,2H),3.99(s,3H),3.91(s,3H).

Embodiment 67

Step 1: At room temperature, dissolve the intermediate 3 (200 mg) obtained in step 3 of the preparation method of Example 36 in DMF (2 mL), and add iodomethane (115 mg). After the above mixture is cooled to 0°C, sodium hydride (40 mg) is added in batches. After the above mixture is slowly warmed to room temperature, continue stirring for 2 hours until the reaction is complete. After the reaction is completed, quench the reaction with ice water. The mixture is extracted three times with ethyl acetate, and the organic phases are combined. The organic phase is washed with water and saturated brine, and the solvent is removed after drying over anhydrous sodium sulfate. The residue is purified by column chromatography to obtain the title compound (140 mg).

Step 2: Dissolve the product obtained in step 1 (140 mg) in 1,4-dioxane (2 mL) at room temperature, and add bis-pinacol borate (138 mg), potassium acetate (111 mg) and Pd(dppf)Cl ₂ (33 mg). After the above mixture is fully replaced with nitrogen, continue stirring at 80°C for 2 hours until the reaction is complete. After the reaction is completed, filter and concentrate the filtrate under reduced pressure. The residue is purified by column chromatography to obtain the target compound (60 mg).

Step 3: At room temperature, the product obtained in step 2 (60 mg) and intermediate A3 (45 mg) were dissolved in a mixed solution of 1,4-dioxane and water (2 mL, v/v = 5/1), and potassium carbonate (55 mg) and Pd(dppf)Cl ₂ (11 mg) were added. The above mixture was fully replaced with nitrogen and heated to 90 degrees Celsius, and stirred for 2 hours until the reaction was complete. After the reaction was completed, ethyl acetate was added to the above mixture, and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by column chromatography to obtain the title compound (6 mg). LCMS (ES, m/z): 445.1 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.02(s,1H),7.49(s,1H),7.11(s,1H),7.10(s,1H),7.06(s,1H),7.04 -6.97(m,2H),4.01(s,3H),3.89(s,3H),3.38(s,3H),3.06(s,3H),2.40(s,3H).

Embodiment 86

The synthesis method is similar to the preparation method of Example 38, except that oxetan-3-ol is replaced by cyclobutanol to obtain the title compound. LCMS (ES, m/z): 434.1 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.20(d,J＝8.0Hz,1H),7.98(s,1H),7.48(s,1H),7.19(s,1H),7.17(s,1H),7.10(d,J＝8.0Hz,1H),7.01(s,1H), 5.11-5.03(m,1H),4.01(s,3H),3.91(s,3H),2.44-2.37(m,2H),2.22-2.15(m,2H),1.81-1.69(m,1H),1.64-1.62(m,1H).

Embodiment 89

The synthesis method is similar to the preparation method of Example 29, except that the intermediate 2 used in step 3 of the preparation method of Example 29 is replaced by tert-butyl (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzo[d][1,3]dioxolan-4-yl)carbamate to obtain the title compound. LCMS (ES, m/z): 450.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.99(s,1H),7.62-7.60(m,1H),7.45(s,1H),7.23(s,1H),7.15(s,1H),6 .91-6.90(m,1H),6.52(s,1H),6.03(s,2H),5.95(s,2H),3.99(s,3H),1.54(s,9H).

Embodiment 102

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 1,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole to obtain the title compound. LCMS (ES, m/z): 450.2 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ(ppm):8.27(s,1H),7.99(d,J＝7.6Hz,2H),7.83-7.81(m,2H),7.30(d,J＝8.4Hz,1H),7.12(d,J =2.0Hz,1H),7.04-7.00(m,1H),7.00(s,1H),3.88(s,3H),3.64(s,3H),2.34(s,3H),1.48(s,9H).

Embodiment 113

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5,6,7-tetrahydropyrazolo[1,5-A]pyridine to obtain the title compound. LCMS (ES, m/z): 476.1 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ(ppm):10.44(s,1H),8.25(d,J＝8.0Hz,1H),7.90(s,1H),7.32(s,1H),7.19(s,1H),7.05(d,J＝8.4Hz,1H),6.92(d,J＝9.2Hz ,2H),6.48(s,1H),4.28(t,J＝6.0Hz,2H),3.91(s,3H),2.91(t,J＝6.4Hz,2H),2.12(s,2H),1.94(d,J＝4.8Hz,2H),1.54(s,9H).

Embodiment 114

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine to obtain the title compound. LCMS (ES, m/z): 478.1 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ )δ(ppm):8.18(d,J＝8.0Hz,1H),8.00(s,1H),7.15(s,2H),7.09(dd,J＝8.0,1.6Hz,1H),7.01(d,J＝1.6Hz,1H), 6.96(s,1H),5.71(s,2H),4.93(s,2H),4.28(t,J＝5.2Hz,2H),4.16(t,J＝5.2Hz,2H),3.90(s,3H),1.54(s,9H).

Embodiment 116

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole to obtain the title compound. LCMS (ES, m/z): 437.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.40(s,1H),8.03(d,J＝28.8Hz,2H),7.84(d,J＝8.0Hz,1H),7.20-7. 11(m,2H),7.05(dd,J=8.0,2.0Hz,1H),4.24(s,3H),3.88(s,3H),1.48(s,9H).

Embodiment 117

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-triazole to obtain the title compound. LCMS (ES, m/z): 437.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.67(s,1H),8.06(s,1H),8.01(s,1H),7.86(d,J＝8.4Hz,1H),7.23(s,1H ),7.16(d,J＝1.6Hz,1H),7.09-7.05(m,1H),4.17(s,3H),3.88(s,3H),1.48(s,9H).

Embodiment 118

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 4,5-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole to obtain the title compound. LCMS (ES, m/z): 467.1 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.40(s,1H),8.07(s,1H),8.00(s,1H),7.85(d,J＝8.0Hz,1H),7. 15-7.13(m,2H),7.06-7.04(m,1H),4.24(s,3H),3.88(s,3H),1.48(s,9H).

Embodiment 119

Step 1: At -78°C, n-butyl lithium (0.5 ml, 2.5 M) was added dropwise to anhydrous tetrahydrofuran (6 ml) in which 5,7-dibromo-4-methoxypyrrolo[2,1-f][1,2,4]triazine (305 mg) was dissolved. The mixture was stirred at -78°C for 30 minutes, and then oxetane-3-one (86 mg) was added dropwise. After the addition was completed, the mixture was slowly heated to 0°C and stirred for 30 minutes until the reaction was complete. After the reaction was completed, saturated ammonium chloride solution was added to the mixture to quench the reaction. Ethyl acetate and water were added to the mixture, and the mixture was separated after sufficient stirring. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by column chromatography to obtain the target product (160 mg). LCMS (ES, m/z): 299.7 [M+H] ⁺ .

Step 2: Dissolve the product obtained in step 1 (160 mg) in DMF (2 mL), add ammonia water (2 mL, 30%), and stir the mixture at 80 ° C for 2 hours until the reaction is complete. After the reaction is completed, transfer the above mixture to ice water, stir it thoroughly and filter it, and wash the filter cake with a small amount of water. The obtained solid is dried under vacuum to obtain the target compound as a crude product (100 mg). LCMS (ES, m/z): 284.7 [M+H] ⁺ .

Step 3: At room temperature, the product obtained in step 2 (100 mg) and tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (182 mg) were dissolved in a mixture of 1,4-dioxane/water (2.5 mL, v/v=4/1), and potassium carbonate (145 mg) and Pd(PPh ₃ ) ₄ (40 mg) were added. After the nitrogen was fully replaced in the above mixture, it was heated to 100° C. and the reaction was continued for 1 hour until the reaction was complete. After the reaction was completed, the liquids were separated and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the title compound (6 mg). LCMS (ES, m/z): 427.9 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.98(s,1H),7.91(s,1H),7.93(d,J＝8.0Hz,1H),7.09-7.08(d,J＝2.0Hz,1H),7.01-6.99(m, 1H), 6.84 (s, 1H), 6.22 (s, 1H), 5.08 (d, J = 7.0Hz, 2H), 4.78 (d, J = 6.8Hz, 2H), 3.86 (s, 3H), 1.48 (s, 9H).

Embodiment 120

The synthesis method is similar to the preparation method of Example 119, except that the intermediate oxetane-3-one is replaced by dihydro-3(2H)-furanone to obtain the title compound. LCMS (ES, m/z): 441.8 [M+H] ⁺ .

Embodiment 121

The synthesis method is similar to the preparation method of Example 119, except that the intermediate oxetane-3-one is replaced by N-methyl-4-piperidone to obtain the title compound. LCMS (ES, m/z): 468.9 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.97(s,1H),7.88(s,1H),7.82-7.79(d,J＝8.4Hz,1H),7.06(s,1H),6.99-6.97(d,J＝8.0Hz,1H),6.66(s,1H),5.08(s,1H),3. 86(s,3H),2.68-2.66(m,1H),2.43-2.41(m,2H),2.38(m,2H),2.34-2.32(m,1H),2.22(s,3H),1.81-1.78(d,J＝8.4Hz,2H),1.47(s,9H).

Embodiment 122

Step 1: At room temperature, dissolve cyclopropanecarboxylic acid (860 mg) in dichloromethane (20 mL) and add triethylamine (1.01 g). Then add CDI (1.62 g) in batches. The above mixture is kept at room temperature for 30 minutes, and (3-chloropyrazine-2-yl)methylamine hydrochloride (1.80 g) is added in batches. The above mixture is stirred at room temperature for 2 hours until the reaction is complete. After the reaction is completed, water and dichloromethane are added to the above mixture, and the mixture is separated after sufficient stirring. The aqueous phase is extracted three times with dichloromethane, and the organic phases are combined. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is removed. The residue is purified by column chromatography to obtain the target compound (1.21 g).

Step 2: At room temperature, dissolve the product obtained in step 1 (1.15 g) in acetonitrile (10 mL) and add phosphorus oxychloride (2 mL). Stir the above mixture at 80 degrees Celsius overnight until the reaction is complete. After the reaction is completed, remove the solvent under reduced pressure. Dissolve the residue in dichloromethane and add ice water to quench the reaction. Adjust the pH value of the mixture to 8 with aqueous sodium bicarbonate solution, stir well and separate the liquids. Extract the aqueous phase three times with dichloromethane, and combine the organic phases. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent. The residue is purified by column chromatography to obtain the target compound (0.88 g).

Step 3: Dissolve the product obtained in step 2 (0.85 g) in acetonitrile (10 mL) and add NBS (0.78 g) in batches. The above mixture is stirred at room temperature for 3 hours until the reaction is complete. After the reaction is completed, transfer the above mixture to ice water. The mixture is extracted three times with ethyl acetate and the organic phases are combined. The organic phase is washed with saturated brine and dried over anhydrous sodium sulfate to remove the solvent. The residue is purified by column chromatography to obtain the target compound (0.72 g).

Step 4: Dissolve the product obtained in step 3 (0.71 g) in isopropanol (5 mL) at room temperature and add ammonia (2 mL, 30%). Stir the mixture at 90°C overnight until the reaction is complete. After the reaction is complete, remove the solvent and purify the residue by column chromatography to obtain the target compound (0.56 g).

Step 5: At room temperature, the product obtained in step 4 (100 mg) and tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (167 mg) were dissolved in a mixture of 1,4-dioxane and water (3 mL, v/v = 5/1), and potassium carbonate (137 mg) and Pd(dppf)Cl ₂ (29 mg) were added. The above mixture was fully replaced with nitrogen and heated to 100°C and stirred for 2 hours until the reaction was complete. After the reaction was completed, the liquids were separated and the organic phase was concentrated. The residue was purified by column chromatography to obtain the title compound (22 mg). LCMS (ES, m/z): 396.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.02(s,1H),7.86(d,J＝8.0Hz,1H),7.70(d,J＝4.8Hz,1H),7.25-7.19(m,2H),7.16(dd,J＝8.0,2. 0Hz,1H),6.22(s,2H),3.88(s,3H),2.41–2.38(m,1H),1.65-1.56(m,2H),1.49(s,9H),1.35-1.25(m,2H).

Embodiment 123

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 1-fluorocyclopropanecarboxylic acid to obtain the title compound. LCMS (ES, m/z): 414.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.02(s,1H),7.86(d,J＝8.0Hz,1H),7.72(d,J＝4.8Hz,1H),7.23-7.18(m,2H),7.13(dd, J＝8.0,2.0Hz,1H),6.21(s,2H),3.87(s,3H),1.65-1.56(m,2H),1.48(s,9H),1.34-1.27(m,2H).

Embodiment 124

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 1-methylpyrazole-3-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 436.1 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.55(d,J＝4.8Hz,1H),8.02(s,1H),7.88-7.82(m,2H),7.25(d,J＝2.0Hz,1H),7.2 2-7.13(m,2H),6.83(d,J＝2.4Hz,1H),6.10(s,2H),4.00(s,3H),3.88(s,3H),1.49(s,9H).

Embodiment 125

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 1-methylpyrazole-4-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 436.1 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.44(s,1H),8.03-8.02(m,2H),7.87(d,J＝8.4Hz,1H),7.71(d,J＝5.2Hz,1H),7.24(d,J＝1.6Hz,1 H),7.18(dd,J＝8.0,2.0Hz,1H),7.13(d,J＝5.2Hz,1H),6.09(s,2H),3.95(s,3H),3.87(s,3H),1.48(s,9H).

Embodiment 126

Step 1: Dissolve 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-A]pyrazine-2-amine (500 mg) in acetonitrile (5 mL) at room temperature, add diboric acid pinacol ester (920 mg), tert-butyl nitrite (510 mg) and benzoyl peroxide (80 mg). The above mixture is reacted at 80°C for 2 hours until the reaction is complete. After the reaction is completed, remove the solvent. The residue is purified by column chromatography to obtain the target compound (220 mg).

Step 2: At room temperature, the product obtained in step 1 (100 mg) and intermediate B2 (198 mg) were dissolved in a mixture of 1,4-dioxane and water (3 mL, v/v = 5/1), and potassium carbonate (132 mg) and Pd(dppf)Cl ₂ (28 mg) were added. The above mixture was fully replaced with nitrogen and heated to 100°C and stirred for 2 hours until the reaction was complete. After the reaction was completed, the liquids were separated and the organic phase was concentrated. The residue was purified by column chromatography to obtain the title compound (18 mg). LCMS (ES, m/z): 491.2 [M+H] ⁺ .

Embodiment 127

At room temperature, compound Example 121 (20 mg) was dissolved in dichloromethane (0.5 mL), and trimethyloxonium tetrafluoroboric acid (10 mg) was added. The mixture was stirred at room temperature for 2 hours until the reaction was complete. After the reaction was completed, the solvent was removed and the residue was purified by preparative plate to obtain the title compound (6 mg). LCMS (ES, m/z): 469.9 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.97(s,1H),7.89(s,1H),7.83-7.81(d,J＝8.0Hz,1H),7.10-7.09(d,J＝2.0Hz,1H),7.02-6.99(m,1H),6.74(s, 1H),3.86(s,3H),3.76-3.71(m,2H),3.66-3.63(m,2H),2.92(s,3H),2.36-2.32(m,2H),2.25-2.19(m,2H),1.48(s,9H).

Embodiment 128

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole is replaced with 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester to obtain the title compound. LCMS (ES, m/z): 437.9 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 7.98 (s, 1H), 7.95 (s, 1H), 7.83 -7.81(d,J＝8.0Hz,1H),7.12-7.11(m,1H),7.09-7.08(d,J＝4.0Hz,1H),7.01-6.98(m,1H),6. 79(s,1H),4.31-4.29(m,2H),3.86(s,3H),3.85-3.83(m,2H),2.61-2.57(m,2H),1.48(s,9H).

Embodiment 129

Step 1: Dissolve 7-iodopyrrolo[2,1-F][1,2,4]triazine-4-amine (7.8 g) in anhydrous DMF (300 mL) at room temperature and add MMTrCl (9.3 g). After the mixture is cooled to 0°C, sodium hydride (3.0 g) is added in batches. The mixture is stirred at room temperature until the reaction is complete. After the reaction is completed, the mixture is transferred to ice water, stirred thoroughly and filtered. The filter cake is washed with ice water until the filtrate is neutral. The filter cake is vacuum dried to obtain the target compound (15.6 g).

Step 2: At room temperature, dissolve the product obtained in step 1 (5.3 g) in DMF (50 mL), add allyl tributyltin (4.5 g), tetrakistriphenylphosphine palladium (1.2 g) and lithium chloride (0.4 g). After the above mixture is fully replaced with nitrogen, it is heated to 100 degrees Celsius and stirred overnight until the reaction is complete. After the reaction is completed, the above mixture is quenched with ice water. The resulting mixture is extracted three times with ethyl acetate, and the organic phases are combined. The organic phase is washed with water and saturated brine, and the solvent is removed after drying over anhydrous sodium sulfate. The residue is purified by column chromatography to obtain the target compound (3.6 g).

Step 3: At room temperature, dissolve the product obtained in step 2 (3.5 g) in 1,4-dioxane (50 mL), add potassium osmate dihydrate (115 mg), NMO (2.8 g) and water (3 mL). The above mixture is stirred at room temperature overnight until the reaction is complete. After the reaction is completed, ethyl acetate is added to the above mixture. The mixture is washed with water and saturated brine, and the solvent is removed after drying over anhydrous ammonium sulfate. The residue is dissolved in 1,4-dioxane (30 mL) and sodium periodate (2.1 g) is added. The above mixture is stirred at room temperature overnight until the reaction is complete. After the reaction is complete, water and ethyl acetate are added to the above mixture, and the mixture is separated after sufficient stirring. The aqueous phase is extracted three times with ethyl acetate, and the organic phases are combined. The organic phase is washed with water and saturated brine, and the solvent is removed after drying over anhydrous sodium sulfate. The residue is purified by column chromatography to obtain the target compound (1.77 g).

Step 4: Dissolve the product obtained in step 3 (250 mg) in dichloromethane (2 mL) at room temperature, and add 4-dimethylaminopiperidine (85 mg), acetic acid (40 mg) and sodium triacetoxyborohydride (238 mg). The above mixture is stirred at room temperature for 2 hours until the reaction is complete. After the reaction is completed, the above mixture is quenched with ice water. The resulting mixture is extracted three times with ethyl acetate, and the organic phases are combined. The organic phase is washed with water and saturated brine, and the solvent is removed after drying over anhydrous sodium sulfate. The residue is purified by column chromatography to obtain the target compound (210 mg).

Step 5: At room temperature, dissolve the product obtained in step 4 (210 mg) in dichloromethane (3 mL) and add trifluoroacetic acid (0.5 mL). The above mixture is stirred at room temperature until the reaction is complete. After the reaction is completed, remove the solvent under reduced pressure. Dissolve the residue in ethyl acetate, adjust the pH value of the mixture to 8-9 with saturated sodium bicarbonate aqueous solution, stir well and separate the liquids. Extract the aqueous phase three times with ethyl acetate, and combine the organic phases. Wash the organic phase with water and saturated brine, dry over anhydrous sodium sulfate, and remove the solvent. The residue is purified by column chromatography to obtain the target compound (120 mg).

Step 6: Dissolve the product obtained in step 5 (120 mg) in acetonitrile (1 mL) at room temperature and add NBS (89 mg). Stir the mixture at room temperature until the reaction is complete. After the reaction is completed, remove the solvent under reduced pressure and purify the residue by column chromatography to obtain the target compound (105 mg).

Step 7: At room temperature, the product obtained in step 6 (105 mg) and tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (120 mg) were dissolved in a mixed solution of 1,4-dioxane and water (2 mL, v/v = 5/1), and potassium carbonate (120 mg) and Pd(PPh ₃ ) ₄ (33 mg) were added. After nitrogen was fully replaced in the above mixture, it was stirred at 100° C. for 2 hours until the reaction was complete. Water and ethyl acetate were added to the above mixture, and the mixture was separated after sufficient stirring. The aqueous phase was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by column chromatography to obtain the title compound (36 mg). LCMS (ES, m/z): 510.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 7.97 (s, 1H), 7.89 (s, 1H), 7.81 -7.78(d,J＝12.0Hz,1H),7.05-7.04(d,J＝2.0Hz,1H),6.98-6.95(m,1H),6.60(s,1H),3.27(s,3H),3.06-3.02(m,1H),2.99-2.97 (m,2H),2.67-2.62(m,2H),2.20(s,6H),2.10-2.08(m,1H),2.00-1.94(m,2H),1.75-1.72(m,2H),1.47(s,9H),1.42-1.36(m,2H).

Embodiment 130

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 3-dimethylaminopropionic acid hydrochloride to obtain the title compound. LCMS (ES, m/z): 427.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.99(s,1H),7.83(d,J＝8.0Hz,1H),7.57(d,J＝4.8Hz,1H),7.18(d,J＝1.6Hz,1H),7.12(dd,J＝8.2,1.6Hz ,1H),7.02(d,J=5.2Hz,1H),6.01(s,2H),3.86(s,3H),2.72-2.64(m,5H),2.33(m,3H),2.21(s,6H),1.48(s,9H).

Embodiment 131

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by methanesulfonylacetic acid to obtain the title compound. LCMS (ES, m/z): 448.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.04(s,1H),7.89-7.86(m,2H),7.24(d,J＝1.6Hz,1H),7.18(dd,J＝8.0,1. 6Hz, 1H), 7.14 (d, J = 8.0Hz, 1H), 5.17 (s, 2H), 3.87 (s, 3H), 3.12 (s, 3H), 1.48 (s, 9H).

Embodiment 132

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 4-(4-methylpiperazin-1-yl)butyric acid hydrochloride to obtain the title compound. LCMS (ES, m/z): 496.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.99(s,1H),7.83(d,J＝8.0Hz,1H),7.54(d,J＝8.0Hz,1H),7.18(d,J＝1.8Hz,1H),7.12(dd,J＝8.0,4.0Hz,1H),7.01( d,J＝4.0Hz,1H),6.00(s,2H),3.86(s,3H),2.94(t,J＝8.0Hz,2H),2.40-2.17(m,10H),2.11(s,3H),1.89(m,2H),1.48(s,9H).

Embodiment 133

Step 1: At room temperature, dissolve (3-chloropyrazin-2-yl)methylamine hydrochloride (720 mg) and 1-(tert-butyloxycarbonyl)pyrrolidine-3-carboxylic acid (860 mg) in acetonitrile (8 mL), and add pyridine (2 g) to the reaction solution. The mixture is cooled to 0°C, phosphorus oxychloride (1.52 g) is slowly added dropwise to the reaction system, and the reaction is stirred for 1 hour after the temperature naturally drops to room temperature. After the reaction is complete, the system is poured into water, extracted three times with ethyl acetate, and the organic phases are combined. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by column chromatography to obtain the target compound (400 mg) as a yellow oil.

Step 2: Dissolve the product obtained in step 1 (400 mg) in acetonitrile (10 mL) at room temperature. Cool the above mixture to zero degrees Celsius and add N-bromosuccinimide (418 mg). The above mixture is reacted at room temperature for 2 hours until the raw material reacts completely. After the reaction is complete, the reaction solution is diluted with ethyl acetate. The organic phase is washed with saturated sodium bicarbonate aqueous solution, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue is purified by column chromatography to obtain the target compound (300 mg) as a yellow oil.

Step 3: Dissolve the product obtained in step 2 (300 mg) in a mixed solution of isopropanol (3 mL) and aqueous ammonia (3 mL) at room temperature. Heat the mixture to 100°C and continue the reaction for 16 hours until the raw material reacts completely. After the reaction is completed, cool the mixture to room temperature, concentrate under reduced pressure, and add ethyl acetate and water to the residue. After sufficient stirring, separate the liquids, extract the aqueous phase with ethyl acetate three times, and combine the organic phases. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue is purified by column chromatography to obtain the target compound (270 mg) as a yellow solid.

Step 4: Dissolve the product obtained in step 3 (240 mg) in dichloromethane (8 mL) at room temperature and add dioxane hydrochloride (4 mL, 4 M). Stir the mixture at room temperature for 2 hours until the reaction is complete. After the reaction is complete, concentrate under reduced pressure to obtain the crude product of the target compound (170 mg) as a yellow solid, which is used directly in the next step.

Step 5: At room temperature, dissolve the product obtained in step 4 (170 mg) in dichloromethane (5 mL), add acetic acid (28 mg) and CDI (98 mg). The above mixture is reacted at room temperature for 2 hours until the raw material reacts completely. After the reaction is complete, the reaction solution is diluted with ethyl acetate, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue is purified by column chromatography to obtain the target compound (70 mg) as a yellow oil.

Step 6: At room temperature, the product obtained in step 5 (70 mg) was dissolved in a mixed solution of dioxane and water (2 mL, v/v = 5/1), and K ₂ CO ₃ (100 mg), Pd(dppf)Cl ₂ (35 mg), and tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (100 mg) were added. The above mixture was fully replaced with nitrogen and heated to 100°C and stirred for 2 hours until the raw materials reacted completely. After the reaction was completed, the reaction solution was diluted with ethyl acetate, and the resulting mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the title compound (11 mg). LCMS (ES, m/z): 467.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 8.00 (s, 1H), 7.87-7.81 (m, 1H), 7.68 (dd, J = 12.0 4.0Hz,1H),7.20-7.15(m,1H),7.12(m,1H),7.06(m,1H),6.11(s,2H),3.99(s,1H),3.86( m,4H),3.76-3.68(m,1H),3.63-3.50(m,2H),2.30-2.10(m,2H),1.97(s,3H),1.48(s,9H).

Embodiment 134

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by N,N-dimethyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide to obtain the title compound. LCMS (ES, m/z): 507.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.01(s,1H),7.99(s,1H),7.84(d,J＝8.4Hz,1H),7.75(d,J＝2.4Hz,1H),7.14(dd,J＝8.0 ,2.0Hz,2H),7.05-7.02(m,2H),5.19(s,2H),3.87(s,3H),3.05(s,3H),2.86(s,3H),1.48(s,9H).

Embodiment 135

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 3-(4-methylpiperazine-1-yl)propionic acid to obtain the title compound. LCMS (ES, m/z): 482.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.21(s,1H),7.99(s,1H),7.83(d,J＝8.0Hz,1H),7.56(d,J＝4.8Hz,1H),7.18(d,J＝1.6Hz,1H),7.11(dd,J＝8.0,2.0Hz,1H),7. 02(d,J＝5.2Hz,1H),3.86(s,3H),3.10(dd,J＝8.4,6.8Hz,2H),2.73(dd,J＝8.4,6.8Hz,2H),2.44-2.21(m,4H),2.15(s,3H),1.48(s,9H).

Embodiment 136

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 3-[4-(propane-2-yl)piperazine-1-yl]propanoic acid dihydrochloride to obtain the title compound. LCMS (ES, m/z): 510.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.20(s,1H),7.99(s,1H),7.83(d,J＝8.0Hz,1H),7.56(d,J＝5.2H z,1H),7.18(d,J＝2.0Hz,1H),7.11(dd,J＝8.0,2.0Hz,1H),7.02(d,J＝5.2H z,1H),3.86(s,3H),3.10(dd,J＝8.0,6.8Hz,2H),2.73(dd,J＝8.4,6.8Hz,2 H), 2.61 (p, J = 6.8Hz, 1H), 2.46 (s, 7H), 1.48 (s, 9H), 0.96 (d, J = 6.8Hz, 6H).

Embodiment 137

Step 1: At room temperature, intermediate B2 (218 mg) was dissolved in a mixed solution of 1,4-dioxane and water (5 mL, v/v = 5/1), and (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (297 mg), potassium carbonate (173 mg) and Pd(dppf)Cl ₂ (37 mg) were added. The above mixture was fully replaced with nitrogen and heated to 90°C and continued to react for 2 hours until the reaction was complete. After the reaction was completed, the liquids were separated, the aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by column chromatography to obtain the title compound (156 mg).

Step 2: At room temperature, dissolve the product obtained in step 1 (60 mg) in methanol (3 mL) and add palladium carbon (10 mg, 10%). The above mixture is fully replaced with hydrogen and stirred overnight in a hydrogen atmosphere until the reaction is complete. After the reaction is completed, filter and wash the filter cake with a small amount of methanol. The filtrate is concentrated and the residue is purified by column chromatography to obtain the title compound (15 mg). LCMS (ES, m/z): 428.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.97(s,1H),7.89(s,1H),7.81(d,J＝8.0Hz,1H),7.05(d,J＝2.0Hz,1H),6.98(dd,J＝8.0,2.0Hz,1H),6.61(s,1 H), 3.85 (s, 3H), 3.70 (t, J = 7.2Hz, 2H), 3.47 (q, J = 7.2Hz, 2H), 3.13 (t, J = 7.2Hz, 2H), 1.47 (s, 9H), 1.11 (t, J = 7.2Hz, 3H).

Embodiment 138

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 1-methyl-2-oxo-1,2-dihydropyridine-4-boronic acid to obtain the title compound. LCMS (ES, m/z): 463.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.09(s,1H),8.00(s,1H),7.86(d,J＝8.0Hz,1H),7.73(d,J＝7.2Hz,1H),7.51(d,J＝2.0Hz,1H),7.3 7(s,1H),7.15(d,J＝1.6Hz,1H,7.06-7.03(m,1H),6.94-6.92(m,1H),3.87(s,3H),3.44(s,3H),1.48(s,9H).

Embodiment 139

The synthesis method is similar to the preparation method of Example 133, except that the intermediate acetic acid is replaced by N,N-dimethylglycine to obtain the title compound. LCMS (ES, m/z): 510.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.17(s,2H),8.01(s,1H),7.84(dd,J＝8.0,4.0Hz,1H),7.68(t,J ＝4.0Hz,1H),7.18(m,1H),7.12(m,1H),7.07(m,1H),6.07(s,2H),3.99(m,1 H),3.86(s,3H),3.78(m,1H),3.71-3.56(m,2H),3.47-3.35(m,1H),3.32( s, 2H), 2.42 (m, 1H), 2.34 (d, J = 8.0Hz, 6H), 2.25-2.09 (m, 1H), 1.48 (s, 9H).

Embodiment 140

The synthesis method is similar to the preparation method of Example 129, except that the intermediate 4-dimethylaminopiperidine is replaced by 1-methylpiperazine to obtain the title compound. LCMS (ES, m/z): 482.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.96(s,1H),7.89(s,1H),7.79(d,J＝8.0Hz,1H),7.04(d,J＝4.0Hz,1H),6.97(dd,J＝8.0,2.0Hz,1 H),6.60(s,1H),3.85(s,3H),3.07-3.01(m,3H),2.66(s,3H),2.36-2.23(m,6H),2.15(s,3H),1.47(s,9H).

Embodiment 141

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 5-pyrimidineboronic acid to obtain the title compound. LCMS (ES, m/z): 434.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):9.52(s,2H),9.14(s,1H),8.07(s,1H),8.02(s,1H),7.87(d,J＝8.0Hz,1H),7. 44(s,1H),7.15(d,J＝2.0Hz,1H),7.08(dd,J＝8.0,2.0Hz,1H),3.87(s,3H),1.48(s,9H).

Embodiment 142

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 3-(4-(dimethylamino)piperidin-1-yl)propionic acid to obtain the title compound. LCMS (ES, m/z): 510.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.99(s,1H),7.84(d,J＝8.0Hz,1H),7.56(d,J＝5.2Hz,1H),7.18(d,J＝2.0Hz,1H),7.11(dd,J＝8.0,2.0Hz,1H),7.02(d,J＝4.8Hz,1H),6.0 1(s,2H),3.86(s,3H),3.12(m,2H),2.99(m,2H),2.73(m,2H),2.16(s,6H ),2.06-1.92(m,3H),1.73-1.70(m,2H),1.48(s,9H),1.38-1.29(m,2H).

Embodiment 143

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 3-methoxypropionic acid to obtain the title compound. LCMS (ES, m/z): 414.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.00(s,1H),7.84(d,J＝8.0Hz,1H),7.58(d,J＝5.2Hz,1H),7.19(d,J＝1.6Hz,1H),7.12(dd,J＝8.0,2. 0Hz, 1H), 7.01 (d, J = 5.2Hz, 1H), 6.02 (s, 2H), 3.86 (s, 3H), 3.74 (m, 2H), 3.25 (s, 3H), 3.20 (m, 2H), 1.48 (s, 9H).

Embodiment 144

Step 1: Potassium carbonate (1.9 g) and Pd(dppf)Cl 2 (340 mg) were added to a mixture of 7-bromopyrrolo[2,1-f][1,2,4]triazine-4-amine (1 g) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.8 g) in 1,4-dioxane/water (25 mL, v/v=5/2) at room temperature. The mixture was fully replaced with nitrogen, heated to 100°C and stirred for 2 hours until the reaction was complete. After the reaction was completed, the liquids were separated and the organic phase was concentrated to obtain a crude product. The _crude product was purified by column chromatography to obtain the product (1.4 g) as a light yellow solid. LCMS (ES, m/z): 302.0 [M+H] ⁺ .

Step 2: At room temperature, dissolve the product obtained in step 1 (1.4 g) in methanol (50 mL), add palladium carbon (200 mg, 10%), fully replace the hydrogen, and stir at 50°C for 2 days until the reaction is complete. Filter out the insoluble matter, and concentrate the filtrate to obtain a crude product. The crude product is purified by column chromatography to obtain the product (0.9 g) as a light yellow solid. LCMS (ES, m/z): 304.0 [M+H] ⁺ .

Step 3: Dissolve the product obtained in step 2 (900 mg) in dichloromethane (20 mL) at room temperature, add hydrochloric acid-1,4-dioxane solution (10 mL), and stir overnight at room temperature until the reaction is complete. Concentrate to obtain a crude product (800 mg) as a light yellow solid. LCMS (ES, m/z): 204.0 [M+H] ⁺ .

Step 4: At room temperature, triethylamine (445 mg) was added to a mixture of dimethylglycine (181 mg) and N,N'-carbonyldiimidazole (286 mg) in dichloromethane (10 mL). After the mixture was stirred at room temperature for 30 minutes, the product obtained in step 3 (300 mg) was added. The mixture was stirred at room temperature for 2 hours until the reaction was complete. After the reaction was completed, saturated brine was added to quench the reaction, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified to obtain the product (240 mg) as a light yellow solid. LCMS (ES, m/z): 289.0 [M+H] ⁺ .

Step 5: Dissolve the product obtained in step 4 (240 mg) in acetonitrile (5 mL) solution. After the mixture is cooled to 0 degrees Celsius, add NBS (148 mg) in batches. Stir the mixture in an ice-water bath for 1 hour until the reaction is complete. After the reaction is completed, remove the solvent to obtain a crude product. The crude product is purified by column chromatography to obtain the product (270 mg) as a light yellow solid. LCMS (ES, m/z): 366.8 [M+H] ⁺ .

Step 6: Potassium carbonate (386 mg) and Pd(PPh 3 ) 4 (108 mg) were added to a mixture of the product obtained in step 5 (270 mg) and tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl ₎ carbamate (391 mg) in 1,4-dioxane/water (2.5 mL, v/v=4/1) at room temperature. After nitrogen was fully replaced in _the above mixture, it was heated to 100°C and reacted for 2 hours until the reaction was complete. After the reaction was completed, the liquids were separated and the organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain the product (62 mg).

The title compound was separated using the following method to obtain Example 144A (retention time: 8.818 minutes) and Example 144B (retention time: 17.557 minutes). Example 144A and Example 144B are enantiomers of each other. When the chiral center of 144A is in R configuration, the chiral center configuration of Example 144B is S type; when the chiral center of 144A is in S configuration, the chiral center configuration of Example 144B is in R configuration.

Instrument: GILSON-GX-281, preparation column: CHIRALCEL OD-H, 2*25mm, 5μm, preparation method: dissolve the crude product in ethanol and prepare a 5mg/ml sample solution. Mobile phase system: Mobile phase A: Hex (0.5% 2M NH ₃ -MeOH)--HPLC, mobile phase B: IPA--HPLC; mobile phase B 50%, flow rate: 20ml/min, elution time: 24min.

Chiral test method: (Instrument: SHIMADZU-LC-20AD xr, preparation column: CHIRALCEL OD-3, size: 4.6*100mm, 3um. Preparation method: dissolve the crude product in methanol and prepare the sample solution. Mobile phase system: Hex (0.1% DEA): IPA. Elution gradient: 2-50%; flow rate: 1ml/min, elution time: 6min).

LCMS (ES, m/z): 510.0 [M+H] ⁺ .

144A: ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 7.97 (s, 1H), 7.93 (s, 1H), 7.83-7.80 (m, 1H), 7.07-7.06 (m, 1H), 7.00-6.98 (m, 1H), 6.70 (s 1H),4.04-4.00(m,1H),3.96-3.92(m,1H),3.86(s,3H),3.80-3.70(m,1H),3.66-3.56(m,1 H),3.46-3.32(m,2H),3.23(s,2H),2.32(s,3H),2.30(s,3H),2.19-06(m,1H),1.48(s,9H).

144B: ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 7.97 (s, 1H), 7.93 (s, 1H), 7.82-7.81 (m, 1H), 7.07-7.06 (m, 1H), 7.00-6.98 (m, 1H), 6.70 (s 1H),4.04-4.00(m,1H),3.96-3.92(m,1H),3.86(s,3H),3.80-3.70(m,1H),3.65-3.57(m,1H ),3.48-3.32(m,2H),3.21(s,2H),2.31(s,3H),2.29(s,3H),2.19-2.08(m,1H),1.48(s,9H).

Embodiment 145

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-3(2H)-one to obtain the title compound. LCMS (ES, m/z): 464.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.60(d,J＝2.0Hz,1H),8.15(s,1H),8.02(s,1H),7.97(d,J＝2.0Hz,1H),7.87(d,J＝8.0Hz,1H), 7.60(s,1H),7.15(d,J＝2.0Hz,1H),7.05(dd,J＝8.0,2.0Hz,1H),3.87(s,3H),3.67(s,3H),1.48(s,9H).

Embodiment 146

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 3-tetrahydrofurancarboxylic acid to obtain the title compound.

The title compound was separated using the following method to obtain Example 146A (retention time: 18.382 minutes) and Example 146B (retention time: 21.372 minutes). Example 146A and Example 146B are enantiomers of each other. When the chiral center of 146A is in R configuration, the chiral center configuration of Example 146B is S type; when the chiral center of 146A is in S configuration, the chiral center configuration of Example 146B is in R configuration.

Instrument: GILSON-GX-281, preparation column: CHIRAL ART Cellulose-SC, 2*25cm, 5μm, preparation method: dissolve the crude product in ethanol and prepare a 5mg/ml sample solution. Mobile phase system: Mobile phase A: Hex (0.5% 2M NH ₃ -MeOH)--HPLC, mobile phase B: MeOH:DCM＝1:1--HPLC; mobile phase B 20%, flow rate: 20ml/min, elution time: 24min.

Chiral test method: (Instrument: SHIMADZU-LC-20AD xr, preparation column: CHIRALPAK IC-3, size: 4.6*50mm, 3μm. Preparation method: dissolve the crude product in methanol and prepare the sample solution. Mobile phase system: Hex (0.1% DEA): (MeOH:DCM=1:1). Elution gradient: 2-25%; flow rate: 1ml/min, elution time: 6min).

LCMS (ES, m/z): 426.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.00(s,1H),7.84(d,J＝8.4Hz,1H),7.62(d,J＝5.2Hz,1H),7.18(d,J＝1.6Hz,1H),7.12(dd,J＝8.4,1.6Hz,1H),7.04(d,J＝5.2Hz,1 H),6.03(s,2H),4.19-4.11(m,1H),3.97-3.89(m,3H),3.86(s,3H),3.85-3.80(m,1H),2.42-2.35(m,1H),2.29-2.21(m,1H),1.48(s,9H).

146A: ¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.02(s,1H),7.86(d,J＝8.4Hz,1H),7.65(d,J＝4.8Hz,1H),7.18(d,J＝1.6Hz,1H),7.13–7.11(m,1H),7.05(d ,J＝5.2Hz,1H),6.14(s,2H),4.19-4.11(m,1H),3.95-3.83(m,7H),2.40-2.38(m,1H),2.27-2.25(m,1H),1.48(s,9H).

146B: ¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.02(s,1H),7.86(d,J＝8.4Hz,1H),7.67(d,J＝5.2Hz,1H),7.19(d,J＝2.0Hz,1H),7.14–7.12(m,1H),7.05(d ,J＝5.2Hz,1H),6.28(s,2H),4.19-4.11(m,1H),3.95-3.83(m,7H),2.41-2.35(m,1H),2.33-2.27(m,1H),1.48(s,9H).

Embodiment 147

The synthesis method is similar to the preparation method of Example 129, except that the intermediate 4-dimethylaminopiperidine is replaced by dimethylamine hydrochloride to obtain the title compound. LCMS (ES, m/z): 427.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.96(s,1H),7.89(s,1H),7.80(d,J＝8.0Hz,1H),7.05(d,J＝2.0Hz,1H),7.00-6.95(m, 1H),6.60(s,1H),3.85(s,3H),3.05-3.02(m,2H),2.65-2.61(m,2H),2.22(s,6H),1.47(s,9H).

Embodiment 148

The synthesis method is similar to the preparation method of Example 129, except that the intermediate 4-dimethylaminopiperidine is replaced by 2-(methylamino)ethanol-1-ol to obtain the title compound. LCMS (ES, m/z): 457.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.96(s,1H),7.89(s,1H),7.80(d,J＝8.0Hz,1H),7.05(d,J＝2.0Hz,1H),6.97(dd,J＝8.0,2.0Hz,1H),6 .61(s,1H),3.85(s,3H),3.49(t,J=8.0Hz,4H),3.06-3.02(m,2H),2.78-2.74(m,2H),2.29(s,3H),1.47(s,9H).

Embodiment 149

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 3-((2-(dimethylamino)ethyl)(methyl)amino)propionic acid to obtain the title compound. LCMS (ES, m/z): 484.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.21(s,1H),8.01(s,1H),7.84(d,J＝8.0Hz,1H),7.58(d,J＝5.2Hz,1H),7.18(d,J＝1.6Hz,1H),7.11(dd,J＝8 .0,2.0Hz,1H),7.02(d,J＝5.2Hz,1H),3.86(s,3H),2.81(m,2H),2.39(m,2H),2.26(s,3H),2.16(s,6H),1.48(s,9H).

Embodiment 150

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole is replaced by 2-(4-methylpiperazine-1-yl)pyridine-5-boronic acid pinacol ester to obtain the title compound. LCMS (ES, m/z): 531.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.81(d,J＝4.0Hz,1H),8.24(dd,J＝8.0,2.0Hz,1H),7.99(s,1H),7.95(s,1H),7.84(d,J＝8.0Hz,1H),7.14(d,J＝4.0Hz,1H),7.07 (s,1H),7.04(dd,J＝8.0,4.0Hz,1H),6.94(d,J＝8.0Hz,1H),3.87(s,3H),3.57-3.54(m,4H),2.43-2.40(m,4H),2.23(s,3H),1.48(s,9H).

Embodiment 151

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide to obtain the title compound. LCMS (ES, m/z): 507.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.41(d,J＝0.8Hz,1H),8.09(d,J＝0.8Hz,1H),7.99(d,J＝3.6Hz,2H),7.85(d,J＝8.0Hz,1H),7.1 3(d,J＝1.6Hz,1H),7.06-7.03(m,2H),5.20(s,2H),3.87(s,3H),3.05(s,3H),2.87(s,3H),1.48(s,9H).

Embodiment 152

The synthesis method is similar to the preparation method of Example 144, except that the intermediate acetic acid is replaced by N,N-dimethyl-β-alanine to obtain the title compound. LCMS (ES, m/z): 524.3 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ(ppm):8.23(s,2H),8.01(d,J＝1.2Hz,1H),7.89-7.79(m,1H),7.70-7.66(m ,1H),7.18-7.17(m,1H),7.14-7.11(m,1H),7.08-7.06(m,1H),4.04-3.97(m,1 H),3.92-3.84(m,1H),3.86(s,3H),3.80-3.73(m,1H),3.65-3.55(m,1H),3.43 -3.36(m,1H),2.80-2.75(m,2H),2.57-2.54(m,2H),2.35(s,6H),1.48(s,9H).

Embodiment 153

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 3-((1-methylpiperidin-4-yl)oxy)propionic acid to obtain the title compound. LCMS (ES, m/z): 497.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.18(s,1H),8.00(s,1H),7.83(d,J＝8.2Hz,1H),7.59(d,J＝5.2Hz ,1H),7.18(d,J＝1.6Hz,1H),7.11(dd,J＝8.2,1.6Hz,1H),7.01(d,J＝5.2Hz, 1H),3.86(s,3H),3.80(m,2H),3.18(m,2H),2.67(m,1H),2.33(m,1H),2.11 (s,3H),2.03(m,2H),1.72(d,J=6.8Hz,2H),1.48(s,9H),1.45-1.37(m,1H).

Embodiment 154

The synthesis method is similar to the preparation method of Example 129, except that the intermediate 4-dimethylaminopiperidine is replaced by (S)-pyrrolidin-2-ylmethanol to obtain the title compound. LCMS (ES, m/z): 483.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.96(s,1H),7.89(s,1H),7.80(d,J＝8.0Hz,1H),7.05(d,J＝2.0Hz,1H),6.97(dd,J＝8.0,2.0Hz,1H),6.62(s,1H), 3.85(s,3H),3.42(m,2H),3.27-2.99(m,7H),2.67(m,1H),2.34-2.27(m,1H),1.80(m,1H),1.71-1.60(m,2H),1.47(s,9H).

Embodiment 155

Step 1: At room temperature, dissolve (3-chloropyrazin-2-yl)methylamine hydrochloride (2.0 g) in anhydrous acetonitrile (20 mL), add pyridine (4.4 g) and 3,3-diethoxypropionic acid (1.8 g). After the mixture is cooled to 0°C, phosphorus oxychloride (5.1 g) is added dropwise. The mixture continues to react at 0°C for 30 minutes until the raw materials react completely. After the reaction is completed, quench the reaction with saturated sodium bicarbonate at 0°C. The mixture is diluted and extracted three times with ethyl acetate, and the organic phases are combined. The organic phase is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by column chromatography to obtain the target compound (1.5 g) as a white solid.

Step 2: Dissolve the product (1.4 g) obtained in step 1 in anhydrous acetonitrile (10 mL) at room temperature. After the mixture is cooled to 0°C, add a solution of NBS (927 mg) in acetonitrile (5 mL) dropwise. Stir the above mixture at 0°C for 1 hour until the raw material reacts completely. After the reaction is completed, the reaction solution is diluted with ethyl acetate. The resulting mixture is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by column chromatography to obtain the target compound (1.77 g) as a yellow solid.

Step 3: At room temperature, dissolve the product obtained in step 2 (1.7 g) in isopropanol (10 mL) and add ammonia water (5 mL, 25%). Heat the mixture to 95°C and continue the reaction for 16 hours until the raw material reacts completely. The reaction solution is diluted with ethyl acetate, and the mixture is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is purified by column chromatography to obtain the target compound (1.4 g) as a yellow solid.

Step 4: Dissolve the product obtained in step 3 (1.4 g) in THF (10 mL) and add HCl (20 mL, 6 M) at room temperature. The above mixture is reacted at room temperature for 1 hour until the raw materials are completely reacted. After the reaction is completed, adjust the pH of the reaction solution to 7-8 with saturated sodium bicarbonate aqueous solution. Filter, wash the filter cake with a small amount of water, collect the solid, and vacuum dry to obtain the target compound (800 mg) as a yellow solid.

Step 5: Dissolve (3-fluoroazetidine-3-yl)methanol hydrochloride (118 mg) in dichloromethane (5 mL) at room temperature, add sodium acetate (205 mg) and the product obtained in step 4 (273 mg). After the mixture reacts at room temperature for 30 minutes, sodium triacetoxyborohydride (354 mg) is added. The mixture continues to react at room temperature for 16 hours until the raw material reacts completely. After the reaction is completed, the reaction solution is diluted with ethyl acetate. The organic phase is washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue is purified by column chromatography to obtain the target compound (120 mg) as a yellow oil.

Step 6: The product obtained in step 5 (120 mg), K ₂ CO ₃ (95 mg), Pd(PPh ₃ ) ₄ (40 mg) and tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (146 mg) were dissolved in a mixed solution of 1,4-dioxane and water (v/v=4/1) (5.0 mL) at room temperature. The mixture was reacted at 100°C for 2 hours until the raw materials reacted completely. After the reaction was completed, the reaction solution was diluted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography to obtain the title compound (33 mg) as a white solid. LCMS (ES, m/z): 487.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.00(s,1H),7.85(d,J＝8.0Hz,1H),7.56(d,J＝5.2Hz,1H),7.18(d,J＝1.6Hz,1H),7.12(dd,J＝8.0,2.0Hz,1H),7.03(d,J＝5. 2Hz,1H),6.02(s,2H),3.86(s,3H),3.61(s,1H),3.55(s,1H),3.09-3.04(m,1H),3.04-2.95(m,3H),2.90-2.87(m,2H),1.47(s,9H).

Embodiment 156

The synthesis method is similar to the preparation method of Example 155, except that the intermediate (3-fluoroazetidin-3-yl)methanol hydrochloride is replaced by 4-methylpiperidin-4-ol to obtain the title compound. LCMS (ES, m/z): 497.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.99(s,1H),7.85(d,J＝8.0Hz,1H),7.56(d,J＝4.8Hz,1H),7.18(d,J＝1.6Hz,1H),7.13(dd,J＝8.4,2.0Hz,1H),7.02(d,J =5.2Hz,1H),6.02(s,2H),3.86(s,3H),3.13-3.10(m,2H),2.79-2.75(m,2H),2.59-2.52(m,4H),1.50-1.45(m,13H),1.10(s,3H).

Embodiment 157

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 3-methylisoxazole-5-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 437.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.07-8.05(m,2H),7.92(d,J＝8.0Hz,1H),7.33(d,J＝4.8Hz,1H),7.27(d,J＝1.6Hz ,1H),7.21-7.19(m,1H),7.07(s,1H),6.32(s,2H),3.89(s,3H),2.37(s,3H),1.49(s,9H).

Embodiment 158

The synthesis method is similar to the preparation method of Example 129, except that the intermediate 4-dimethylaminopiperidine is replaced by 4-methyl-4-hydroxypiperidine to obtain the title compound. LCMS (ES, m/z): 497.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.97(s,1H),7.89(s,1H),7.81(d,J＝8.0Hz,1H),7.05(d,J＝2.0Hz,1H),6.97(dd,J＝8.0,2. 0Hz,1H),6.60(s,1H),3.85(s,3H),3.08-3.04(m,2H),2.72–2.68(m,2H),1.47(s,13H),1.10(s,3H).

Embodiment 159

The synthesis method is similar to the preparation method of Example 129, except that the intermediate 4-dimethylaminopiperidine is replaced by (S)-pyrrolidine-3-methanol to obtain the title compound. LCMS (ES, m/z): 483.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.96(s,1H),7.89(s,1H),7.80(d,J＝8.0Hz,1H),7.05(d,J＝2.0Hz,1H),6.98(dd,J＝8.0,1.8Hz,1H),6.61(s,1H),3.85(s,3H),3.31 -3.28(m,5H),3.06-3.02(m,2H),2.76-2.71(m,2H),2.63-2.59(m,1H) ,2.38-2.36(m,2H),2.21-2.19(m,1H),1.80-1.78(m,1H),1.47(s,9H).

Embodiment 160

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 1-(methylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidine to obtain the title compound. LCMS (ES, m/z): 515.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.98(s,1H),7.96(s,1H),7.83(d,J＝8.0Hz,1H),7.07-7.11(m,1H),7.04-6.97(m,2H),6.82( s,1H),4.16-4.26(m,2H),3.86(s,3H),3.33-3.38(m,2H),2.98(s,3H),2.49-2.41(m,2H),1.48(s,9H).

Embodiment 161

The synthesis method is similar to the preparation method of Example 144, except that the intermediate dimethylglycine is replaced by methylsulfonic anhydride to obtain the title compound. LCMS (ES, m/z): 502.8 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm): 7.97 (s, 1H), 7.93 (s, 1H), 7.82 -7.80(d,J＝8.0Hz,1H),7.08-7.07(m,1H),7.00-6.97(m,1H),6.73(s,1H),3.93-3.89(m,1H),3.89(s,3H ),3.81-3.77(m,1H),3.64-3.61(s,1H),3.52-3.46(m,2H),2.94(s,3H),2.21-2.12(m,2H),1.47(s,9H).

Embodiment 162

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine to obtain the title compound. LCMS (ES, m/z): 448.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.62(d,J＝2.4Hz,1H),8.06(dd,J＝8.4,2.8Hz,1H),7.97(dd,J＝19.6,2.4Hz,2H),7.87-7.78(m,1H),7.14 (t,J＝2.4Hz,1H),7.08-6.95(m,2H),6.54(dd,J＝8.4,2.8Hz,1H),6.15(d,J＝2.8Hz,2H),3.87(s,3H),1.48(s,9H).

Embodiment 163

Example 160 (30 mg) was dissolved in anhydrous methanol (3 mL) at room temperature, and palladium on carbon (10 mg, 5%) was added. The mixture was stirred overnight under a hydrogen atmosphere until the reaction was complete. After the reaction was completed, the mixture was filtered and the filter cake was washed with a small amount of methanol. The filtrate was concentrated and the residue was purified by reverse phase column to obtain the title compound (3 mg). LCMS (ES, m/z): 517.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.97(s,1H),7.93(s,1H),7.81(d,J＝8.0Hz,1H),7.05(d,J＝2.0Hz,1H),6.98(dd,J＝8.0,2.0Hz,1H),6.67(s,1H),3.85( s,4H),3.52-3.62(m,1H),2.88(s,3H),2.87-2.75(m,2H),2.05-2.04(m,1H),1.82-1.91(m,1H),1.61-1.77(m,2H),1.47(s,9H).

Embodiment 164

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by tetrahydro-2H-pyran-3-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 440.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ(ppm):7.99(s,1H),7.85(d,J＝8.0Hz,1H),7.69(d,J＝4.8Hz,1H),7.17(d,J＝1 .6Hz,1H),7.12(dd,J＝8.0,1.6Hz,1H),7.02(d,J＝4.8Hz,1H),6.02(s,2H),4.04 -3.98(m,1H),3.93-3.90(m,1H),3.86(s,3H),3.59(t,J＝10.8Hz,1H),3.46-3.3 6(m,2H),2.09-2.06(m,1H),1.97-1.82(m,1H),1.82-1.65(m,2H),1.48(s,9H).

Embodiment 166

The synthesis method is similar to the preparation method of Example 144, except that the intermediate 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester is replaced with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester to obtain the title compound. LCMS (ES, m/z): 524.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.97(s,1H),7.91(d,J＝12.0Hz,1H),7.80(d,J＝12.0Hz,1H),7.06(s,1H),6.98(d,J＝8.0Hz,1H),6.62(s, 1H),3.85(s,3H),3.23-3.20(m,2H),3.18-2.69(m,5H),2.20(s,3H),2.15(s,3H),1.80-1.77(m,2H),1.47(s,9H).

Embodiment 168

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 2-methylpyrimidine-5-boronic acid to obtain the title compound. LCMS (ES, m/z): 448.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):9.39(s,2H),8.03(d,J＝15.2Hz,2H),7.86(d,J＝8.0Hz,1H),7.37(s,1H),7.1 5(d,J＝2.0Hz,1H),7.06(dd,J＝8.0,2.0Hz,1H),3.87(s,3H),2.67(s,3H),1.48(s,9H).

Embodiment 169

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole is replaced by 2-methylpyridine-5-boronic acid pinacol ester to obtain the title compound. LCMS (ES, m/z): 447.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):9.13(d,J＝2.4Hz,1H),8.39(dd,J＝8.0,2.4Hz,1H),8.00(d,J＝2.4Hz,2H),7.85(d,J＝8.0Hz,1H),7.3 7(d,J＝8.0Hz,1H),7.23(s,1H),7.15(d,J＝2.0Hz,1H),7.06(dd,J＝8.0,2.0Hz,1H),3.88(s,3H),1.48(s,9H).

Embodiment 170

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 2-methylpyrimidine-5-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 448.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):9.17(s,2H),8.04(s,1H),7.89(d,J＝8.0Hz,1H),7.86(d,J＝4.8Hz,1H),7.28(d,J＝2.0Hz,1H),7 .20-7.18(m,1H),7.16(s,1H),7.14(d,J＝4.8Hz,1H),6.23(s,2H),3.88(s,3H),2.73(s,3H),1.49(s,9H).

Embodiment 171

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 6-methylnicotinic acid to obtain the title compound. LCMS (ES, m/z): 447.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.91(d,J＝2.4Hz,1H),8.21-8.11(m,1H),8.03(s,1H),7.89(d,J＝8.0Hz,1H),7.66(d,J＝5.2Hz,1H),7.46(d,J＝8.0 Hz,1H),7.28(d,J＝1.6Hz,1H),7.20–7.18(m,1H),7.11(d,J＝5.2Hz,1H),6.19(s,2H),3.88(s,3H),2.58(s,3H),1.49(s,9H).

Embodiment 172

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 463.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.06(s,1H),7.90-7.85(m,3H),7.26(d,J＝1.6Hz,1H),7.20-7.18(m,2H),6.84 (d,J=2.0Hz,1H),6.74-6.72(m,1H),6.25(s,2H),3.88(s,3H),3.50(s,3H),1.49(s,9H).

Embodiment 174

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 1-(oxetane-3-yl)-1H-pyrazole-3-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 478.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.62(d,J＝5.2Hz,1H),8.08(d,J＝2.4Hz,1H),8.04(s,1H),7.90(d,J＝8.4Hz,1H),7.27-7.24(m,2H),7.21 -7.18(m,1H),6.91(d,J=2.4Hz,1H),6.14(s,2H),5.76-5.73(m,1H),5.05-4.98(m,4H),3.89(s,3H),1.49(s,9H).

Embodiment 175

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 5-methylisoxazole-3-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 437.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.33(d,J＝5.2Hz,1H),8.06(s,1H),7.91-7.89(m,1H),7.34-7.33(m,1H),7.27(d,J＝1.6Hz ,1H),7.21-7.19(m,1H),6.86(d,J＝1.2Hz,1H),6.29(s,2H),3.88(s,3H),2.53(s,3H),1.49(s,9H).

Embodiment 176

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 3-methyl-1,2,4-oxadiazole-5-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 438 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.57(d,J＝4.8Hz,1H),8.10(s,1H),7.94(d,J＝8.0Hz,1H),7.52(d,J＝4.8Hz,1 H), 7.30 (d, J = 2.4Hz, 1H), 7.24 (d, J = 8.0Hz, 1H), 6.48 (s, 2H), 3.89 (s, 3H), 1.49 (s, 9H).

Embodiment 177

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 5-methyl-1,2,4-oxadiazole-3-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 438.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.38(d,J＝5.2Hz,1H),8.08(s,1H),7.93(d,J＝8.0Hz,1H),7.39(d,J＝4.8Hz,1H),7 .29(d,J＝1.2Hz,1H),7.23-7.21(m,1H),6.37(s,2H),3.90(s,3H),2.75(s,3H),1.50(s,9H).

Embodiment 178

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 5-methyl-[1,3,4]oxadiazole-2-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 438.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.50(d,J＝4.8Hz,1H),8.09(s,1H),7.93(d,J＝8.0Hz,1H),7.46(d,J＝4.8Hz,1H),7 .29(d,J＝1.6Hz,1H),7.24-7.22(m,1H),6.43(s,2H),3.90(s,3H),2.66(s,3H),1.50(s,9H).

Embodiment 179

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 2-methyloxazole-5-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 437.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.06(s,1H),7.91(s,1H),7.90(s,1H),7.76(s,1H),7.26-7.23(m,3H),6.23(s,2H),3.89(s,3H),2.58(s,3H),1.49(s,9H).

Embodiment 180

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 2-methyloxazole-4-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 437.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.19(d,J＝2.4Hz,1H),9.11(d,J＝4.8Hz,1H),8.06(s,1H),7.95(s,1H),7.85(d,J＝8.8Hz, 1H),7.57-7.54(m,1H),7.08(s,2H),7.08(d,J＝4.8Hz,1H),3.84(s,3H),2.60(s,3H),1.48(s,9H).

Embodiment 181

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 4-methyloxazole-2-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 437.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.55(s,1H),8.06(s,1H),7.90-7.86(m,2H),7.27(d,J＝1.6Hz,1 H),7.22-7.19(m,2H),6.23(s,2H),3.88(s,3H),2.47(s,3H),1.49(s,9H).

Embodiment 182

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 5-methyloxazole-2-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 437 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.60(d,J＝4.8Hz,1H),8.07(s,1H),7.92-7.90(d,J＝8.4Hz,1H),7.36-7.35(d,J＝4.8Hz,1H) ,7.29-7.28(d,J=1.6Hz,1H),7.23-7.20(m,2H),6.32(s,2H),3.40(s,3H),2.45(s,3H),1.49(s,9H).

Embodiment 183

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one to obtain the title compound. LCMS (ES, m/z): 463.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.52-8.49(m,1H),7.99(d,J＝13.2Hz,2H),7.84(d,J＝8.4Hz,1H),7.79-7.77(m,1H),7.43(s,1 H),7.09(d,J=2.0Hz,1H),7.03-7.01(m,1H),6.42-6.39(m,1H),3.87(s,3H),3.54(s,3H),1.48(s,9H).

Embodiment 184

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced with 1,5-dimethyl-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole to obtain the title compound. LCMS (ES, m/z): 450.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.98(d,J＝1.6Hz,2H),7.82(d,J＝8.0Hz,1H),7.13(d,J＝1.6Hz,1H),7.0 6-7.01(m,2H),6.92(s,1H),3.88(s,3H),3.79(s,3H),2.33(s,3H),1.48(s,9H).

Embodiment 185

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 1-(methylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole to obtain the title compound. LCMS (ES, m/z): 501.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.06(s,1H),8.00(s,1H),7.85-7.83(d,J＝8.4Hz,1H),7.10-7.09(m,1H),7.02-7.00(m,1H),6.9 1(s,1H),6.85-6.84(m,1H),4.62-4.59(m,2H),4.35-4.33(m,2H),3.86(s,3H),2.97(s,3H),1.48(s,9H).

Embodiment 186

Step 1: At room temperature, (S)-1-Boc-pyrrolidine-3-carboxylic acid (2.2 g) and (3-chloropyrazin-2-yl)methylamine hydrochloride (1.8 g) were dissolved in acetonitrile (20 mL), and pyridine (4.0 g) was added. After the reaction system was cooled to 0°C, phosphorus oxychloride (3.8 g) was added dropwise. The above mixture was slowly warmed to room temperature and continued to stir overnight until the reaction was complete. After the reaction was completed, the above mixture was poured into ice water. The mixture was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed with water and saturated brine, and then dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by column chromatography to obtain the target compound (2.4 g).

Step 2: Dissolve the product (2.4 g) obtained in step 1 in acetonitrile (25 mL) at room temperature, cool the mixture to 0 degrees Celsius, and add NBS (1.6 g) in batches. Stir the above mixture at room temperature for 2 hours until the reaction is complete. After the reaction is completed, dilute the mixture with ethyl acetate. Wash the resulting mixture with saturated sodium bicarbonate aqueous solution, water and saturated brine, and then dry over anhydrous sodium sulfate. After removing the organic phase solvent, the residue is purified by column chromatography to obtain the target compound (2.6 g).

Step 3: Dissolve the product obtained in step 2 (1.3 g) in dichloromethane (20 mL) at room temperature and add HCl/1,4-dioxane solution (10 mL, 4 M). Stir the mixture at room temperature for 2 hours until the reaction is complete. After the reaction is complete, remove the solvent and vacuum dry the residue to obtain the target compound (1.1 g).

Step 4: Dissolve the product (1.1 g) obtained in step 3 in dichloromethane (15 mL) at room temperature and add triethylamine (1.2 g). Cool the mixture to 0°C and add a dichloromethane solution (10 mL) of methylsulfonic anhydride (700 mg) dropwise. After the addition is complete, stir the mixture at room temperature for 2 hours until the reaction is complete. After the reaction is complete, wash the mixture with water and saturated brine, dry it over anhydrous sodium sulfate, and remove the solvent. The residue is purified by column chromatography to obtain the target compound (700 mg).

Step 5: Dissolve the compound obtained in step 4 (700 mg) in isopropanol (5 mL) at room temperature and add ammonia water (5 mL). Heat the mixture to 90 degrees Celsius under closed conditions and stir overnight until the reaction is complete. After the reaction is complete, remove the solvent and purify the residue by column chromatography to obtain the target compound (500 mg).

Step 6: At room temperature, the compound obtained in step 5 (500 mg) was dissolved in a mixed solution of 1,4-dioxane and water (5 mL, v/v = 4/1), and potassium carbonate (550 mg), Pd(PPh ₃ ) ₄ (190 mg) and tert-butyl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (650 mg) were added. The above mixture was fully replaced with nitrogen and heated to 100°C until the reaction was complete. After the reaction was completed, the reaction solution was diluted with ethyl acetate. The obtained mixture was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After removing the solvent, the residue was purified by column chromatography to obtain the title compound (380 mg). LCMS (ES, m/z): 503.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ(ppm):8.00(s,1H),7.85(d,J＝8.0Hz,1H),7.68(d,J＝8.0Hz,1H),7.19-7.18 (m,1H),7.14-7.11(m,1H),7.07(d,J＝4.0Hz,1H),6.08(s,2H),4.01-3.97(m,1 H),3.86(s,3H),3.81-3.77(m,1H),3.62-3.58(m,1H),3.51-3.45(m,1H),3.42 -3.35(m,1H),3.00(s,3H),2.44-2.39(m,1H),2.24-2.19(m,1H),1.48(s,9H).

Embodiment 187

The synthesis method is similar to the preparation method of Example 186, except that the intermediate (S)-1-Boc-pyrrolidine-3-carboxylic acid is replaced with (R)-1-Boc-pyrrolidine-3-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 503.2 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ(ppm):8.00(s,1H),7.84(d,J＝8.0Hz,1H),7.68–7.67(m,1H),7.18(s,1H) ,7.12(d,J＝8.0Hz,1H),7.07(d,J＝4.0Hz,1H),6.08(s,2H),3.99-3.97(m,1H) ,3.86(s,3H),3.81-3.76(m,1H),3.62-3.60(m,1H),3.49-3.47(m,1H),3.41- 3.35(m,1H),3.00(s,3H),2.44-2.39(m,1H),2.24-2.19(m,1H),1.48(s,9H).

Embodiment 188

The synthesis method is similar to the preparation method of Example 186, except that the intermediate methanesulfonic anhydride is replaced by ethylsulfonyl chloride to obtain the title compound. LCMS (ES, m/z): 517.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.20(s,1H),8.06(d,J＝8.0Hz,1H),7.88(d,J＝4.8Hz,1H),7.40-7.39(m,1H),7 .34-7.32(m,1H),7.27(d,J＝4.8Hz,1H),6.29(s,2H),4.22-4.19(t,J＝7.4Hz,1H),4.07( s,3H),4.03-3.99(m,1H),3.84-3.80(m,1H),3.75-3.72(m,1H),3.64-3.62(m,1H),3.41 -3.35(m,2H),2.63-2.59(m,1H),2.45-2.40(m,1H),1.68(s,9H),1.44(t,J＝7.6Hz,3H).

Embodiment 189

The synthesis method is similar to the preparation method of Example 187, except that the intermediate methanesulfonic anhydride is replaced by ethylsulfonyl chloride to obtain the title compound. LCMS (ES, m/z): 517.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.00(s,1H),7.85(d,J＝8.4Hz,1H),7.68(d,J＝5.2Hz,1H),7.19-7.18(m,1H) ,7.14-7.11(m,1H),7.07(d,J＝4.8Hz,1H),6.07(s,2H),4.00-3.98(m,1H),3.86(s,3H ),3.83-3.78(m,1H),3.64-3.60(m,1H),3.54-3.52(m,1H),3.44-3.41(m,1H),3.21-3 .15(m,2H),2.43-2.39(m,1H),2.24-2.19(m,1H),1.48(s,9H),1.23(t,J＝7.2Hz,3H).

Embodiment 190

The synthesis method is similar to the preparation method of Example 144, except that the intermediate dimethylglycine is replaced by ethylsulfonyl chloride to obtain the title compound. LCMS (ES, m/z): 516.9 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):7.97(s,1H),7.92(s,1H),7.82-7.80(d,J＝8.0Hz,1H),7.07(d,J＝4.0H z,1H),7.00-6.97(m,1H),6.72(s,1H),3.95-3.91(m,1H),3.86(s,3H),3.83-3. 81(m,1H),3.53-3.50(m,1H),3.47-3.43(m,1H),3.40–3.36(m,1H),3.17-3.12( m,2H),2.44-2.37(m,1H),2.22-2.14(m,1H),1.47(s,9H),1.25(t,J＝8.0Hz,3H).

Embodiment 191

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by pyridine-3-boronic acid to obtain the title compound. LCMS (ES, m/z): 433.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):9.27(d,J＝2.4Hz,1H),8.54-8.50(m,2H),8.02(d,J＝8.0Hz,2H),7.85(d,J＝8.0Hz,1H), 7.52-7.49(m,1H),7.29(s,1H),7.16-7.15(m,1H),7.08-7.05(m,1H),3.88(s,3H),1.48(s,9H).

Embodiment 192

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by nicotinic acid to obtain the title compound. LCMS (ES, m/z): 433.2 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):9.06-9.05(m,1H),8.71-8.69(m,1H),8.28-8.25(m,1H),8.04(s,1H),7.89(d,J＝8.0Hz,1H),7.80(d,J＝5.2Hz,1H) ,7.62-7.59(m,1H),7.29(d,J＝2.0Hz,1H),7.22-7.20(m,1H),7.14(d,J＝5.2Hz,1H),6.22(s,2H),3.88(s,3H),1.49(s,9H).

Embodiment 195

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 1-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 477 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.05(s,1H),7.90-7.86(m,3H),7.26(d,J＝1.6Hz,1H),7.20-7.18(m,2H),6.83(d,J＝1.6Hz,1H),6.75- 6.73(m,1H),6.25(s,2H),4.90(d,J＝8Hz,2H),3.97(d,J＝8.0Hz,3H),1.49(d,J＝12.0Hz,9H),1.29-1.25(m,3H).

Embodiment 196

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 5-pyrimidinecarboxylic acid to obtain the title compound. LCMS (ES, m/z): 434 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):9.30(s,3H),8.06(s,3H),7.93-7.89(m,2H),7.29(d,J＝2.4Hz,1H),7 .23-7.20(m,1H),7.18(d,J＝4.8Hz,1H),6.27(s,2H),3.88(s,3H),1.49(s,9H).

Embodiment 197

The synthesis method is similar to the preparation method of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced by 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid to obtain the title compound. LCMS (ES, m/z): 463 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.03(s,1H),7.99(d,J＝6.4Hz,1H),7.88(d,J＝7.6Hz,2H),7.26(s,1H),7.20-7.18(m,2 H),7.04(d,J＝4.8Hz,1H),6.46-6.42(m,1H),6.09(s,2H),3.88(s,3H),3.59(s,3H),1.48(s,9H).

Embodiment 198

The synthesis method is similar to the preparation method of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole is replaced by 1-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one to obtain the title compound. LCMS (ES, m/z): 477 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm):8.47(d,J＝12.0Hz,1H),7.99(s,1H),7.96(s,1H),7.83(d,J＝8.0Hz,1H),7.77(d,J＝8.0Hz,1H),7.43(s,1H),7. 09(s,1H),7.01(d,J＝8.0Hz,1H),6.40(t,J＝8.0Hz,1H),4.05-4.00(m,2H),3.87(s,3H),1.48(s,9H),1.29-1.26(m,3H).

3. Performance Measurement

Test Example 1: YES1 enzyme inhibition activity

1.1 Compound preparation See Table 2

Table 2. Preparation of compounds with YES1 enzyme activity inhibitory activity

1) Prepare 2× ATP/substrate solution and 2× kinase solution using kinase reaction buffer.

2) Use Echo 655 to transfer 50 nL of compound dilution to the 384 assay plate; after centrifugation, add 2.5 μL of 2× kinase solution to the 384 assay plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 10 min;

3) Add 2.5 μL of 2× substrate and ATP solution to the 384 assay plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 30 min.

4) Prepare 2×XL 665 and antibody detection reagents with detection buffer.

5) Add 5 μL of kinase detection reagent to the test plate and incubate at 25°C. Centrifuge at 1000 rpm for 1 min and incubate at 25°C for 1 h.

6) Use BMG high-throughput drug screening multifunctional microplate reader to read the fluorescence signals at 620 nm (Cryptate) and 665 nm (XL665).

1.2 Data Analysis

The reading of the negative control (1% DMSO well) was set as 0% inhibition rate, and the reading of the positive control (the well with the highest concentration of the control compound) was set as 100% inhibition rate. After calculating the inhibition rate, the IC ₅₀ values (half-maximal inhibition concentration) of the control compound and the test compound were obtained using the nonlinear fitting formula of the software;

The average of the values of the positive control wells; The values of negative control wells are averaged.

Data analysis was performed using Graphpad 7.0 software, and the IC ₅₀ (half maximal inhibitory concentration) of the compound was obtained using the following nonlinear fitting formula:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope))

X: log value of compound concentration; Y: compound inhibition rate (% inh); Z' factor calculation equation: Z' = 1-3 (SD _min + SD _max ) / (AVE _max - AVE _min )

Wherein: SD _min is the standard error of the Data value of the positive control DMSO, SD _max is the standard error of the Data value of the negative control DMSO, AVE _min is the average difference of the Data value of the positive control DMSO, and AVE _max is the average value of the Data value of the negative control DMSO. The test results are shown in Table 3.

Table 3. _IC50 values of the example compounds for inhibiting YES1 enzymatic activity

The reagent information used in the experiment is shown in Table 4:

Table 4. Information on reagents used in the experiment

Test Example 2: Pharmacokinetics test in rats

1.1 Instruments: High performance liquid chromatograph: SHIMADZU LC-30AD, mass spectrometer: AB SCIEX mass spectrometer Triple Quad 5500, all measured data were calculated and processed by Microsoft Excel, and WinNonlin software was used to calculate relevant pharmacokinetic parameters. The main kinetic parameters obtained include T _max , T _1/2 , C _max , AUC _0-24h , AUC _inf . Chromatographic column: XSelect Hss T3 2.5μm (2.1x50mm) Column XP, column temperature 40℃, mobile phase A is water (0.1% formic acid), mobile phase B is acetonitrile, flow rate is 0.60 ml/min, gradient elution is used, the elution gradient is 0.30min: 5% B; 1.00min: 98% B; 1.48min: 98% B; 1.51min: 5% B; 2.00min: stop. Injection volume: 1μL.

1.2 Animals: Three SD male rats, weighing 180g-300g, were purchased and raised in the experimental animal center for two days before use. They were fasted for 12 hours before administration and 4 hours after administration, and had free access to water during the experiment. Blood samples were taken at the designated time points after oral gavage.

1.3 Solvent: DMSO/PEG400/H ₂ O (volume ratio 1/3/6). Preparation of intragastric administration solution: accurately weigh the compound, add the solvent, and perform ultrasound at room temperature for 5 minutes to completely dissolve the drug, and prepare a 0.5 mg/ml solution.

Blood was collected at 0.083h, 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 7.0h and 24h after intragastric administration. The blood collection method was as follows: 0.2mL of blood was collected from the jugular vein. Anticoagulant: EDTA-K ₂ . The collected blood samples were transferred to microcentrifuge tubes containing anticoagulants and centrifuged at 4°C and 4000g for 5min to separate plasma. All collected plasma samples were stored at -75±15°C until analysis.

The compounds were accurately weighed to prepare standard curve working solutions and quality control working solutions of different concentrations, blank plasma was added, plasma standard curves and quality control samples were prepared, and LC/MS/MS analysis was performed after pretreatment by protein precipitation, and then the concentration of the above plasma compounds was tested. All the measurement data were collected and processed by relevant software, and Winnonlin software was used to calculate pharmacokinetic parameters. The kinetic parameters of some representative compounds are shown in Table 5.

Table 5. Pharmacokinetic parameters of the example compounds in rats

The pharmacokinetic test results in rats shown in Table 5 show that the compounds of the present application are rapidly absorbed in the gastrointestinal tract and have good oral bioavailability.

Test Example 3: Pharmacokinetics test in mice

1.1 Instruments: High performance liquid chromatograph: SHIMADZU LC-40AD, mass spectrometer: AB SCIEX mass spectrometer Triple Quad 5500, all measured data were calculated and processed by Microsoft Excel, and WinNonlin software was used to calculate relevant pharmacokinetic parameters. The main kinetic parameters obtained include T _max , T _1/2 , C _max , AUC _0-24h , AUC _inf . Chromatographic column: HALO 90A AQ-C18, 2μm2.1×30mm, column temperature 40℃, mobile phase A is water (0.1% formic acid), mobile phase B is acetonitrile, flow rate is 0.60 ml/min, gradient elution is used, the elution gradient is 0.20min: 5% B; 1.20min: 95% B; 1.60min: 95% B; 1.61min: 5% B; 1.80min: stop. Injection volume: 5μL.

1.2 Animals: Three male Babl/C mice, weighing 20g-30g, were purchased and raised in the experimental animal center for two days before use. They were fasted for 12 hours before administration and 4 hours after administration, and had free access to water during the experiment. Blood samples were collected at the designated time points after gavage.

1.3 Solvent: DMSO/PEG400/H ₂ O (volume ratio 1/3/6). Preparation of intragastric administration solution: accurately weigh the compound, add the corresponding solvent according to the volume, vortex and sonicate to prepare a 1 mg/mL solution.

Blood samples were collected at 0.083h, 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 6.0h, 8.0h and 24h after intragastric administration. The blood collection method was: 0.03mL of blood was collected from the dorsal vein of the foot. The anticoagulant was EDTA-K ₂ . The collected blood samples were transferred to microcentrifuge tubes containing anticoagulants and centrifuged at 4°C and 4000g for 5min to separate plasma. All collected plasma samples were stored at -75±15°C until analysis.

The compound was accurately weighed to prepare standard curve working solution and quality control working solution of different concentrations, blank plasma was added, plasma standard curve and quality control sample were prepared, and LC/MS/MS analysis was performed after pretreatment by protein precipitation method, and then the concentration of the analyte in the above plasma was tested. All the measurement data were collected and processed by relevant software, and Winnonlin software was used to calculate the pharmacokinetic parameters. The kinetic parameters of some representative compounds are shown in Table 6.

Table 6. Pharmacokinetic parameters of the example compounds in mice

The pharmacokinetic test results in mice shown in Table 6 show that the compounds of the present application can be rapidly absorbed, have high blood concentrations and exposure amounts, and have good oral bioavailability.

The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the claims. Any person skilled in the art may make several possible changes and modifications without departing from the concept of the present application. Therefore, the scope of protection of the present application shall be based on the scope defined by the claims of the present application.

Claims (10)

An aromatic amine compound, or an enantiomer, a diastereomer, a pharmaceutically acceptable salt, a prodrug, an isotope derivative, or a solvate of the aromatic amine compound, characterized in that the aromatic amine compound includes a compound represented by formula (I):
In formula (I): X ₁ , X ₂ and X ₃ are each independently selected from CH or N, wherein X ₁ , X ₂ and X ₃ are not N at the same time; Ring Cy is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl; n is 1 to 4, 1 to 4 R _1s are the same or different; R ₁ is selected from C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, 4-10 membered heterocyclyl or 3-10 membered cycloalkyl which is mono- or poly-substituted _by R 4; R ₄ substituents are selected from hydrogen, hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ hydroxyalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkoxy, di(C ₁ -C ₁₀ alkyl)amino, C ₁ -C ₁₀ alkylsulfonyl or 5-10 membered heterocyclyl; _R2 is selected from _C1 - _C10 alkoxy-CO-N( _R6 )-, _C1 - _C10 alkyl-SO2 _-N ( _R6 )-, _C1 - _C10 alkyl-CO-N( _R6 )-, _C3 - _C10 cycloalkyl-CO-N( _R6 )-, _C3 - _C10 cycloalkyloxy-CO-N( _R6 )-, _C3 - _C10 cycloalkyl-( _C1 - _C10 )alkylene-CO-N( _R6 )-, _C1 - _C10 alkoxy-CO-( _C1 - _C10 )alkylene, 5-10 membered heteroaryl-( _C1 - _C10 )alkylene, 5-10 membered heterocyclyl-( _C1 - _C10 )alkylene, 5-10 membered heteroaryl-N( _R6 )-, _C6 -C ₁₀ aryl-(C ₁ -C ₁₀ ) alkyleneoxy or 4-10 membered heterocyclyl-O-CO-N(R ₆ )-; wherein R ₆ is selected from hydrogen, C ₁ -C ₁₀ alkyl; m is 1 to 4, 1 to 4 R ₃ are the same or different; R ₃ is selected from hydrogen, halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkyl or C ₁ -C ₁₀ haloalkoxy. The aromatic amine compound according to claim 1, or the enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug, isotope derivative, solvate, stereoisomer, tritiated product of the aromatic amine compound, characterized in that _X1 is selected from CH, _X2 and _X3 are selected from N; or _X1 and _X2 are selected from CH, _X3 is selected from N; or _X1 and _X3 are selected from CH, _X2 is selected from N; Preferably, _X2 is selected from CH, and _X1 and _X3 are selected from N. The aromatic amine compound according to claim 1 or 2, or the enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug, isotope derivative, solvate, stereoisomer, tritiated product of the aromatic amine compound, characterized in that the ring Cy is selected from substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, wherein the 5-6 membered heteroaryl contains 1-3 heteroatoms selected from N, O, S; Preferably, ring Cy is selected from 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C ₃ -C ₁₀ cycloalkyl; wherein the 5-10 membered heteroaryl or 3-10 membered heterocyclyl contains 1-3 heteroatoms selected from N, O, S; Preferably, ring Cy is selected from 8-10 membered bicyclic heteroaryl; Preferably, the cyclic Cy group is selected from 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl; Preferably, ring Cy is selected from 3-10 membered heterocyclic groups; Preferably, the cyclic Cy group is selected from oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydro-2H-pyranyl, 1,2,5,6-tetrahydropyridinyl, pyranyl, 3,6-dihydro-2H-pyranyl, 2,5-dihydro-1H-pyrrolyl, 1,2-dihydropyridinyl, 1,6-dihydropyridazinyl; Preferably, the number n of R ₁ is 1 to 4, 1 to 4 R ₁ are the same or different, wherein each R ₁ is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, oxo, or the following groups which are optionally substituted or polysubstituted by R ₄ : C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkylacyl, C ₁ -C ₁₀ alkylsulfonyl, 4-10 membered heterocyclyl or 3-10 membered cycloalkyl, wherein the 4-10 membered heterocyclyl contains 1 to 3 heteroatoms selected from N, O, S; Preferably, each R ₁ is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, oxo, or the following groups which are optionally substituted or polysubstituted by R ₄ : C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylacyl, C ₁ -C ₆ alkylsulfonyl, 4-6 membered heterocyclyl or 3-6 membered cycloalkyl, wherein the 4-6 membered heterocyclyl contains 1-2 heteroatoms selected from N, O, S; More preferably, each R ₁ is independently selected from hydrogen, halogen, hydroxy, cyano, amino, oxo, or the following groups which are optionally substituted or polysubstituted by R ₄ : C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkylacyl, C ₁ -C ₄ alkylsulfonyl, 4-6 membered heterocyclyl or 3-4 membered cycloalkyl, wherein the 4-6 membered heterocyclyl contains 1-2 heteroatoms selected from N, O, S; Further preferably, each R ₁ is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, oxo, or the following groups which are optionally monosubstituted, disubstituted, or trisubstituted by R ₄ : C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylacyl, C ₁ -C ₃ alkylsulfonyl, 4-6 membered heterocyclyl or 3-4 membered cycloalkyl, wherein the 4-6 membered heterocyclyl contains 1-2 heteroatoms selected from N, O, and S. Also preferably, the R ₁ group is selected from hydrogen, halogen, hydroxy, cyano, amino, oxo, N,N-dimethylaminoethyl, N,N-dimethylaminomethyl, N,N-dimethylaminoacylmethyl, N,N-dimethylaminomethylacyl, N,N-dimethylaminoethylacyl, methyl, difluoromethyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxyethyl, hydroxyethyl, methylsulfonylethyl, cyanoethyl, 2-hydroxy-propyl, 2-hydroxy-2-methylpropyl, methylsulfonyl, ethylsulfonyl, acetyl, propionyl, or the following groups optionally substituted, disubstituted, or trisubstituted by R ₄ : cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, 4-methylpiperazinyl; Preferably, the _R4 group is independently selected from hydrogen, hydroxyl, halogen, cyano, amino, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl, _C1 - _C6 hydroxyalkyl, _C1 - _{C6 alkoxy, C1-C6 haloalkoxy ,} di( _C1 - _C6 alkyl)amino, ( _C1 - _C6 alkyl)aminoacyl, di( _C1 - _C6 alkyl)aminoacyl, _C1 - _C6 alkylsulfonyl or 4-6 membered heterocyclyl; Preferably, the _R4 group is independently selected from hydrogen, hydroxyl, halogen, cyano, amino, _C1 - _C3 alkyl, _C1 - _C3 haloalkyl, _C1 - _C3 hydroxyalkyl, _C1 - _{C3 alkoxy, C1-C3 haloalkoxy ,} di( _C1 - _C3 alkyl)amino, ( _C1 - _C3 alkyl)aminoacyl, di( _C1 - _C3 alkyl)aminoacyl, _C1 - _C3 alkylsulfonyl or 5-6 membered heterocyclic group; Also preferably, the R ₄ group is selected from: hydrogen, hydroxy, halogen, cyano, amino, methyl, ethyl, propyl, isopropyl, hydroxyethyl, oxetane, dimethylamino, methylaminoacyl, dimethylaminoacyl, methoxy or methylsulfonyl. The aromatic amine compound shown below, or the enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug, isotope derivative, solvate, stereoisomer, tritiated product of the aromatic amine compound, characterized in that the aromatic amine compound is selected from any one of the following compounds:
wherein X ₁ , X ₂ , X ₃ , R ₁ , R ₂ , R ₃ and m have the meanings as defined in any one of claims 1 to 3; R ₁₁ is selected from H, hydroxyl, halogen, cyano, amino, or the following groups which are optionally monosubstituted, disubstituted or polysubstituted by R ₂₁ : C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkylacyl, C ₁ -C ₁₀ alkylsulfonyl, C ₁ -C ₁₀ alkylsulfinyl, mono(C ₁ -C ₁₀ alkyl)amino, di(C ₁ -C ₁₀ alkyl)amino, di(C ₁ -C ₁₀ alkyl)aminoacyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C ₃ -C ₁₀ cycloalkyl, 5-10 membered heteroaryloxy, 4-10 membered heterocyclyloxy or C ₃ -C ₁₀ cycloalkyloxy; wherein the heteroaryl or heterocyclyl contains 1 to 3 heteroatoms selected from N, O and S; _R21 are the same or different and are independently selected from hydrogen, hydroxy, halogen, cyano, amino, _C1 - _C10 alkyl, _C1 - _C10 haloalkyl, _C1 - _C10 hydroxyalkyl, _C1 - _C10 alkoxy, _C1 - _C10 haloalkoxy, mono( _C1 - _C10 alkyl)amino, di( _C1 - _C10 alkyl)amino, ( _C1 - _C10 alkyl)aminoacyl, di( _C1 - _C10 alkyl)aminoacyl, _C1 - _C10 alkylsulfonyl or 5-10 membered heterocyclyl; p is selected from integers of 1-4. The aromatic amine compound according to any one of claims 1 to 3, or the enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug, isotope derivative, solvate, stereoisomer, tritiated product of the aromatic amine compound, characterized in that the _R2 group contains a monosubstituted or polysubstituted _R5 group, and the _R5 group is selected from hydrogen, halogen, cyano, _C1 - _C10 alkyl, halogenated _C1 - _C10 alkyl or oxy. The aromatic amine compound shown below, or the enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug, isotope derivative, solvate, stereoisomer, tritiated product of the aromatic amine compound: tert-Butyl (4-(4-amino-7-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(1-(2-hydroxyethyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-isopropyl-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-methyl-1H-pyrazol-5-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1,3-dimethyl-1H-pyrazol-5-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1,5-dimethyl-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; 2-(4-(4-amino-5-(4-((4-fluoro-1H-pyrazol-1-yl)methyl)-3-methoxyphenyl)pyrrolo[2,1-F][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)ethan-1-ol; 1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxybenzyl)-1H-pyrazole-4-carbonitrile; 2-(4-(5-(4-((1H-pyrazol-1-yl)methyl)-3-methoxyphenyl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)ethan-1-ol; 2-(4-(4-amino-5-(3-methoxy-4-((4-methyl-1H-pyrazol-1-yl)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)ethan-1-ol; tert-Butyl (4-(4-amino-7-(1-ethyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; 2-(4-(4-amino-5-(3-methoxy-4-((3-methyl-1H-pyrazol-1-yl)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)ethan-1-ol; tert-Butyl (4-(4-amino-7-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-cyclobutyl-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; N-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)ethanesulfonamide; tert-Butyl 2-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)acetate; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)pivalamide; 2-(4-(4-amino-5-(3-methoxy-4-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)phenyl)pyrrolo[2,1-F][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)ethan-1-ol; 2-(4-(4-amino-5-(3-methoxy-4-((4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)phenyl)pyrrolo[2,1-F][1,2,4]triazin-7-yl)-1H-pyrazol-1-yl)ethan-1-ol; 5-(4-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)methyl)-3-methoxyphenyl)-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-4-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-5-methylisoxazol-3-amine; tert-Butyl 2-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)acetate; tert-Butyl (4-(4-amino-7-(1-isopropyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(difluoromethyl)-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-cyclopropylpyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; 5-(3-methoxy-4-((5-methyloxazol-2-yl)methyl)phenyl)-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine; 5-(4-benzyloxy)-3-methoxyphenyl)-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-4-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-N,5-dimethylisoxazol-3-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)cyclopropanecarboxamide; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-2-cyclopropylacetamide; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)oxazol-2-amine; 5-(4-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)amino)-3-methoxyphenyl)-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-4-amine; (4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazine-5-yl)-2-methoxyphenyl)carbamic acid tetrahydrofuran-3-yl; Oxetane-3-yl(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazine-5-yl)-2-methoxyphenyl)carbamate; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-N-methyloxazol-2-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-5-methyloxazol-2-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-N,5-dimethyloxazol-2-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-4-methyloxazol-2-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-N,4-dimethyloxazol-2-amine; 5-(3-methoxy-4-((4-methyloxazol-2-yl)methyl)phenyl)-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-4-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-5-methyl-1,3,4-oxadiazol-2-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-N,5-dimethyl-1,3,4-oxadiazol-2-amine; 5-(3-methoxy-4-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)phenyl)-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-4-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-3-methyl-1,2,4-oxadiazol-5-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-N,3-dimethyl-1,2,4-oxadiazol-5-amine; 5-(3-methoxy-4-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)phenyl)-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-4-amine; 5-(4-((4,5-dimethyl-4H-1,2,4-triazol-3-yl)(methyl)amino)-3-methoxyphenyl)-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-4-amine; 5-(3-methoxy-4-((5-methylisoxazol-3-yl)methyl)phenyl)-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-5-methyl-1,2,4-oxadiazol-3-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-N,5-dimethyl-1,2,4-oxadiazol-3-amine; 5-(3-methoxy-4-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)phenyl)-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-4-amine; 5-(3-methoxy-4-((1-methyl-1H-pyrazol-3-yl)amino)phenyl)-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-4-amine; 5-(3-methoxy-4-(methyl(1-methyl-1H-pyrazol-3-yl)amino)phenyl)-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-4-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-5-methylisothiazol-3-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-N,5-dimethylisothiazol-3-amine; 5-(3-methoxy-4-((5-methylisothiazol-3-yl)methyl)phenyl)-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-4-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-5-methylthiazol-2-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-N,5-dimethylthiazol-2-amine; 5-(3-methoxy-4-((5-methylthiazol-2-yl)methyl)phenyl)-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-4-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-5-methyl-1,3,4-thiadiazol-2-amine; N-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)-N,5-dimethyl-1,3,4-thiadiazol-2-amine; 5-(3-methoxy-4-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)phenyl)-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-4-amine; 5-(4-methoxybenzo[d]isoxazol-6-yl)-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine; 3-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxybenzyl)oxazolidin-2-one; 1-(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxybenzyl)pyrrolidin-2-one; 1-Methylcyclopropyl(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; Cyclobutyl (4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; Cyclopentyl (4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; 1-Methylcyclobutyl(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; 3-Methyloxetan-3-yl(4-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazine-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (7-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)benzo[D][1,3]dioxol-4-yl)carbamate; tert-Butyl (4-(4-amino-7-(5-((dimethylamino)methyl)-1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(2-((dimethylamino)methyl)oxazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(2-((dimethylamino)methyl)oxazol-5-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (5-(4-amino-7-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-3-methoxypyridin-2-yl)carbamate; tert-Butyl 2-(5-(4-amino-7-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-3-methoxypyridin-2-yl)acetate; tert-Butyl 2-(4-(4-amino-7-(2-methyloxazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)acetate; tert-Butyl 2-(4-(4-amino-7-(2-methylthiazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)acetate; tert-Butyl 2-(4-(4-amino-7-(1,2-dimethyl-1H-imidazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)acetate; tert-Butyl 2-(4-(4-amino-7-(2-methyloxazol-5-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)acetate; tert-Butyl 2-(4-(4-amino-7-(2-methylthiazol-5-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)acetate; tert-Butyl (4-(4-amino-7-(2-methyloxazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(2-methylthiazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1,2-dimethyl-1H-imidazol-4-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(2-methyloxazol-5-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(2-methylthiazol-5-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl 2-(4-(4-amino-7-(5-methylthiazol-2-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)acetate; tert-Butyl 2-(4-(4-amino-7-(5-methylisoxazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)acetate; tert-Butyl 2-(4-(4-amino-7-(5-methylisothiazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)acetate; tert-Butyl (4-(4-amino-7-(5-methylthiazol-2-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(5-methylisoxazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(5-methylisothiazol-3-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(3-methylisoxazol-5-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(3-methylisothiazol-5-yl)pyrrolo[2,1-F][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl 2-(4-(4-amino-7-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)acetate; tert-Butyl (4-(4-amino-7-(2-methyl-2H-1,2,3-triazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-methyl-1H-1,2,3-triazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(4,5-dimethylthiazol-2-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(3-hydroxyoxetan-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(3-hydroxytetrahydrofuran-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(4-hydroxy-1-methylpiperidin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-cyclopropylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(1-fluorocyclopropyl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(1-methyl-1H-pyrazol-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(1-methyl-1H-pyrazol-4-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(4-methoxytetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(2-(dimethylamino)ethyl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-((methylsulfonyl)methyl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(3-(4-methylpiperazin-1-yl)propyl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(3-(1-acetylpyrrolidin-3-yl)-8-aminoimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(2-(4-isopropylpiperazin-1-yl)ethyl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(2-ethoxyethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(1-(dimethylglycerol)pyrrolidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(2-(4-methylpiperazin-1-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(pyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(2-(4-(dimethylamino)piperidin-1-yl)ethyl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(2-methoxyethyl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(dimethylglycerol)pyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; (R)-tert-butyl(4-(4-amino-7-(1-(dimethylglycerol)pyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; (S)-tert-butyl (4-(4-amino-7-(1-(dimethylglycerol)pyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; (S)-tert-butyl (4-(8-amino-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; (R)-tert-butyl (4-(8-amino-3-(tetrahydrofuran-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(2-(dimethylamino)ethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(2-(2-hydroxyethyl)(methyl)amino)ethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(2-(2-(dimethylamino)ethyl)(methyl)amino)ethyl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(3-(dimethylamino)propionyl)pyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(2-((1-methylpiperidin-4-yl)oxy)ethyl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; (S)-tert-butyl(4-(4-amino-7-(2-(2-(hydroxymethyl)pyrrolidin-1-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(2-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)ethyl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(2-(4-hydroxy-4-methylpiperidin-1-yl)ethyl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(3-methylisoxazol-5-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(2-(4-hydroxy-4-methylpiperidin-1-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; (S)-tert-butyl (4-(4-amino-7-(2-(3-(hydroxymethyl)pyrrolidin-1-yl)ethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(methylsulfonyl)-1,2,5,6-tetrahydropyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(methylsulfonyl)pyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(6-aminopyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(methylsulfonyl)piperidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(tetrahydro-2H-pyran-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(1-(dimethylglyceryl)piperidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(dimethylglyceryl)piperidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(1-(methylsulfonyl)piperidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(2-methylpyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(6-methylpyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(2-methylpyrimidin-5-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(6-methylpyridin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(1-(oxetan-3-yl)-1H-pyrazol-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(5-methylisoxazol-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(3-methyl-1,2,4-oxadiazol-5-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(5-methyl-1,2,4-oxadiazol-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(5-methyl-1,3,4-oxadiazol-2-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(2-methyloxazol-5-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(2-methyloxazol-4-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(4-methyloxazol-2-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(5-methyloxazol-2-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1,5-dimethyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(methylsulfonyl)-2,5-dihydro-1H-pyrrol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; (S)-tert-butyl (4-(8-amino-3-(1-(methylsulfonyl)pyrrolidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; (R)-tert-butyl (4-(8-amino-3-(1-(methylsulfonyl)pyrrolidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; (S)-tert-butyl (4-(8-amino-3-(1-(ethylsulfonyl)pyrrolidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; (R)-tert-butyl (4-(8-amino-3-(1-(ethylsulfonyl)pyrrolidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(1-(ethylsulfonyl)pyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(pyridin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(pyridin-4-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(4-amino-7-(pyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(1-ethyl-2-oxo-1,2-dihydropyridin-4-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(pyrimidin-5-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; tert-Butyl (4-(8-amino-3-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)imidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenyl)carbamate; Tert-butyl (4-(4-amino-7-(1-ethyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-methoxyphenyl)carbamate. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises the aromatic amine compound according to any one of claims 1 to 6, and any one of the enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs, isotope derivatives, solvates, stereoisomers, tritiated products and pharmaceutically acceptable carriers of the aromatic amine compound. The pharmaceutical composition according to claim 7 is characterized in that the preparation form of the pharmaceutical composition includes an oral preparation or an injection. Use of the pharmaceutical composition according to claim 7 or 8 in the preparation of a drug for treating diseases associated with YES1 amplification or YES1 overexpression. The use according to claim 9 is characterized in that the disease associated with YES1 amplification or YES1 overexpression includes cancer, and the cancer includes at least one of acute myeloid leukemia, chloroma, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, B-cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, myelodysplastic syndrome, pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, reproductive tract cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, uterine cancer, gestational trophoblastic disease, gastric cancer, bile duct cancer, gallbladder cancer, small intestine cancer, esophageal cancer, oropharyngeal cancer, hypopharyngeal cancer, eye cancer, neural cancer, head and neck cancer, melanoma, plasmacytoma, endocrine gland tumors, neuroendocrine cancer, brain tumors, bone cancer and sarcoma.