Aromatic amine compound, and pharmaceutical composition and use thereof

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

[0001] This application claims priority to the following prior applications: Chinese invention patent application No. 202311694800.3, filed with the State Intellectual Property Office of China on December 11, 2023, entitled “Aromatic Amine Compounds, Pharmaceutical Compositions Thereof, and Applications Thereof”; and Chinese invention patent application No. 202411463789.4, filed with the State Intellectual Property Office of China on October 18, 2024, entitled “Aromatic Amine Compounds, Pharmaceutical Compositions Thereof, and Applications Thereof”. The entire contents of both prior applications are incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of medical technology, and in particular to an aromatic amine compound and its pharmaceutical composition and application. Background Art

[0003] Protein kinases are important enzymes that catalyze protein phosphorylation. They regulate protein activity through phosphorylation and, through sequential phosphorylation, amplify signals and trigger cellular responses. Protein kinases play a critical regulatory role in life processes, and abnormalities in protein kinases often lead to malignant diseases such as cancer. Dysregulation of protein kinase function, such as through gain-of-function genetic mutations, gene amplification, autonomous activation, and chromosomal rearrangements, is closely associated with cancer development and progression, and is involved in cancer cell transformation, growth, proliferation, and survival.

[0004] Protein kinases are currently considered important targets for the development of molecularly targeted therapies. The Src family of kinases (SFKs) are a class of non-receptor protein tyrosine kinases. The Src family of kinases is a membrane-bound protein family consisting of approximately nine members: Src, Fyn, YES1, Lck, Lyn, Hck, Fgr, and Blk. Src proteins are non-receptor tyrosine kinases that can be activated by multiple signal transduction pathways. Activated Src kinases, in turn, phosphorylate tyrosine residues on target proteins, thereby activating signaling pathways such as MAPK, STAT, PI3K / AKT, and EGFR. Aberrant Src protein activation is associated with many tumors, and its activity is closely correlated with tumor progression. Inhibiting the activity of Src family kinases in tumor tissues holds great promise as an effective cancer treatment. Currently available Src family kinase inhibitors include dasatinib and bosutinib. However, due to their poor selectivity, these inhibitors have not demonstrated sufficient efficacy as Src family kinase inhibitors in clinical practice. Therefore, more selective and effective Src family kinase inhibitors are clinically needed. Summary of the Invention

[0005] The present invention provides an aromatic amine compound that 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 to treat diseases or conditions related to the YES1 protein, such as cancer.

[0006] In a first aspect, the embodiments of the present application provide an aromatic amine compound, or an enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug, isotopic derivative, or solvate of the aromatic amine compound, wherein the aromatic amine compound includes a compound represented by formula (I):

[0007] In formula (I):

[0008] X1, X2 and X3 are each independently selected from CH or N, wherein X1, X2 and X3 are not N at the same time;

[0009] Ring Cy is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C3-C 10 Cycloalkyl;

[0010] n is 1 to 4, 1 to 4 R1 are the same or different; R1 is selected from C1-C 10 Alkyl, C1-C 10 Alkoxy, 4-10 membered heterocyclic group or 3-10 membered cycloalkyl; R4 substituent is selected from hydrogen, hydroxyl, halogen, C1-C6 alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Hydroxyalkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, di(C1-C 10 Alkyl)amino, C1-C 10 Alkylsulfonyl or 5-10 membered heterocyclic group;

[0011] R2 is selected from C1-C 10 Alkoxy-CO-N(R6)-, C1-C 10 Alkyl-SO2-N(R6)-, C1-C 10 Alkyl-CO-N(R6)-, C3-C 10 Cycloalkyl-CO-N(R6)-, C3-C 10 Cycloalkoxy-CO-N(R6)-, C3-C 10 Cycloalkyl-(C1-C 10 )alkylene-CO-N(R6)-, C1-C 10 Alkoxy-CO-(C1-C 10)alkylene, 5-10 membered heteroaryl-(C1-C 10 )alkylene, 5-10 membered heterocyclic group-(C1-C 10 )alkylene, 5-10 membered heteroaryl-N(R6)-, C6-C 10 Aryl-(C1-C 10 )alkyloxy or 4-10 membered heterocyclyl-O-CO-N(R6)-; R5 is selected from hydrogen, halogen, cyano, C1-C 10 Alkyl, halogenated C1-C 10 Alkyl or oxy; R6 is selected from hydrogen, C1-C 10 alkyl;

[0012] m is 1 to 4, 1 to 4 R3 are the same or different; R3 is selected from hydrogen, halogen, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl or C1-C 10 Halogenated alkoxy.

[0013] In a second aspect, an embodiment of the present application provides a pharmaceutical composition, comprising 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 substances and pharmaceutically acceptable carriers of the aromatic amine compound represented by formula (I).

[0014] In a third aspect, the embodiments of the present application provide 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

[0015] To better illustrate the present application and facilitate understanding of the technical solution of the present application, the present application is further described below. It should be understood that the embodiments described are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0016] 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.

[0017] When a range of values ​​is listed, it is intended to include every value within the range. For example, "C1-C 10 "Alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10, 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.

[0018] The substituents listed in this application are Indicates the connection site.

[0019] The term "alkyl" refers to a straight or branched chain 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.

[0020] Unless otherwise specified, the term "alkylene" means a divalent group derived from a straight or branched chain alkyl group, such as but not limited to -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-; the above definition of alkylene is applicable to the "alkylene" mentioned in the heterocyclyl-alkylene, cycloalkyl-alkylene and other groups mentioned herein.

[0021] "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, spiro [4.5] decyl, etc. 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 can be saturated or partially unsaturated.

[0022] "Heterocyclyl" or "heterocycle" refers to a 3- to 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, and 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. A heterocyclyl group may be a monocyclic ring (a "monocyclic heterocyclyl") or a fused, bridged, or spiro ring system, such as a bicyclic ring system (a "bicyclic heterocyclyl"), and may be saturated or partially unsaturated. A heterocyclyl bicyclic ring system may include one or more heteroatoms in one or both rings. In some embodiments, a heterocyclyl group is a 3- to 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, a heterocyclyl group is a 3- to 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.

[0023] Examples of heterocyclic groups include, but are not limited to, aziridine, oxirane, thiirane; azetidinyl, oxetanyl, and thietanyl; tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 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 and 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.

[0024] "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 can be described as, for example, C6-C 10The term "membered" refers to a non-hydrogen ring atom within the moiety. Aryl moieties include, but are not limited to, phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each occurrence of an aryl group may, independently, be optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted with one or more substituents (a "substituted aryl").

[0025] "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, the 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, the 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, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Each instance of a heteroaryl group can, independently, be optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted with one or more substituents (a "substituted heteroaryl").

[0026] Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furyl, and thienyl; imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl; triazolyl, oxadiazolyl, and thiadiazolyl; tetrazolyl; pyridinyl; pyridazinyl, pyrimidinyl, and pyrazinyl; triazinyl and tetrazinyl; azacyclopentadienyl, oxepinyl, and thiepinyl; indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl; naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0027] or “heteroaryl” refers to any monocyclic, bicyclic, or tricyclic heteroaromatic system comprising 5 to 20 ring atoms (5-20 membered) wherein at least one ring atom is a heteroatom selected from O, N, Si, and S. In some embodiments, the heteroaryl group comprises 5 to 14 ring atoms (5-14 membered) wherein 1 to 5 ring atoms are heteroatoms selected from O, N, and S. In some embodiments, the heteroaryl group comprises 5 to 10 ring atoms (5-10 membered) wherein 1 to 3 ring heteroatoms are heteroatoms selected from O, N, and S. In other embodiments, the heteroaryl group is a 5-20, 5-15, 5-12, 5-11, 5-10, 5-9, 5-8, 5-7, or 5-6 membered heteroaryl group wherein 1 to 5, 1 to 3, or 1 to 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, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from O, N, and S.

[0028] 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.

[0029] 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, the bicyclic heteroaryl can be an entire 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.

[0030] The term "halogen" means F, Cl, Br or I.

[0031] The term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo-C1-C6 alkyl" or "C1-C6 haloalkyl" includes but is not limited to fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, etc.

[0032] The term "alkoxy" refers to alkyl-O-, wherein alkyl is as defined herein. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, and the like.

[0033] The term "cycloalkyloxy" or "cycloalkoxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined herein.

[0034] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined herein.

[0035] The term "alkylacyl" refers to alkyl-C(O)-, wherein alkyl is as defined herein. Alkylacyl includes, but is not limited to, acetyl, propionyl, butyryl, and the like.

[0036] The term "acyl" refers to -C(O)-.

[0037] The term "oxo" means =0, or the term "oxy" alone also means =0. When "oxy" is combined with other groups to form a group, such as "5-10 membered heteroaryloxy", "4-10 membered heterocyclyloxy" or "C3-C 10 When the group "cycloalkyloxy" is used, the "oxy" group refers to -O-.

[0038] The term "C1-C 10 "Hydroxyalkyl" means C1-C 10 In the case where 1, 2, 3, 4, 5, 6 or more H on the alkyl group is substituted by OH, wherein the C1-C 10 Alkyl has the above-mentioned definition. 10 The hydroxyalkyl group is preferably a C1-C6 hydroxyalkyl group, and examples thereof include a hydroxymethyl group, a hydroxyethyl group, or a hydroxypropyl group.

[0039] The term "C1-C 10 "Haloalkoxy" means -O-C1-C 10 Haloalkyl, wherein the C1-C 10 Haloalkyl has the same meaning as defined herein.

[0040] The term "di(C1-C 10 Alkyl)amino" or "disubstituted (C1-C 10 "alkyl)amino" means -N(C1-C 10 Alkyl) 2, wherein the C1-C 10 Alkyl has the meaning as defined herein.

[0041] The term "mono(C1-C 10 "alkyl)amino" means -NHC1-C 10 Alkyl, wherein the C1-C 10 Alkyl has the meaning as defined herein.

[0042] The term "C1-C 10 "Alkylsulfonyl" means -SO2-C1-C 10 Alkyl, wherein the C1-C 10 Alkyl has the meaning as defined herein.

[0043] The term "C1-C 10 "Alkylsulfinyl" means -SO-C1-C 10 Alkyl, wherein the C1-C 10Alkyl has the meaning as defined herein.

[0044] The term "di(C1-C6 alkyl)aminoacyl" refers to -CO-N(C1-C6 alkyl)2, wherein the C1-C6 alkyl group has the same meaning as defined herein.

[0045] The term "(C1-C6 alkyl)aminoacyl" refers to -CO-NHC1-C6 alkyl, wherein the C1-C6 alkyl group has the same meaning as defined herein.

[0046] Unless otherwise indicated, "mono- or polysubstituted" 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.

[0047] It should be understood that "polysubstituted" in "monosubstituted, disubstituted or polysubstituted" means that the number of substituents is greater than disubstituted (2 substituents) (such as the number of substituents is 3, 4, 5, 6 or more).

[0048] When a group is defined as "substituted or unsubstituted", the substitution refers to "mono- or poly-substitution".

[0049] The present invention provides an aromatic amine compound, or an enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug, isotope derivative, or solvate thereof. The aromatic amine compound includes a compound represented by formula (I):

[0050] In formula (I):

[0051] X1, X2 and X3 are each independently selected from CH or N, wherein X1, X2 and X3 are not N at the same time;

[0052] Ring Cy is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C3-C 10 Cycloalkyl;

[0053] n is 1 to 4, 1 to 4 R1 are the same or different; R1 is selected from C1-C 10 Alkyl, C1-C 10 Alkoxy, 4-10 membered heterocyclic group or 3-10 membered cycloalkyl; R4 substituent is selected from hydrogen, hydroxyl, halogen, C1-C6 alkyl, C1-C10 Halogenated alkyl, C1-C 10 Hydroxyalkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, disubstituted (C1-C 10 Alkyl)amino, C1-C 10 Alkylsulfonyl or 5-10 membered heterocyclic group;

[0054] R2 is selected from C1-C 10 Alkoxy-CO-N(R6)-, C1-C 10 Alkyl-SO2-N(R6)-, C1-C 10 Alkyl-CO-N(R6)-, C3-C 10 Cycloalkyl-CO-N(R6)-, C3-C 10 Cycloalkoxy-CO-N(R6)-, C3-C 10 Cycloalkyl-(C1-C 10 )alkylene-CO-N(R6)-, C1-C 10 Alkoxy-CO-(C1-C 10 )alkylene, 5-10 membered heteroaryl-(C1-C 10 )alkylene, 5-10 membered heterocyclic group-(C1-C 10 )alkylene-5-10 membered heteroaryl-N(R6)-, C6-C 10 Aryl-(C1-C 10 ) alkyleneoxy or 4-10 membered heterocyclyl-O-CO-N(R6)-; R5 is selected from hydrogen, halogen, cyano, C1-C 10 Alkyl, halogenated C1-C 10 Alkyl or oxy; R6 is selected from hydrogen, C1-C 10 alkyl;

[0055] m is 1 to 4, 1 to 4 R3 are the same or different; R3 is selected from hydrogen, halogen, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl or C1-C 10 Halogenated alkoxy.

[0056] In some embodiments, X1 is selected from CH, and X2 and X3 are selected from N.

[0057] In some embodiments, X1 and X2 are selected from CH, and X3 is selected from N.

[0058] In some embodiments, X1 and X3 are selected from CH, and X2 is selected from N.

[0059] In some embodiments, X2 is selected from CH, and X1 and X3 are selected from N.

[0060] In some embodiments, in the compound represented by formula (I), ring Cy is selected from 5-10 membered heteroaryl or C3-C 10 Cycloalkyl. The 5-10 membered heteroaryl group contains 1-3 heteroatoms selected from N, O, and S.

[0061] Preferably, 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 1-2 heteroatoms selected from N, O, and S.

[0062] Preferably, the ring Cy is selected from C3-C6 cycloalkyl; more preferably, the ring Cy is selected from C3-C4 cycloalkyl.

[0063] As examples of cyclic Cy groups, the cyclic Cy group is selected from pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl or cyclopropyl.

[0064] In some embodiments, in the compound represented by formula (I), ring Cy is selected from 5-10 membered heteroaryl, 3-10 membered heterocyclic group, C3-C 10 Cycloalkyl. The 5-10 membered heteroaryl or 3-10 membered heterocyclic group contains 1-3 heteroatoms selected from N, O, and S.

[0065] In some embodiments, ring Cy is selected from an 8-10 membered bicyclic heteroaryl group, preferably a 9-10 membered bicyclic heteroaryl group, more preferably a partially aromatic 9-10 membered bicyclic heteroaryl group, wherein the heteroaryl group contains 1-3 heteroatoms selected from N, O, and S, preferably 1-2 heteroatoms selected from N, O, and S.

[0066] 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, and 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, and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl.

[0067] 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.

[0068] As an example of a heterocyclic ring, 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.

[0069] In some embodiments, in the compound represented by formula (I), n(R1)-ring Cy- is selected from the following groups:

[0070] In some embodiments, in the compound represented by formula (I), n(R1)-ring Cy- is selected from the following groups:

[0071] In some embodiments, R1 can be substituted on the carbon atom to which the above-mentioned cyclic Cy group is attached or on a non-attached ring atom.

[0072] In some embodiments, when the ring Cy group is a 5- to 10-membered heteroaryl group or a 3- to 10-membered heterocyclyl group, R1 may be substituted on a heteroatom of the 5- to 10-membered heteroaryl group or the 3- to 10-membered heterocyclyl group.

[0073] In some embodiments, when R1 is not H, the number n of R1 is 1 or 2.

[0074] In some embodiments, in the compound represented by formula (I), the number n of R1 is 1 to 4, wherein 1 to 4 R1 are the same or different, wherein each R1 is independently selected from the following groups which are optionally substituted or polysubstituted by R4: C1-C 10 Alkyl, C1-C 10 Alkoxy, 4-10 membered heterocyclic group or 3-10 membered cycloalkyl group, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O and S.

[0075] Preferably, each R1 is independently selected from the following groups which are optionally monosubstituted or polysubstituted by R4: C1-C6 alkyl, C1-C6 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.

[0076] More preferably, each R1 is independently selected from the following groups which are optionally monosubstituted or polysubstituted by R4: C1-C4 alkyl, C1-C4 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.

[0077] Further preferably, each R1 is independently selected from the following groups which are optionally monosubstituted, disubstituted, or trisubstituted by R4: C1-C3 alkyl, C1-C3 alkoxy, 4-6 membered heterocyclic group or 3-4 membered cycloalkyl, wherein the heterocyclic group contains 1-2 heteroatoms selected from N, O, and S.

[0078] As an example of an R1 group, the R1 group is selected from the following groups, which are optionally monosubstituted, disubstituted, or trisubstituted by R4: N,N-dimethylaminoethyl, N,N-dimethylaminomethyl, cyclopropyl, cyclobutyl, methyl, difluoromethyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxyethyl, hydroxyethyl, methylsulfonylethyl, cyanoethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl or piperidinyl.

[0079] In other embodiments, in the compound represented by general formula (I), the number n of R1 is 1 to 4, and the 1 to 4 R1 are the same or different, wherein each R1 is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, oxo, or the following groups which are optionally substituted or polysubstituted by R4: C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkyl acyl, C1-C 10 Alkylsulfonyl, 4-10 membered heterocyclic group or 3-10 membered cycloalkyl group, wherein the 4-10 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S.

[0080] Preferably, each R1 is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, oxo, or the following groups which are optionally monosubstituted or polysubstituted by R4: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylacyl, C1-C6 alkylsulfonyl, 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.

[0081] More preferably, each R1 is independently selected from hydrogen, halogen, hydroxy, cyano, amino, oxo, or the following groups which are optionally monosubstituted or polysubstituted by R4: C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylacyl, C1-C4 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.

[0082] Further preferably, each R1 is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, oxo, or the following groups which are optionally monosubstituted, disubstituted, or trisubstituted by R4: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylacyl, C1-C3 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.

[0083] As examples of R1 groups, R1 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 monosubstituted, disubstituted, or trisubstituted with R4: cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, 4-methylpiperazinyl.

[0084] In some embodiments, in the compound represented by 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.

[0085] 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)amine, C1-C3 alkylsulfonyl or 5-6 membered heterocyclic group.

[0086] As examples of R4 groups, R4 groups are selected from hydrogen, hydroxy, halogen, methyl, ethyl, propyl, isopropyl, hydroxyethyl, oxetane, dimethylamino, methoxy or methanesulfonyl.

[0087] 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.

[0088] 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 heterocyclic group.

[0089] As an example, the R4 group is selected from hydrogen, hydroxy, halogen, cyano, amino, methyl, ethyl, propyl, isopropyl, hydroxyethyl, oxetane, dimethylamino, methylaminoacyl, dimethylaminoacyl, methoxy or methylsulfonyl.

[0090] In some embodiments, in the compound represented by general formula (I), R3 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 haloalkoxy.

[0091] Preferably, R3 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy.

[0092] More preferably, R3 is selected from hydrogen, halogen, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl or C1-C2 haloalkoxy.

[0093] Particularly preferably, R3 is selected from hydrogen, halogen, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl or C1-C2 haloalkoxy, and R3 is located in the ortho position of R2.

[0094] In some embodiments, m is 1.

[0095] As examples of R3 groups, R3 is selected from: halogen, methyl, ethyl, methoxy, ethoxy, halomethoxy, haloethoxy, halomethyl or haloethyl; and R3 is located in the ortho position to R2.

[0096] In some embodiments, in the compound represented by general formula (I), R2 is selected from C1-C 10 Alkoxy-CO-N(R6)-, C1-C 10 Alkyl-SO2-N(R6)-, C1-C 10 Alkyl-CO-N(R6)-, C3-C 10 Cycloalkyl-CO-N(R6)-, C3-C 10 Cycloalkoxy-CO-N(R6)-, C3-C 10 Cycloalkyl-(C1-C 10 )alkylene-CO-N(R6)-, C1-C 10Alkoxy-CO-(C1-C 10 )alkylene, 5-10 membered heteroaryl-(C1-C 10 )alkylene, 5-10 membered heterocyclic group-(C1-C 10 )alkylene, 5-10 membered heteroaryl-N(R6)-, C6-C 10 Aryl-(C1-C 10 )alkyleneoxy or 4-10 membered heterocyclyl-O-CO-N(R6)-; wherein the heteroaryl contains 1-3 heteroatoms selected from N, O, and S.

[0097] R5 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, halo-C1-C6 alkyl or oxy;

[0098] R6 is selected from hydrogen or C1-C6 alkyl;

[0099] 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-C6 10 Aryl-(C1-C6)alkyleneoxy- or 4-6 membered heterocyclyl-O-CO-N(R6)-; wherein the heteroaryl contains 1-3 heteroatoms selected from N, O, and S.

[0100] More preferably, R2 is selected from C1-C4 alkoxy-CO-N(R6)-, C1-C4 alkyl-SO2-N(R6)-, C1-C4 alkyl-CO-N(R6)-, C3-C4 cycloalkyl-CO-N(R6)-, C3-C5 cycloalkoxy-CO-N(R6)-, C3-C4 cycloalkyl-(C1-C3)alkylene-CO-N(R6)-, C1-C4 alkoxy-CO-(C1-C3)alkylene, 5-6 membered heteroaryl-(C1-C3)alkylene, 5-6 membered heterocyclyl-(C1-C3)alkylene, 5-6 membered heteroaryl-N(R6)-, C6-C 10 Aryl-(C1-C3)alkyleneoxy-or 4-6 membered heterocyclyl-O-CO-N(R6)-; wherein the heteroaryl contains 1-3 heteroatoms selected from N, O, and S; R6 is independently selected from H, C1-C3 alkyl.

[0101] Further preferably, R2 is selected from C1-C4 alkoxy-CO-N(R6)-, C1-C4 alkyl-SO2-N(R6)-, C1-C4 alkyl-CO-N(R6)-, C3-C4 cycloalkyl-CO-N(R6)-, C3-C5 cycloalkoxy-CO-N(R6)-, C3-C4 cycloalkyl-(C1-C2)alkylene-CO-N(R6)-, C1-C4 alkoxy-CO-(C1-C2)alkylene, 5-6 membered heteroaryl-(C1-C2)alkylene, 5-6 membered heterocyclyl-(C1-C2)alkylene, 5-6 membered heteroaryl-N(R6)-, C6-C 10 Aryl-(C1-C2)alkyleneoxy- or 4-6 membered heterocyclyl-O-CO-N(R6)-; wherein the heteroaryl contains 1-3 heteroatoms selected from N, O, and S.

[0102] R5 is selected from hydrogen, halogen, cyano, C1-C3 alkyl, halogenated C1-C3 alkyl or oxy.

[0103] R6 is selected from hydrogen or methyl.

[0104] Particularly preferably, R2 is selected from C1-C4 alkoxy-CO-N(R6)-, C1-C4 alkyl-SO2-N(R6)-, C1-C4 alkyl-CO-N(R6)-, C3-C4 cycloalkyl-CO-N(R6)-, C3-C5 cycloalkyloxy-CO-N(R6)-, C3-C4 cycloalkyl-(C1)alkylene-CO-N(R6)-, C1-C 4-membered alkoxy-CO-(C1)alkylene, 5-6-membered heteroaryl-(C1)alkylene, 5-6-membered heterocyclyl-(C1)alkylene, 5-6-membered heteroaryl-N(R6)-, benzyloxy- or 4-6-membered heterocyclyl-O-CO-N(R6)-; 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.

[0105] R5 is selected from hydrogen, halogen, cyano, methyl, ethyl, trifluoromethyl, trifluoroethyl or oxy.

[0106] R6 is selected from hydrogen or methyl.

[0107] 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,

[0108] In some embodiments, the R2 group together with the benzene ring to which it is attached constitutes a benzoC3- C4 cycloalkyl or benzo 3-4 membered heterocyclic group, for example, R2 group together with the benzene ring to which it is connected constitutes

[0109] 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 X1, X2, X3, R1, R2, R3, and m in formula (II) are as defined in formula (I);

[0110] 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 isotopic derivative, or a solvate thereof, wherein the definitions of X1, X2, X3, R1, R2, and R3 in formula (III) are as defined in general formula (I);

[0111] 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 thereof, wherein the definitions of X1, X2, X3, R1, R2, and R3 in formula (IV) are as defined in general formula (I);

[0112] 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 isotopic derivative, or a solvate thereof:

[0113] Wherein, the definitions of X1, X2, X3, R2, R3 and m in formula (V) are as defined in general formula (I);

[0114] R 11 Selected from H, hydroxy, halogen, cyano, amino, or optionally R 21 Mono-, di- or poly-substituted groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkyl acyl, C1-C 10 Alkylsulfonyl, C1-C 10 Alkylsulfinyl, mono(C1-C 10 Alkyl)amino, di(C1-C 10 Alkyl)amino, di(C1-C 10alkyl) aminoacyl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C3-C 10 Cycloalkyl, 5-10 membered heteroaryloxy, 4-10 membered heterocyclyloxy or C3-C 10 Cycloalkyloxy. Wherein the heteroaryl or heterocyclic group contains 1-3 heteroatoms selected from N, O, and S;

[0115] R 21 are the same or different and are independently selected from hydrogen, hydroxy, halogen, cyano, amino, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Hydroxyalkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, mono(C1-C 10 Alkyl)amino, di(C1-C 10 Alkyl)amino, (C1-C 10 Alkyl) aminoacyl, di(C1-C 10 Alkyl) aminoacyl, C1-C 10 Alkylsulfonyl or 5-10 membered heterocyclic group;

[0116] p is an integer selected from 1 to 4, and may be an integer selected from 1, 2, 3, and 4.

[0117] In some embodiments, R 11 Selected from H, hydroxy, halogen, cyano, amino, or optionally R 21 The following groups are monosubstituted, disubstituted or polysubstituted: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylacyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)aminoacyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-C6 cycloalkyl, 5-6 membered heteroaryloxy, 4-6 membered heterocyclyloxy, or C3-C6 cycloalkyloxy, wherein the heteroaryl or heterocyclyl contains 1-2 heteroatoms selected from N, O, and S.

[0118] Preferably, R 11 Selected from R 21The following groups are monosubstituted, disubstituted or polysubstituted: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylacyl, C1-C6 alkylsulfonyl, C1-C6 alkylsulfinyl, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, di(C1-C6 alkyl)aminoacyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, C3-C6 cycloalkyl, 5-6 membered heteroaryloxy, 4-6 membered heterocyclyloxy, or C3-C6 cycloalkyloxy, wherein the heteroaryl or heterocyclyl contains 1-2 heteroatoms selected from N, O, and S.

[0119] As an example, R 11 The 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,

[0120] In some embodiments, R 21 are the same or different and are independently selected from hydrogen, hydroxy, 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.

[0121] Preferably, R 21 are the same or different and are independently selected from hydrogen, hydroxy, 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.

[0122] As an example, R 21 The group is selected from hydrogen, hydroxy, halogen, cyano, amino, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, oxetane, dimethylamino, methylaminoacyl, dimethylaminoacyl, methoxy or methylsulfonyl.

[0123] As an example, the aromatic amine compound of the present application is selected from any one of the compounds shown in Table 1 below:

[0124] Table 1. Aromatic amine compounds

[0125] 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, isotopic derivatives, solvates, stereoisomers, tritiated compounds, and a pharmaceutically acceptable carrier.

[0126] The pharmaceutical composition of the present application can be used to prepare drugs for treating diseases related to YES1 amplification or YES1 overexpression.

[0127] In addition to the active ingredients of the above-mentioned compounds, the pharmaceutical compositions disclosed in the present application may also contain one or more excipients, including fillers, excipients, disintegrants, binders and wetting agents. Depending on the mode of administration, the composition of the present application may contain 10% to 90% by mass of the compound represented by the above formula (I).

[0128] 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., which is not limited in the present application.

[0129] The present application also provides the use of any one of the compounds represented by general formula (I)-(V) or any one of its enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs, isotope derivatives, solvates, stereoisomers, and tritiated compounds in the preparation of drugs for preventing and treating diseases related to YES1 amplification or YES1 overexpression.

[0130] The present application also provides methods for preventing and treating diseases associated with YES1 amplification or YES1 overexpression, for example, by administering a therapeutically effective amount and / or a prophylactically effective amount of a compound represented by formula (I)-(V) or the above-mentioned pharmaceutical composition to a patient in need thereof, thereby preventing and treating diseases associated with YES1 amplification or YES1 overexpression.

[0131] In the present application, the disease associated with YES1 amplification or YES1 overexpression can be selected from cancer, including 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, nerve cancer, head and neck cancer, melanoma, plasmacytoma, endocrine gland tumors, neuroendocrine cancer, brain tumor, bone cancer and sarcoma.

[0132] The present application also provides a method for synthesizing the compounds represented by general formula (I)-(IV), wherein the method is selected from one of the following:

[0133] Option 1:

[0134] wherein the ring Cy, X1, X2, X3, R1, R2, R3, m, and n are as defined in the general formula (I)-(IV); P1 is selected from Cl, Br, I, or trifluoromethanesulfonyl OTf; two R's are the same or different, and any one R' is independently selected from OH, C1-C 10 Alkyl, C1-C 10 Alkoxy or two R' together with the B atom to which it is attached form a 5-6 membered heterocyclic group containing two additional O atoms, the 5-6 membered heterocyclic group is optionally substituted by C1-C 10 The alkyl group may be mono- or poly-substituted.

[0135] Intermediate Z-1 and intermediate Z-2 undergo a 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 a 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. The catalyst is selected from Pd(dppf)Cl2, Pd2(dba)3, Pd(PPh3)4 or Pd(OAc)2; the ligand is selected from triphenylphosphine, tri(o-tolyl)phosphine and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine)BINAP; the base is selected from sodium carbonate, cesium carbonate, potassium carbonate, sodium hydroxide, cesium fluoride, potassium fluoride or potassium phosphate.

[0136] Option 2:

[0137] Wherein, the definitions of ring Cy, X1, X2, X3, R1, R2, R3, m, n, P1, and R' are as described in Scheme 1.

[0138] Intermediate Z-3 and intermediate Z-4 ​​undergo a 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 a Suzuki coupling reaction, for example, in the presence of a metal catalyst such as palladium or nickel, with the optional addition of a ligand or a base to carry out the reaction. The catalyst is selected from Pd(dppf)Cl2, Pd2(dba)3, Pd(PPh3)4, or Pd(OAc)2; the ligand is selected from triphenylphosphine, tri(o-tolyl)phosphine, and BINAP; and the base is selected from sodium carbonate, cesium carbonate, potassium carbonate, sodium hydroxide, cesium fluoride, potassium fluoride, potassium phosphate, and the like.

[0139] The present invention also provides a method for preparing a compound represented by formula (V) or its enantiomers, diastereomers, pharmaceutically acceptable salts, prodrugs, isotopic derivatives, solvates, stereoisomers, and tritiated forms, comprising reacting intermediate V-1 with intermediate V-2 to obtain a compound represented by general formula (V) of the present application:

[0140] Wherein, X1, X2, X3, R2, R3, m, and p are as defined in Formula (V);

[0141] L is a leaving group (eg, halogen). Beneficial effects

[0142] The compounds provided herein can inhibit YES1 protein activity, inhibit the transcription of related genes, and inhibit cell growth by binding to the YES1 protein, thereby being used to treat YES1 protein-related diseases or conditions, such as cancer.

[0143] Preparation Example

[0144] 1. Preparation of intermediates

[0145] Intermediate A1:

[0146] Step 1: Dissolve 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (400 mg) and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (670 mg) in a mixture of 1,4-dioxane and water (10 mL, v / v = 5 / 2) at room temperature. Add Pd(dppf)Cl2 (140 mg) and potassium carbonate (777 mg). After fully displacing nitrogen, heat the mixture to 100°C and stir continuously for 2 hours until the reaction is complete. After completion of the reaction, cool the reaction mixture to room temperature, and add ethyl acetate and water. Stir the mixture thoroughly and separate the layers. Wash the organic phase with water and brine, then dry over anhydrous sodium sulfate. After concentration, the 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] + .

[0147] 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 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 A1 (230 mg) as an off-white solid. LCMS (ES, m / z): 370.7 [M+H] + .

[0148] Intermediate A2:

[0149] Step 1: Dissolve 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) in a mixture of 1,4-dioxane and water (10 mL, v / v = 5 / 2) at room temperature. Add Pd(dppf)Cl2 (140 mg) and potassium carbonate (777 mg). After fully displacing the nitrogen atmosphere, heat the mixture to 100°C and stir continuously for 2 hours until the reaction is complete. After completion of the reaction, cool the reaction mixture to room temperature, and add ethyl acetate and water. Stir the mixture thoroughly and separate the layers. Wash the organic phase with water and brine, then dry over anhydrous sodium sulfate. After concentration, the 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] + .

[0150] Step 2: At room temperature, the intermediate 1 obtained in step 1 (290 mg) was dissolved in glacial acetic acid (10 mL), and NIS (260 mg) was added in batches. After the addition was complete, 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] + .

[0151] Intermediate A3:

[0152] Step 1: At room temperature, add Pd(dppf)Cl2 (1.2 g) to a mixed solution of 7-bromopyrrolo[2,1-F][1,2,4]triazine-4-amine (7 g), bis-pinacol boronate (6.85 g), and potassium carbonate (9.08 g) in 1,4-dioxane and water (120 mL, v / v = 5 / 1). After fully replacing the nitrogen atmosphere with the above mixture, the reaction solution was heated to 80°C and stirred continuously 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 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 (6.8 g). LCMS (ES, m / z): 213.0, 215.0 [M+H] + .

[0153] Step 2: At 0°C, add NBS (5.64 g) to a DMF solution (100 mL) of intermediate 1 (6.8 g) obtained in step 1. The reaction mixture is stirred at 0°C for 3 h until the reaction is complete. After the reaction is complete, the mixture is poured into water and extracted with ethyl acetate. The organic phases are combined. The organic phases are washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by column chromatography to yield intermediate A3 (4.3 g). LCMS (ES, m / z): 293.0, 295.0 [M+H] + .

[0154] Intermediate B1:

[0155] Step 1: To a solution of 2-(4-bromo-2-methoxyphenyl)acetic acid (500 mg) in tert-butanol (5 mL) at room temperature, add Boc anhydride (890 mg) and DMAP (25 mg). The mixture was stirred at room temperature overnight until the reaction was complete. After the reaction was complete, the organic phase was concentrated to obtain a crude product. The crude product was 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] + .

[0156] Step 2: At room temperature, dissolve the intermediate 1 (450 mg) obtained in step 1 and bis(pinacolato) borate (762 mg) in 1,4-dioxane (5 mL), and add potassium acetate (441 mg) and Pd(dppf)Cl2 (164 mg). After fully replacing the nitrogen atmosphere in the mixture, heat to 100°C and continue stirring for 2 hours until the reaction is complete. After the reaction is complete, add ethyl acetate to the above mixture. The mixture is washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product intermediate 2 (900 mg) as a brown solid. The crude product is directly used in the next reaction without purification. LCMS (ES, m / z): 349.0 [M+H] + .

[0157] Step 3: At room temperature, dissolve Intermediate 2 (900 mg) obtained in Step 2 and 7-bromo-5-iodopyrrolo[2.1-F][1.2.4]triazine-4-amine (350 mg) in a mixture of 1,4-dioxane and water (5 mL, v / v = 4 / 1). Add potassium carbonate (425 mg) and Pd(dppf)Cl2 (113 mg). After thoroughly displacing the nitrogen atmosphere, heat the mixture to 80°C and stir continuously for 2 hours. After the reaction is complete, add ethyl acetate. Wash the mixture with water and saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain a crude product. The crude product is 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] + .

[0158] Intermediate B2:

[0159] 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) in portions to the above mixture, and stir the resulting mixture at room temperature overnight until the reaction is complete. After the reaction is complete, add ethyl acetate to the above mixture. Wash the resulting mixture with saturated aqueous sodium bicarbonate solution, then with water and saturated brine. Dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure. The resulting residue is purified by column chromatography to obtain Intermediate 1 (1.52 g) as a white solid.

[0160] Step 2: At room temperature, intermediate 1 (820 mg) obtained in step 1 was dissolved in a mixture of 1,4-dioxane and water (10 mL, v / v = 4 / 1). Tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (845 mg), Pd(dppf)Cl2 (141 mg), and potassium carbonate (836 mg) were added. The mixture was thoroughly purged with nitrogen and heated to 70°C until the reaction was complete. After completion of the reaction, the 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 yield intermediate B2 (1.06 g). LCMS (ES, m / z): 434.0, 436.0 [M+H] + .

[0161] 2. Preparation steps of some aromatic amine compounds in this application

[0162] Example 1:

[0163] Step 1: At room temperature, dissolve 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) in a mixture of 1,4-dioxane and water (3 mL, v / v = 4 / 1). Add potassium carbonate (247 mg) and Pd(PPh3)4 (83 mg). After fully displacing the nitrogen atmosphere, heat the mixture to 90°C and stir continuously for 2 hours until the reaction is complete. Cool the mixture to room temperature, add water and ethyl acetate, stir thoroughly, and separate the layers. Wash the organic phase with water and saturated brine, then dry over anhydrous sodium sulfate. Concentrate the organic phase under reduced pressure to obtain the crude product. Purify the crude product by column chromatography to obtain Intermediate 1 (380 mg). LCMS (ES, m / z): 504.9 [M+H] + .

[0164] Step 2: At room temperature, dissolve the intermediate 1 (130 mg) obtained in step 1 in a mixture of methanol and tetrahydrofuran (2 mL, v / v = 1 / 1). Add tert-butyldimethylsilyl acetaldehyde (67 mg) and acetic acid (10 μL). The mixture is allowed to react at room temperature for 0.5 h, and sodium cyanoborohydride (49 mg) is added. The mixture is allowed to react at room temperature for another 2 h until the reaction is complete. After completion of the reaction, the solvent is removed to obtain a crude product. The crude product is purified by column chromatography to obtain intermediate 2 (80 mg) as a yellow solid. LCMS (ES, m / z): 662.9 [M+H] + .

[0165] Step 3: Dissolve the intermediate 2 (80 mg) obtained in Step 2 in a mixture of tetrahydrofuran and water (2 mL, v / v = 1 / 1) at room temperature and add glacial acetic acid (1.5 mL). The mixture is allowed to react at room temperature overnight until the reaction is complete. After completion of the reaction, the solvent is removed to obtain a crude product. The crude product is purified by column chromatography to obtain Example 1 (18 mg). LCMS (ES, m / z): 549.1 [M+H] + .

[0166] 1 H NMR (400MHz, DMSO-d6) 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).

[0167] Example 2:

[0168] At room temperature, Intermediate A1 (100 mg) was dissolved in a mixture of 1,4-dioxane and water (2.5 mL, v / v = 4 / 1). Tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (141 mg), Pd(PPh3)4 (32 mg), and potassium carbonate (112 mg) were added. After the mixture was fully purged of nitrogen, it was heated to 100°C and the reaction continued for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. The organic phase was washed with water and saturated brine, then dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain Example 2 (30 mg). LCMS (ES, m / z): 466.0 [M+H] + .

[0169] 1 H NMR (400MHz, DMSO-d6) 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).

[0170] Example 3:

[0171] 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(PPh3)4 (32 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. The organic phase was washed with water and saturated brine, then 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 (40 mg). LCMS (ES, m / z): 492.9 [M+H] + .

[0172] 1H NMR (400MHz, DMSO-d6) 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), 7.1 2(d,J=4.0Hz,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).

[0173] Example 4:

[0174] 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). Potassium carbonate (143 mg) and Pd(dppf)Cl2 (25 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 the crude product. The crude product was purified by column chromatography to obtain Example 4 (24 mg). LCMS (ES, m / z): 462.0 [M+H] + .

[0175] 1 H NMR (400MHz, DMSO-d6) 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).

[0176] Example 5:

[0177] 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). Potassium carbonate (143 mg) and Pd(dppf)Cl2 (38 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 the crude product. The crude product was purified by column chromatography to obtain Example 5 (16 mg). LCMS (ES, m / z): 436.0 [M+H] + .

[0178] 1 H NMR(400MHz,DMSO-d6)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).

[0179] Example 6

[0180] 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). Potassium carbonate (143 mg) and Pd(dppf)Cl2 (38 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and the reaction was continued for 2 hours 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 stirred thoroughly before separation. 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 the crude product. The crude product was purified by column chromatography to obtain Example 6 (56 mg). LCMS (ES, m / z): 450.0 [M+H] + .

[0181] 1H NMR (400MHz, DMSO-d6) 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).

[0182] Example 7

[0183] 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). Potassium carbonate (143 mg) and Pd(dppf)Cl2 (38 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 the crude product. The crude product was purified by column chromatography to obtain Example 7 (51 mg). LCMS (ES, m / z): 464.0 [M+H] + .

[0184] 1 H NMR (400MHz, DMSO-d6) 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).

[0185] Example 8

[0186] At room temperature, intermediate B2 (150 mg) and 1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (137 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v / v = 4 / 1). Potassium carbonate (143 mg) and Pd(dppf)Cl2 (38 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 the crude product. The crude product was purified by column chromatography to obtain Example 8 (55 mg). LCMS (ES, m / z): 492.0 [M+H] + .

[0187] 1 H NMR (400MHz, DMSO-d6) 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).

[0188] Example 9

[0189] 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). Potassium carbonate (143 mg) and Pd(dppf)Cl2 (38 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 the crude product. The crude product was purified by column chromatography to obtain Example 9 (70 mg). LCMS (ES, m / z): 506.0 [M+H] + .

[0190] 1H NMR (400MHz, DMSO-d6) 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, 1 H),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).

[0191] Example 10:

[0192] 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). Potassium carbonate (138 mg) and Pd(dppf)Cl2 (25 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 the crude product. The crude product was purified by column chromatography to obtain Example 10 (15 mg). LCMS (ES, m / z): 436.0 [M+H] + .

[0193] 1 H NMR (400MHz, DMSO-d6) 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).

[0194] Example 11

[0195] 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 stirred thoroughly and separated. 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] + .

[0196] Step 2: At room temperature, dissolve the intermediate 1 (190 mg) obtained in step 1 in 1,4-dioxane (4 mL) and add bis-pinacol boronate (465 mg), potassium acetate (270 mg), and Pd(dppf)Cl2 (32 mg). After the nitrogen atmosphere is fully replaced, the mixture is heated to 100°C and the reaction is continued for 2 hours until the reaction is complete. After the reaction is complete, the solvent is removed, ethyl acetate is added, and the mixture is stirred thoroughly before filtering. 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 2 (270 mg) as a light yellow solid. LCMS (ES, m / z): 333.0 [M+H] + .

[0197] Step 3: To a mixture of intermediate 2 (150 mg) obtained in step 2 and intermediate A1 (100 mg) in 1,4-dioxane and water (2.5 mL, v / v = 4 / 1) was added potassium carbonate (78 mg) and Pd(PPh3)4 (44 mg) at room temperature. After the nitrogen atmosphere was fully replaced, the mixture was heated to 80°C and the reaction was continued for 2 hours 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 stirred thoroughly before separation. 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] + .

[0198] 1H NMR (400MHz, DMSO-d6) 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).

[0199] Example 12

[0200] 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 stirred thoroughly and separated. 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] + .

[0201] Step 2: At room temperature, dissolve the intermediate 1 (260 mg) obtained in step 1 in 1,4-dioxane (4 mL), and add bis-pinacol boronate (465 mg), potassium acetate (270 mg), and Pd(dppf)Cl2 (32 mg). After the nitrogen atmosphere is fully replaced, the mixture is heated to 100°C and the reaction is continued for 2 hours until the reaction is complete. After the reaction is complete, the solvent is removed, ethyl acetate is added, and the mixture is stirred thoroughly before filtering. 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 2 (270 mg) as a light yellow solid. LCMS (ES, m / z): 340.2 [M+H] + .

[0202] Step 3: To a mixture of intermediate 2 (150 mg) and intermediate A1 (100 mg) obtained in step 2 in 1,4-dioxane and water (2.5 mL, v / v = 4 / 1) was added potassium carbonate (78 mg) and Pd(PPh3)4 (44 mg) at room temperature. After the nitrogen atmosphere was fully replaced, the mixture was heated to 80°C and the reaction was continued for 2 hours 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 stirred thoroughly before separation. 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 (22 mg). LCMS (ES, m / z): 456.1 [M+H] + .

[0203] 1 H NMR (400MHz, DMSO-d6) 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).

[0204] Example 13

[0205] 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 stirred thoroughly and separated. 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] + .

[0206] Step 2: At room temperature, dissolve the intermediate 1 obtained in step 1 (180 mg) in 1,4-dioxane (4 mL) and add bis-pinacol boronate (340 mg), potassium acetate (180 mg), and Pd(dppf)Cl2 (55 mg). After the nitrogen atmosphere is fully replaced, the mixture is heated to 100°C and the reaction is continued for 2 hours until the reaction is complete. After the reaction is complete, the solvent is removed, ethyl acetate is added, and the mixture is stirred thoroughly before filtering. 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 2 (240 mg) as a light yellow solid. LCMS (ES, m / z): 315.0 [M+H] + .

[0207] Step 3: To a mixture of intermediate 2 (240 mg) obtained in step 2 and intermediate A1 (100 mg) in 1,4-dioxane and water (2.5 mL, v / v = 4 / 1) was added potassium carbonate (78 mg) and Pd(PPh3)4 (44 mg) at room temperature. After the nitrogen atmosphere was fully replaced, the mixture was heated to 80°C and the reaction was continued for 2 hours 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 stirred thoroughly before separation. 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] + .

[0208] 1 H NMR (400MHz, DMSO-d6) 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, 2 H), 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).

[0209] Example 14

[0210] 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 stirred thoroughly and separated. 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] + .

[0211] Step 2: At room temperature, dissolve the intermediate 1 obtained in step 1 (190 mg) in 1,4-dioxane (4 mL) and add bis-pinacol boronate (350 mg), potassium acetate (200 mg), and Pd(dppf)Cl2 (50 mg). After the nitrogen atmosphere is fully replaced, the mixture is heated to 100°C and the reaction is continued for 2 hours until the reaction is complete. After the reaction is complete, the solvent is removed, ethyl acetate is added, and the mixture is stirred thoroughly before filtering. 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 2 (200 mg) as a light yellow solid. LCMS (ES, m / z): 329.0 [M+H] + .

[0212] Step 3: To a mixture of intermediate 2 (200 mg) obtained in step 2 and intermediate A1 (100 mg) in 1,4-dioxane and water (2.5 mL, v / v = 4 / 1) was added potassium carbonate (78 mg) and Pd(PPh3)4 (44 mg) at room temperature. After the nitrogen atmosphere was fully replaced, the mixture was heated to 80°C and the reaction was continued for 2 hours 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 stirred thoroughly before separation. 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] + .

[0213] 1H NMR(400MHz,DMSO-d6)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).

[0214] Example 15

[0215] 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). Potassium carbonate (100 mg) and Pd(dppf)Cl2 (20 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 the crude product. The crude product was purified by column chromatography to obtain Example 15 (20 mg). LCMS (ES, m / z): 450.0 [M+H] + .

[0216] 1 H NMR (400MHz, DMSO-d6) 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=4Hz,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).

[0217] Example 16

[0218] At room temperature, Intermediate B2 (150 mg) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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). Potassium carbonate (138 mg) and Pd(dppf)Cl2 (38 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 (48 mg). LCMS (ES, m / z): 480.0 [M+H] + .

[0219] 1 H NMR (400MHz, DMSO-d6) 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).

[0220] Example 17

[0221] At room temperature, Intermediate B2 (150 mg) and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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). Potassium carbonate (138 mg) and Pd(dppf)Cl2 (38 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 (53 mg). LCMS (ES, m / z): 494.0 [M+H] + .

[0222] 1H NMR(400MHz,DMSO-d6)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,2 H),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).

[0223] Example 18

[0224] 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). Potassium carbonate (238 mg) and Pd(dppf)Cl2 (63 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and stirred for 2 hours until the reaction was complete. After the reaction was complete, ethyl acetate was added to the 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 (88 mg). LCMS (ES, m / z): 435.0 [M+H] + .

[0225] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.01 (s, 1H), 7.80 (d, J = 2.0 Hz, 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).

[0226] Example 19

[0227] At room temperature, intermediate B2 (150 mg) and 1-cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (129 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v / v = 4 / 1). Potassium carbonate (143 mg) and Pd(dppf)Cl2 (38 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 the crude product. The crude product was purified by column chromatography to obtain Example 19 (62 mg). LCMS (ES, m / z): 476.0 [M+H] + .

[0228] 1 H NMR (400MHz, DMSO-d6) 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).

[0229] Example 20

[0230] 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 in an ice-water bath, ethylsulfonyl chloride (770 mg) is added dropwise. After the addition is complete, the mixture is slowly warmed to room temperature and stirred continuously until the reaction is complete. After the reaction is complete, 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] + .

[0231] Step 2: At room temperature, the intermediate 1 (900 mg) obtained in step 1 and bis-pinacol boronate (1.56 g) were dissolved in 1,4-dioxane (10 mL), and potassium acetate (950 mg) and Pd(dppf)Cl2 (336 mg) were added. After the nitrogen atmosphere in the above mixture was fully replaced, 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] + .

[0232] Step 3: To a mixture of Intermediate 2 (1.01 g) obtained in Step 2 and 7-bromo-5-iodopyrrolo[2.1-F][1.2.4]triazine-4-amine (500 mg) in 1,4-dioxane and water (10 mL, v / v = 4 / 1) was added potassium carbonate (1.2 g) and Pd(dppf)Cl2 (320 mg) at room temperature. After fully displacing the mixture with nitrogen, the mixture was heated to 80°C and stirred for 2 h until the reaction was complete. After completion of the reaction, the liquid phases were separated, and the organic phase was concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain Intermediate 3 (690 mg) as a brownish-yellow solid. LCMS (ES, m / z): 426.0, 428.0 [M+H] + .

[0233] Step 4: At room temperature, intermediate 3 (200 mg) obtained in Step 3 and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (168 mg) were dissolved in a mixture of 1,4-dioxane and water (5 mL, v / v = 4 / 1). Potassium carbonate (195 mg) and Pd(dppf)Cl2 (53 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and stirred for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 the crude product. The crude product was purified by column chromatography to obtain Example 20 (100 mg). LCMS (ES, m / z): 458.0 [M+H] + .

[0234] 1H NMR (400MHz, DMSO-d6) 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).

[0235] Example 21

[0236] Step 1: Dissolve N-(4-bromo-2-methoxyphenyl) pivalamide (300 mg) and bis(boronic acid) pinacol ester (514 mg) in 1,4-dioxane (4 mL) at room temperature, then add potassium acetate (310 mg) and Pd(dppf)Cl2 (77 mg). After fully replacing the nitrogen atmosphere in the mixture, heat to 100°C and continue the reaction for 2 hours until the reaction is complete. After the reaction is complete, remove the solvent, add ethyl acetate, stir thoroughly, and filter. Concentrate the filtrate, add n-hexane to the residue, stir thoroughly, and filter. Concentrate the filtrate 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] + .

[0237] Step 2: At room temperature, dissolve Intermediate 1 (260 mg) obtained in Step 1 and 7-bromo-5-iodopyrrolo[2.1-F][1.2.4]triazine-4-amine (200 mg) in a mixture of 1,4-dioxane and water (2.5 mL, v / v = 4 / 1). Add potassium carbonate (250 mg) and Pd(PPh3)4 (140 mg). After fully displacing the nitrogen atmosphere, heat the mixture to 80°C and continue the reaction for 2 hours until the reaction is complete. After completion of the reaction, cool the mixture to room temperature, add water and ethyl acetate, stir thoroughly, and separate the layers. Wash the organic phase with water and saturated brine, then dry over anhydrous sodium sulfate. Concentrate the organic phase under reduced pressure to obtain the crude product. The crude product is purified by column chromatography to obtain Intermediate 2 (230 mg) as a light yellow solid. LCMS (ES, m / z): 414.9 [M+H] + .

[0238] Step 3: At room temperature, intermediate 2 (100 mg) obtained in Step 2 and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (75 mg) were dissolved in a mixture of 1,4-dioxane and water (2.5 mL, v / v = 4 / 1). Potassium carbonate (100 mg) and Pd(dppf)Cl2 (35 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 the crude product. The crude product was purified by column chromatography to obtain Example 21 (14 mg). LCMS (ES, m / z): 420.0 [M+H] + .

[0239] 1 H NMR (400MHz, DMSO-d6) 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).

[0240] Example 22

[0241] 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] + .

[0242] Step 2: At room temperature, dissolve the intermediate 1 (200 mg) obtained in step 1 in 1,4-dioxane (4 mL) and add bis-pinacol boronate (228 mg), potassium acetate (177 mg), and Pd(dppf)Cl2 (44 mg). After the above mixture is fully replaced with nitrogen, heat it to 100°C and continue the reaction for 2 hours until the reaction is complete. After the reaction is complete, remove the solvent, add ethyl acetate, stir thoroughly, and filter. Concentrate the filtrate, add n-hexane to the residue, stir thoroughly, and filter. The filtrate is 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] + .

[0243] Step 3: To a mixture of intermediate 2 (200 mg) obtained in step 2 and intermediate A1 (100 mg) in 1,4-dioxane and water (2.5 mL, v / v = 4 / 1) was added potassium carbonate (78 mg) and Pd(PPh3)4 (44 mg) at room temperature. After the nitrogen atmosphere was fully replaced, the mixture was heated to 80°C and the reaction was continued for 2 hours 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 stirred thoroughly before separation. 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 (30 mg). LCMS (ES, m / z): 499.0 [M+H] + .

[0244] 1 H NMR (400MHz, DMSO-d6) 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).

[0245] Example 23

[0246] 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 stirred thoroughly and separated. 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] + .

[0247] Step 2: At room temperature, dissolve the intermediate 1 (205 mg) obtained in step 1 in 1,4-dioxane (4 mL) and add bis(boronic acid) pinacol ester (228 mg), potassium acetate (177 mg), and Pd(dppf)Cl2 (44 mg). After the nitrogen atmosphere is fully replaced, the mixture is heated to 100°C and the reaction is continued for 2 hours until the reaction is complete. After the reaction is complete, the solvent is removed, ethyl acetate is added, and the mixture is stirred thoroughly before filtering. 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 2 (240 mg) as a light yellow solid. LCMS (ES, m / z): 383.0 [M+H] + .

[0248] Step 3: To a mixture of intermediate 2 (240 mg) obtained in step 2 and intermediate A1 (100 mg) in 1,4-dioxane and water (2.5 mL, v / v = 4 / 1) was added potassium carbonate (78 mg) and Pd(PPh3)4 (44 mg) at room temperature. After the nitrogen atmosphere was fully replaced, the mixture was heated to 80°C and the reaction was continued for 2 hours 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 stirred thoroughly before separation. 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 (14 mg). LCMS (ES, m / z): 499.0 [M+H] + .

[0249] 1H NMR(400MHz,DMSO-d6)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,2 H),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).

[0250] Example 24

[0251] At room temperature, Intermediate B1 (150 mg) and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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). Potassium carbonate (143 mg) and Pd(dppf)Cl2 (38 mg) were added. After the mixture was fully purged of nitrogen, it was heated to 100°C and stirred for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 (50 mg). LCMS (ES, m / z): 465.0 [M+H] + .

[0252] 1 H NMR (400MHz, DMSO-d6) 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).

[0253] Example 25

[0254] 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). Potassium carbonate (138 mg) and Pd(dppf)Cl2 (38 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 the crude product. The crude product was purified by column chromatography to obtain Example 25 (80 mg). LCMS (ES, m / z): 464.0 [M+H] + .

[0255] 1 H NMR (400MHz, DMSO-d6) 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).

[0256] Example 26

[0257] 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). Potassium carbonate (143 mg) and Pd(dppf)Cl2 (38 mg) were added. After the mixture was fully purged of nitrogen, it was heated to 100°C and stirred for 2 hours until the reaction was complete. After the reaction was complete, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 the crude product. The crude product was purified by column chromatography to obtain Example 26 (35 mg). LCMS (ES, m / z): 422.0 [M+H] + .

[0258] 1H NMR (400MHz, DMSO-d6) δ (ppm): 13.05 (s, 1H), 8.27-7.99 (m, 2H), 7.85 (d, J = 8.0Hz, 1H), 7.65 -7.55(m,1H),7.14-7.12(m,2H),7.08(s,1H),7.09-7.03(m,2H),3.87(s,3H),1.48(s,9H).

[0259] Example 27

[0260] 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). Potassium carbonate (143 mg) and Pd(dppf)Cl2 (38 mg) were added. The mixture was thoroughly purged of nitrogen, heated to 100°C, and stirred for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. The organic phase was washed with water and saturated brine, then dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain Example 27 (55 mg). LCMS (ES, m / z): 472.0 [M+H] + .

[0261] 1 H NMR (400MHz, DMSO-d6) 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=64.4Hz,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).

[0262] Example 28

[0263] 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). Potassium carbonate (143 mg) and Pd(dppf)Cl2 (38 mg) were added. After the mixture was fully purged of nitrogen, it was heated to 100°C and stirred for 2 hours until the reaction was complete. After the reaction was complete, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 the crude product. The crude product was purified by column chromatography to obtain Example 28 (10 mg). LCMS (ES, m / z): 422.0 [M+H] + .

[0264] 1 H NMR (400MHz, DMSO-d6) 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).

[0265] Example 29

[0266] Step 1: At room temperature, Ephos Pd G4 (73 mg) was added 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 was fully replaced with nitrogen, the reaction solution was heated to 100°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 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 (50 mg). LCMS (ES, m / z): 269.0, 271.0 [M+H] + .

[0267] Step 2: At room temperature, add Pd(dppf)Cl2 (21 mg) to a 1,4-dioxane solution (5 mL) of intermediate 1 (80 mg), bis(pinacol boronate) (113 mg), and potassium acetate (58 mg) obtained in step 1. After the nitrogen atmosphere is fully replaced with 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 complete, 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 2 (90 mg). LCMS (ES, m / z): 317.1 [M+H] + .

[0268] Step 3: At room temperature, intermediate 2 (86 mg) and intermediate A3 (100 mg) obtained in step 2 were added to a mixed solution of Pd(dppf)Cl2 (24 mg) and potassium carbonate (94 mg) in 1,4-dioxane (5 mL, v / v = 10 / 1). After the nitrogen atmosphere was fully replaced with the above mixture, 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 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 reverse phase preparative chromatography to obtain Example 29 (8.9 mg). LCMS (ES, m / z): 403.0 [M+H] + .

[0269] 1 H NMR (400MHz, CDCl3) 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,1H),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).

[0270] Example 30

[0271] Step 1: At room temperature, diisopropylethylamine (3.18 g) and T3P (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 mixture was stirred at room temperature for 2 hours until the reaction was complete. After the reaction was complete, water was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phases were 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] + .

[0272] Step 2: Add Lawesson's reagent (1.17 g) to a toluene solution (20 mL) of intermediate 1 (1.50 g) obtained in step 1. Heat the 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] + .

[0273] 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, followed by acetic acid (230 mg). The mixture was stirred at room temperature for 16 hours until the reaction was complete. After completion of the reaction, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to yield intermediate 3 (700 mg). LCMS (ES, m / z): 296.0, 298.0 [M+H] + .

[0274] Step 4: Potassium acetate (696 mg) and Pd(dppf)Cl2 (193 mg) were added to a 1,4-dioxane solution (15 mL) of intermediate 3 (700 mg) and bis-pinacol boronate (660 mg) obtained in step 3 at room temperature. After the mixture was fully purged of nitrogen, the reaction mixture was heated to 80°C and stirred for 16 hours until the reaction was complete. After the reaction was completed, the reaction mixture was cooled to room temperature and ethyl acetate was added. 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 4 (500 mg). LCMS (ES, m / z): 344.1 [M+H]+ .

[0275] Step 5: At room temperature, potassium carbonate (242 mg) and Pd(dppf)Cl2 (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 mixture was fully purged of nitrogen, the reaction mixture was heated to 80°C and stirred for 16 hours until the reaction was complete. After completion of the reaction, the reaction mixture was cooled to room temperature and ethyl acetate was added. 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 reverse-phase preparative chromatography to obtain Example 30 (45 mg). LCMS (ES, m / z): 430.3 [M+H] + .

[0276] 1 H NMR (400MHz, CDCl3) δ (ppm): 8.20 (s, 1H), 7.94 (s, 1H), 7.48 (d, J = 2.0Hz, 1H), 7.21-7.17 (m ,3H),7.05-7.03(m,2H),4.18(s,2H),4.00(s,3H),3.89(s,3H),3.47(s,3H),2.46(s,3H).

[0277] Example 31

[0278] Step 1: To a solution of 4-bromo-1-iodo-2-methoxybenzene (2.10 mg) and 5-methyl-1,2-oxazol-3-amine (724 mg) in n-butanol (20 mL) at room temperature, sodium tert-butoxide (1.35 g), t-BuXPhos (285 mg), and Xphos Pd G1 (247 mg) were added. The mixture was heated to 100°C under N2 protection and stirred for 16 hours until the reaction was complete. After completion, the reaction solution was cooled to room temperature, and water and ethyl acetate were added. The mixture was stirred thoroughly, separated, and the filtrate was extracted with ethyl acetate. The organic phases were combined. The organic phases were 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 yield Intermediate 1 (440 mg). LCMS (ES, m / z): 283.0, 285.0 [M+H] + .

[0279] Step 2: At room temperature, add bis-pinacol boronate (161 mg) to a 1,4-dioxane solution (5 mL) of intermediate 1 (120 mg) obtained in step 1, followed by potassium acetate (104 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (172 mg). The mixture was fully purged of nitrogen and heated to 90°C with continuous stirring for 16 hours until the reaction was complete. After completion of the reaction, the reaction solution was cooled to room temperature and ethyl acetate was added. The resulting mixture was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate and the solvent removed. The resulting residue was purified by column chromatography to obtain the product Example 31 compound (50 mg). LCMS (ES, m / z): 331.1 [M+H] + .

[0280] Step 3: At room temperature, intermediate A3 (44 mg) and intermediate 2 (50 mg) obtained in step 2 were dissolved in a mixture of 1,4-dioxane and water (5 mL, v / v = 5 / 1). K2CO3 (42 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (12 mg) were added. The mixture was fully purged of nitrogen and heated to 90°C with continuous stirring for 16 hours until the reaction was complete. After completion of the reaction, the reaction solution was cooled to room temperature and ethyl acetate was added. 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 reverse-phase preparative chromatography to obtain Example 31 (3.4 mg). LCMS (ES, m / z): 417.0 [M+H] + .

[0281] 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).

[0282] Example 32

[0283] 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 at room temperature for 3 hours 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] + .

[0284] 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 reaction mixture was stirred at room temperature for 16 hours 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] + .

[0285] Step 3: At room temperature, the intermediate 2 (100 mg) obtained in step 2 and the bis-pinacol boronate (134 mg) were dissolved in a 1,4-dioxane solution (5 mL), and Pd(dppf)Cl2 (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 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 (100 mg). LCMS (ES, m / z): 330.2 [M+H] + .

[0286] Step 4: At room temperature, add Pd(dppf)Cl2 (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 fully replacing the nitrogen atmosphere with the above mixture, 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 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 reverse phase preparative chromatography to obtain Example 32 (30 mg). LCMS (ES, m / z): 415.9 [M+H] + .

[0287] 1 H NMR (400MHz, CD3OD-d4) 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,1H),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).

[0288] Example 33

[0289] Step 1: At 0°C, sodium hydride (81 mg, 60%) was added portionwise to a solution of intermediate 1 (190 mg) obtained in step 1 of Example 31 in anhydrous tetrahydrofuran (5 mL). After the addition was complete, the reaction solution was warmed to room temperature and stirred for 30 minutes, followed by the addition of iodomethane (143 mg). The reaction solution was stirred at room temperature for 2 hours until the reaction was complete. After completion of the reaction, 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 phases were 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] + .

[0290] Step 2: At room temperature, add bis-pinacol boronate (427 mg) to a 1,4-dioxane solution (5 mL) of Intermediate 1 (200 mg) obtained in Step 1. Potassium acetate (165 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (273 mg) are also added. The mixture is heated to 90°C under nitrogen and stirred for 16 hours until the reaction is complete. After completion, the reaction solution is concentrated under reduced pressure. The resulting residue is purified by column chromatography to yield Intermediate 2 (200 mg). LCMS (ES, m / z): 345.1 [M+H] + .

[0291] Step 3: 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) at room temperature, add K2CO3 (96 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (28 mg). After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and stirred for 16 hours until the reaction was complete. After completion of the reaction, the reaction solution was cooled to room temperature and ethyl acetate was added. The resulting mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by reverse-phase preparative chromatography to yield Example 33 (17.5 mg). LCMS (ES, m / z): 431.3 [M+H] + .

[0292] 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).

[0293] Example 34

[0294] Step 1: At room temperature, 4-bromo-2-methoxyaniline (600 mg), cyclopropylacetic acid (466 mg), and TEA (601 mg) were dissolved in DMF (6 mL) and HATU (1.70 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): 270.0, 272.0 [M+H] + .

[0295] Step 2: At room temperature, add bis-pinacol boronate (940 mg) to a 1,4-dioxane solution (5 mL) of Intermediate 1 (500 mg) obtained in Step 1. Potassium acetate (454 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (75 mg) are then added. The mixture is heated to 90°C under a nitrogen atmosphere and stirred for 16 hours until the reaction is complete. After completion, the reaction solution is concentrated under reduced pressure, and the resulting residue is purified by column chromatography to yield Intermediate 2 (600 mg). LCMS (ES, m / z): 318.1 [M+H] + .

[0296] Step 3: Potassium carbonate (96 mg) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (28 mg) were added to a mixture of Intermediate A3 (102 mg) and Intermediate 2 (120 mg) obtained in Step 2 in 1,4-dioxane and water (5 mL, v / v = 10 / 1) at room temperature. The mixture was heated to 100°C under a nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After completion, the reaction solution was cooled to room temperature and water was added. The resulting mixture was extracted with ethyl acetate, and the organic phases were combined. The resulting organic phases were 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 reverse-phase preparative chromatography to yield Example 34 (13.9 mg). LCMS (ES, m / z): 404.2 [M+H] + .

[0297] 1HNMR (400MHz, CD3OD) 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=1.6Hz,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).

[0298] Example 35

[0299] Step 1: At room temperature, dissolve 4-bromo-2-methoxyaniline (600 mg), cyclopropylacetic acid (446 mg), and triethylamine (601 mg) in DMF (6 mL), and add HATU (1.69 g). The reaction solution was stirred at room temperature for 4 hours 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] + .

[0300] Step 2: At room temperature, add bis-pinacol boronate (894 mg) to a 1,4-dioxane solution (5 mL) of Intermediate 1 (500 mg) obtained in Step 1. Potassium acetate (432 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (71 mg) are then added. The mixture is heated to 90°C under a nitrogen atmosphere and stirred for 16 hours until the reaction is complete. After completion, the reaction solution is concentrated under reduced pressure, and the resulting residue is purified by column chromatography to yield Intermediate 2 (600 mg). LCMS (ES, m / z): 332.1 [M+H] + .

[0301] Step 3: Potassium carbonate (42 mg) and 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (12 mg) were added to a mixture of Intermediate A3 (44 mg) and Intermediate 2 (50 mg) obtained in Step 2 in 1,4-dioxane and water (5 mL, v / v = 10 / 1) at room temperature. The mixture was heated to 100°C under a nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After completion, the reaction solution was cooled to room temperature and water was added. The resulting mixture was extracted with ethyl acetate, and the organic phases were combined. The resulting organic phases were 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 reverse-phase preparative chromatography to yield Example 35 (28.5 mg). LCMS (ES, m / z): 418.3 [M+H] + .

[0302] 1 HNMR(400MHz,CD3OD)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,2H),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).

[0303] Example 36

[0304] Step 1: Add ethanediothiocyanate (720 mg) to an acetonitrile solution (20 mL) of 4-bromo-2-methoxyaniline (1800 mg) at room temperature. Stir the reaction mixture at room temperature for 16 hours until the reaction is complete. After completion of the reaction, add dichloromethane and water to the reaction mixture. Stir the mixture and separate the liquids. Wash the organic phase with water and saturated brine and dry it over anhydrous sodium sulfate. Concentrate the organic phase under reduced pressure, and purify the resulting residue by column chromatography to obtain the product intermediate 1 (2.0 g). LCMS (ES, m / z): 275.0, 277.0 [M+H] + .

[0305] 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 hours until the reaction is complete. After the reaction is complete, 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 over 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] + .

[0306] Step 3: At room temperature, add acetic acid hydrazide (169 mg) to a 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 hours until the reaction is complete. After the reaction is complete, add ethyl acetate and water to the reaction solution. After the above mixture is thoroughly stirred, separate the liquids, wash the organic phase with water and saturated brine, and dry it over 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] + .

[0307] Step 4: Potassium acetate (99 mg) and Pd(dppf)Cl2 (27 mg) were added to a 1,4-dioxane solution (10 mL) of intermediate 3 (100 mg) and bis-pinacol boronate (97.0 mg) obtained in step 3 at room temperature. The mixture was fully purged of nitrogen and heated to 90 degrees Celsius with continuous stirring for 16 hours until the reaction was complete. After completion of the reaction, the reaction solution was cooled to room temperature and ethyl acetate was added. 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 4 (80 mg). LCMS (ES, m / z): 345.1 [M+H] + .

[0308] Step 5: Potassium carbonate (96 mg) and Pd(dppf)Cl2 (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 mixture was thoroughly purged of nitrogen and heated to 100°C with continuous stirring for 16 hours until the reaction was complete. After completion of the reaction, the reaction solution was cooled to room temperature and ethyl acetate was added. The resulting mixture was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate and the solvent removed. The resulting residue was purified by column chromatography to yield Example 36 (4 mg). LCMS (ES, m / z): 431.1 [M+H]+ .

[0309] 1 H NMR (400MHz, CDCl3) 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).

[0310] Example 37

[0311] Step 1: 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) at 0°C. After the addition was complete, the reaction solution was slowly warmed to room temperature and stirred for 3 hours until the reaction was complete. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to yield Intermediate 1 (2.10 g). LCMS (ES, m / z): 367.0, 369.0 [M+H] + .

[0312] Step 2: Diisopropylethylamine (317 mg) and oxolane-3-ol (144 mg) were added to an acetonitrile solution (7.0 mL) of Intermediate 1 (300 mg) obtained in Step 1 at room temperature. The mixture was stirred at 80°C for 1 hour until the reaction was complete. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to yield Intermediate 2 (270 mg). LCMS (ES, m / z): 316.0, 318.0 [M+H] + .

[0313] Step 3: At room temperature, potassium acetate (228 mg) and Pd(dppf)Cl2 (63 mg) were slowly added to a 1,4-dioxane solution (10 mL) of intermediate 2 (216 mg) and bis-pinacol boronate (245 mg) obtained in step 2. The mixture was heated to 90°C under a nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield intermediate 3 (115 mg). LCMS (ES, m / z): 364.3 [M+H] + .

[0314] Step 4: At room temperature, potassium carbonate (97.0 mg) and Pd(dppf)Cl2 (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 mixture was heated to 90°C under a nitrogen atmosphere and stirred continuously for 16 hours until the reaction was complete. After the reaction was complete, the reaction solution was cooled to room temperature and ethyl acetate was added. The resulting mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under pressure. The resulting residue was purified by reverse-phase preparative chromatography to obtain Example 37 (21.0 mg). LCMS (ES, m / z): 450.0 [M+H] + .

[0315] 1 H NMR (400MHz, DMSO-d6) 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).

[0316] Example 38

[0317] Step 1: Add oxetane-3-ol (121 mg) and diisopropylethylamine (317 mg) to an acetonitrile solution (5.0 mL) of Intermediate 1 (300 mg) obtained in Step 1 of Example 37 at room temperature. The mixture was stirred at 80°C for 1 hour until the reaction was complete. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford Intermediate 1 (250 mg). LCMS (ES, m / z): 302.0, 304.0 [M+H] + .

[0318] Step 2: At room temperature, potassium acetate (244 mg) and Pd(dppf)Cl2 (67.6 mg) were slowly added to a 1,4-dioxane solution (10 mL) of intermediate 1 (250 mg) and bis-pinacol boronate (231 mg) obtained in step 1. The mixture was heated to 90°C under a nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After the reaction was complete, the reaction solution was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield intermediate 2 (200 mg). LCMS (ES, m / z): 350.1 [M+H]+ .

[0319] Step 3: At room temperature, potassium carbonate (262 mg) and Pd(dppf)Cl2 (51.6 mg) were slowly added in batches to a mixed solution of intermediate 2 (200 mg) and intermediate A3 (185 mg) obtained in step 2 in 1,4-dioxane and water (10 mL, v / v = 10 / 1). The mixture was heated to 90°C under a nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After completion, the reaction solution was cooled to room temperature and ethyl acetate was added. The resulting mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative chromatography to yield Example 38 (32.6 mg). LCMS (ES, m / z): 436.0 [M+H] + .

[0320] 1 H NMR (400MHz, CDCl3) 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, 1 H), 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).

[0321] Example 39

[0322] Step 1: At 0°C, NaN3 (1.4 g) was added portionwise to a 1-chloro-2-propanone (1 g) acetone solution (10 mL). 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 complete, 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).

[0323] Step 2: At room temperature, 4-bromo-2-methoxyaniline (500 mg) was added to a mixed solution of saturated aqueous ammonium bicarbonate solution (5 mL) and dichloromethane (5 mL). After thorough stirring, thiophosgene (569 mg) was added dropwise. After the addition was complete, the reaction solution was stirred at 25 degrees for 16 hours until the reaction was complete. After the reaction was complete, dichloromethane and water were added to the reaction solution. After the above mixture was thoroughly 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 to obtain intermediate 2 (400 mg).

[0324] 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 mixture was stirred at 25 degrees for 16 hours until the reaction was complete. After the reaction was complete, dichloromethane and water were added to the reaction solution. The mixture was thoroughly 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, and the resulting residue was purified by column chromatography to obtain intermediate 3 (200 mg). LCMS (ES, m / z): 282.8, 284.8 M+H] + .

[0325] Step 4: At room temperature, Pd(dppf)Cl2 (25 mg) was added to a 1,4-dioxane solution (5 mL) of intermediate 3 (100 mg) obtained in step 3, bis-pinacol boronate (134 mg), and potassium acetate (69 mg). After the nitrogen atmosphere was fully replaced with the above mixture, 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 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 intermediate 4 (70 mg). LCMS (ES, m / z): 330.9 [M+H] + .

[0326] Step 5: At room temperature, add Pd(dppf)Cl2 (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 fully replacing the nitrogen atmosphere with the above mixture, the reaction solution was heated to 100°C and stirred continuously 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 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 organic phase was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase preparative chromatography to obtain the compound (2 mg). LCMS (ES, m / z): 416.9 [M+H] + .

[0327] 1H NMR (400MHz, CDCl3) 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).

[0328] Example 40

[0329] 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 mixture to 80°C and continue stirring for 4 hours until the reaction is complete. After completion, the reaction mixture is concentrated under reduced pressure, and ethyl acetate is added to the residue. After thorough stirring, the mixture is filtered, and the filtrate is concentrated to obtain crude intermediate 1 (3.80 g, purity: 88%). LCMS (ES, m / z): 259.0, 261.0 [M+H] + .

[0330] Step 2: At room temperature, dissolve acetic anhydride (1.5 g) in pyridine (10 mL). Add the resulting solution dropwise to a pyridine solution (30 mL) of intermediate 1 (3.80 g) obtained in step 1, pre-cooled to 0°C. After the addition is complete, heat the reaction mixture to 120°C and continue stirring for 4 hours until the reaction is complete. After the reaction is complete, cool the reaction mixture to room temperature and add water. Extract the resulting mixture with ethyl acetate, and combine the organic phases. Wash the organic phases with 10% aqueous ammonium chloride solution, water, and saturated brine. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the resulting residue by column chromatography to yield intermediate 2 (1.80 g). LCMS (ES, m / z): 282.8, 284.8 [M+H] + .

[0331] Step 3: At room temperature, add bis-pinacol boronate (359 mg) to a solution of intermediate 2 (200 mg) obtained in step 2 in 1,4-dioxane (3 mL). Potassium acetate (173 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (286 mg) are added. The mixture is heated to 90°C under a nitrogen atmosphere and stirred for 16 hours until the reaction is complete. After completion of the reaction, the reaction mixture is concentrated under reduced pressure, and the resulting residue is purified by column chromatography to yield intermediate 3 (80 mg). LCMS (ES, m / z): 331.0 [M+H] + .

[0332] Step 4: At room temperature, add Intermediate A3 (71 mg) to a mixed solution of Intermediate 3 (80 mg) obtained in Step 3 in 1,4-dioxane and water (3 mL, v / v = 10 / 1). Potassium carbonate (67 mg) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (19 mg) were added. The mixture was heated to 90°C under a nitrogen atmosphere and stirred continuously for 16 hours until the reaction was complete. After completion, the reaction solution was cooled to room temperature and water and ethyl acetate were added. The mixture was thoroughly stirred and separated. The aqueous phase 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 reverse-phase preparative chromatography to yield Example 40 (3.5 mg). LCMS (ES, m / z): 417.3 [M+H] + .

[0333] 1 HNMR (400MHz, CDCl3) 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).

[0334] Example 41

[0335] Step 1: At 0°C, 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 mixture is slowly warmed to room temperature and stirred for 2 hours until the reaction is complete. After completion, the reaction mixture is concentrated under reduced pressure, and the resulting residue is purified by column chromatography to yield Intermediate 1 (150 mg). LCMS (ES, m / z): 336.1, 338.1 [M+Na] + .

[0336] Step 2: Potassium acetate (46.8 mg) and Pd(dppf)Cl2 (13.0 mg) were added to a 1,4-dioxane solution (5.0 mL) of Intermediate 1 (50.0 mg) and bis(pinacol)boronic acid ester (44.4 mg) at room temperature. The mixture was heated to 90°C under a nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield Intermediate 2 (57 mg). LCMS (ES, m / z): 362.1 [M+H]+ .

[0337] Step 3: At room temperature, potassium carbonate (65.4 mg) and Pd(dppf)Cl2 (12.9 mg) were slowly added to a mixed solution of Intermediate 2 (57.0 mg) and Intermediate A3 (46.3 mg) obtained in Step 2 in 1,4-dioxane and water (11 mL, v / v = 10 / 1). The mixture was heated to 90°C under a nitrogen atmosphere and stirred for 16 hours until the reaction was complete. After completion, the reaction 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 concentrated under reduced pressure. The residue was purified using a preparative thin-layer plate to yield Example 41 (13.6 mg). LCMS (ES, m / z): 448.0 [M+H] + .

[0338] 1 H NMR (400MHz, CDCl3) 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,3 H),3.91(s,3H),1.95-1.88(m,2H),1.81-1.73(m,4H),1.69-1.63(m,2H).

[0339] Example 42

[0340] 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). Potassium carbonate (138 mg) and Pd(dppf)Cl2 (25 mg) were added. After the nitrogen atmosphere was fully replaced, the mixture was heated to 100°C and the reaction was continued for 2 hours until the reaction was complete. After completion of the reaction, the mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was stirred thoroughly before separation. 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 the crude product. The crude product was purified by column chromatography to obtain Example 42 (8 mg). LCMS (ES, m / z): 480.0 [M+H] + .

[0341] 1 H NMR (400MHz, DMSO-d6) 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).

[0342] Example 43

[0343] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0344] 1 H NMR (400MHz, DMSO-d6) 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),4.38-4.36(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).

[0345] Example 44

[0346] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0347] 1 H NMR (400MHz, DMSO-d6) 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).

[0348] Example 45

[0349] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0350] 1 H NMR (400MHz, DMSO-d6) 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).

[0351] Example 46

[0352] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0353] 1H NMR (400MHz, DMSO-d6) 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).

[0354] Example 47

[0355] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0356] 1 H NMR (400MHz, DMSO-d6) 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).

[0357] Example 48

[0358] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 1-methyl-1H-pyrazole-5-boronic acid pinacol ester to obtain the title compound. LCMS (ES, m / z): 436.2 [M+H] + .

[0359] 1H NMR (400MHz, DMSO-d6) 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).

[0360] Example 49

[0361] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was 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] + .

[0362] 1 H NMR (400MHz, DMSO-d6) 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).

[0363] Example 50

[0364] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was 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] + .

[0365] 1H NMR (400MHz, DMSO-d6) 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).

[0366] Example 51

[0367] The synthesis method is similar to that of Example 11, except that the intermediate 4-fluoropyrazole is replaced with 3-methylpyrazole to obtain the title compound. LCMS (ES, m / z): 445.2 [M+H] + .

[0368] 1 H NMR (400MHz, DMSO-d6) 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), 6.9 5(d,J=8.0Hz,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).

[0369] Example 52

[0370] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0371] 1H NMR (400MHz, DMSO-d6) 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 = 2.0 Hz,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).

[0372] Example 53

[0373] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was 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] + .

[0374] 1 H NMR (400MHz, DMSO-d6) 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).

[0375] Example 54

[0376] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with cyclopropylboronic acid to obtain the title compound. LCMS (ES, m / z): 396.2 [M+H] + .

[0377] Example 55

[0378] The synthesis method was similar to that of Example 11, except that the intermediate used in Step 2 of Example 11 was replaced with 1-(benzyloxy)-4-bromo-2-methoxybenzene, and Intermediate A1 in Step 3 of Example 11 was replaced with Intermediate A3 to obtain the title compound. LCMS (ES, m / z): 426.9 [M+H] + .

[0379] 1 H NMR(400MHz,DMSO-d6)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).

[0380] Example 67

[0381] Step 1: At room temperature, the intermediate 3 (200 mg) obtained in step 3 of the preparation method of Example 36 was dissolved in DMF (2 mL) and iodomethane (115 mg) was added. After the above mixture was cooled to 0°C, sodium hydride (40 mg) was added in batches. The above mixture was slowly warmed to room temperature and continued to stir for 2 hours until the reaction was complete. After the reaction was completed, the reaction was quenched with 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, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by column chromatography to obtain the title compound (140 mg).

[0382] Step 2: Dissolve the product from Step 1 (140 mg) in 1,4-dioxane (2 mL) at room temperature. Add bis-pinacol boronate (138 mg), potassium acetate (111 mg), and Pd(dppf)Cl2 (33 mg). After thoroughly displacing the nitrogen atmosphere, stir the mixture at 80°C for 2 hours until the reaction is complete. After completion, filter the mixture, and concentrate the filtrate under reduced pressure. The residue is purified by column chromatography to yield the title compound (60 mg).

[0383] Step 3: Dissolve the product (60 mg) obtained in step 2 and intermediate A3 (45 mg) in a mixed solution of 1,4-dioxane and water (2 mL, v / v = 5 / 1) at room temperature, and add potassium carbonate (55 mg) and Pd(dppf)Cl2 (11 mg). After fully replacing the nitrogen atmosphere, the mixture is heated to 90 degrees Celsius and stirred for 2 hours until the reaction is complete. After the reaction is complete, ethyl acetate is added to the mixture, and the 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 the title compound (6 mg). LCMS (ES, m / z): 445.1 [M+H] + .

[0384] 1 H NMR(400MHz,DMSO-d6)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).

[0385] Example 86

[0386] The synthesis method is similar to that of Example 38, except that oxetan-3-ol is replaced with cyclobutanol to obtain the title compound. LCMS (ES, m / z): 434.1 [M+H] + .

[0387] 1 H NMR (400MHz, DMSO-d6) 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).

[0388] Example 89

[0389] The synthesis method was similar to that of Example 29, except that Intermediate 2 used in Step 3 of Example 29 was replaced with tert-butyl (7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d][1,3]dioxolan-4-yl)carbamate to obtain the title compound. LCMS (ES, m / z): 450.2 [M+H] + .

[0390] 1 H NMR(400MHz,DMSO-d6)δ(ppm):7.99(s,1H),7.62-7.60(m,1H),7.45(s,1H),7.23(s,1H),7.1 5(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).

[0391] Example 102

[0392] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0393] 1 H NMR (400MHz, CDCl3) 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).

[0394] Example 113

[0395] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0396] 1 H NMR (400MHz, CDCl3) 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).

[0397] Example 114

[0398] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0399] 1 H NMR (400MHz, CDCl3) 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).

[0400] Example 116

[0401] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0402] 1 H NMR (400MHz, DMSO-d6) 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).

[0403] Example 117

[0404] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0405] 1 H NMR (400MHz, DMSO-d6) 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).

[0406] Example 118

[0407] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0408] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.40 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.85 (d, J = 8.0 Hz,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).

[0409] Example 119

[0410] Step 1: At -78°C, n-butyl lithium (0.5 ml, 2.5 M) was added dropwise to a solution of 5,7-dibromo-4-methoxypyrrolo[2,1-f][1,2,4]triazine (305 mg) in anhydrous tetrahydrofuran (6 ml). The mixture was stirred at -78°C for 30 minutes, and then oxetane-3-one (86 mg) was added dropwise. After the addition was complete, the mixture was slowly warmed to 0°C and stirred for 30 minutes until the reaction was complete. After the reaction was complete, saturated ammonium chloride solution was added to the mixture to quench the reaction. Ethyl acetate and water were added to the mixture, stirred thoroughly, and the layers were separated. 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] + .

[0411] Step 2: Dissolve the product obtained in Step 1 (160 mg) in DMF (2 mL) and add aqueous ammonia (2 mL, 30%). Stir the mixture at 80°C for 2 hours until the reaction is complete. After the reaction is complete, transfer the mixture to ice water, stir thoroughly, and filter. Wash the filter cake with a small amount of water. The resulting solid is dried under vacuum to obtain the target compound as a crude product (100 mg). LCMS (ES, m / z): 284.7 [M+H] + .

[0412] Step 3: Dissolve 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) in a mixture of 1,4-dioxane / water (2.5 mL, v / v = 4 / 1) at room temperature. Add potassium carbonate (145 mg) and Pd(PPh3)4 (40 mg). After fully displacing the nitrogen atmosphere, heat the mixture to 100°C and continue the reaction for 1 hour until the reaction is complete. After completion of the reaction, separate the liquids, and concentrate the organic phase under reduced pressure to obtain the crude product. The crude product is purified by column chromatography to obtain the title compound (6 mg). LCMS (ES, m / z): 427.9 [M+H] + .

[0413] 1 H NMR (400MHz, DMSO-d6) 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), 7.0 1-6.99(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).

[0414] Example 120

[0415] The synthesis method is similar to that of Example 119, except that the intermediate oxetane-3-one is replaced with dihydro-3(2H)-furanone to obtain the title compound. LCMS (ES, m / z): 441.8 [M+H] + .

[0416] Example 121

[0417] The synthesis method is similar to that of Example 119, except that the intermediate oxetane-3-one is replaced with N-methyl-4-piperidone to obtain the title compound. LCMS (ES, m / z): 468.9 [M+H] + .

[0418] 1H NMR (400MHz, DMSO-d6) 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).

[0419] Example 122

[0420] Step 1: At room temperature, cyclopropanecarboxylic acid (860 mg) was dissolved in dichloromethane (20 mL) and triethylamine (1.01 g) was added. CDI (1.62 g) was then added in batches. The above mixture was stirred at room temperature for 30 minutes, and (3-chloropyrazin-2-yl)methylamine hydrochloride (1.80 g) was added in batches. The above mixture was stirred at room temperature for 2 hours until the reaction was complete. After the reaction was completed, water and dichloromethane were added to the above mixture, stirred thoroughly and separated. The aqueous phase was extracted three times with dichloromethane, 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 compound (1.21 g).

[0421] 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). The above mixture is stirred 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. 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 (0.88 g).

[0422] Step 3: Dissolve the product obtained in Step 2 (0.85 g) in acetonitrile (10 mL) and add NBS (0.78 g) in portions. Stir the mixture at room temperature for 3 hours until the reaction is complete. After the reaction is complete, transfer the mixture to ice water. Extract the mixture three times with ethyl acetate, and combine the organic phases. Wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, and remove the solvent. The residue is purified by column chromatography to obtain the title compound (0.72 g).

[0423] Step 4: Dissolve the product obtained in Step 3 (0.71 g) in isopropanol (5 mL) at room temperature and add aqueous ammonia (2 mL, 30%). Stir the mixture at 90°C overnight until the reaction is complete. After completion of the reaction, remove the solvent and purify the residue by column chromatography to yield the title compound (0.56 g).

[0424] Step 5: Dissolve 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) in a mixture of 1,4-dioxane and water (3 mL, v / v = 5 / 1) at room temperature. Add potassium carbonate (137 mg) and Pd(dppf)Cl2 (29 mg). After fully displacing nitrogen, the mixture was heated to 100°C and stirred for 2 hours until the reaction was complete. After completion of the reaction, 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] + .

[0425] 1 H NMR (400MHz, DMSO-d6) 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).

[0426] Example 123

[0427] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 1-fluorocyclopropanecarboxylic acid to obtain the title compound. LCMS (ES, m / z): 414.2 [M+H] + .

[0428] 1H NMR (400MHz, DMSO-d6) 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).

[0429] Example 124

[0430] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 1-methylpyrazole-3-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 436.1 [M+H] + .

[0431] 1 H NMR(400MHz, DMSO-d6)δ(ppm):8.55(d,J=4.8Hz,1H),8.02(s,1H),7.88-7.82(m,2H),7.25(d,J=2.0H z,1H),7.22-7.13(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).

[0432] Example 125

[0433] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 1-methylpyrazole-4-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 436.1 [M+H] + .

[0434] 1 H NMR (400MHz, DMSO-d6) 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,1H),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).

[0435] Example 126

[0436] Step 1: Dissolve 5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-amine (500 mg) in acetonitrile (5 mL) at room temperature. Add pinacol diboron (920 mg), tert-butyl nitrite (510 mg), and benzoyl peroxide (80 mg). Incubate the mixture at 80°C for 2 hours until complete. After completion, remove the solvent. The residue is purified by column chromatography to yield the title compound (220 mg).

[0437] Step 2: Dissolve the product (100 mg) obtained in Step 1 and Intermediate B2 (198 mg) in a mixture of 1,4-dioxane and water (3 mL, v / v = 5 / 1) at room temperature. Add potassium carbonate (132 mg) and Pd(dppf)Cl2 (28 mg). After fully displacing the nitrogen atmosphere, heat the mixture to 100°C and continue stirring for 2 hours until the reaction is complete. After completion of the reaction, separate the liquids and concentrate the organic phase. The residue is purified by column chromatography to yield the title compound (18 mg). LCMS (ES, m / z): 491.2 [M+H] + .

[0438] Example 127

[0439] Compound Example 121 (20 mg) was dissolved in dichloromethane (0.5 mL) at room temperature, and trimethyloxonium tetrafluoroborate (10 mg) was added. The mixture was stirred at room temperature for 2 hours until the reaction was complete. After the reaction was complete, the solvent was removed and the residue was purified on a preparative plate to obtain the title compound (6 mg). LCMS (ES, m / z): 469.9 [M+H] + .

[0440] 1 H NMR (400MHz, DMSO-d6) 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).

[0441] Example 128

[0442] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was 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] + .

[0443] 1 H NMR(400MHz,DMSO-d6)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).

[0444] Example 129

[0445] 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). Cool the mixture to 0°C and add sodium hydride (3.0 g) in portions. Stir the mixture at room temperature until the reaction is complete. After the reaction is complete, transfer the mixture to ice water, stir thoroughly, and filter. Wash the filter cake with ice water until the filtrate is neutral. Dry the filter cake in vacuo to obtain the target compound (15.6 g).

[0446] Step 2: At room temperature, the product obtained in step 1 (5.3 g) was dissolved in DMF (50 mL), and allyltributyltin (4.5 g), tetrakistriphenylphosphine palladium (1.2 g) and lithium chloride (0.4 g) were added. After the nitrogen was fully replaced, the mixture was heated to 100 degrees Celsius and stirred overnight until the reaction was complete. After the reaction was completed, the mixture was quenched with ice water. The resulting mixture 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 target compound (3.6 g).

[0447] Step 3: Dissolve the product obtained in step 2 (3.5 g) in 1,4-dioxane (50 mL) at room temperature, and add potassium osmate dihydrate (115 mg), NMO (2.8 g), and water (3 mL). Stir the mixture at room temperature overnight until the reaction is complete. After the reaction is complete, add ethyl acetate to the mixture. Wash the mixture with water and saturated brine, dry it over anhydrous ammonium sulfate, and remove the solvent. Dissolve the residue in 1,4-dioxane (30 mL) and add sodium periodate (2.1 g). Stir the mixture at room temperature overnight until the reaction is complete. After the reaction is complete, add water and ethyl acetate to the mixture, stir thoroughly, and separate the layers. Extract the aqueous phase three times with ethyl acetate, and combine the organic phases. Wash the organic phase with water and saturated brine, dry it over anhydrous sodium sulfate, and remove the solvent. Purify the residue by column chromatography to obtain the target compound (1.77 g).

[0448] 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, dried over anhydrous sodium sulfate, and the solvent is removed. The residue is purified by column chromatography to obtain the target compound (210 mg).

[0449] 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. 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, dried over anhydrous sodium sulfate, and the solvent is removed. The residue is purified by column chromatography to obtain the target compound (120 mg).

[0450] Step 6: Dissolve the product from 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 completion, remove the solvent under reduced pressure, and purify the residue by column chromatography to yield the title compound (105 mg).

[0451] Step 7: Dissolve 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) in a mixture of 1,4-dioxane and water (2 mL, v / v = 5 / 1) at room temperature. Add potassium carbonate (120 mg) and Pd(PPh3)4 (33 mg). After fully replacing the nitrogen atmosphere in the mixture, stir at 100°C for 2 hours until the reaction is complete. Add water and ethyl acetate to the mixture, stir thoroughly, and separate the layers. 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. Purify the residue by column chromatography to obtain the title compound (36 mg). LCMS (ES, m / z): 510.0 [M+H] + .

[0452] 1 H NMR(400MHz,DMSO-d6)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).

[0453] Example 130

[0454] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 3-dimethylaminopropionic acid hydrochloride to obtain the title compound. LCMS (ES, m / z): 427.2 [M+H] + .

[0455] 1H NMR (400MHz, DMSO-d6) 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).

[0456] Example 131

[0457] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with methanesulfonylacetic acid to obtain the title compound. LCMS (ES, m / z): 448.2 [M+H] + .

[0458] 1 H NMR (400MHz, DMSO-d6) 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).

[0459] Example 132

[0460] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 4-(4-methylpiperazin-1-yl)butyric acid hydrochloride to obtain the title compound. LCMS (ES, m / z): 496.3 [M+H] + .

[0461] 1H NMR (400MHz, DMSO-d6) 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).

[0462] Example 133

[0463] Step 1: At room temperature, (3-chloropyrazin-2-yl)methylamine hydrochloride (720 mg) and 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (860 mg) were dissolved in acetonitrile (8 mL), and pyridine (2 g) was added to the reaction solution. The mixture was cooled to 0°C, and phosphorus oxychloride (1.52 g) was slowly added dropwise to the reaction system. After the reaction naturally cooled to room temperature, stirring was continued for 1 hour. After the reaction was complete, the system was poured into water, 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 concentrated. The residue was purified by column chromatography to obtain the target compound (400 mg) as a yellow oil.

[0464] Step 2: Dissolve the product obtained in Step 1 (400 mg) in acetonitrile (10 mL) at room temperature. Cool the mixture to 0°C and add N-bromosuccinimide (418 mg). Allow the mixture to react at room temperature for 2 hours until the starting materials are completely reacted. After the reaction is complete, dilute the reaction solution with ethyl acetate. Wash the organic phase with saturated aqueous sodium bicarbonate solution, then saturated brine, dry over anhydrous sodium sulfate, and concentrate. Purify the residue by column chromatography to obtain the target compound (300 mg) as a yellow oil.

[0465] 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 materials are completely reacted. 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 three times with ethyl acetate, 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.

[0466] Step 4: Dissolve the product from 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 completion, concentrate under reduced pressure to obtain the crude target compound (170 mg) as a yellow solid, which is used directly in the next step.

[0467] Step 5: Dissolve the product obtained in Step 4 (170 mg) in dichloromethane (5 mL) at room temperature, add acetic acid (28 mg) and CDI (98 mg). Incubate the mixture at room temperature for 2 hours until the starting materials react completely. After completion, dilute the reaction mixture with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate. Purify the residue by column chromatography to obtain the title compound (70 mg) as a yellow oil.

[0468] Step 6: Dissolve the product obtained in Step 5 (70 mg) in a mixture of dioxane and water (2 mL, v / v = 5 / 1) at room temperature. Add K2CO3 (100 mg), Pd(dppf)Cl2 (35 mg), and tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (100 mg). After fully replacing the nitrogen atmosphere, the mixture was heated to 100°C and stirred for 2 hours until the starting materials reacted completely. After completion of the reaction, 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] + .

[0469] 1 H NMR (400MHz, DMSO-d6) 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).

[0470] Example 134

[0471] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0472] 1 H NMR (400MHz, DMSO-d6) 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).

[0473] Example 135

[0474] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 3-(4-methylpiperazin-1-yl)propionic acid to obtain the title compound. LCMS (ES, m / z): 482.3 [M+H] + .

[0475] 1 H NMR (400MHz, DMSO-d6) 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, 2.0 Hz,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).

[0476] Example 136

[0477] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 3-[4-(propan-2-yl)piperazin-1-yl]propanoic acid dihydrochloride to obtain the title compound. LCMS (ES, m / z): 510.3 [M+H] + .

[0478] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.20 (s, 1H), 7.99 (s, 1H), 7.83 (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=5.2Hz,1H),3.86(s,3H),3.10(dd,J=8.0,6.8Hz,2H),2.73(dd,J=8.4,6.8 Hz, 2H), 2.61 (p, J = 6.8 Hz, 1H), 2.46 (s, 7H), 1.48 (s, 9H), 0.96 (d, J = 6.8 Hz, 6H).

[0479] Example 137

[0480] Step 1: Dissolve Intermediate B2 (218 mg) in a mixture of 1,4-dioxane and water (5 mL, v / v = 5 / 1) at room temperature. Add (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (297 mg), potassium carbonate (173 mg), and Pd(dppf)Cl2 (37 mg). After fully displacing the nitrogen atmosphere, heat the mixture to 90°C and continue the reaction for 2 hours until the reaction is complete. After completion of the reaction, separate the layers, extract the aqueous phase twice 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 title compound (156 mg).

[0481] Step 2: Dissolve the product obtained in step 1 (60 mg) in methanol (3 mL) at room temperature and add palladium on carbon (10 mg, 10%). The mixture is fully replaced with hydrogen and stirred overnight under a hydrogen atmosphere until the reaction is complete. After the reaction is complete, 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] + .

[0482] 1H NMR (400MHz, DMSO-d6) 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,1H),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).

[0483] Example 138

[0484] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 1-methyl-2-oxo-1,2-dihydropyridine-4-boronic acid to obtain the title compound. LCMS (ES, m / z): 463.2 [M+H] + .

[0485] 1 H NMR (400MHz, DMSO-d6) 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 = 2.0H z,1H),7.37(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).

[0486] Example 139

[0487] The synthesis method is similar to that of Example 133, except that the intermediate acetic acid is replaced with N,N-dimethylglycine to obtain the title compound. LCMS (ES, m / z): 510.2 [M+H] + .

[0488] 1H NMR (400MHz, DMSO-d6) 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,1H),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).

[0489] Example 140

[0490] The synthesis method is similar to that of Example 129, except that the intermediate 4-dimethylaminopiperidine is replaced with 1-methylpiperazine to obtain the title compound. LCMS (ES, m / z): 482.2 [M+H] + .

[0491] 1 H NMR (400MHz, DMSO-d6) 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,1H),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).

[0492] Example 141

[0493] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 5-pyrimidineboronic acid to obtain the title compound. LCMS (ES, m / z): 434.2 [M+H] + .

[0494] 1H NMR (400MHz, DMSO-d6) δ (ppm): 9.52 (s, 2H), 9.14 (s, 1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.87 (d, J = 8.0 Hz, 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).

[0495] Example 142

[0496] The synthesis method was similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid was replaced with 3-(4-(dimethylamino)piperidin-1-yl)propionic acid to obtain the title compound. LCMS (ES, m / z): 510.3 [M+H] + .

[0497] 1 H NMR (400MHz, DMSO-d6) 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=4.8H z,1H),6.01(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).

[0498] Example 143

[0499] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 3-methoxypropionic acid to obtain the title compound. LCMS (ES, m / z): 414.2 [M+H] + .

[0500] 1H NMR (400MHz, DMSO-d6) 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).

[0501] Example 144

[0502] Step 1: 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) was added potassium carbonate (1.9 g) and Pd(dppf)Cl2 (340 mg) at room temperature. After fully displacing the mixture with nitrogen, the mixture was heated to 100°C and stirred for 2 hours until the reaction was complete. After completion of the reaction, the liquids were separated and the organic phase was concentrated to obtain the 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] + .

[0503] Step 2: Dissolve the product obtained in Step 1 (1.4 g) in methanol (50 mL) at room temperature, add palladium on carbon (200 mg, 10%), fully replace the hydrogen atmosphere, and stir at 50°C for 2 days until the reaction is complete. Filter the insoluble material, and concentrate the filtrate to obtain the 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] + .

[0504] 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 at room temperature overnight until the reaction is complete. Concentrate to obtain the crude product (800 mg) as a light yellow solid. LCMS (ES, m / z): 204.0 [M+H] + .

[0505] 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 stirring the mixture 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] + .

[0506] Step 5: Dissolve the product obtained in Step 4 (240 mg) in acetonitrile (5 mL). After cooling the mixture to 0°C, add NBS (148 mg) in portions. Stir the mixture in an ice-water bath for 1 hour until the reaction is complete. After completion of the reaction, remove the solvent to obtain the 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] + .

[0507] Step 6: 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, potassium carbonate (386 mg) and Pd(PPh3)4 (108 mg) were added. After fully displacing the nitrogen atmosphere, the mixture was heated to 100°C and allowed to react for 2 hours until the reaction was complete. After completion of the reaction, the liquid phases were separated, and the organic phase was concentrated under reduced pressure to yield the crude product. The crude product was purified by column chromatography to yield the product (62 mg).

[0508] The title compound was separated using the following method to provide 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 the R configuration, the chiral center of Example 144B is in the S configuration; when the chiral center of 144A is in the S configuration, the chiral center of Example 144B is in the R configuration.

[0509] Instrument: GILSON-GX-281, Preparative Column: CHIRALCEL OD-H, 2 x 25 mm, 5 μm. Preparation: Dissolve the crude product in ethanol to prepare a 5 mg / ml sample solution. Mobile Phase System: Mobile Phase A: Hexane (0.5% 2M NH3-MeOH) - HPLC, Mobile Phase B: IPA - HPLC; Mobile Phase B 50%, Flow Rate: 20 ml / min, Elution Time: 24 min.

[0510] Chiral test method: (Instrument: SHIMADZU-LC-20AD xr, preparative column: CHIRALCEL OD-3, size: 4.6*100 mm, 3 μm. Preparation method: the crude product is dissolved in methanol to prepare the sample solution. Mobile phase system: Hex (0.1% DEA): IPA. Elution gradient: 2-50%; flow rate: 1 ml / min, elution time: 6 min).

[0511] LCMS (ES, m / z): 510.0 [M+H] + .

[0512] 144A: 1 H NMR(400MHz,DMSO-d6)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).

[0513] 144B: 1 H NMR(400MHz, DMSO-d6)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).

[0514] Example 145

[0515] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0516] 1 H NMR (400MHz, DMSO-d6) 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).

[0517] Example 146

[0518] 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.

[0519] The title compound was separated using the following method to provide 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 the R configuration, the chiral center of Example 146B is in the S configuration; when the chiral center of 146A is in the S configuration, the chiral center of Example 146B is in the R configuration.

[0520] Instrument: GILSON-GX-281, Preparative Column: CHIRAL ART Cellulose-SC, 2 x 25 cm, 5 μm. Preparation: Dissolve the crude product in ethanol to prepare a 5 mg / ml sample solution. Mobile Phase System: Mobile Phase A: Hex (0.5% 2M NH3-MeOH) - HPLC, Mobile Phase B: MeOH:DCM = 1:1 - HPLC; Mobile Phase B 20%, Flow Rate: 20 ml / min, Elution Time: 24 min.

[0521] Chiral test method: (Instrument: SHIMADZU-LC-20AD xr, preparative column: CHIRALPAK IC-3, size: 4.6*50 mm, 3 μm. Preparation method: The crude product was dissolved in methanol to prepare a sample solution. Mobile phase system: Hex (0.1% DEA): (MeOH:DCM=1:1). Elution gradient: 2-25%; flow rate: 1 ml / min, elution time: 6 min).

[0522] LCMS (ES, m / z): 426.2 [M+H] + .

[0523] 1 H NMR (400MHz, DMSO-d6) 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,1H),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).

[0524] 146A: 1 H NMR (400MHz, DMSO-d6) 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, 1 H),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).

[0525] 146B: 1H NMR (400MHz, DMSO-d6) 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, 1 H),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).

[0526] Example 147

[0527] The synthesis method is similar to that of Example 129, except that the intermediate 4-dimethylaminopiperidine is replaced with dimethylamine hydrochloride to obtain the title compound. LCMS (ES, m / z): 427.2 [M+H] + .

[0528] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.96 (s, 1H), 7.89 (s, 1H), 7.80 (d, J = 8.0Hz, 1H), 7.05 (d, J = 2.0Hz, 1H), 7.0 0-6.95(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).

[0529] Example 148

[0530] The synthesis method is similar to that of Example 129, except that the intermediate 4-dimethylaminopiperidine is replaced with 2-(methylamino)ethanol-1-ol to obtain the title compound. LCMS (ES, m / z): 457.2 [M+H] + .

[0531] 1H NMR (400MHz, DMSO-d6) 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).

[0532] Example 149

[0533] The synthesis method was similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid was replaced with 3-((2-(dimethylamino)ethyl)(methyl)amino)propionic acid to obtain the title compound. LCMS (ES, m / z): 484.3 [M+H] + .

[0534] 1 H NMR (400MHz, DMSO-d6) 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).

[0535] Example 150

[0536] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 2-(4-methylpiperazin-1-yl)pyridine-5-boronic acid pinacol ester to obtain the title compound. LCMS (ES, m / z): 531.2 [M+H] + .

[0537] 1H NMR(400MHz, DMSO-d6)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),3.8 7(s,3H),3.57-3.54(m,4H),2.43-2.40(m,4H),2.23(s,3H),1.48(s,9H).

[0538] Example 151

[0539] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0540] 1 H NMR (400MHz, DMSO-d6) 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 = 8.0H z,1H),7.13(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).

[0541] Example 152

[0542] The synthesis method was similar to that of Example 144, except that the intermediate acetic acid was replaced with N,N-dimethyl-β-alanine to obtain the title compound. LCMS (ES, m / z): 524.3 [M+H] + .

[0543] 1H NMR (400MHz, DMSO-d6) 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,1H),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).

[0544] Example 153

[0545] The synthesis method was similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid was replaced with 3-((1-methylpiperidin-4-yl)oxy)propionic acid to obtain the title compound. LCMS (ES, m / z): 497.3 [M+H] + .

[0546] 1 H NMR (400MHz, DMSO-d6) 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).

[0547] Example 154

[0548] The synthesis method is similar to that of Example 129, except that the intermediate 4-dimethylaminopiperidine is replaced with (S)-pyrrolidin-2-ylmethanol to obtain the title compound. LCMS (ES, m / z): 483.3 [M+H] + .

[0549] 1H NMR (400MHz, DMSO-d6) 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).

[0550] Example 155

[0551] Step 1: Dissolve (3-chloropyrazin-2-yl)methylamine hydrochloride (2.0 g) in anhydrous acetonitrile (20 mL) at room temperature, 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 are completely reacted. 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.

[0552] Step 2: Dissolve the product obtained in Step 1 (1.4 g) in anhydrous acetonitrile (10 mL) at room temperature. After cooling the mixture to 0°C, add a solution of NBS (927 mg) in acetonitrile (5 mL) dropwise. Stir the mixture at 0°C for 1 hour until the reaction is complete. After completion of the reaction, dilute the reaction solution with ethyl acetate. Wash the resulting mixture with water and saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue is purified by column chromatography to obtain the title compound (1.77 g) as a yellow solid.

[0553] Step 3: Dissolve the product obtained in Step 2 (1.7 g) in isopropanol (10 mL) at room temperature and add aqueous ammonia (5 mL, 25%). Heat the mixture to 95°C and continue the reaction for 16 hours until the starting material is completely reacted. Dilute the reaction solution with ethyl acetate, wash the mixture with water and saturated brine, dry over anhydrous sodium sulfate, and concentrate. The residue is purified by column chromatography to yield the title compound (1.4 g) as a yellow solid.

[0554] Step 4: Dissolve the product from Step 3 (1.4 g) in THF (10 mL) at room temperature and add HCl (20 mL, 6 M). Incubate the mixture at room temperature for 1 hour until the reaction is complete. After completion, adjust the pH of the reaction mixture to 7–8 with saturated sodium bicarbonate solution. Filter the filter cake, wash with a small amount of water, collect the solid, and dry under vacuum to yield the title compound (800 mg) as a yellow solid.

[0555] Step 5: Dissolve (3-fluoroazetidin-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 is allowed to react at room temperature for 30 minutes, sodium triacetoxyborohydride (354 mg) is added. The mixture is allowed to react at room temperature for another 16 hours until the starting material is completely reacted. After completion of the reaction, 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.

[0556] Step 6: The product obtained in step 5 (120 mg), K2CO3 (95 mg), Pd(PPh3)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 sequentially 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 starting materials were completely reacted. After completion of the reaction, 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] + .

[0557] 1 H NMR (400MHz, DMSO-d6) 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).

[0558] Example 156

[0559] The synthesis method was similar to that of Example 155, except that the intermediate (3-fluoroazetidin-3-yl)methanol hydrochloride was replaced with 4-methylpiperidin-4-ol to obtain the title compound. LCMS (ES, m / z): 497.2 [M+H] + .

[0560] 1 H NMR (400MHz, DMSO-d6) 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).

[0561] Example 157

[0562] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 3-methylisoxazole-5-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 437.2 [M+H] + .

[0563] 1 H NMR (400MHz, DMSO-d6) 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).

[0564] Example 158

[0565] The synthesis method is similar to that of Example 129, except that the intermediate 4-dimethylaminopiperidine is replaced with 4-methyl-4-hydroxypiperidine to obtain the title compound. LCMS (ES, m / z): 497.2 [M+H] + .

[0566] 1 H NMR (400MHz, DMSO-d6) 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).

[0567] Example 159

[0568] The synthesis method is similar to that of Example 129, except that the intermediate 4-dimethylaminopiperidine is replaced with (S)-pyrrolidine-3-methanol to obtain the title compound. LCMS (ES, m / z): 483.2 [M+H] + .

[0569] 1 H NMR (400MHz, DMSO-d6) 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).

[0570] Example 160

[0571] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0572] 1H NMR (400MHz, DMSO-d6) 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).

[0573] Example 161

[0574] The synthesis method is similar to that of Example 144, except that the intermediate dimethylglycine is replaced with methylsulfonic anhydride to obtain the title compound. LCMS (ES, m / z): 502.8 [M+H] + .

[0575] 1 H NMR(400MHz,DMSO-d6)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).

[0576] Example 162

[0577] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0578] 1H NMR(400MHz, DMSO-d6)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).

[0579] Example 163

[0580] 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 complete, 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 on a reverse phase column to obtain the title compound (3 mg). LCMS (ES, m / z): 517.2 [M+H] + .

[0581] 1 H NMR (400MHz, DMSO-d6) 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).

[0582] Example 164

[0583] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with tetrahydro-2H-pyran-3-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 440.2 [M+H] + .

[0584] 1H NMR (400MHz, DMSO-d6) 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),3.4 6-3.36(m,2H),2.09-2.06(m,1H),1.97-1.82(m,1H),1.82-1.65(m,2H),1.48(s,9H).

[0585] Example 166

[0586] The synthesis method was similar to that 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 was 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] + .

[0587] 1 H NMR (400MHz, DMSO-d6) 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).

[0588] Example 168

[0589] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 2-methylpyrimidine-5-boronic acid to obtain the title compound. LCMS (ES, m / z): 448.2 [M+H] + .

[0590] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 9.39 (s, 2H), 8.03 (d, J = 15.2Hz, 2H), 7.86 (d, J = 8.0Hz, 1H), 7.37 ( s, 1H), 7.15 (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).

[0591] Example 169

[0592] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 2-methylpyridine-5-boronic acid pinacol ester to obtain the title compound. LCMS (ES, m / z): 447.2 [M+H] + .

[0593] 1 H NMR (400MHz, DMSO-d6) 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 = 8.0H z, 1H), 7.37 (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).

[0594] Example 170

[0595] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 2-methylpyrimidine-5-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 448.2 [M+H] + .

[0596] 1H NMR (400MHz, DMSO-d6) 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).

[0597] Example 171

[0598] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 6-methylnicotinic acid to obtain the title compound. LCMS (ES, m / z): 447.2 [M+H] + .

[0599] 1 H NMR (400MHz, DMSO-d6) 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), 7.4 6(d,J=8.0Hz,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).

[0600] Example 172

[0601] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 463.2 [M+H] + .

[0602] 1H NMR (400MHz, DMSO-d6) 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).

[0603] Example 174

[0604] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 1-(oxetane-3-yl)-1H-pyrazole-3-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 478.2 [M+H] + .

[0605] 1 H NMR (400MHz, DMSO-d6) 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).

[0606] Example 175

[0607] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 5-methylisoxazole-3-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 437.2 [M+H] + .

[0608] 1 H NMR (400MHz, DMSO-d6) 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).

[0609] Example 176

[0610] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 3-methyl-1,2,4-oxadiazole-5-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 438 [M+H] + .

[0611] 1 H NMR(400MHz, DMSO-d6)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,1H),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).

[0612] Example 177

[0613] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 5-methyl-1,2,4-oxadiazole-3-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 438.3 [M+H] + .

[0614] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.38 (d, J = 5.2 Hz, 1H), 8.08 (s, 1H), 7.93 (d, J = 8.0 Hz, 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).

[0615] Example 178

[0616] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 5-methyl-[1,3,4]oxadiazole-2-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 438.2 [M+H] + .

[0617] 1H NMR (400MHz, DMSO-d6) 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).

[0618] Example 179

[0619] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 2-methyloxazole-5-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 437.2 [M+H] + .

[0620] 1 H NMR(400MHz,DMSO-d6)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).

[0621] Example 180

[0622] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 2-methyloxazole-4-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 437.2 [M+H] + .

[0623] 1 H NMR (400MHz, DMSO-d6) 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).

[0624] Example 181

[0625] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 4-methyloxazole-2-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 437.2 [M+H] + .

[0626] 1 H NMR(400MHz,DMSO-d6)δ(ppm):8.55(s,1H),8.06(s,1H),7.90-7.86(m,2H),7.27(d, J=1.6Hz,1H),7.22-7.19(m,2H),6.23(s,2H),3.88(s,3H),2.47(s,3H),1.49(s,9H).

[0627] Example 182

[0628] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 5-methyloxazole-2-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 437 [M+H] + .

[0629] 1 H NMR (400MHz, DMSO-d6) 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).

[0630] Example 183

[0631] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0632] 1H NMR (400MHz, DMSO-d6) 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,1H),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).

[0633] Example 184

[0634] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was 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] + .

[0635] 1 H NMR(400MHz, DMSO-d6)δ(ppm):7.98(d,J=1.6Hz,2H),7.82(d,J=8.0Hz,1H),7.13(d,J=1.6H z,1H),7.06-7.01(m,2H),6.92(s,1H),3.88(s,3H),3.79(s,3H),2.33(s,3H),1.48(s,9H).

[0636] Example 185

[0637] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0638] 1H NMR (400MHz, DMSO-d6) 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),6.91(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).

[0639] Example 186

[0640] 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, 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).

[0641] Step 2: Dissolve the product obtained in step 1 (2.4 g) in acetonitrile (25 mL) at room temperature, cool the mixture to 0 degrees Celsius, and add NBS (1.6 g) in portions. Stir the mixture at room temperature for 2 hours until the reaction is complete. After the reaction is complete, dilute the mixture with ethyl acetate. Wash the resulting mixture with saturated sodium bicarbonate solution, water, and saturated brine, 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).

[0642] Step 3: Dissolve the product from 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 completion, remove the solvent and dry the residue in vacuo to yield the title compound (1.1 g).

[0643] Step 4: Dissolve the product obtained in Step 3 (1.1 g) in dichloromethane (15 mL) at room temperature and add triethylamine (1.2 g). Cool the mixture to 0°C and add a solution of methanesulfonic anhydride (700 mg) in dichloromethane (10 mL) 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 over anhydrous sodium sulfate, and remove the solvent. The residue is purified by column chromatography to obtain the title compound (700 mg).

[0644] Step 5: Dissolve the compound obtained in Step 4 (700 mg) in isopropanol (5 mL) at room temperature and add aqueous ammonia (5 mL). Heat the mixture to 90°C in a sealed container and stir overnight until the reaction is complete. After completion, remove the solvent and purify the residue by column chromatography to yield the title compound (500 mg).

[0645] Step 6: Dissolve the compound obtained in Step 5 (500 mg) in a mixed solution of 1,4-dioxane and water (5 mL, v / v = 4 / 1) at room temperature. Add potassium carbonate (550 mg), Pd(PPh3)4 (190 mg), and tert-butyl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (650 mg). The mixture is thoroughly purged with nitrogen and heated to 100°C until the reaction is complete. After completion of the reaction, the reaction solution is diluted with ethyl acetate. The resulting mixture is washed with water and saturated brine, then dried over anhydrous sodium sulfate. After removing the solvent, the residue is purified by column chromatography to obtain the title compound (380 mg). LCMS (ES, m / z): 503.2 [M+H] + .

[0646] 1 H NMR (400MHz, DMSO-d6) 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,1H),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).

[0647] Example 187

[0648] The synthesis method is similar to that 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] + .

[0649] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.00 (s, 1H), 7.84 (d, J = 8.0Hz, 1H), 7.68–7.67 (m, 1 H),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).

[0650] Example 188

[0651] The synthesis method is similar to that of Example 186, except that the intermediate methylsulfonic anhydride is replaced with ethylsulfonyl chloride to obtain the title compound. LCMS (ES, m / z): 517.2 [M+H] + .

[0652] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 8.20 (s, 1H), 8.06 (d, J = 8.0Hz, 1H), 7.88 (d, J = 4.8Hz, 1H), 7.4 0-7.39(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).

[0653] Example 189

[0654] The synthesis method is similar to that of Example 187, except that the intermediate methanesulfonic anhydride is replaced with ethylsulfonyl chloride to obtain the title compound. LCMS (ES, m / z): 517.2 [M+H] + .

[0655] 1 H NMR (400MHz, DMSO-d6) 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).

[0656] Example 190

[0657] The synthesis method is similar to that of Example 144, except that the intermediate dimethylglycine is replaced with ethylsulfonyl chloride to obtain the title compound. LCMS (ES, m / z): 516.9 [M+H] + .

[0658] 1 H NMR (400MHz, DMSO-d6) δ (ppm): 7.97 (s, 1H), 7.92 (s, 1H), 7.82-7.80 (d, J = 8.0Hz, 1H) ,7.07(d,J=4.0Hz,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).

[0659] Example 191

[0660] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with pyridine-3-boronic acid to obtain the title compound. LCMS (ES, m / z): 433.2 [M+H] + .

[0661] 1 H NMR (400MHz, DMSO-d6) 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).

[0662] Example 192

[0663] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with nicotinic acid to obtain the title compound. LCMS (ES, m / z): 433.2 [M+H] + .

[0664] 1 H NMR (400MHz, DMSO-d6) 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).

[0665] Example 195

[0666] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 1-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 477 [M+H] + .

[0667] 1 H NMR (400MHz, DMSO-d6) 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).

[0668] Example 196

[0669] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 5-pyrimidinecarboxylic acid to obtain the title compound. LCMS (ES, m / z): 434 [M+H] + .

[0670] 1 H NMR (400MHz, DMSO-d6) 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).

[0671] Example 197

[0672] The synthesis method is similar to that of Example 122, except that the intermediate cyclopropanecarboxylic acid is replaced with 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid to obtain the title compound. LCMS (ES, m / z): 463 [M+H] + .

[0673] 1 H NMR (400MHz, DMSO-d6) 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,2H),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).

[0674] Example 198

[0675] The synthesis method was similar to that of Example 42, except that the intermediate 1-(2-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was replaced with 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] + .

[0676] 1 H NMR (400MHz, DMSO-d6) 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).

[0677] 3. Performance Measurement

[0678] Test Example 1: YES1 enzyme inhibition activity

[0679] 1.1 Compound preparation see Table 2

[0680] Table 2. Preparation of compounds with YES1 enzyme activity inhibitory activity

[0681] 1) Prepare 2× ATP / substrate solution and 2× kinase solution using kinase reaction buffer.

[0682] 2) Transfer 50 nL of compound dilution to a 384-well assay plate using an Echo 655. After centrifugation, add 2.5 μL of 2× kinase solution to the 384-well assay plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 10 min.

[0683] 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.

[0684] 4) Prepare 2×XL 665 and antibody detection reagent with detection buffer.

[0685] 5) Add 5 μL of kinase assay reagent to the assay plate and incubate at 25°C. Centrifuge at 1000 rpm for 1 minute and incubate at 25°C for 1 hour.

[0686] 6) The fluorescence signals at 620 nm (Cryptate) and 665 nm (XL665) were read using a BMG high-throughput drug screening multifunctional microplate reader.

[0687] 1.2 Data Analysis

[0688] 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 values ​​of the control compound and the test compound were obtained using the nonlinear fitting formula of the software. 50 value (half maximal inhibitory concentration);

[0689] The average value of the positive control wells; The values ​​of the negative control wells are averaged.

[0690] Data analysis was performed using Graphpad 7.0 software, and the IC values ​​of the compounds were obtained using the following nonlinear fitting formula: 50 (half inhibitory concentration): Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0691] 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 )

[0692] Among them: SD min The standard error of the Data value of the positive control DMSO, SD max The standard error of the Data value of the negative control DMSO, AVE min AVE is the average difference of the Data value of the positive control DMSO max The test results are shown in Table 3.

[0693] Table 3. IC values ​​of Example compounds for inhibition of YES1 enzymatic activity 50 value

[0694] The reagent information used in the experiment is shown in Table 4:

[0695] Table 4. Information on reagents used in the experiment

[0696] Test Example 2: Pharmacokinetics test in rats

[0697] 1.1 Instruments: High-performance liquid chromatograph: SHIMADZU LC-30AD, mass spectrometer: AB SCIEX Triple Quad 5500. All measured data were calculated and processed using Microsoft Excel, and relevant pharmacokinetic parameters were calculated using WinNonlin software. 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°C, mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate 0.60 mL / min, gradient elution: 0.30 min: 5% B; 1.00 min: 98% B; 1.48 min: 98% B; 1.51 min: 5% B; 2.00 min: stop. Injection volume: 1 μL.

[0698] 1.2 Animals: Three male Sprague-Dawley rats, weighing 180-300 g, were purchased and housed at the Laboratory Animal Center for two days before use. They were fasted for 12 hours before dosing and for 4 hours after dosing, with free access to water during the experiment. Blood samples were collected at designated time points after gavage.

[0699] 1.3 Solvent: DMSO / PEG400 / H2O (volume ratio 1 / 3 / 6). Preparation of oral administration solution: Accurately weigh the compound, add the solvent, and sonicate at room temperature for 5 minutes to completely dissolve the drug, to prepare a 0.5 mg / ml solution.

[0700] Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 7, and 24 hours after oral administration. 0.2 mL of blood was collected from the jugular vein using EDTA-K2 as the anticoagulant. The collected blood samples were transferred to microcentrifuge tubes containing the anticoagulant and centrifuged at 4000 g for 5 minutes at 4°C to separate the plasma. All collected plasma samples were stored at -75 ± 15°C until analysis.

[0701] Compounds were accurately weighed to prepare standard curve working solutions and quality control working solutions at varying concentrations. Blank plasma was then added to prepare plasma standard curves and quality control samples. After pretreatment by protein precipitation, the plasma samples were analyzed by LC / MS / MS. The plasma compound concentrations were then measured. All measurement data were collected and processed using relevant software, and pharmacokinetic parameters were calculated using Winnonlin software. Kinetic parameters for some representative compounds are shown in Table 5.

[0702] Table 5. Pharmacokinetic parameters of the example compounds in rats

[0703] The pharmacokinetic test results in rats shown in Table 5 indicate that the compounds of the present application are rapidly absorbed in the gastrointestinal tract and have good oral bioavailability.

[0704] Test Example 3: Pharmacokinetics test in mice

[0705] 1.1 Instruments: High-performance liquid chromatograph: SHIMADZU LC-40AD, mass spectrometer: AB SCIEX Triple Quad 5500. All measured data were calculated and processed using Microsoft Excel, and relevant pharmacokinetic parameters were calculated using WinNonlin software. The main kinetic parameters obtained included T max ,T 1 / 2 ,C max ,AUC 0-24h ,AUC inf Chromatographic column: HALO 90A AQ-C18, 2 μm, 2.1 × 30 mm, column temperature 40°C, mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate 0.60 mL / min, gradient elution: 0.20 min: 5% B; 1.20 min: 95% B; 1.60 min: 95% B; 1.61 min: 5% B; 1.80 min: stop. Injection volume: 5 μL.

[0706] 1.2 Animals: Three male Babl / C mice weighing 20-30 g were purchased and housed at the Laboratory Animal Center for two days before use. They were fasted for 12 hours before dosing and for 4 hours after dosing, with free access to water during the experiment. Blood samples were collected at designated time points after gavage.

[0707] 1.3 Solvent: DMSO / PEG400 / H2O (volume ratio 1 / 3 / 6). Preparation of oral administration solution: Accurately weigh the compound, add the corresponding solvent according to volume, vortex and sonicate to prepare a 1 mg / mL solution.

[0708] Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration. 0.03 mL of blood was drawn from the dorsal foot vein using EDTA-K2 as the anticoagulant. The collected blood samples were transferred to microcentrifuge tubes containing the anticoagulant and centrifuged at 4000 g for 5 minutes at 4°C to separate the plasma. All collected plasma samples were stored at -75 ± 15°C until analysis.

[0709] Compounds were accurately weighed to prepare standard curve working solutions and quality control working solutions at varying concentrations. Blank plasma was then added to prepare plasma standard curves and quality control samples. These samples were pretreated by protein precipitation and analyzed by LC / MS / MS. The plasma concentrations of the analytes were then measured. All measurement data were collected and processed using relevant software, and pharmacokinetic parameters were calculated using Winnonlin software. Kinetic parameters for some representative compounds are shown in Table 6.

[0710] Table 6. Pharmacokinetic parameters of the example compounds in mice

[0711] The pharmacokinetic test results in mice shown in Table 6 indicate that the compounds of the present application can be rapidly absorbed, have high blood concentrations and exposure amounts, and have good oral bioavailability.

[0712] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, 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 can 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

1. An aromatic amine compound, or an enantiomer, diastereomer, pharmaceutically acceptable salt, prodrug, isotope derivative, or solvate of the aromatic amine compound, characterized in that: The aromatic amine compound includes a compound represented by formula (I): In formula (I): X1, X2 and X3 are each independently selected from CH or N, wherein X1, X2 and X3 are not N at the same time; Ring Cy is selected from substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C3-C 10 Cycloalkyl; n is 1 to 4, 1 to 4 R1 are the same or different; R1 is selected from C1-C 10 Alkyl, C1-C 10 alkoxy, 4-10 membered heterocyclyl or 3-10 membered cycloalkyl; R4 substituent is selected from hydrogen, hydroxyl, halogen, C1-C6 alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Hydroxyalkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, di(C1-C 10 Alkyl)amino, C1-C 10 Alkylsulfonyl or 5-10 membered heterocyclic group; R2 is selected from C1-C 10 Alkoxy-CO-N(R6)-, C1-C 10 Alkyl-SO2-N(R6)-, C1-C 10 Alkyl-CO-N(R6)-, C3-C 10 Cycloalkyl-CO-N(R6)-, C3-C 10 Cycloalkoxy-CO-N(R6)-, C3-C 10 Cycloalkyl-(C1-C 10 )alkylene-CO-N(R6)-, C1-C 10 Alkoxy-CO-(C1-C 10 )alkylene, 5-10 membered heteroaryl-(C1-C 10 )alkylene, 5-10 membered heterocyclic group-(C1-C 10 )alkylene, 5-10 membered heteroaryl-N(R6)-, C6-C 10 Aryl-(C1-C 10 ) alkyleneoxy or 4-10 membered heterocyclyl-O-CO-N(R6)-; wherein R6 is selected from hydrogen, C1-C 10 alkyl; m is 1 to 4, 1 to 4 R3 are the same or different; R3 is selected from hydrogen, halogen, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl or C1-C 10 Halogenated alkoxy.

2. 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: Said X1 is selected from CH, X2 and X3 are selected from N; or said X1 and X2 are selected from CH, X3 is selected from N; or said 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.

3. 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 C3-C6 cycloalkyl, wherein the 5-6 membered heteroaryl contains 1-3 heteroatoms selected from N, O, and S; Preferably, the ring Cy is selected from 5-10 membered heteroaryl, 3-10 membered heterocyclyl, C3-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; 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 R1 is 1 to 4, 1 to 4 R1 are the same or different, wherein each R1 is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, oxo, or the following groups which are optionally substituted or polysubstituted by R4: C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkyl acyl, C1-C 10 Alkylsulfonyl, 4-10 membered heterocyclic group or 3-10 membered cycloalkyl group, wherein the 4-10 membered heterocyclic group contains 1-3 heteroatoms selected from N, O and S; Preferably, each R1 is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, oxo, or the following groups which are optionally substituted or polysubstituted by R4: C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl acyl, C1-C6 alkyl sulfonyl, 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 R1 is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, oxo, or the following groups which are optionally substituted or polysubstituted by R4: C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylacyl, C1-C4 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 R1 is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, oxo, or the following groups which are optionally monosubstituted, disubstituted, or trisubstituted by R4: C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkyl acyl, C1-C3 alkyl sulfonyl, 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 R1 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 R4: 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 R4 group is selected from: hydrogen, hydroxy, halogen, cyano, amino, methyl, ethyl, propyl, isopropyl, hydroxyethyl, oxetane, dimethylamino, methylaminoacyl, dimethylaminoacyl, methoxy or methanesulfonyl.

4. The aromatic amine compound as 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, X1, X2, X3, R1, R2, R3 and m have the definitions as described in any one of claims 1 to 3; R 11 is selected from H, hydroxy, halogen, cyano, amino, or optionally replaced by R 21 Mono-, di- or poly-substituted groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Alkyl acyl, C1-C 10 Alkylsulfonyl, C1-C 10 Alkylsulfinyl, mono(C1-C 10 Alkyl)amino, di(C1-C 10 Alkyl)amino, di(C1-C 10 alkyl)aminoacyl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, C3-C 10 Cycloalkyl, 5-10 membered heteroaryloxy, 4-10 membered heterocyclyloxy or C3-C 10 Cycloalkyloxy; wherein the heteroaryl or heterocyclic group contains 1-3 heteroatoms selected from N, O, S; R 21 are the same or different and are independently selected from hydrogen, hydroxy, halogen, cyano, amino, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Hydroxyalkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy, mono(C1-C 10 Alkyl)amino, di(C1-C 10 Alkyl)amino, (C1-C 10 Alkyl) aminoacyl, di(C1-C 10 Alkyl) amino acyl, C1-C 10 Alkylsulfonyl or 5-10 membered heterocyclic group; p is selected from integers of 1-4.

5. 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-C 10 Alkyl, halogenated C1-C 10 Alkyl or oxy.

6. The aromatic amine compound as 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-(dimethylglycerol)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.

7. 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.

8. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutical composition may be in the form of an oral preparation or an injection.

9. 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.

10. The use according to claim 9, characterized in that: The diseases associated with YES1 amplification or YES1 overexpression include cancers, including 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.

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