WO2024131265A1

WO2024131265A1 - COMPOUND FOR TREATING PI3Kγ-MEDIATED DISEASES AND USE THEREOF

Info

Publication number: WO2024131265A1
Application number: PCT/CN2023/126472
Authority: WO
Inventors: 刘青松; 刘静; 梁小飞; 王纯; 邓茂青; 王傲莉; 王蓓蕾; 齐紫平; 邹凤鸣; 刘青旺; 亓爽; 王俊杰; 沈丽娟; 刘娟; 梁华民; 王黎
Original assignee: 中国科学院合肥物质科学研究院
Priority date: 2022-12-23
Filing date: 2023-10-25
Publication date: 2024-06-27
Also published as: CN118239953A

Abstract

A PI3Kγ kinase inhibitor and the use thereof in a drug for treating diseases associated with the activity of PI3Kγ kinase and related signaling pathways. The PI3Kγ kinase inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, metabolite or prodrug thereof, wherein R1, R2, R3, X, A and B are as defined in the description.

Description

Compounds for treating PI3Kγ-mediated diseases and their uses

Technical Field

The present invention relates to the field of medicine, and in particular to compounds for treating cancer, inflammatory diseases or autoimmune diseases and uses thereof.

Background technique

Phosphatidylinositol-3-kinase (PI3K) plays an important role in cell growth, development, division, differentiation and apoptosis, and is closely related to the occurrence and development of tumors. According to the different structures and substrate specificities, PI3K can be divided into three types: type I, type II and type III. Among them, type I PI3K is the most intensively studied and widely studied subtype, and it is also most closely related to tumors, while type I PI3K is divided into type IA and type IB. The catalytic subunits of type IA PI3K include three proteins, p110α, p110β, and p110δ, while type I PI3K has only one catalytic subunit, p110γ. According to the different catalytic subunits, these PI3Ks are called PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ, respectively. In terms of expression, PI3Kα and PI3Kβ are expressed in a variety of cells, while PI3Kγ is only expressed in the immune system. p110γ plays an important role in the tumor microenvironment, so the development of targeted p110γ inhibitors will become a research hotspot in the future.

The PI3Kγ signaling pathway of macrophages promotes immunosuppression by inhibiting the activation of T cells. Inhibition of PI3Kγ can activate immune responses and significantly inhibit the growth of transplanted tumors. Preclinical studies have shown that PI3Kγ plays a very important role in maintaining the immunosuppressive state of tumor-associated macrophages in the tumor microenvironment. Eganelisib, which targets PI3Kγ, can reprogram key immunosuppressive macrophages (M2) in the tumor microenvironment to anti-tumor macrophages (M1), downregulate immunosuppression, increase immune activity, and ultimately lead to the activation and proliferation of cytotoxic T cells.

Furthermore, pharmacological or genetic blockade of p110γ inhibits inflammation, growth, and metastasis of transplanted and spontaneous tumors, suggesting that PI3Kγ may be an important therapeutic agent in oncology (Schmid et al., Cancer Cell, 2011, 19, 715-27). For example, PI3Kγ has been shown to have tumor-specific high accumulation in human pancreatic ductal adenocarcinoma (PDAC), indicating a role for PI3Kγ in pancreatic cancer (Edling et al., Human Cancer Biology, 2010, 16(2), 4928-37).

Therefore, the development of PI3Kγ inhibitors can change the balance of these immunosuppressive cells and promote the activation of anti-tumor immunity. PI3Kγ has become a very attractive drug target, but there is still a need to develop safer and more effective PI3Kγ inhibitors for the prevention and/or treatment of cancer, immune diseases, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction or neurological diseases.

Summary of the invention

The object of the present disclosure is to provide a novel PI3Kγ kinase inhibitor and its use in treating a PI3Kγ-mediated disease selected from cancer, inflammatory disease or autoimmune disease, and to provide a method for treating or preventing a PI3Kγ-mediated disease in a subject.

In one aspect, the present disclosure provides a PI3Kγ kinase inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable an acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug,

in,

represents a fused heteroaryl group having 2 or 3 nitrogen atoms, preferably selected from:

X is selected from CH or N;

R ₁ is selected from C1-6 alkoxy, halogen, C1-6 haloalkyl, or C1-6 haloalkoxy;

_R2 is selected from H, Heteroaryl, heteroarylC1-6alkyl, C2-6dialkylaminosulfonyl, or dihydropyran-4-yl;

_R3 is selected from H, halogen, or C1-6 alkoxy;

m, n and p are each 0 or 1;

_R4 and _R5 are each independently selected from H, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C3-6 cycloalkylC1-6 hydroxyalkyl, C1-6 alkoxyC1-6 alkyl, C3-6 cycloalkylC1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, C1-6 aminoalkyl optionally substituted with an amino protecting group, C3-6 cycloalkyl, 4-8 membered heterocyclyl, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl, or heteroarylaminoC1-6 alkyl,

or R ₄ , R ₅ together with the N to which they are attached form a 4-8 membered heterocyclic group;

_R6 and _R7 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy C1-6 alkyl, C2-6 dialkylamino C1-6 alkyl, amino protecting group, aminoacyl C1-6 alkyl, C1-6 alkylaminoacyl C1-6 alkyl, or 4-8 membered heterocyclyl C1-6 alkyl,

or R ₆ , R ₇ together with the N to which they are attached form a 4-8 membered heterocyclic group;

R ₈ is selected from C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, phenyl, phenoxy, phenylC1-6 alkyl, phenylC1-6 alkoxy, heteroaryl, heteroarylC1-6 alkyl, 4-8 membered heterocyclyl, or 4-8 membered heterocyclylC1-6 alkyl;

R ₉ is selected from H or methyl;

R ₁₀ is selected from 1-methyl-pyrrolidin-3-yl, tetrahydrofuran-3-yl, or pyrrolidin-2-one-5-ylmethyl;

wherein the above-mentioned C3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, and heteroaryl are each optionally substituted by 1-3 substituents independently selected from the following: hydroxy, oxo, aminoacyl, sulfamoyl, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino protecting group, amino optionally substituted by amino protecting group, C2-6 dialkylamino, C2-6 alkanoyl, C2-6 haloalkanoyl, C1-6 alkylsulfonyl, 4-8 membered heterocyclyl, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl, heteroarylC1-6 alkylaminoacyl, or C1-6 alkoxyC1-6 alkylaminoacyl, or two adjacent substituents together form a 4-6 membered fused heterocyclyl.

In a preferred aspect, the present disclosure relates to a PI3Kγ kinase inhibitor, which is a compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug thereof,

in,

_R3 is selected from H, halogen, or C1-6 alkoxy;

m, n and p are each 0 or 1;

R ₉ is selected from H or methyl;

According to the PI3Kγ kinase inhibitor of the present disclosure, the heterocyclic group is selected from azetidinyl (e.g., azetidin-3-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl), azepanyl (e.g., azepan-3-yl), piperazinyl (e.g., piperazin-1-yl), diazepanyl (e.g., 1,4-diazepan-1-yl), tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl, tetrahydrofuran-3-yl), tetrahydropyranyl (e.g., tetrahydropyran-4-yl), morpholinyl (e.g., morpholin-4-yl), imidazolinyl (e.g., imidazolin-1-yl), dioxolanyl, or dioxane The heteroaryl group is selected from pyrazolyl (e.g., pyrazol-4-yl), pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), imidazolyl (e.g., imidazol-1-yl, imidazol-4-yl), isoxazolyl (e.g., isoxazol-3-yl), triazolyl (e.g., 1,2,4-triazol-1-yl), thienyl (e.g., thien-2-yl, thien-3-yl), furanyl (e.g., furan-2-yl, furan-3-yl), or pyrimidinyl (e.g., pyrimidin-4-yl); the amino protecting group is selected from tert-butyloxycarbonyl (Boc), pivaloyl, benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl (PMB), allyloxycarbonyl (Alloc), or trifluoroacetyl (Tfa).

In one embodiment, R ₁ is selected from methoxy, fluorine, trifluoromethyl, or difluoromethoxy; more preferably methoxy.

In one embodiment, R ₃ is selected from H, fluoro, or methoxy; more preferably H.

In one embodiment, R ₂ is selected from Heteroaryl optionally substituted by 1-3 independently selected Ra, preferably pyrazolyl or pyridinyl; heteroaryl C1-6 alkyl optionally substituted by 1-3 independently selected Ra, preferably imidazolylmethyl; C2-6 dialkylaminosulfonyl, preferably diethylaminosulfonyl; or dihydropyran-4-yl;

_R2 is more preferably selected from pyrazol-4-yl optionally substituted by 1-3 independently R a; or imidazol-1-ylmethyl optionally substituted by 1-3 independently R a;

Wherein, each Ra is independently selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, 4-8 membered heterocyclyl; more preferably, each Ra is independently selected from methyl, ethyl, isopropyl, difluoromethyl, 2-hydroxy-2-methylpropyl, tetrahydropyran-4-yl, morpholin-4-yl; most preferably, each Ra is independently selected from methyl, or 2-hydroxy-2-methylpropyl.

In a preferred embodiment, _R2 is

wherein m is 0 or 1, more preferably 0;

_R4 and _R5 are each independently selected from H, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C3-6 cycloalkylC1-6 hydroxyalkyl, C1-6 alkoxyC1-6 alkyl, C3-6 cycloalkylC1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, C1-6 aminoalkyl optionally substituted with an amino protecting group, C3-6 cycloalkyl optionally substituted with 1-3 independently Rb, 4-8 membered heterocyclyl optionally substituted with 1-3 independently Rb, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl optionally substituted with 1-3 independently Rb, heteroarylaminoC1-6 alkyl, or R4, R5 together with the N to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-3 independently Rb; more preferably, _R4 and R5 are each independently selected from H, C1-6 alkyl, C ...3-6 cycloalkyl, C1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 _{R 5} is each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hydroxyethyl, 2-hydroxy-2-methylpropyl, 1-hydroxy-3-methylbutan-2-yl, 2,2,2,-trifluoroethyl, 2,2-difluoroethyl, 2-fluoroethyl, 1-cyclopropyl-2-hydroxyethyl, methoxyethyl, ethoxyethyl, 2-(cyclopropylmethoxy)ethyl, dimethylaminoethyl, Boc-aminoethyl, cyclopropyl, cyclopentyl or cyclohexyl optionally substituted with 1-3 independently R b, pyrrolidinyl or tetrahydropyranyl optionally substituted with 1-3 independently R b, morpholinoethyl, isoxazolyl or pyridinyl optionally substituted with 1-3 independently R b, or pyridinylaminoethyl, or R ₄ , R _R4 and R5 are each independently selected from H, methyl, ethyl, propyl, isopropyl, _hydroxyethyl , 2-hydroxy-2-methylpropyl, 2-fluoroethyl, methoxyethyl, dimethylaminoethyl, Boc-aminoethyl, cyclopentyl optionally substituted by 1-3 Rb independently, pyrrolidine- ₃ -yl optionally substituted by 1-3 Rb independently ... R4, _R5 together with the N to which they are attached form pyrrolidin-1-yl, piperazin-1-yl, morpholin- ₄ -yl, or piperidin-1-yl optionally substituted with 1-3 independently Rb;

Each Rb is independently selected from hydroxy, oxo, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C2-6 dialkylamino, C2-6 alkanoyl, C1-6 alkylsulfonyl, an amino protecting group, a 4-8 membered heterocyclyl, or a heteroaryl; more preferably, each Rb is independently selected from hydroxy, oxo, fluoro, methyl, ethyl, isopropyl, isobutyl, hydroxymethyl, ethoxy, dimethylamino, acetyl, ethylsulfonyl, Boc, pyrrolidinyl, morpholinyl, or pyridinyl; most preferably, each Rb is independently selected from hydroxy, oxo, methyl, ethyl, isopropyl, isobutyl, hydroxymethyl, dimethylamino, acetyl, ethylsulfonyl, pyrrolidin-1-yl, or pyridin-2-yl.

In another preferred embodiment, _R2 is

Where p is 0 or 1;

R ₆ and R ₇ are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, an amino protecting group, aminoacylC1-6 alkyl, C1-6 alkylaminoacylC1-6 alkyl, or a 4-8 membered heterocyclylC1-6 alkyl, or R ₆ , R ₇ together with the N to which they are attached form a 4-8 membered heterocyclyl optionally substituted by 1-3 independently R c; more preferably, R ₆ and R ₇ are each independently selected from H, ethyl, propyl, isopropyl, 2-fluoroethyl, 2,2-difluoroethyl, methoxyethyl, methoxypropyl, ethoxyethyl, dimethylaminoethyl, Boc, aminoacylmethyl, methylaminoacylmethyl, or 2-morpholinoethyl, or R ₆ , R R 6 and R ₇ are taken together with the N to which they are attached to form a pyrrolidinyl, piperidinyl, or imidazolinyl group optionally substituted by 1-3 independently R c ; most preferably, R ₆ and R ₇ are each independently selected from H, ethyl, isopropyl, 2-fluoroethyl, methoxyethyl, methoxypropyl, ethoxyethyl, Boc, or 2-morpholinoethyl, or R ₆ , R ₇ are taken together with the N to which they are attached to form a pyrrolidin-1-yl, or imidazolin-1-yl group optionally substituted by 1-3 independently R c ;

Each Rc is independently selected from hydroxy, oxo, aminoacyl, halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 dialkylamino, amino optionally substituted with an amino protecting group, heteroarylC1-6 alkylaminoacyl, or C1-6 alkoxyC1-6 alkylaminoacyl; more preferably, each Rc is independently selected from hydroxy, oxo, aminoacyl, fluoro, methyl, difluoromethyl, dimethylamino, Boc-amino, amino, 1,2,4-triazolylethylaminoacyl, or methoxyethylaminoacyl; most preferably, each Rc is independently selected from oxo, aminoacyl, methyl, dimethylamino, Boc-amino, 1,2,4-triazol-1-ylethylaminoacyl, or methoxyethylaminoacyl.

In another preferred embodiment, _R2 is

wherein n is 0 or 1, more preferably 1;

R ₉ is selected from H or methyl; preferably, R ₉ is H;

_R8 is selected from C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, phenyl optionally substituted by 1-3 independently Rd, phenoxy, phenylC1-6 alkyl optionally substituted by 1-3 independently Rd, phenylC1-6 alkoxy, heteroaryl optionally substituted by 1-3 independently Rd, heteroarylC1-6 alkyl optionally substituted by 1-3 independently Rd, 4-8 membered heterocyclyl optionally substituted by 1-3 independently Rd, or 4-8 membered heterocyclylC1-6 alkyl optionally substituted by 1-3 independently Rd; preferably, R ₈ is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, trifluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, methoxy, methoxymethyl, dimethylaminomethyl, phenyl optionally substituted by 1-3 Rd independently, phenoxy, benzyl or phenethyl optionally substituted by 1-3 Rd independently, phenylmethoxy, heteroaryl optionally substituted by 1-3 Rd independently selected from thienyl, furanyl, pyridyl, pyrimidinyl, or imidazolyl, any is a heteroarylC1-6 alkyl group optionally substituted by 1-3 independently Rd selected from thienylmethyl, furanylmethyl, pyridinylmethyl, or pyridinylethyl, a heterocyclyl group optionally substituted by 1-3 independently Rd selected from pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, or azepanyl, or a heterocyclylC1-6 alkyl group optionally substituted by 1-3 independently Rd selected from tetrahydropyranylmethyl, morpholinylmethyl, piperazinylmethyl, piperidinylethyl, or pyrrolidinylmethyl; most preferably, R ₈ is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, methoxy, methoxymethyl, dimethylaminomethyl, phenyl optionally substituted by 1-3 independently Rd, phenoxy, phenylmethoxy, heteroaryl optionally substituted by 1-3 independently Rd selected from thien-2-yl, furan-2-yl, furan-3-yl, pyrimidin-4-yl, or imidazol-4-yl, heteroarylC1-6alkyl optionally substituted by 1-3 Rd independently selected from thien-3-ylmethyl, or furan-2-ylmethyl, heterocyclyl optionally substituted by 1-3 Rd independently selected from pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, or azetidin-3-yl, or heterocyclylC1-6alkyl optionally substituted by 1-3 Rd independently selected from tetrahydropyran-4-ylmethyl, morpholin-4-ylmethyl, or piperazin-1-ylmethyl;

Each Rd is independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino protecting group, C2-6 haloalkanoyl, sulfamoyl, or 4-8 membered heterocyclyl C1-6 alkyl, or two adjacent Rd together form a 4-6 membered fused heterocyclyl; preferably, each Rd is independently selected from fluorine, methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, Boc, trifluoropropionyl, sulfamoyl, or morpholineethyl, or two adjacent Rd together form a dioxolane or dioxanyl; more preferably, each Rd is independently selected from methyl, methoxy, Boc, sulfamoyl, or morpholineethyl.

Particularly preferably, the present disclosure provides a PI3Kγ kinase inhibitor selected from the following compounds or pharmaceutically acceptable salts, solvates, polymorphs, esters, acids, isomers, metabolites or prodrugs thereof:

In another aspect, the present disclosure relates to a pharmaceutical composition comprising the aforementioned PI3Kγ kinase inhibitor, and a pharmaceutically acceptable carrier or excipient.

In other aspects, the present disclosure relates to the use of the aforementioned PI3Kγ kinase inhibitor in the preparation of a medicament for treating a PI3Kγ-mediated disease selected from cancer, inflammatory disease or autoimmune disease. Wherein the cancer is selected from solid tumors or blood cancers, and the solid tumors are preferably selected from: head and neck cancer, nasal cancer, paranasal sinus cancer, nasopharyngeal cancer, oral cancer, oropharyngeal cancer, laryngeal cancer, hypopharyngeal cancer, salivary gland cancer, paraganglioma, pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), gastric cancer, gastrointestinal cancer (e.g., carcinoid or stromal cancer), skin cancer, esophageal cancer, uterine cancer, endometrial cancer, liver cancer, hepatocellular carcinoma, bile duct cancer, bone cancer, gastrointestinal cancer, intestinal cancer, colon cancer, rectal cancer carcinoma, ovarian cancer, prostate cancer, breast cancer (e.g., triple-negative breast cancer), central nervous system tumors, brain cancer, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), melanoma, glioblastoma, renal cell carcinoma, thyroid cancer, sarcoma (e.g., soft tissue sarcoma, fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovialoma, mesothelioma, leiomyosarcoma ), cervical cancer, vulvar cancer, esophageal cancer, adrenal cancer, renal cancer, urinary system cancer, medulloblastoma, basal cell carcinoma, glioma, testicular cancer, bladder cancer, neuroectodermal tumor, epithelial cancer, squamous cell carcinoma, bronchial carcinoma, neuroendocrine carcinoma, carcinoid tumor, or diffuse giant cell tumor, or its metastatic lesion; the blood cancer is preferably selected from: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS) The inflammatory disease or autoimmune disease is selected from one or more of the following: asthma, emphysema, allergy, dermatitis, arthritis, psoriasis, lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, eczema, scleroderma, Crohn's disease, or multiple sclerosis.

Detailed ways

the term

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

Unless otherwise indicated, the present invention adopts conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology within the technical scope of the art. Unless specific definitions are provided, the nomenclature and laboratory operations and techniques related to chemical processes such as analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein are known to those skilled in the art. In general, the aforementioned techniques and steps can be implemented by conventional methods well known in the art and described in various general and more specific literatures, which are cited and discussed in this specification.

The term "alkyl" refers to an aliphatic hydrocarbon group, which can be a branched or straight chain alkyl. According to the structure, the alkyl can be a monovalent group or a divalent group (i.e., an alkylidene group). In the present invention, the alkyl is preferably an alkyl having 1 to 8 carbon atoms, more preferably a "low alkyl" having 1 to 6 carbon atoms, and even more preferably an alkyl having 1 to 4 carbon atoms. Typical alkyls include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. It should be understood that the "alkyl" mentioned herein includes the alkyl of all possible configurations and conformations, such as the "propyl" mentioned herein includes n-propyl and isopropyl, "butyl" includes n-butyl, isobutyl and tert-butyl, and "pentyl" includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and penta-3-yl, etc.

The term "alkoxy" refers to -O-alkyl, wherein alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.

The term "alkoxyalkyl" means an alkyl group, as defined herein, substituted with an alkoxy group, as defined herein.

The term "cycloalkyl" refers to a monocyclic or polycyclic radical containing only carbon and hydrogen. Cycloalkyl includes a group having 3-12 ring atoms. According to the structure, cycloalkyl can be a monovalent group or a divalent group (e.g., cycloalkylidene). In the present invention, cycloalkyl is preferably a cycloalkyl having 3-8 carbon atoms, more preferably a "low cycloalkyl" having 3-6 carbon atoms. The example of cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and adamantyl.

The term "alkyl (cycloalkyl)" or "cycloalkylalkyl" refers to an alkyl group, as defined herein, substituted with a cycloalkyl group, as defined herein. Non-limiting cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

The term "aromatic" refers to a planar ring with a delocalized π electron system and containing 4n+2 π electrons, where n is an integer. The aromatic ring can be composed of five, six, seven, eight, nine or more than nine atoms. The aromatic group can be optionally substituted. The term "aromatic" includes carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic (or "heteroaryl" or "heteroaromatic") groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups.

The term "aryl" as used herein means that each of the atoms constituting the ring in the aromatic ring is a carbon atom. The aryl ring can be composed of five, six, seven, eight, nine or more than nine atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl. Depending on the structure, the aryl group can be a monovalent group or a divalent group (i.e., an arylene group).

The term "aryloxy" refers to an -O-aryl group wherein aryl is as defined herein.

The term "heteroaryl" refers to an aromatic group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An N-containing "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms in the ring is a nitrogen atom. Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, naphthyridinyl, and furopyridinyl.

The term "alkyl (aryl)" or "aralkyl" refers to an alkyl group, as defined herein, substituted with an aryl group, as defined herein. Non-limiting examples of alkyl (aryl) groups include benzyl, phenethyl, and the like.

The term "alkyl(heteroaryl)" or "heteroarylalkyl" means an alkyl group, as defined herein, substituted with a heteroaryl group, as defined herein.

The term "heteroalkyl" as used herein refers to an alkyl group as defined herein where one or more of the backbone chain atoms is a heteroatom, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or a combination thereof. The heteroatom(s) may be located at any position within the heteroalkyl group or at a position where the heteroalkyl group is attached to the rest of the molecule.

The term "heterocycloalkyl" or "heterocyclic group" as used herein refers to a non-aromatic ring in which one or more atoms constituting the ring are heteroatoms selected from nitrogen, oxygen and sulfur. The heterocycloalkyl ring can be a monocyclic or polycyclic ring consisting of three, four, five, six, seven, eight, nine or more atoms. The heterocycloalkyl ring can be optionally substituted. Examples of heterocycloalkyls include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimides, cyclic carbamates, tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1,3-dioxins, 1,3-dioxanes, 1,4-dioxins, 1,4-dioxanes, piperazines, 1,3-oxathiacyclohexanes, 1,4-oxathiacyclohexanes, 1,4-oxathiacyclohexanes, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbital Acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazolidine, pyrrolidone, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine and 1,3-oxathiolane. Depending on the structure, the heterocycloalkyl group can be a monovalent group or a divalent group (i.e., a heterocycloalkylene group).

The term "alkyl(heterocycloalkyl)" or "heterocycloalkylalkyl" means an alkyl group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

The term "alkoxy(heterocycloalkyl)" or "heterocycloalkylalkoxy" means an alkoxy group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

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

The terms "haloalkyl", "haloalkoxy" and "haloheteroalkyl" include structures of alkyl, alkoxy or heteroalkyl, wherein at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same or different from each other.

The term "hydroxy" refers to an -OH group.

The term "cyano" refers to a -CN group.

The term "ester group" refers to a chemical moiety having the formula -COOR, wherein R is selected from the group consisting of alkyl, cycloalkyl, aromatic The invention also includes aryl, heteroaryl (attached through a ring carbon), and heterocyclyl (attached through a ring carbon).

The term "amino" refers to a _-NH2 group.

The term "aminoacyl" refers to a -CO- _NH2 group.

The term "alkylaminoacyl" means a -CO-NH-R group wherein R is alkyl as defined herein.

The term "amido" or "amido" refers to -NR-CO-R', wherein R and R' are each independently hydrogen, alkyl, aryl or heteroaryl.

The term "alkylamino" refers to an amino substituent further substituted with one or two alkyl groups, specifically the group -NRR', wherein R and R' are each independently selected from hydrogen or lower alkyl, provided that -NRR' is not _-NH2 . "Alkylamino" includes groups of compounds wherein the nitrogen of _-NH2 is attached to at least one alkyl group. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, and the like. "Dialkylamino" includes groups wherein the nitrogen of _-NH2 is attached to at least two other alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino, diethylamino, and the like.

The terms "arylamino" and "diarylamino" refer to amino substituents further substituted with one or two aryl groups, specifically to the group -NRR', wherein R and R' are each independently selected from hydrogen, lower alkyl, or aryl, wherein N is attached to at least one or two aryl groups, respectively.

The term "cycloalkylamino" refers to an amino substituent further substituted with one or two cycloalkyl groups as defined herein.

The term "heteroalkylamino" refers to an amino substituent further substituted with one or two heteroalkyl groups as defined herein.

The term "aralkylamino" herein refers to the group -NRR' wherein R is lower aralkyl and R' is hydrogen, lower alkyl, aryl or lower aralkyl.

The term "heteroarylamino" refers to an amino substituent further substituted with one or two heteroaryl groups as defined herein.

The term "heterocycloalkylamino" means an amino group, as defined herein, substituted with a heterocycloalkyl group, as defined herein.

The term "alkylaminoalkyl" means an alkyl group, as defined herein, substituted with an alkylamino group, as defined herein.

The term "aminoalkyl" refers to an alkyl substituent further substituted with one or more amino groups.

The term "aminoalkoxy" refers to an alkoxy substituent further substituted with one or more amino groups.

The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl substituent further substituted with one or more hydroxy groups.

The term "cyanoalkyl" refers to an alkyl substituent further substituted with one or more cyano groups.

The term "acyl" refers to a monovalent atomic group remaining after removing the hydroxyl group from an organic or inorganic oxygen-containing acid, and has the general formula R-M(O)-, where M is usually C.

The term "carbonyl" refers to an organic functional group consisting of carbon and oxygen atoms connected by a double bond (C=O).

The term "alkanoyl" or "alkylcarbonyl" refers to a carbonyl group further substituted with an alkyl group. Typical alkanoyl groups include, but are not limited to, acetyl, propionyl, butyryl, valeryl, hexanoyl, and the like.

The term "arylcarbonyl" means a carbonyl group, as defined herein, substituted with an aryl group, as defined herein.

The term "alkoxycarbonyl" refers to a carbonyl group further substituted with an alkoxy group.

The term "heterocycloalkylcarbonyl" refers to a carbonyl group further substituted with a heterocycloalkyl group.

The terms "alkylaminocarbonyl", "cycloalkylaminocarbonyl", "arylaminocarbonyl", "aralkylaminocarbonyl", "heteroarylaminocarbonyl" respectively refer to a carbonyl group, as defined herein, substituted with an alkylamino, cycloalkylamino, arylamino, aralkylamino, or heteroarylamino group, as defined herein respectively.

The term "alkylcarbonylalkyl" or "alkanoylalkyl" refers to an alkyl group further substituted with an alkylcarbonyl group.

The term "alkylcarbonylalkoxy" or "alkanoylalkoxy" refers to an alkoxy group further substituted with an alkylcarbonyl group.

The term "heterocycloalkylcarbonylalkyl" refers to an alkyl group further substituted with a heterocycloalkylcarbonyl group.

The term "mercapto" refers to a -SH group. The term "alkylthio" refers to a mercapto group, as defined herein, substituted with an alkyl group, as defined herein.

The term "sulfone" or "sulfonyl" refers to the functional group of sulfonic acid after losing the hydroxyl group, specifically refers to the -S(=O) ₂ - group.

The term "sulfoxide" or "sulfinyl" refers to -S(=O)-.

The term "aminosulfonyl" or "aminosulfonyl" refers to a -S(=O) ₂ - _NH2 group.

The term "alkylsulfoxide" or "alkylsulfinyl" refers to an alkyl-S(=O)- group.

The term "alkylsulfonyl" or "alkylsulfonyl" refers to -S(=O) ₂ -R, where R is alkyl.

The term "alkylaminosulfone" means a sulfone group, as defined herein, substituted with an alkylamino group, as defined herein.

The terms "alkylsulfonylamino" or "alkylsulfonylamino" and "cycloalkylsulfonylamino" or "cycloalkylsulfonylamino" refer to an amino group as defined herein substituted with an alkylsulfonyl or cycloalkylsulfonyl group as defined herein, i.e. -NH-S(=O) ₂ -R, wherein R is alkyl and cycloalkyl, respectively.

The terms "cycloalkylsulfonyl" and "cycloalkylsulfonyl" refer to -S(=O) ₂ -R, where R is cycloalkyl.

The term "optionally" refers to one or more events described later that may or may not occur, and includes both events that occur and events that do not occur. The term "optionally substituted" or "substituted" refers to that the group mentioned can be substituted by one or more additional groups, and the additional groups are each and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic radical, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methylsulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroarylalkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc. Among them, the amino protecting group is preferably selected from pivaloyl, tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, and trifluoroacetyl, etc.

As used herein, "pharmaceutically acceptable forms" of the disclosed compounds include, but are not limited to, pharmaceutically acceptable salts, hydrates, solvates, polymorphs, esters, acids, isomers, metabolites, prodrugs, and isotopically labeled derivatives of the disclosed compounds.

The term "pharmaceutically acceptable salt" herein refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesirable toxicological effects, i.e., is suitable for use in contact with the tissues of a subject without excessive toxicity, irritation, allergic reaction, etc., within the scope of reasonable medical judgment, and is consistent with a reasonable benefit/risk ratio. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the free acid or free base form of the purified compound with a suitable base or acid, respectively. For example, Berge et al. described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the compounds provided herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or by using other methods used in the art such as ion exchange formed amino salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionic acid Salt, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, naphthalene-m,n-disulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

"Solvate" or "solvate" refers to a solvent addition form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcoholate. "Hydrate" is formed by the combination of one or more water molecules with one molecule of the substance, wherein the water remains in its molecular state as _H2O .

The "metabolites" of the compounds disclosed herein are derivatives of the compounds formed when the compounds are metabolized. The term "active metabolite" refers to biologically active derivatives of the compounds formed when the compounds are metabolized. The term "metabolized" as used herein refers to the sum of processes by which a particular substance is changed by an organism (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Therefore, enzymes can produce specific structural changes into compounds. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while diphosphoglucosyltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Further information on metabolism can be obtained from The Pharmacological Basis of Therapeutics, Ninth Edition, McGraw-Hill (1996). The metabolites of the compounds disclosed herein can be identified by administering the compounds to a host and analyzing tissue samples from the host, or by incubating the compounds with hepatocytes in vitro and analyzing the resulting compounds. Both methods are known in the art. In some embodiments, the metabolites of the compounds are formed by oxidation processes and correspond to the corresponding hydroxyl-containing compounds. In some embodiments, the compound is metabolized to a pharmaceutically active metabolite.

As used herein, the term "modulate" refers to interacting directly or indirectly with a target to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

The term "prodrug" or "prodrug" refers to a derivative that may not be pharmacologically active but, under certain circumstances, can be administered orally or parenterally and thereafter metabolized in vivo to form a pharmacologically active Compounds of the present invention. Non-limiting examples of prodrugs include: esters, carbonates, half-esters, phosphates, nitroesters, sulfates, sulfoxides, amides, carbamates, nitrogen-containing compounds, phosphoramides, glycosides, ethers, acetals, ketals, and the like.

"Effective amount" refers to the amount of a drug or pharmaceutical preparation that will elicit a biological or medical response in a tissue, system, animal or human being, such as that being studied by a researcher or physician. In addition, the term "therapeutically effective amount" refers to any amount that results in improved treatment, cure, prevention, or alleviation of a disease, disorder, or side effect, or a reduced rate of progression of a disease or disorder, compared to a corresponding subject not receiving that amount. Also included within the scope of the term is an amount that is effective to enhance normal physiological function.

As used herein, the term "treat" refers to the alleviation of at least one symptom of a disease, disorder, or condition. The term includes administering and/or applying one or more compounds described herein to a subject to provide management or treatment of a condition. "Treatment" for the purposes of this disclosure may, but need not, provide a cure; rather, it is meant that "treatment" may be a form of management of a condition. When the compounds described herein are used to treat harmful proliferating cells (including cancer), "treatment" includes partial or complete destruction of the harmful proliferating cells, but with minimal destructive effects on normal cells. The desired treatment mechanism for harmful rapidly proliferating cells (including cancer cells) at the cellular level is apoptosis.

As used herein, the term "prevention" includes co-preventing or slowing the onset of clinically significant disease development or preventing or slowing the onset of a preclinically significant disease stage in an at-risk individual. This includes prophylactic treatment of an individual at risk of developing a disease.

The term "subject" or "patient" includes organisms that can suffer from a disorder or a disorder associated with reduced or insufficient programmed cell death (apoptosis) or can otherwise benefit from the administration of the compounds of the invention, such as humans and non-human animals. Preferred humans include human patients suffering from or prone to suffering from a disorder or related condition as described herein. The term "non-human animal" includes vertebrates, such as mammals, such as non-human primates, sheep, cattle, dogs, cats, and rodents such as mice, as well as non-mammals, such as chickens, amphibians, reptiles, etc.

As used herein, GI ₅₀ refers to the drug concentration required to inhibit 50% of cell growth, that is, the drug concentration at which the growth of 50% of cells (such as cancer cells) is inhibited or controlled.

As used herein, _IC50 refers to the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximal effect in an assay measuring the effect.

As used herein, _EC50 refers to the dose, concentration or amount of a test compound which elicits a dose-dependent response that elicits 50% of the maximal expression of a specific response induced, stimulated or potentiated by the particular test compound.

Kinase inhibitors

The present disclosure relates to a PI3Kγ kinase inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug thereof,

in,

X is selected from CH or N;

_R3 is selected from H, halogen, or C1-6 alkoxy;

m, n and p are each 0 or 1;

R ₉ is selected from H or methyl;

in,

_R3 is selected from H, halogen, or C1-6 alkoxy;

m, n and p are each 0 or 1;

R ₉ is selected from H or methyl;

According to the PI3Kγ kinase inhibitor of the present disclosure, the heterocyclic group is selected from azetidinyl (e.g., azetidin-3-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl), azepanyl (e.g., azepan-3-yl), piperazinyl (e.g., piperazin-1-yl), diazepanyl (e.g., 1,4-diazepan-1-yl), tetrahydrofuranyl (e.g., tetrahydrofuran-2-yl, tetrahydrofuran-3-yl), tetrahydropyranyl (e.g., tetrahydropyran-4-yl), morpholinyl (e.g., morpholin-4-yl), imidazolinyl (e.g., imidazolin-1-yl), dioxolanyl, or dioxane ; The heteroaryl group is selected from pyrazolyl (e.g., pyrazol-4-yl), pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), imidazolyl (e.g., imidazol-1-yl, imidazol-4-yl), isoxazolyl (e.g., isoxazol-3-yl), triazolyl (e.g., 1,2,4-triazol-1-yl), thienyl (e.g., thien-2-yl, thien-3-yl), furanyl (e.g., furan-2-yl, furan-3-yl), or pyrimidinyl (e.g., pyrimidin-4-yl); the amino protecting group is selected from tert-butyloxycarbonyl (Boc), pivaloyl, benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyl (Bn), p-methoxybenzyl (PMB), allyloxycarbonyl (Alloc), or trifluoroacetyl (Tfa).

In a preferred embodiment, _R2 is

wherein m is 0 or 1, more preferably 0;

In another preferred embodiment, _R2 is

Where p is 0 or 1;

In another preferred embodiment, _R2 is

wherein n is 0 or 1, more preferably 1;

R ₉ is selected from H or methyl; preferably, R ₉ is H;

_R8 is selected from C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkoxy C1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, phenyl optionally substituted by 1-3 independently Rd, phenoxy, phenylC1-6 alkyl optionally substituted by 1-3 independently Rd, phenylC1-6 alkoxy, heteroaryl optionally substituted by 1-3 independently Rd, heteroarylC1-6 alkyl optionally substituted by 1-3 independently Rd, 4-8 membered heterocyclyl optionally substituted by 1-3 independently Rd, or 4-8 membered heterocyclylC1-6 alkyl optionally substituted by 1-3 independently Rd; preferably, R ₈ is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, trifluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, methoxy, methoxymethyl, dimethylaminomethyl, phenyl optionally substituted by 1-3 Rd independently, phenoxy, benzyl or phenethyl optionally substituted by 1-3 Rd independently, phenylmethoxy, heteroaryl optionally substituted by 1-3 Rd independently selected from thienyl, furanyl, pyridyl, pyrimidinyl, or imidazolyl, any is a heteroarylC1-6 alkyl group optionally substituted by 1-3 independently Rd selected from thienylmethyl, furanylmethyl, pyridinylmethyl, or pyridinylethyl, a heterocyclyl group optionally substituted by 1-3 independently Rd selected from pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, or azepanyl, or a heterocyclylC1-6 alkyl group optionally substituted by 1-3 independently Rd selected from tetrahydropyranylmethyl, morpholinylmethyl, piperazinylmethyl, piperidinylethyl, or pyrrolidinylmethyl; most preferably, R ₈ is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, methoxy, methoxymethyl, dimethylaminomethyl, phenyl optionally substituted by 1-3 independently Rd, phenoxy, phenylmethoxy, heteroaryl optionally substituted by 1-3 independently Rd selected from thien-2-yl, furan-2-yl, furan-3-yl, pyrimidin-4-yl, or imidazol-4-yl, heteroarylC1-6alkyl optionally substituted by 1-3 Rd independently selected from thien-3-ylmethyl or furan-2-ylmethyl, heterocyclyl optionally substituted by 1-3 Rd independently selected from pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, or azetidin-3-yl, or heterocyclylC1-6alkyl optionally substituted by 1-3 Rd independently selected from tetrahydropyran-4-ylmethyl, morpholin-4-ylmethyl, or piperazin-1-ylmethyl;

For each variable, any combination of the above groups is also contemplated herein. It is understood that substituents and substitution patterns on the compounds provided herein can be selected by one skilled in the art to provide chemically stable compounds that can be synthesized using techniques known in the art and techniques described herein.

Also described herein are pharmaceutically acceptable salts, solvates, polymorphs, esters, acids, isomers, metabolites, or prodrugs of this compound.

In particular, the compounds described herein can be made and/or used as pharmaceutically acceptable salts. Types of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, or the like; or with an organic acid, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, citric acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1 -formic acid, 2-naphthalenesulfonic acid, tert-butylacetic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, salicylic acid, hydroxynaphthoic acid, stearic acid, muconic acid, etc.; (2) base addition salts, which are formed when the acidic protons in the parent compound are replaced by metal ions, such as alkali metal ions (such as lithium, sodium, potassium), alkaline earth metal ions (such as magnesium or calcium) or aluminum ions; or coordinated with organic bases or inorganic bases, acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucamine, etc.; acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

The corresponding counter ions of the pharmaceutically acceptable salts can be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.

The salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization.

Screening and characterizing pharmaceutically acceptable salts, polymorphs and/or solvates can be accomplished using a variety of techniques, including but not limited to thermal analysis, X-ray diffraction, spectrum, microscopy, elemental analysis. The various spectral techniques used include but are not limited to Raman, FTIR, UVIS and NMR (liquid and solid state). Various microscopic techniques include but are not limited to IR microscopy and Raman (Raman) microscopy.

Drug Use

The PI3Kγ kinase inhibitors disclosed herein can be used in drugs for treating PI3Kγ-mediated diseases selected from cancer, inflammatory diseases or autoimmune diseases, and the disorders treated by the methods or compounds disclosed herein are cancer, inflammatory diseases or autoimmune diseases. Wherein the cancer is selected from one or more of the following: blood cancer or solid tumors. The inflammatory disease or autoimmune disease is selected from one or more of the following: asthma, emphysema, allergy, dermatitis, arthritis, psoriasis, lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, eczema, scleroderma, Crohn's disease or multiple sclerosis.

In some embodiments, the solid tumor treated using the methods or compounds disclosed herein is a cancer or tumor selected from one or more of the following: head and neck cancer, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, oral cancer, oropharyngeal cancer, laryngeal cancer, hypopharyngeal cancer, salivary gland cancer, paraganglioma, pancreatic cancer (e.g., pancreatic adenocarcinoma or pancreatic ductal adenocarcinoma), gastric cancer, gastrointestinal cancer (e.g., carcinoid or stromal cancer), skin cancer, esophageal cancer, uterine cancer, endometrial cancer, liver cancer, hepatocellular carcinoma, bile duct cancer, bone cancer, gastrointestinal cancer, intestinal cancer, colon cancer, rectal cancer, Ovarian cancer, prostate cancer, breast cancer (e.g., triple-negative breast cancer), central nervous system tumors, brain cancer, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), melanoma, glioblastoma, renal cell carcinoma, thyroid cancer, sarcoma (e.g., soft tissue sarcoma, fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, leiomyosarcoma), cervical cancer, vulvar cancer, esophageal cancer, adrenal cancer, kidney cancer, urinary system cancer, medulloblastoma, basal cell carcinoma, glioma, testicular cancer, bladder cancer, neuroectodermal tumor, epithelial cancer, squamous cell carcinoma, bronchial carcinoma, neuroendocrine carcinoma, carcinoid tumor, or diffuse giant cell tumor, or metastatic lesions thereof.

In one embodiment, the blood cancer is a cancer selected from one or more of the following: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), myeloproliferative disorders, mast cell cancer, Hodgkin's disease, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, human lymphotropic virus type 1 (HTLV-1) leukemia/lymphoma, AIDS-related lymphoma, adult T-cell lymphoma, acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia, B-cell acute lymphocytic leukemia, chronic lymphocytic leukemia or multiple myeloma (MM). In one embodiment, the cancer is a leukemia or lymphoma. In one embodiment, the leukemia is B-cell acute lymphoblastic leukemia (B-ALL), acute myeloid leukemia (AML), acute lymphoblastic leukemia, chronic myeloid leukemia, hairy cell leukemia, myeloproliferative disorder, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myelodysplastic syndrome (MDS), or mast cell cancer.

In one embodiment, the lymphoma is diffuse large B-cell lymphoma, B-cell lymphoblastoid lymphoma, small non-cleaved cell lymphoma or Burkitt's lymphoma, human lymphotropic virus type I (HTLV-1) leukemia/lymphoma, adult T-cell lymphoma, Hodgkin's disease or non-Hodgkin's lymphoma or its metastatic lesions. In some embodiments, the disorder treated by the methods or compounds disclosed herein is an inflammatory disease or an autoimmune disease. In one embodiment, the inflammatory disease or autoimmune disease is asthma, emphysema, allergy, dermatitis, arthritis (e.g., rheumatoid arthritis), psoriasis, lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, eczema, scleroderma, Crohn's disease, or multiple sclerosis. In one embodiment, the disorder is rheumatoid arthritis. In one embodiment, the disorder is rheumatoid arthritis and the amount of the compound is effective to improve one or more symptoms associated with rheumatoid arthritis, wherein the symptoms associated with rheumatoid arthritis are independently reduced joint swelling, reduced serum anti-collagen levels, reduced joint pathology, reduced bone resorption, reduced cartilage destruction, reduced pannus and/or reduced inflammation.

In some embodiments, the disorder treated by the methods or compounds disclosed herein is a respiratory disease. In one embodiment, the respiratory disease is asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, or bronchiectasis. In one embodiment, the disorder is asthma.

In an embodiment of the present invention, a medicament comprising a compound of the present invention may be administered to a patient by at least one of injection, oral administration, inhalation, rectal administration, and transdermal administration. When treating a patient according to the present invention, the amount of a given medicament depends on a number of factors, such as the specific dosing regimen, the type of disease or condition, and its severity. The specific surrounding conditions include, for example, specific drugs, routes of administration, diseases for treatment, and patients or hosts for treatment, but, according to specific surrounding conditions, including, for example, specific drugs, routes of administration, diseases for treatment, and patients or hosts for treatment, the dosage can be determined by methods known in the art. Usually, with regard to the dosage used for adult treatment, the dosage is typically in the range of 0.02-5000mg/day, for example, about 1-1500mg/day. The required dosage can be conveniently expressed as a dose, or a dose administered simultaneously (or in a short time) or in a divided dose at appropriate intervals, for example, two, three, four, or more divided doses per day. It will be appreciated by those skilled in the art that, although the above-mentioned dosage range is given, the specific effective amount can be appropriately adjusted according to the patient's situation and in conjunction with the physician's diagnosis.

In some embodiments of the methods or uses disclosed herein, a compound as described herein in any one of the compounds is administered to a subject at a dosage (e.g., a therapeutically effective dose) of about 2 mg, 1-3 mg, 1-5 mg, 1-10 mg, 0.5-20 mg, or 0.1-50 mg. In some embodiments, the dosage (e.g., a therapeutically effective dose) is about 2 mg, 1-3 mg, 1-5 mg, 1-10 mg, 0.5-20 mg, 0.1-50 mg, 0.1-75 mg, 0.5-75 mg, 1-75 mg, 0.1-100 mg, 0.5-100 mg, or 1-100 mg. In some embodiments, the dosage is about 1-10 mg. In some embodiments, the dosage is about 1-50 mg. In some embodiments, the dosage is about 1-100 mg.

Preparation of compounds

The compounds disclosed herein, including salts thereof, can be prepared using known organic synthesis techniques, and can be synthesized according to any of a variety of possible synthetic routes.

The reactions used to prepare the compounds disclosed herein can be carried out in suitable solvents that can be readily selected by one skilled in the art of organic synthesis.

The choice of appropriate protecting groups can be readily determined by one skilled in the art.

The reaction can be monitored according to any suitable method known in the art, such as NMR, LC-MS and TLC.

Compounds can be purified by a variety of methods including HPLC and normal phase silica chromatography.

Example 1. Synthesis of 5-(5,6-dimethoxypyridin-3-yl)-N-(pyridin-2-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 1

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidine-2-amine (50 mg), 2-iodopyridine (35 mg), cesium carbonate (140 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakis(triphenylphosphine)palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The crude product was obtained by vacuum distillation of the organic phase, and the crude product was purified by silica gel column chromatography. The yellow product after precipitation is 5-(5,6-dimethoxypyridin-3-yl)-N-(pyridin-2-yl)pyrazolo[1,5-A]pyrimidin-2-amine. ¹ H NMR (500 MHz, DMSO) δ 9.96 (s, 1H), 8.97 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.25 (d, J = 3.6 Hz, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.70-7.63 (m, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 6.85 (dd, J = 6.7, 5.4 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H). MS m/z (ESI): 349.14 [M+H] ⁺ .

Example 2. Synthesis of 2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N,N-diethylpyrimidine-4-carboxamide Compound 2

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 2-bromo-N,N-diethylpyrimidine-4-carboxamide (52 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N,N-diethylpyrimidine-4-carboxamide. ¹ H NMR (500 MHz, DMSO) δ 10.69 (s, 1H), 8.99 (d, J = 7.3 Hz, 1H), 8.68 (d, J = 4.9 Hz, 1H), 8.56 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.11 (s, 1H), 6.97 (d, J = 4.9 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.47 (q, J = 7.1 Hz, 2H), 3.25 (q, J = 7.0 Hz, 2H), 1.18 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.0 Hz, 3H). MS m/z (ESI): 449.20 [M+H] ⁺ .

Example 3. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N,N-diethyl-5-methoxypyridine-2-amide Compound 3

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 6-bromo-N,N-diethyl-5-methoxypyridine-2-amide (57 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg) and tetrakis(triphenylphosphine)palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was chromatographed on a silica gel column to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N,N-diethyl-5-methoxypyridine-2-amide. ¹ H NMR (500 MHz, DMSO) δ 8.94 (d, J = 7.2 Hz, 1H), 8.71 (s, 1H), 8.53 (d, J = 1.7 Hz, 1H), 7.97 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.10 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 3.96 (s, 3H), 3.93 (d, J = 3.7 Hz, 6H), 3.48 (s, 2H), 3.37 (s, 2H), 1.19 (s, 3H), 1.05 (s, 3H). MS m/z (ESI): 478.22 [M+H] ⁺ .

Example 4. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N,N-diethylpyridine-2-sulfonamide Compound 4

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 6-bromo-N,N-diethylpyridine-2-sulfonamide (59 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakis(triphenylphosphine)palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N,N-diethylpyridine-2-sulfonamide. ¹ H NMR (500 MHz, DMSO) δ 10.43 (s, 1H), 8.99 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.91-7.87 (m, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 7.3 Hz, 1H), 6.98 (s, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.38-3.33 (m, 4H), 1.08 (t, J = 7.1 Hz, 6H). MS m/z (ESI): 484.18 [M+H] ⁺ .

Example 5. Synthesis of (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(pyrrolidin-1-yl)methanone Compound 5

20 mL of 1,4-dioxane was added to a 100 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (300 mg), 6-bromopyridine-2-carboxylic acid methyl ester (287 mg), cesium carbonate (1.1 g), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (64 mg) and tetrakistriphenylphosphine palladium (127 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, methyl 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)aminopyridine-2-carboxylate. MS m/z (ESI): 407.15 [M+H] ⁺ .

4 mL of methanol was added to a 100 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)aminopyridine-2-carboxylic acid methyl ester (243 mg) and sodium hydroxide solution (8 mL, 1 mol/L) were added under stirring at room temperature. The reaction system was then reacted for 8 hours at room temperature. After the reaction was completed, the reaction was neutralized with 1 mol/L hydrochloric acid solution. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid. MS m/z(ESI):393.13[M+H] ⁺ .

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and tetrahydropyrrole (11 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(pyrrolidin-1-yl)methanone. ¹ H NMR (500 MHz, DMSO) δ 10.10 (s, 1H), 8.99 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.82-7.74 (m, 1H), 7.54 (d, J = 7.4 Hz, 2H), 7.09 (d, J = 7.3 Hz, 1H), 6.75 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.59 (t, J = 6.4 Hz, 2H), 3.52 (t, J = 6.6 Hz, 2H), 1.87 (dq, J = 13.2, 6.8 Hz, 4H). MS m/z (ESI): 446.19 [M+H] ⁺ .

Example 6. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-ethylpyridine-2-amide Compound 6

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and ethylamine (8 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-ethylpyridine-2-amide. MS m/z(ESI):420.18[M+H] ⁺ .

Example 7. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-(2-methoxyethyl)pyridine-2-amide Compound 7

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-methoxyethylamine (12 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(2-methoxyethyl)pyridine-2-amide. ¹ H NMR (500 MHz, DMSO) δ 10.20 (s, 1H), 9.00 (d, J = 7.3 Hz, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.31 (d, J = 5.2 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.86-7.81 (m, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.53-7.49 (m, 2H), 6.84 (s, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.58-3.53 (m, 4H), 3.48 (s, 3H). MS m/z (ESI): 450.19 [M+H] ⁺ .

Example 8. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)pyridine-2-amide Compound 8

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and ethanolamine (10 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)pyridine-2-amide. MS m/z(ESI):436.17[M+H] ⁺ .

Example 9. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N,N-diethylpyridine-2-amide Compound 9

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and diethylamine (12 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N,N-diethylpyridine-2-amide. MS m/z(ESI):448.21[M+H] ⁺ .

Example 10. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-(2-(dimethylamino)ethyl)pyridine-2-amide Compound 10

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and N,N-dimethylethylenediamine (14 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(2-(dimethylamino)ethyl)pyridine-2-amide. MS m/z (ESI): 463.22 [M+H] ⁺ .

Example 11. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-isopropylpyridine-2-amide Compound 11

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and isopropylamine (9 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-isopropylpyridine-2-amide. ¹ H NMR (500 MHz, DMSO) δ 10.10 (s, 1H), 9.01 (d, J = 7.3 Hz, 1H), 8.56 (d, J = 1.8 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.89-7.84 (m, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 6.62 (s, 1H), 4.09 (td, J = 13.3, 6.6 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 1.25 (d, J = 6.6 Hz, 6H). MS m/z(ESI):434.19[M+H] ⁺ .

Example 12. 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(2-hydroxy Synthesis of 2-methylpropyl)pyridine-2-amide compound 12

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 1-amino-2-methyl-2-propanol (14 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(2-hydroxy-2-methylpropyl)pyridine-2-amide. ¹ H NMR (500 MHz, DMSO) δ 10.20 (s, 1H), 9.00 (d, J = 7.3 Hz, 1H), 8.58 (d, J = 1.8 Hz, 1H), 8.27 (t, J = 5.9 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 7.88-7.83 (m, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 6.79 (s, 1H), 4.76 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.17 (d, J = 5.3 Hz, 2H), 1.20 (s, 6H). MS m/z (ESI): 464.20 [M+H] ⁺ .

Example 13. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-(2-(dimethylamino)ethyl)-N-ethylpyridine-2-amide Compound 13

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and N,N-dimethyl-N'-ethylethylenediamine (19 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(2-(dimethylamino)ethyl)-N-ethylpyridine-2-amide. ¹ H NMR (500MHz, DMSO) δ10.15 (d, J＝6.6Hz, 1H), 8.99 (t, J = 6.4 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 7.98 (s, 1H), 7.77 (dd, J = 14.9, 7.2 Hz, 1H), 7.49 (dd, J = 54.3, 7.8 Hz, 2H), 6.94 (t, J = 6.5 Hz, 1H), 6.78 (d, J = 60.5 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.67 (s, 1H), 3.50 (dd, J = 14.0, 7.0 Hz, 1H), 3.42 (s, 1H), 2.87 (s, 1H), 2.10 (s, 2H), 1.2-1.05 (m, 3H). MS m/z (ESI): 491.25 [M+H] ⁺ .

Example 14. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-ethyl-N-methylpyridine-2-amide Compound 14

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and N-ethylmethylamine (9 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-ethyl-N-methylpyridine-2-amide. ¹ H NMR (500MHz, DMSO) δ10.14 (d, J = 8.9 Hz, 1H), 8.98 (d, J = 7.2 Hz, 1H), 8.55 (s, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.76 (dd, J = 14.6, 7.1 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.46 (dd, J = 32.8, 8. 4 Hz, 1H), 6.92 (dd, J = 18.6, 7.3 Hz, 1H), 6.79 (d, J = 24.3 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.51 (q, J = 7.1 Hz, 1H), 3.31-3.26 (m, 1H), 2.98 (d, J = 24.4 Hz, 3H), 1.2-1.05 (m, 3H). MS m/z (ESI): 434.19 [M+H] ⁺ .

Example 15. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N,N-diisopropylpyridine-2-amide Compound 15

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and diisopropylamine (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N,N-diisopropylpyridine-2-amide. ¹ H NMR (500 MHz, DMSO) δ 10.10 (s, 1H), 8.99 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.78-7.71 (m, 1H), 7.54 (dd, J = 11.5, 7.9 Hz, 2H), 6.81 (d, J = 7.2 Hz, 1H), 6.69 (s, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.69 (s, 1H), 3.60 (s, 1H), 1.48 (d, J = 5.8 Hz, 6H), 1.13 (d, J = 5.7 Hz, 6H). MS m/z (ESI): 476.24 [M+H] ⁺ .

Example 16. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-methyl-N-propylpyridine-2-amide Compound 16

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and N-methyl-n-propylamine (12 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-methyl-N-propylpyridine-2-amide. ¹ H NMR (500 MHz, DMSO) δ 10.14 (d, J = 10.0 Hz, 1H), 8.98 (d, J = 7.2 Hz, 1H), 8.55 (s, 1H), 7.99 (s, 1H), 7.76 (td, J = 7.9, 5.4 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.44 (dd, J = 17.8, 8.4 Hz, 1H), 6.91 (dd, J = 17.0, 7.2 Hz, 1H), 6.81 (d, J = 2.5 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.45 (t, J = 7.2 Hz, 1H), 3.28-3.23 (m, 1H), 2.97 (d, J = 28.3 Hz, 3H), 1.69-1.59 (m, 1H), 1.57-1.48 (m, 1H), 0.96 (t, J = 7.4 Hz, 1.5H), 0.67 (t, J = 7.4 Hz, 1.5H). MS m/z (ESI): 448.21 [M+H] ⁺ .

Example 17. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-ethyl-N-isopropylpyridine-2-amide Compound 17

In a 25 mL round-bottom flask, add 2 mL of tetrahydrofuran and add 6-(5-(5,6- 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and N-ethylisopropylamine (14 mg). The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-ethyl-N-isopropylpyridine-2-amide. MS m/z(ESI):462.23[M+H] ⁺ .

Example 18. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-ethyl-N-propylpyridine-2-amide Compound 18

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and N-ethyl-n-propylamine (14 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-ethyl-N-propylpyridine-2-amide. ¹ H NMR (500 MHz, DMSO) δ 10.14 (d, J = 4.1 Hz, 1H), 8.98 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.79-7.74 (m, 1H), 7.55-7.48 (m, 2H), 6.89 (d, J = 7.3 Hz, 1H), 6.77 (d, J = 24.1 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.48 ( q, J = 7.0 Hz, 1H), 3.43-3.39 (m, 1H), 3.28 (q, J = 6.9 Hz, 1H), 3.25-3.20 (m, 1H), 1.68-1.60 (m, 1H), 1.52 (dq, J = 14.8, 7.4 Hz, 1H), 1.19 (t, J = 7.0 Hz, 1.5H), 1.05 (t, J = 7.0 Hz, 1.5H), 0.96 (t, J = 7.4 Hz, 1.7H), 0.66 (t, J = 7.4 Hz, 1.3H). MS m/z (ESI): 462.23 [M+H] ⁺ .

Example 19. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-(2-(dimethylamino)ethyl)-N-methylpyridine-2-amide Compound 19

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and N,N,N'-trimethylethylenediamine (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(2-(dimethylamino)ethyl)-N-methylpyridine-2-amide. ¹ H NMR (500MHz, DMSO) δ10.18 (d, J=13.0Hz, 1H), 9.00-8.96 (m, 1H), 8.55 (s, 1H), 7.99 (s, 1H), 7.79-7.74 (m, 1H), 7.55 (d, J=7.3Hz, 1H), 7.42 (dd, J=32.9, 8.4Hz, 1H), 6.99-6. 81 (m, 2H), 3.96 (s, 3H), 3.93 (d, J = 2.3 Hz, 3H), 3.68 (t, J = 6.4 Hz, 1H), 3.45 (t, J = 6.7 Hz, 1H), 3.02 (d, J = 16.8 Hz, 3H), 2.76 (s, 1H), 2.57 (s, 1H), 2.46 (s, 3H), 2.05 (s, 3H). MS m/z (ESI): 477.24 [M+H] ⁺ .

Example 20. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N,N-dimethylpyridine-2-amide Compound 20

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and dimethylamine (7 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N,N-dimethylpyridine-2-amide. ¹ H NMR (500 MHz, DMSO) δ 10.19 (s, 1H), 8.98 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 7.3 Hz, 1H), 6.84 (s, 1H), 3.96 (s, 3H), 3.93 (d, J = 9.6 Hz, 3H), 3.05 (s, 3H), 3.00 (s, 3H). MS m/z (ESI): 420.18 [M+H] ⁺ .

Example 21. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N,N-dipropylpyridine-2-amide Compound 21

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and di-n-propylamine (16 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N,N-dipropylpyridine-2-amide. ¹ H NMR (500 MHz, DMSO) δ 10.14 (s, 1H), 8.98 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.78-7.73 (m, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 6.88 (d, J =7.3 Hz, 1H), 6.80 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.44-3.38 (m, 2H), 3.27-3.20 (m, 2H), 1.69-1.60 (m, 2H), 1.54-1.45 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H), 0.65 (t, J = 7.4 Hz, 3H). MS m/z (ESI): 476.24 [M+H] ⁺ .

Example 22. Synthesis of N,N-dibutyl-6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridine-2-amide Compound 22

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and di-n-butylamine (21 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N,N-dibutyl-6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-amide. ¹ H NMR (500MHz, DMSO)δ10.16(s,1H),8.97(d,J＝7.3Hz,1H),8.55(d,J＝1.8Hz,1H),7.99(d,J＝1.8Hz,1H),7.78-7.73(m,1H),7.54(d,J＝7.3Hz,1H),7.41(d,J＝8.4Hz,1H),6.90-6.85(m,2H),3.96(s,3H),3.92(s , 3H), 3.46 (t, J = 7.2 Hz, 2H), 3.30-3.22 (m, 2H), 1.65-1.58 (m, 2H), 1.48 (dd, J = 14.7, 7.4 Hz, 2H), 1.41 (dt, J = 14.7, 7.4 Hz, 2H), 1.06 (dt, J = 14.7, 7.4 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H), 0.65 (t, J = 7.3 Hz, 3H). MS m/z (ESI): 504.27 [M+H] ⁺ .

Example 23. Synthesis of tert-butyl (2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-ethylpyridine-2-amido)carbamate Compound 23

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 1-(Boc-amino)-2-(ethylamino)ethane (30 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, tert-butyl (2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-ethylpyridine-2-amide)carbamate. MS m/z(ESI):563.27[M+H] ⁺ .

Example 24. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N,N-bis(2-hydroxyethyl)pyridine-2-amide Compound 24

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and diethanolamine (17 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N,N-bis(2-hydroxyethyl)pyridine-2-amide. ¹ H NMR (500MHz, DMSO) δ10.14 (s, 1H), 8.99 (d, J＝7.3Hz, 1H), 8.55 (d, J＝1.8Hz, 1H), 7.99 (d, J＝1.7Hz, 1H), 7.80-7.72 (m, 1H), 7.54 (dd, J＝7.8,4.4Hz, 2H), 6.92 (d, J＝7.3Hz, 1H), 6.7 4 (s, 1H), 4.88 (t, J = 5.2 Hz, 1H), 4.75 (t, J = 5.1 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.65 (dd, J = 11.5, 5.8 Hz, 2H), 3.58 (t, J = 6.0 Hz, 2H), 3.49-3.46 (m, 2H), 3.44 (d, J = 5.1 Hz, 2H). MS m/z (ESI): 480.20 [M+H] ⁺ .

Example 25. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-ethyl-N-(2-hydroxyethyl)pyridine-2-amide Compound 25

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-ethylaminoethanol (14 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-ethyl-N-(2-hydroxyethyl)picolinyl-2-amine. MS m/z(ESI):464.20[M+H] ⁺ .

Example 26. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-(1-methyl-2-oxopyrrolidin-3-yl)pyridine-2-amide Compound 26

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 3-amino-1-methylpyrrolidin-2-one (18 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, and then washed with Dry over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(1-methyl-2-oxopyrrolidin-3-yl)pyridine-2-amide. ¹ H NMR (500MHz, DMSO) δ 10.10 (s, 1H), 9.01 (d, J = 7.3 Hz, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.52 (d, J = 7.5 Hz, 1H), 8.00 (d, J = 1.9 Hz, 1H), 7.90-7.84 (m, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 7.3 Hz, 1H). z, 1H), 7.50 (d, J = 7.3 Hz, 1H), 6.73 (s, 1H), 4.55 (dd, J = 17.1, 9.1 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.40-3.35 (m, 2H), 2.81 (s, 3H), 2.49-2.45 (m, 1H), 1.99 (dq, J = 12.1, 9.2 Hz, 1H). MS m/z (ESI): 489.20 [M+H] ⁺ .

Example 27. Synthesis of (S)-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(3-(dimethylamino)pyrrolidin-1-yl)methanone Compound 27

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and (S)-3-dimethylaminopyrrolidine (18 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(3-(dimethylamino)pyrrolidin-1-yl)methanone. MS m/z(ESI):489.24[M+H] ⁺ .

Example 28. Synthesis of (S)-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylpyrrolidin-1-yl)methanone Compound 28

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and (S)-2-methylpyrrolidine (14 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, Combine the organic phases. Wash the organic phases with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dry them with anhydrous Na ₂ SO _4. After distilling the organic phase under reduced pressure, a crude product was obtained. The crude product was chromatographed on a silica gel column to obtain a yellow product (S)-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylpyrrolidin-1-yl)methanone. ¹ H NMR (500 MHz, DMSO) δ 10.07 (d, J = 3.9 Hz, 1H), 8.98 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.81-7.74 (m, 1H), 7.64-7.50 (m, 2H), 7.04 (dd, J = 25.9, 7.2 Hz, 1H), 6.69 ( d, J = 18.5 Hz, 1H), 4.52-4.15 (m, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.71-3.44 (m, 2H), 2.12-2.00 (m, 1H), 2.00-1.70 (m, 2H), 1.67-1.54 (m, 1H), 1.28 (d, J = 6.3 Hz, 2H), 0.87 (t, J = 7.5 Hz, 1H). MS m/z (ESI): 460.21 [M+H] ⁺ .

Example 29. Synthesis of (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(piperazin-1-yl)methanone Compound 29

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and piperazine (14 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(piperazine-1-yl)methanone. ¹ H NMR (500 MHz, DMSO) δ 10.17 (s, 1H), 8.99 (d, J = 7.3 Hz, 1H), 8.56 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.82-7.74 (m, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.82 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.77 (d, J = 19.2 Hz, 2H), 3.56 (s, 2H), 2.95 (d, J = 53.4 Hz, 4H). MS m/z (ESI): 461.20 [M+H] ⁺ .

Example 30. Synthesis of 1-(4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)piperazin-1-yl)ethan-1-one Compound 30

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(piperazine-1-yl)methanone (30 mg), acetyl chloride (6 mg) and triethylamine (0.018 mL) with stirring at 0°C. The reaction system was reacted at 0°C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 1-(4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)piperazin-1-yl)ethan-1-one. ¹ H NMR (500 MHz, DMSO) δ 10.18 (s, 1H), 8.97 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.4 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.48 (s, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.81 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.72 (s, 1H), 3.66 (s, 1H), 3.58 (s, 2H), 3.54-3.45 (m, 4H), 2.03 (d, J = 36.0 Hz, 3H).MS m/z(ESI):503.22[M+H] ⁺ .

Example 31. Synthesis of (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(4-(ethylsulfonyl)piperazin-1-yl)methanone Compound 31

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(piperazine-1-yl)methanone (30 mg), ethylsulfonyl chloride (10 mg) and triethylamine (0.018 mL) with stirring at 0°C. The reaction system was reacted at 0°C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(4-(ethylsulfonyl)piperazine-1-yl)methanone. ¹ H NMR (500MHz, DMSO) δ10.18 (s, 1H), 8.97 (d, J = 7.3 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.81-7.77 (m, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.86 (s, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.78 (s, 2H), 3.58 (s, 2H), 3.34 (s, 2H), 3.26 (s, 2H), 3.09 (q, J = 7.4 Hz, 2H), 1.19 (t, J = 7.4 Hz, 3H). MS m/z (ESI): 553.20 [M+H] ⁺ .

Example 32. Synthesis of (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone Compound 32

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-methylmorpholine (16 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone. ¹ H NMR (500 MHz, DMSO) δ 10.16 (s, 1H), 8.99 (d, J = 7.2 Hz, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.00 (d, J = 1.9 Hz, 1H), 7.78 (dd, J = 8.2, 7.5 Hz, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.01 (d, J = 7.1 Hz, 1H), 6.82 (s, 1H), 4.36 (dd, J = : 25.0, 12.8 Hz, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.76 (t, J = 11.7 Hz, 1H), 3.65 (d, J = 13.5 Hz, 0.5H), 3.60-3.43 (m, 2H), 3.20 (dd, J = 21.3, 10.2 Hz, 0.5H), 2.93 (dt, J = 23.1, 11.5 Hz, 1H), 2.65 (t, J = 11.6 Hz, 0.5H), 1.2-0.9 (m, 3H). MS m/z (ESI): 476.20 [M+H] ⁺ .

Example 33. Synthesis of (R)-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone Compound 33

In a 25 mL round-bottom flask, 2 mL of tetrahydrofuran was added, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and (R)-2-methylmorpholine (16 mg). The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography to obtain a yellow product (R)-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone. MS m/z(ESI):476.20[M+H] ⁺ .

Example 34. Synthesis of (S)-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone Compound 34

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and (S)-2-methylmorpholine (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a ^yellow product (S)-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone. NMR (500 MHz, DMSO) δ 10.16 (s, 1H), 8.97 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.80-7.76 (m, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.01 (d, J = 6.9 Hz, 1H), 6.82 (s, 1H), 4.36 (dd, J = 24.0, 13.1 Hz , 1H), 3.96(s, 3H), 3.93(s, 3H), 3.81-3.73(m, 1H), 3.66(d, J＝13.1Hz, 0.5H), 3.60-3.43(m, 2H), 3.21(t, J＝11.5Hz, 0.5H), 2.93(dt, J＝23.5, 11.6Hz, 1H), 2.69-2.59(m, 0.5H), 1.18(d, J＝5.9Hz, 1.6H), 1.00(d, J＝5.8Hz, 1.4H).MS m/z(ESI): 476.20[M+H] ⁺ .

Example 35. Synthesis of (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(morpholinyl)methanone Compound 35

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and morpholine (14 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(morpholinyl)methanone. ¹ H NMR (500 MHz, DMSO) δ 10.16 (s, 1H), 8.98 (d, J = 7.1 Hz, 1H), 8.56 (s, 1H), 7.99 (s, 1H), 7.83-7.74 (m, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.82 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.68-3.49 (m, 8H). MS m/z (ESI): 462.19 [M+H] ⁺ .

Example 36. Synthesis of (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-isopropylmorpholinyl)methanone Compound 36

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-isopropylmorpholine (21 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-isopropylmorpholinyl)methanone. MS m/z(ESI):504.24[M+H] ⁺ .

Example 37. 4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-yl Synthesis of tert-butyl 2-methylpiperazine-1-carboxylate compound 37

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and N-1-Boc-2-methylpiperazine (32 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-acyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester. MS m/z(ESI):575.27[M+H] ⁺ .

Example 38. Synthesis of (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(3,4-dimethylpiperazin-1-yl)methanone Compound 38

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 1,2-dimethylpiperazine (18 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(3,4-dimethylpiperazin-1-yl)methanone. MS m/z(ESI):489.24[M+H] ⁺ .

Example 39. Synthesis of (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(2-isobutylpyrrolidin-1-yl)methanone Compound 39

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-isobutylpyrrolidine (20 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-isobutylpyrrolidin-1-yl)methanone. MS m/z(ESI):502.26[M+H] ⁺ .

Example 40. Synthesis of (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(piperidin-1-yl)methanone Compound 40

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and piperidine (14 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(piperidin-1-yl)methanone. ¹ H NMR (500 MHz, DMSO) δ 10.13 (s, 1H), 8.98 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.84-7.72 (m, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 6.82 (s, 1H), 3.96 (s, 3H), 3.94 (d, J = 14.3 Hz, 3H), 3.64 (s, 2H), 3.35 (s, 2H), 1.73-1.43 (m, 6H). MS m/z (ESI): 460.21 [M+H] ⁺ .

Example 41. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(tetrahydro-2H-pyran-4-yl)pyridine-2-amide Compound 41

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 4-aminotetrahydropyran (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(tetrahydro-2H-pyran-4-yl)pyridine-2-amide. ¹ H NMR (500MHz, DMSO) δ10.10 (s, 1H), 9.00 (d, J = 7.3 Hz, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.21 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 1.9 Hz, 1H), 7.89-7.82 (m, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.48 (d, J = 6.9 Hz, 1H), 6.70 (s, 1H), 4.10-4.00 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.92-3.87 (m, 2H), 3.54-3.46 (m, 2H), 1.89 (d, J = 9.8 Hz, 2H), 1.62 (qd, J = 10.4, 4.1 Hz, 2H). MS m/z (ESI): 476.20 [M+H] ⁺ .

Example 42. Synthesis of [1,3'-bipyrrolidine]-1'-yl(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methanone Compound 42

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 1,3'-bipyrrolidine (22 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a yellow product [1,3'-bipyrrolidine]-1'-yl (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl Ketone. MS m/z(ESI):515.25[M+H] ⁺ .

Example 43. Synthesis of (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(4-methylpiperazin-1-yl)methanone Compound 43

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and N-methylpiperazine (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(4-methylpiperazin-1-yl)methanone. ¹ H NMR (500 MHz, DMSO) δ 10.21 (s, 1H), 9.01 (d, J = 7.3 Hz, 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.03 (d, J = 1.9 Hz, 1H), 7.81 (dd, J = 8.3, 7.4 Hz, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.03-6.99 (m, 1H), 6.92 (s, 1H), 4.00 (s, 3H), 3.96 (s, 3H), 3.71 (s, 2H), 3.49 (s, 2H), 2.46 (s, 2H), 2.39 (s, 2H), 2.26 (s, 3H). MS m/z (ESI): 475.22 [M+H] ⁺ .

Example 44. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)pyridine-2-amide Compound 44

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and N-(2-aminoethyl)morpholine (21 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted with 20 mL of ethyl acetate. The organic phases were combined three times. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)pyridine-2-amide. ¹ H NMR (500 MHz, DMSO) δ 10.23 (s, 1H), 8.99 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.29 (s, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.84-7.80 (m, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 6.95 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.61 (s, 4H), 3.50 (d, J = 5.4 Hz, 2H), 2.61 (s, 2H), 2.53 (d, J = 8.9 Hz, 4H).MS m/z(ESI):505.23[M+H] ⁺ .

Example 45. Synthesis of (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(4-ethylpiperazin-1-yl)methanone Compound 45

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and N-ethylpiperazine (18 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(4-ethylpiperazine-1-yl)methanone. ¹ H NMR (500 MHz, DMSO) δ 10.19 (s, 1H), 8.98 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.00 (d, J = 1.9 Hz, 1H), 7.81-7.75 (m, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 7.0 Hz, 1H), 6.88 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.57 (dd, J = 97.7, 75.0 Hz, 4H), 1.07 (s, 3H). MS m/z (ESI): 489.24 [M+H] ⁺ .

Example 46. Synthesis of (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(3-ethoxypyrrolidin-1-yl)methanone Compound 46

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 3-ethoxypyrrolidine (18 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(3-ethoxypyrrolidin-1-yl)methanone. MS m/z(ESI):490.22[M+H] ⁺ .

Example 47. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-(2-hydroxycyclopentyl)pyridine-2-amide Compound 47

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-pyrrolidinol (14 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(2-hydroxycyclopentyl)pyridine-2-amide. MS m/z (ESI): 476.20 [M+H] ⁺ .

Example 48. Synthesis of N-(1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)-6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-amide Compound 48

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and (1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)-1-aminocyclopentane hydrochloride (29 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)-6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-amide. MS m/z(ESI):522.21[M+H] ⁺ .

Example 49. Synthesis of tert-butyl 4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridine-2-yl)-1,4-diazepane-1-carboxylate Compound 49

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and tert-butyl 1,4-diazepane-1-carboxylate (32 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-acyl)-1,4-diazepane-1-carboxylic acid tert-butyl ester. MS m/z(ESI):575.27[M+H] ⁺ .

Example 50. Synthesis of (1,4-diazepan-1-yl)(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methanone Compound 50

Add 3 mL of methanol to a 100 mL round-bottom flask, and add tert-butyl 4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-acyl)-1,4-diazepane-1-carboxylate (30 mg) and 1 mL of hydrochloric acid in ethyl acetate under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by distillation under reduced pressure. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (1,4-diazepan-1-yl)(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methanone. MS m/z(ESI):475.22[M+H] ⁺ .

Example 51. Synthesis of (4,4-difluoropiperidin-1-yl)(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methanone Compound 51

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 4,4-difluoropiperidine (19 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product (4,4-difluoropiperidin-1-yl)(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methanone. ¹ H NMR (500 MHz, DMSO) δ 10.14 (s, 1H), 8.97 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.81-7.77 (m, 1H), 7.52 (t, J = 8.6 Hz, 2H), 7.06 (d, J = 7.2 Hz, 1H), 6.80 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.80 (s, 2H), 3.56 (s, 2H), 2.09 (d, J = 10.5 Hz, 4H). MS m/z (ESI): 496.19 [M+H] ⁺ .

Example 52. (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-yl Synthesis of (3-methylpiperazine-1-yl)methanone compound 52

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-methylpiperazine (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(3-methylpiperazin-1-yl)methanone. MS m/z(ESI):475.22[M+H] ⁺ .

Example 53. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(1R,4R)-4-morpholinocyclohexyl)pyridine-2-amide Compound 53

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and trans-1-amino-4-(morpholin-4-yl)-cyclohexane (29 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(1R,4R)-4-morpholinocyclohexyl)pyridine-2-amide. MS m/z (ESI): 559.28 [M+H] ⁺ .

Example 54. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(1R,4R)-4-hydroxycyclohexyl)pyridine-2-amide Compound 54

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and trans-4-aminocyclohexanol (18 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(1R,4R)-4-hydroxycyclohexyl)pyridine-2-amide. MS m/z (ESI): 490.22 [M+H] ⁺ .

Example 55. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(1S,4S)-4-hydroxycyclohexyl)pyridine-2-amide Compound 55

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and cis-4-aminocyclohexanol (18 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(1S,4S)-4-hydroxycyclohexyl)pyridine-2-amide. MS m/z (ESI): 490.22 [M+H] ⁺ .

Example 56. Synthesis of (R)-N-(1-cyclopropyl-2-hydroxyethyl)-6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridine-2-amide Compound 56

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and (R)-2-amino-2-cyclopropylethanol (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product (R)-N-(1-cyclopropyl-2-hydroxyethyl)-6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-amide. ¹ H NMR (500MHz, DMSO) δ10.20 (s, 1H), 8.99 (d, J = 7.2 Hz, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 1.9 Hz, 1H), 7.89-7.85 (m, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.53 (dd, J = 15.5 ,7.3Hz,2H),6.69(s,1H),5.02(t,J＝5.1Hz,1H),3.97(s,3H),3.93(s,3H),3.65(s,2H),3.45(ddd,J＝13.0,8.6,4.3Hz,1H),0.55-0.51(m,2H),0.47-0.42(m,1H),0.38-0.33(m,1H).MS m/z(ESI):476.20[M+H] ⁺ .

Example 57. Synthesis of (S)-N-(1-cyclopropyl-2-hydroxyethyl)-6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridine-2-amide Compound 57

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and (S)-2-amino-2-cyclopropylethanol (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-N-(1-cyclopropyl-2-hydroxyethyl)-6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-amide. MS m/z(ESI):476.20[M+H] ⁺ .

Example 58. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-(1S,4S)-4-hydroxy-4-methylcyclohexyl)pyridine-2-amide Compound 58

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and cis-4-amino-1-methylcyclohexanol (21 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(1S,4S)-4-hydroxy-4-methylcyclohexyl)pyridine-2-amide. MS m/z(ESI):504.24[M+H] ⁺ .

Example 59. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(1R,4R)-4-hydroxy-4-methylcyclohexyl)pyridine-2-amide Compound 59

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and trans-4-amino-1-methylcyclohexanol (21 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(1R,4R)-4-hydroxy-4-methylcyclohexyl)pyridine-2-amide. MS m/z(ESI):504.24[M+H] ⁺ .

Example 60. 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(1S,3S)-3- Synthesis of 2-hydroxycyclopentyl)pyridine-2-amide compound 60

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and (1S,3S)-3-aminocyclopentanol (22 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2- ^yl )amino)-N-(1S,3S)-3-hydroxycyclopentyl)pyridine-2-amide. NMR (500 MHz, DMSO) δ 10.11 (s, 1H), 9.00 (d, J = 7.3 Hz, 1H), 8.57 (d, J = 1.9 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 8.01 (d, J = 1.9 Hz, 1H), 7.87-7.83 (m, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.46 (d, J = 7.3 Hz, 1H), 6.69 ( s, 1H), 4.62 (d, J = 3.9 Hz, 1H), 4.44 (dt, J = 14.8, 7.4 Hz, 1H), 4.33-4.28 (m, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 2.20-2.12 (m, 1H), 2.04-1.98 (m, 1H), 1.95 (ddd, J = 13.0, 7.6, 3.2 Hz, 1H), 1.77-1.71 (m, 1H), 1.59-1.50 (m, 2H). MS m/z (ESI): 476.20 [M+H] ⁺ .

Example 61. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(2-(pyridin-2-ylamino)ethyl)pyridine-2-amide Compound 61

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and N-(pyridin-2-yl)ethylenediamine (22 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted with 20 mL of ethyl acetate. The reaction mixture was stirred for three times and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(2-(pyridin-2-ylamino)ethyl)pyridine-2-amide. MS m/z(ESI):512.22[M+H] ⁺ .

Example 62. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-(5-methylisoxazol-3-yl)pyridine-2-amide Compound 62

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 3-amino-5-methylisoxazole (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(5-methylisoxazol-3-yl)pyridine-2-amide. ¹ H NMR (500 MHz, DMSO) δ 10.80 (s, 1H), 10.27 (s, 1H), 9.02 (d, J = 7.3 Hz, 1H), 8.56 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.96-7.92 (m, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.59 (dd, J = 7.2, 4.2 Hz, 2H), 6.84 (s, 1H), 6.67 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 2.45 (s, 3H). MS m/z (ESI): 473.17 [M+H] ⁺ .

Example 63. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N-(pyridin-3-yl)pyridine-2-amide Compound 63

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 3-aminopyridine (15 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate and the mixture was added. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N-(pyridin-3-yl)pyridine-2-amide. ¹ H NMR (500 MHz, DMSO) δ 10.45 (s, 1H), 10.16 (s, 1H), 8.99 (dd, J = 8.5, 4.8 Hz, 2H), 8.54 (d, J = 1.6 Hz, 1H), 8.36 (d, J = 3.8 Hz, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 1.5 Hz, 1H), 7.93 (t, J = 7.8 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 7.56 (dd, J = 15.7, 7.3 Hz, 2H), 7.45 (dd, J = 8.2, 4.7 Hz, 1H), 6.82 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H). MS m/z(ESI):469.17[M+H] ⁺ .

Example 64. Synthesis of (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(4-(pyridin-2-yl)piperazin-1-yl)methanone Compound 64

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridine-2-carboxylic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 1-(pyridin-2-yl)piperazine (26 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(4-(pyridin-2-yl)piperazine-1-yl)methanone. ¹ H NMR (500 MHz, DMSO) δ 10.18 (s, 1H), 8.98 (d, J = 7.3 Hz, 1H), 8.53 (d, J = 1.9 Hz, 1H), 8.13 (dd, J = 4.8, 1.5 Hz, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.82-7.77 (m, 1H), 7.56-7.52 (m, 2H), 7.4 8 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 7.3 Hz, 1H), 6.85 (d, J = 8.2 Hz, 2H), 6.66 (dd, J = 7.0, 5.0 Hz, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 3.79 (s, 2H), 3.65 (s, 2H), 3.60 (s, 2H), 3.55 (s, 2H). MS m/z (ESI): 538.23 [M+H] ⁺ .

Example 65. Synthesis of 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)-N,N-dimethylacetamide Compound 65

20 mL of 1,4-dioxane was added to a 100 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (300 mg), 2-(6-bromopyridin-2-yl)acetic acid methyl ester (280 mg), cesium carbonate (1.1 g), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (64 mg) and tetrakis(triphenylphosphine)palladium (127 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, methyl 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)acetate. MS m/z (ESI): 421.16 [M+H] ⁺ .

4 mL of methanol was added to a 100 mL round-bottom flask, and 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)acetic acid methyl ester (200 mg) and sodium hydroxide solution (8 mL, 1 mol/L) were added under stirring at room temperature. The reaction system was then reacted for 8 hours at room temperature. After the reaction was completed, the reaction was neutralized with 1 mol/L hydrochloric acid solution. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)acetic acid. MS m/z(ESI):407.15[M+H] ⁺ .

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)acetic acid (50 mg), HATU (53 mg), DIPEA (0.042 mL) and dimethylamine (6 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-N,N-dimethylacetamide. ¹ H NMR (500 MHz, DMSO) δ 9.91 (s, 1H), 8.94 (d, J = 7.3 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.61-7.57 (m, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 6.95 (s, 1H), 6.74 (d, J = 7.3 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.82 (s, 2H), 3.06 (s, 3H), 2.94 (s, 3H). MS m/z (ESI): 434.19 [M+H] ⁺ .

Example 66. Synthesis of 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)-N,N-diethylacetamide Compound 66

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)acetic acid (50 mg), HATU (53 mg), DIPEA (0.042 mL) and diethylamine (10 mg) were added respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)-N,N-diethylacetamide. ¹ H NMR (500 MHz, DMSO) δ9.92 (s, 1H), 8.93 (d, J = 7.3 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.63-7.56 (m, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 6.97 (s, 1H), 6.76 (d, J = 7.3 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.79 (s, 2H), 3.45 (q, J = 7.1 Hz, 2H), 3.40-3.35 (m, 2H), 1.11 (dt, J = 9.7, 7.1 Hz, 6H).MS m/z(ESI):462.23[M+H] ⁺ .

Example 67. Synthesis of 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)-1-(pyrrolidin-1-yl)ethan-1-one Compound 67

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)acetic acid (50 mg), HATU (53 mg), DIPEA (0.042 mL) and tetrahydropyrrole (10 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)-1-(pyrrolidin-1-yl)ethan-1-one. ¹ H NMR (500MHz, DMSO) δ9.95 (s, 1H), 8.93 (d, J＝7.2Hz, 1H), : 8.54 (d, J = 1.9 Hz, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.61-7.56 (m, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.99 (s, 1H), 6.75 (d, J = 7.3 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.75 (s, 2H), 3.61 (t, J = 6.7 Hz, 2H), 3.46 (t, J = 6.7 Hz, 2H), 1.99-1.94 (m, 2H), 1.93-1.87 (m, 2H). MS m/z (ESI): 460.21 [M+H] ⁺ .

Example 68. Synthesis of 1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one Compound 68

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 1-(6-bromopyridin-2-yl)pyrrolidin-2-one (53 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one. ¹ H NMR (500 MHz, DMSO) δ 9.97 (s, 1H), 8.96 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 1.5 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 6.90 (s, 1H), 4.14 (t, J = 7.0 Hz, 2H), 3.96 (s, 3H), 3.94 (s, 3H), 2.59 (t, J = 8.0 Hz, 2H), 2.15-2.08 (m, 2H). MS m/z (ESI): 432.18 [M+H] ⁺ .

Example 69. Synthesis of (R)-1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidin-3-ol Compound 69

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidine-2-amine (50 mg), (R)-1-(6-bromopyridin-2-yl)pyrrolidin-3-ol (53 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino-9,9-dimethyloxanthene) (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were respectively washed with 20 mL of ethyl acetate and 4,5-diphenylphosphino-9,9-dimethyloxanthene. Water, washed with 20 mL saturated NaCl, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (R)-1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidin-3-ol. MS m/z(ESI):434.19[M+H] ⁺ .

Example 70. Synthesis of (R)-tert-butyl(1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidin-3-yl)carbamate Compound 70

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), (R)-(1-(6-bromopyridin-2-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (75 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg) and tetrakis(triphenylphosphine)palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a yellow product (R)-(1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester. ¹ H NMR (500 MHz, DMSO) δ9.58 (s, 1H), 8.92 (d, J = 7.2 Hz, 1H), 8.53 (d, J = 1.8 Hz, 1H), 7.96 (s, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 7.24 (d, J = 6.4 Hz, 1H), 6.96 (s, 1H), 6.43 (t, J = 10.8 Hz, 1H), 5.86 ( d, J = 8.0 Hz, 1H), 4.16 (d, J = 5.2 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.65 (s, 1H), 3.58 (s, 1H), 3.45 (d, J = 6.9 Hz, 1H), 3.30 (s, 1H), 2.17 (td, J = 13.1, 6.7 Hz, 1H), 1.92 (td, J = 12.9, 6.5 Hz, 1H), 1.40 (s, 9H). MS m/z (ESI): 533.26 [M+H] ⁺ .

Example 71. Synthesis of (R)-N-(6-(3-aminopyrrolidin-1-yl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 71

3 mL of methanol was added to a 100 mL round-bottom flask, and tert-butyl (R)-(1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidin-3-yl)carbamate (30 mg) and 1 mL of ethyl acetate solution of hydrochloric acid were added under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction is completed, the crude product is obtained by distillation under reduced pressure. The reaction is neutralized with saturated NaHCO _3. The mixed solution is extracted three times with 20 mL of ethyl acetate, and the organic phases are combined. The organic phase is washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The organic phase is distilled under reduced pressure to obtain a crude product, and the crude product is chromatographed on a silica gel column to obtain a yellow product (R)-N-(6-(3-aminopyrrolidin-1-yl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine. MS m/z(ESI):433.21[M+H] ⁺ .

Example 72. Synthesis of N-(6-(3-(difluoromethyl)piperidin-1-yl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 72

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 2-bromo-6-(3-(difluoromethyl)piperidin-1-yl)pyridine (64 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(3-(difluoromethyl)piperidin-1-yl) ^pyridin -2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine. NMR (500 MHz, DMSO) δ9.59 (s, 1H), 8.93 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.7 Hz, 1H), 7.98 (d, J = 1.7 Hz, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 6.76 (s, 1H), 6.67 (d, J = 7.8 Hz, 1H), 6.29 (d, J = 8.2 Hz, 1H), 6.16 (d, J = 4.6 Hz, 1H), 6.05 (d, J = 4.7 Hz, 2H), 5.93 (d, J = 4.7 Hz, 1H), 4.38 (d, J = 10.5 Hz, 1H), 4.12 (t, J = 11.9 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 2.89 (dd, J = 24.3, 13.2 Hz, 2H), 2.15-1.98 (m, 1H), 1.88 (d, J = 12.1 Hz, 1H), 1.78 (d, J = 12.7 Hz, 1H), 1.60-1.40 (m, 2H). MS m/z (ESI): 482.21 [M+H] ⁺ .

Example 73. Synthesis of (S)-5-(5,6-dimethoxypyridin-3-yl)-N-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 73

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), (S)-1-(6-bromopyridin-2-yl)-N,N-dimethylpyrrolidin-3-amine (59 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a yellow product (S)-5-(5,6-dimethoxypyridin-3-yl)-N-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)pyrazolo[1,5-A]pyrimidin-2-amine. ¹ H NMR (500 MHz, DMSO) δ9.58 (s, 1H), 8.92 (d, J = 7.2 Hz, 1H), 8.53 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 1.7 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 6.97 (s, 1H), 6.47 (d, J = 7.8 Hz, 1H), 5.90 (d , J＝8.0 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.68 (dt, J＝17.9, 8.6 Hz, 2H), 3.42 (dd, J＝16.9, 9.8 Hz, 1H), 3.18 (t, J＝8.9 Hz, 1H), 2.83 (s, 1H), 2.24 (s, 6H), 2.22-2.15 (m, 1H), 1.89-1.78 (m, 1H). MS m/z (ESI): 461.24 [M+H] ⁺ .

Example 74. Synthesis of (R)-5-(5,6-dimethoxypyridin-3-yl)-N-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 74

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), (R)-1-(6-bromopyridin-2-yl)-N,N-dimethylpyrrolidin-3-amine (59 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a yellow product (R)-5-(5,6-dimethoxypyridin-3-yl)-N-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)pyrazolo[1,5-A]pyrimidin-2-amine. ¹ H NMR (500MHz, DMSO) δ9.64 (s, 1H), 8.92 (d, J = 7.2 Hz, 1H), 8.53 (d, J = 1.7 Hz, 1H), 7.97 (d, J = 1.7 Hz, 1H), 7.48 (t, J = 7.1 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 6.95 (s, 1H), 6.54 (d, J = 7.8 Hz, 1H), 5.94 (d, J = 8.0 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.79 (s, 1H), 3.71 (t, J = 8.5 Hz, 1H), 3.45 (dd, J = 17.2, 9.3 Hz, 3H), 2.56 (s, 6H), 2.35 (dd, J = 13.5, 7.0 Hz, 1H), 2.12 (d, J = 29.6 Hz, 1H). MS m/z (ESI): 461.24 [M+H] ⁺ .

Example 75. Synthesis of (S)-N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidine-2-carboxamide Compound 75

20 mL of 1,4-dioxane was added to a 100 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (300 mg), N-(6-bromopyridin-2-yl)-L-proline methyl ester (378 mg), cesium carbonate (1.1 g), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (64 mg) and tetrakistriphenylphosphine palladium (127 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-L-proline methyl ester. MS m/z(ESI):476.20[M+H] ⁺ .

4 mL of methanol was added to a 100 mL round-bottom flask, and N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-L-proline methyl ester (240 mg) and sodium hydroxide solution (8 mL, 1 mol/L) were added under stirring at room temperature. The reaction system was then reacted for 8 hours at room temperature. After the reaction was completed, the reaction was neutralized with 1 mol/L hydrochloric acid solution. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-L-proline. MS m/z(ESI):462.19[M+H] ⁺ .

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-L-proline (30 mg), HATU (50 mg), DIPEA (0.018 mL) and 2-(1H-1,2,4-triazol-1-yl)ethylamine (15 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a yellow product (S)-N-(2-(1H-1,2,4-triazol-1-yl)ethyl)-1-(6-(5-(5,6-dimethoxy) (pyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidine-2-carboxamide. MS m/z (ESI): 556.25 [M+H] ⁺ .

Example 76. Synthesis of (S)-1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)-N-(2-methoxyethyl)pyrrolidine-2-carboxamide Compound 76

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-L-proline (30 mg), HATU (50 mg), DIPEA (0.018 mL) and 2-methoxyethylamine (10 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-N-(2-methoxyethyl)pyrrolidine-2-carboxamide. MS m/z(ESI):519.25[M+H] ⁺ .

Example 77. Synthesis of (S)-1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidine-2-carboxamide Compound 77

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-L-proline (30 mg), HATU (50 mg), DIPEA (0.018 mL) and methylamine (44 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidine-2-carboxamide. ¹ H NMR (500 MHz, DMSO) δ9.53 (s, 1H), 8.90 (d, J = 7.2 Hz, 1H), 8.53 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.40-7.31 (m, 2H), 7.01 (s, 1H), 6.95 (s, 1H), 6.51 (d, J = 7.8 Hz, 1H), 5.84 (d, J = 8.0 Hz, 1H), 4.27 (d, J = 7.3 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.73 (s, 1H), 3.46 (d, J = 7.9 Hz, 1H), 2.25-2.12 (m, 1H), 2.00 (ddd, J = 12.8, 9.0, 3.7 Hz, 3H). MS m/z (ESI): 461.20 [M+H] ⁺ .

Example 78. Synthesis of N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-N6-(2-(dimethylamino)ethyl)-N6-ethylpyridine-2,6-diamine Compound 78

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), N1-(6-bromopyridin-2-yl)-N1-ethyl-N2,N2-dimethylethane-1,2-diamine (60 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakis(triphenylphosphine)palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-N6-(2-(dimethylamino)ethyl)-N6-ethylpyridine-2,6-diamine. ¹ H NMR (500 MHz, DMSO) δ9.59 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.7 Hz, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 6.74 (s, 1H), 6.63 (d, J = 7.8 Hz, 1H), 6.17 (d, J = 8.2 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.89-3.82 (m, 2H), 3.51 (q, J = 6.9 Hz, 2H), 3.23 (s, 2H), 2.82 (s, 6H), 1.16 (t, J = 6.9 Hz, 3H).MS m/z(ESI):463.26[M+H] ⁺ .

Example 79. Synthesis of N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-N6-(2-morpholinoethyl)-pyridine-2,6-diamine Compound 79

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 6-bromo-N-(2-morpholinoethyl)pyridin-2-amine (63 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (11 mg) and tetrakistriphenylphosphine were added respectively under stirring at room temperature. Palladium (21 mg). The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, the reaction was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product. The crude product was chromatographed on a silica gel column to obtain a yellow product N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)-N6-(2-morpholinoethyl)-pyridine-2,6-diamine. ¹ H NMR (500 MHz, DMSO) δ9.52 (s, 1H), 8.90 (d, J = 7.2 Hz, 1H), 8.52 (d, J = 1.7 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.05 (s, 1H), 6.35 (t, J = 5.7 Hz, 2H), 5.94 (d, J = 8.0 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.66-3.61 (m, 4H), 3.44 (dd, J = 13.4, 6.4 Hz, 2H), 2.57-2.53 (m, 2H), 2.47 (s, 4H).MS m/z(ESI):477.24[M+H] ⁺ .

Example 80. Synthesis of N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-N6-(3-methoxypropyl)-pyridine-2,6-diamine Compound 80

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 6-bromo-N-(3-methoxypropyl)pyridin-2-amine (54 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakis(triphenylphosphine)palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-N6-(3-methoxypropyl)-pyridine-2,6-diamine. ¹ H NMR (500 MHz, DMSO) δ 9.49 (s, 1H), 8.91 (d, J = 6.4 Hz, 1H), 8.53 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 7.0 Hz, 1H), 7.26 (s, 1H), 7.03 (s, 1H), 6.46-6.36 (m, 2H), 5.93 (d, J = 6.9 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.47 (t, J = 6.3 Hz, 2H), 3.34 (s, 5H), 1.87-1.81 (m, 2H). MS m/z (ESI): 436.21 [M+H] ⁺ .

Example 81. Synthesis of N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-N6-(2-ethoxyethyl)-pyridine-2,6-diamine Compound 81

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 6-bromo-N-(2-ethoxyethyl)pyridin-2-amine (54 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-N6-(2-ethoxyethyl)-pyridine-2,6-diamine. ¹ H NMR (500 MHz, DMSO) δ 9.51 (s, 1H), 8.92 (d, J = 6.9 Hz, 1H), 8.53 (s, 1H), 7.97 (s, 1H), 7.48 (d, J = 7.2 Hz, 1H), 7.26 (s, 1H), 6.97 (s, 1H), 6.43 (t, J = 12.2 Hz, 2H), 5.98 (d, J = 7.2 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.58 (t, J = 6.2 Hz, 2H), 3.53-3.50 (m, 2H), 3.48 (d, J = 6.9 Hz, 2H), 1.17 (t, J = 7.0 Hz, 3H). MS m/z (ESI): 436.21 [M+H] ⁺ .

Example 82. Synthesis of N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-N6-ethyl-pyridine-2,6-diamine Compound 82

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidine-2-amine (50 mg), 6-bromo-N-ethylpyridin-2-amine (44 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakis(triphenylphosphine)palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-N6-ethyl-pyridine-2,6-diamine. ¹ H NMR (500MHz, DMSO) δ9.49 (s, 1H), 8.91 (d, J = 7.2 Hz, 1H), 8.53 (d, J = 1.9 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.03 (s, 1H), 6.38 (dd, J = 13.9, 6.6 Hz, 2H), 5.92 (d, J = 8.0 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.30 (dd, J＝12.6, 7.0 Hz, 2H), 1.21 (t, J＝7.2 Hz, 3H). MS m/z (ESI): 392.18 [M+H] ⁺ .

Example 83. Synthesis of N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-N6-propyl-pyridine-2,6-diamine Compound 83

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidine-2-amine (50 mg), 6-bromo-N-propylpyridin-2-amine (47 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakis(triphenylphosphine)palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-N6-propyl-pyridine-2,6-diamine. MS m/z(ESI):406.20[M+H] ⁺ .

Example 84. Synthesis of N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)-N6-isopropyl-pyridine-2,6-diamine Compound 84

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidine-2-amine (50 mg), 6-bromo-N-isopropylpyridin-2-amine (47 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakis(triphenylphosphine)palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-N6-isopropyl-pyridine-2,6-diamine. ¹ H NMR (500 MHz, MeOD) δ 8.70 (d, J = 7.1 Hz, 1H), 8.37 (s, 1H), 7.86 (s, 1H), 7.70 (t, J = 8.1 Hz, 1H), 7.44 (d, J = 7.1 Hz, 1H), 6.27 (dd, J = 18.3, 8.3 Hz, 2H), 6.13 (s, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.91 (dd, J = 12.7, 6.5 Hz, 1H), 1.44 (d, J = 6.4 Hz, 6H). MS m/z (ESI): 406.20 [M+H] ⁺ .

Example 85. Synthesis of N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-N6-(2-methoxyethyl)-pyridine-2,6-diamine Compound 85

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 6-bromo-N-(2-methoxyethyl)pyridin-2-amine (51 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-N6-(2-methoxyethyl)-pyridine-2,6-diamine. ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.62 (s, 1H), 8.31 (s, 1H), 7.89 (s, 1H), 7.41 (t, J=8.1 Hz, 1H), 7.12 (d, J=7.2 Hz, 1H), 6.73 (s, 1H), 6.56 (s, 1H), 6.01 (d, J=8.1 Hz, 1H), 4.10 (s, 3H), 4.01 (s, 3H), 3.68 (t, J=5.0 Hz, 2H), 3.56 (s, 2H), 3.43 (s, 3H). MS m/z (ESI): 422.19 [M+H] ⁺ .

Example 86. Synthesis of N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-N6-(2-fluoroethyl)-pyridine-2,6-diamine Compound 86

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 6-bromo-N-(2-fluoroethyl)pyridin-2-amine (48 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)-N6-(2-fluoroethyl)-pyridine-2,6-diamine. ¹ H NMR (500MHz, DMSO) δ9.50 (s, 1H), 8.92 (d, J = 7.2 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 1.5 Hz, 1H), 7.48 (d, J = 7.3 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 6.87 (s, 1H), 6.65 (t, J = 5.6 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 6.00 (d, J = 8.0 Hz, 1H), 4.66 (t, J = 5.2 Hz, 1H), 4.57 (t, J = 5.2 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.64 (dd, J = 10.7, 5.3 Hz, 1H), 3.59 (dd, J = 10.7, 5.3 Hz, 1H). MS m/z (ESI): 410.17 [M+H] ⁺ .

Example 87. Synthesis of N2-(2,2-difluoroethyl)-N6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine Compound 87

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 6-bromo-N-(2,2-difluoroethyl)pyridin-2-amine (52 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N2-(2,2-difluoroethyl)-N6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine. MS m/z(ESI):428.16[M+H] ⁺ .

Example 88. Synthesis of tert-butyl N-(2-amino-2-oxoethyl)-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)carbamate Compound 88

20 mL of 1,4-dioxane was added to a 100 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (300 mg), N-(6-bromopyridin-2-yl)-N-(tert-butyloxycarbonyl)glycine ethyl ester (477 mg), cesium carbonate (1.1 g), and 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) were added under stirring at room temperature. (64 mg) and tetrakistriphenylphosphine palladium (127 mg). The reaction system was then reacted at 120°C for 14 hours. After the reaction was completed, the reaction was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(tert-butyloxycarbonyl)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)glycine ethyl ester. MS m/z(ESI):550.24[M+H] ⁺ .

4 mL of methanol was added to a 100 mL round-bottom flask, and N-(tert-butyloxycarbonyl)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)glycine ethyl ester (200 mg) and sodium hydroxide solution (8 mL, 1 mol/L) were added respectively under stirring at room temperature. The reaction system was then reacted at room temperature for 8 hours. After the reaction was completed, the reaction was neutralized with 1 mol/L hydrochloric acid solution. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(tert-butyloxycarbonyl)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)glycine. MS m/z (ESI): 522.21 [M+H] ⁺ .

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N-(tert-butyloxycarbonyl)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)glycine (50 mg), HATU (44 mg), DIPEA (0.033 mL) and ammonium chloride (50 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(2-amino-2-oxoethyl)-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)carbamic acid tert-butyl ester. ¹ H NMR (500 MHz, DMSO) δ 9.85 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.00 (d, J = 1.9 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.45 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.08-7.03 (m, 2H), 6.74 (s, 1H), 4.53 (s, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 1.46 (s, 9H). MS m/z (ESI): 521.23 [M+H] ⁺ .

Example 89. Synthesis of tert-butyl (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)-N-(2-(methylamino)-2-oxoethyl)carbamate Compound 89

In a 25 mL round-bottom flask, add 2 mL of tetrahydrofuran, and add N-(tert-butyloxycarbonyl)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl) Glycine (50 mg), HATU (44 mg), DIPEA (0.033 mL) and methylamine (65 mg). The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-N-(2-(methylamino)-2-oxoethyl)carbamic acid tert-butyl ester. ¹ H NMR (500 MHz, DMSO) δ9.88 (s, 1H), 8.93 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.92 (q, J = 4.4 Hz, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.78 (s, 1H), 4.46 (s, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 2.80 (d, J = 4.5 Hz, 3H), 1.45 (s, 9H).MS m/z(ESI):535.24[M+H] ⁺ .

Example 90. Synthesis of 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)amino)acetamide Compound 90

3 mL of methanol was added to a 100 mL round-bottom flask, and tert-butyl (2-amino-2-oxoethyl)(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)carbamate (30 mg) and 1 mL of hydrochloric acid in ethyl acetate were added under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by distillation under reduced pressure. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The crude product was obtained by distillation of the organic phase under reduced pressure, and the yellow product 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)amino)acetamide was obtained after silica gel column chromatography. ¹ H NMR (500 MHz, DMSO) δ 9.46 (s, 1H), 8.89 (s, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.32-7.28 (m, 2H), 7.06 (s, 1H), 6.91 (s, 1H), 6.54 (t, J = 5.9 Hz, 1H), 6.51 (d, J = 7.8 Hz, 1H), 5.98 (d, J = 7.9 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.85 (d, J = 5.9 Hz, 2H). MS m/z (ESI): 421.17 [M+H] ⁺ .

Example 91. Synthesis of 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)amino)-N-methylacetamide Compound 91

Add 3 mL of methanol to a 100 mL round-bottom flask, and add tert-butyl (2-amino-2-oxoethyl)(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)carbamate (30 mg) and 1 mL of hydrochloric acid in ethyl acetate under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by distillation under reduced pressure. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)amino)-N-methylacetamide. ¹ H NMR (500 MHz, DMSO) δ9.46 (s, 1H), 8.90 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.83 (q, J = 4.4 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.29 (t, J = 7.9 Hz, 1H), 6.88 (s, 1H), 6.63 (t, J = 5.9 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 5.98 (d, J = 7.9 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.85 (d, J = 5.9 Hz, 2H), 2.67 (d, J = 4.6 Hz, 3H).MS m/z(ESI):435.19[M+H] ⁺ .

Example 92. Synthesis of 1-(4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol Compound 92

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 1-(4-(6-bromopyridin-2-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol (65 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a yellow product 1-(4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol. ¹ H NMR (500MHz, DMSO) δ10.04 (s, 1H), 9.06 (d, J = 7.2 Hz, 1H), 8.65 (d, J = 1.4 Hz, 1H), 8.35 (s, 1H), 8.11 (s, 2H), 7.73 (t, J = 7.8 Hz, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 7.4 Hz, 1H), 7.08 (s, 1H), 4.95 (d, J = 14.6 Hz, 1H), 4.21 (s, 2H), 4.05 (s, 3H), 4.04 (s, 3H), 1.22 (s, 6H). MS m/z (ESI): 487.22 [M+H] ⁺ .

Example 93. Synthesis of N-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 93

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 2-bromo-6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridine (60 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine. ¹ H NMR (500 MHz, DMSO) δ 10.03 (s, 1H), 8.99 (d, J = 7.3 Hz, 1H), 8.80 (s, 1H), 8.56 (d, J = 1.8 Hz, 1H), 8.37 (s, 1H), 8.05 (s, 0.25H), 8.01 (d, J = 1.8 Hz, 1H), 7.94 (s, 0.5H), 7.82 (s, 0.25H), 7.70 (t, J = 7.9 Hz, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.28 (d, J = 7.4 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 6.99 (s, 1H), 3.96 (s, 3H), 3.94 (s, 3H). MS m/z(ESI):465.16[M+H] ⁺ .

Example 94. Synthesis of N-(6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 94

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 2-bromo-6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridine (61 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino-9,9-dimethyloxanthene) (11 mg) and tetrakis(triphenylphosphine)palladium (21 mg) were added respectively under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phase was combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine. MS m/z(ESI):499.22[M+H] ⁺ .

Example 95. Synthesis of N-(6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 95

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 2-bromo-6-(3,6-dihydro-2H-pyran-4-yl)pyridine (48 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakis(triphenylphosphine)palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine. ¹ H NMR (500 MHz, DMSO) δ9.93 (s, 1H), 8.95 (d, J = 7.3 Hz, 1H), 8.53 (d, J = 1.9 Hz, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.96 (s, 1H), 6.79 (s, 1H), 4.32 (d, J = 2.6 Hz, 2H), 3.96 (s, 3H), 3.94 (s, 3H), 3.88 (t, J = 5.4 Hz, 2H), 2.59 (d, J = 1.5 Hz, 2H).MS m/z(ESI):431.18[M+H] ⁺ .

Example 96. Synthesis of N-(6-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 96

In a 25 mL round-bottom flask, add 4 mL of 1,4-dioxane, and add 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidine-2-amine (50 mg), 2-bromo-6-(1-isopropyl-1H-pyrazol-4-yl)pyridine (53 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino-9,9-dimethyloxanthene) (11 mg) and tetrakistriphenylphosphine palladium (21 mg) respectively under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, the reaction was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were respectively 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine. ¹ H NMR (500 MHz, DMSO) δ9.90 (s, 1H), 8.96 (d, J = 7.4 Hz, 1H), 8.56 (d, J = 1.9 Hz, 1H), 8.32 (s, 1H), 8.04 (s, 1H), 8.01 (d, J = 1.9 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 6.98 (s, 1H), 4.59 (dt, J = 13.3, 6.6 Hz, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 1.50 (s, 3H), 1.48 (s, 3H).MS m/z(ESI):457.21[M+H] ⁺ .

Example 97. Synthesis of N-(6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 97

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 2-bromo-6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridine (50 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine. ¹ H NMR (500 MHz, DMSO) δ 9.82 (s, 1H), 8.96 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.09 (s, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.87 (s, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.85 (s, 3H), 2.48 (s, 3H). MS m/z (ESI): 443.19 [M+H] ⁺ .

Example 98. Synthesis of N-(6-(4,4-difluoropiperidin-1-yl)methyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 98

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 2-bromo-6-(4,4-difluoropiperidin-1-yl)methyl) Pyridine (64 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg) and tetrakis(triphenylphosphine)palladium (21 mg). The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, the reaction was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product. The crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(4,4-difluoropiperidin-1-yl)methyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine. ¹ H NMR (500 MHz, DMSO) δ 9.93 (s, 1H), 8.95 (d, J = 6.4 Hz, 1H), 8.54 (s, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.64 (t, J = 7.0 Hz, 1H), 7.51 (d, J = 6.9 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 6.97-6.88 (m, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.65 (s, 2H), 2.61 (s, 4H), 2.01 (s, 4H). MS m/z (ESI): 482.21 [M+H] ⁺ .

Example 99. Synthesis of N-(6-(2-ethyl-1H-imidazol-1-yl)methyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 99

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 2-bromo-6-(2-ethyl-1H-imidazol-1-yl)methyl)pyridine (59 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(2-ethyl-1H-imidazol-1-yl)methyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine. ¹ H NMR (500 MHz, DMSO) δ 10.01 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.26 (d, J = 0.8 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 6.93 (s, 1H), 6.88 (s, 1H), 6.48 (d, J = 7.0 Hz, 1H), 5.25 (s, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 2.81-2.74 (m, 2H), 1.11 (t, J = 7.0 Hz, 3H).MS m/z(ESI):457.21[M+H] ⁺ .

Example 100. Synthesis of N-(6-(1-methylpyrrolidin-3-yl)oxy)methyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 100

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 2-bromo-6-(1-methylpyrrolidin-3-yl)oxy)methyl)pyridine (60 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(1-methylpyrrolidin-3-yl)oxy)methyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine. MS m/z(ESI):462.23[M+H] ⁺ .

Example 101. Synthesis of N-(6-(tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 101

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 2-bromo-6-(tetrahydrofuran-3-yl)oxy)methyl)pyridine (57 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine. ¹ H NMR (500MHz, DMSO) δ9.96 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.68-7.63 (m, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 6.9 5 (s, 1H), 6.89 (d, J = 7.3 Hz, 1H), 4.53 (d, J = 3.1 Hz, 2H), 4.32-4.29 (m, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.83-3.78 (m, 2H), 3.74-3.69 (m, 2H), 2.01 (td, J = 7.0, 4.2 Hz, 2H). MS m/z (ESI): 449.19 [M+H] ⁺ .

Example 102. Synthesis of (S)-5-((6-((5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methoxy)methyl)pyrrolidin-2-one Compound 102

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), (S)-5-(6-bromopyridin-2-yl)methoxy)methyl)pyrrolidin-2-one (63 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-5-((6-((5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methoxy)methyl)pyrrolidin-2-one. MS m/z(ESI):476.20[M+H] ⁺ .

Example 103. Synthesis of (R)-5-((6-((5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methoxy)methyl)pyrrolidin-2-one Compound 103

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), (R)-5-(6-bromopyridin-2-yl)methoxy)methyl)pyrrolidin-2-one (63 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a yellow product (R)-5-((6-((5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methoxy)methyl)pyrrolidin-2-one. MS m/z (ESI):476.20[M+H] ⁺ .

Example 104. Synthesis of 1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-methylimidazolin-2-one Compound 104

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 1-(6-bromopyridin-2-yl)methyl)-3-methylimidazolin-2-one (54 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-methylimidazolin-2-one. MS m/z(ESI):461.20[M+H] ⁺ .

Example 105. Synthesis of N-(6-(4-methyl-1H-imidazol-1-yl)methyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 105

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 2-bromo-6-(4-methyl-1H-imidazol-1-yl)methyl)pyridine (50 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(4-methyl-1H-imidazol-1-yl)methyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine. MS m/z(ESI):443.19[M+H] ⁺ .

Example 106. Synthesis of N-(6'-morpholinyl-[2,3'-bipyridyl]-6-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 106

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 4-(6-bromo-[2,3'-bipyridyl]-6'-yl)morpholine (64 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakis(triphenylphosphine)palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6'-morpholinyl-[2,3'-bipyridine]-6-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin- ² -amine. NMR (500 MHz, DMSO) δ 10.02 (s, 1H), 8.97 (d, J = 7.2 Hz, 1H), 8.92 (d, J = 1.5 Hz, 1H), 8.54 (s, 1H), 8.24 (dd, J = 8.8, 1.8 Hz, 1H), 7.98 (s, 1H), 7.69 (t, J = 7.9 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.02 (s, 1H), 6.98 (d, J = 8.9 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.75-3.71 (m, 4H), 3.58-3.54 (m, 4H). MS m/z(ESI):511.22[M+H] ⁺ .

Example 107. Synthesis of 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-a]pyridin-2-yl)amino)-N,N-diethylpyridinamide Compound 107

20 mL of 1,4-dioxane was added to a 100 mL round-bottom flask, and 6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-amine (300 mg), methyl 6-bromopicolinate (287 mg), cesium carbonate (1.1 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (64 mg) and tetrakistriphenylphosphine palladium (127 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of The mixture was neutralized in water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)picolinic acid methyl ester. MS m/z(ESI):407.15[M+H] ⁺ .

4 mL of methanol was added to a 100 mL round-bottom flask, and 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)picolinic acid methyl ester (240 mg) and sodium hydroxide solution (8 mL, 1 mol/L) were added under stirring at room temperature. The reaction system was then reacted for 8 hours at room temperature. After the reaction was completed, the reaction was neutralized with 1 mol/L hydrochloric acid solution. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)picolinic acid. MS m/z(ESI):393.13[M+H] ⁺ .

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and diethylamine (12 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)-N,N-diethylpyridineamide. ¹ H NMR (500 MHz, DMSO) δ 10.34 (s, 1H), 9.28 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.14 (d, J = 1.8 Hz, 1H), 8.02 (dd, J = 9.2, 1.5 Hz, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.74-7.69 (m, 2H), 6.99 (d, J = 7.3 Hz, 1H), 3.92 (s, 6H), 3.44 (q, J = 7.0 Hz, 2H), 3.27 (q, J = 7.0 Hz, 2H), 1.16 (t, J = 7.0 Hz, 3H), 1.09 (t, J = 7.0 Hz, 3H). MS m/z (ESI): 448.21 [M+H] ⁺ .

Example 108. Synthesis of 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-a]pyridin-2-yl)amino)-N,N-diethylpyridinamide Compound 108

In a 100 mL round-bottom flask, add 20 mL of 1,4-dioxane and add 7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-amine (300 mg), methyl 6-bromopicolinate (287 mg), cesium carbonate (1.1 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (64 mg) and tetrakis(triphenylphosphine)palladium (127 mg). The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, the reaction was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, methyl 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)picolinate. MS m/z (ESI): 407.15 [M+H] ⁺ .

4 mL of methanol was added to a 100 mL round-bottom flask, and 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)picolinic acid methyl ester (240 mg) and sodium hydroxide solution (8 mL, 1 mol/L) were added under stirring at room temperature. The reaction system was reacted for 8 hours at room temperature. After the reaction was completed, the reaction was neutralized with 1 mol/L hydrochloric acid solution. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)picolinic acid. MS m/z(ESI):393.13[M+H] ⁺ .

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and diethylamine (12 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)-N,N-diethylpyridineamide. ¹ H NMR (500 MHz, DMSO) δ 10.30 (s, 1H), 8.87 (d, J = 7.1 Hz, 1H), 8.24 (d, J = 9.0 Hz, 2H), 8.06 (d, J = 1.2 Hz, 1H), 7.89-7.83 (m, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.51 (dd, J = 7.1, 1.8 Hz, 1H), 6.99 (d, J = 7.3 Hz, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.44 (q, J = 7.0 Hz, 2H), 3.27 (q, J = 6.9 Hz, 2H), 1.16 (t, J = 7.1 Hz, 3H), 1.09 (t, J = 7.0 Hz, 3H).MS m/z(ESI):448.21[M+H] ⁺ .

Example 109. Synthesis of 6-(6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N,N-diethylpyridineamide Compound 109

20 mL of 1,4-dioxane was added to a 100 mL round-bottom flask, and 6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazine-2-amine (300 mg), 6-bromopicolinic acid methyl ester (287 mg), cesium carbonate (1.1 g), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (64 mg) and tetrakis(triphenylphosphine)palladium (127 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, methyl 6-(6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)aminopicolinate. MS m/z (ESI): 407.15 [M+H] ⁺ .

4 mL of methanol was added to a 100 mL round-bottom flask, and 6-(6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)aminopicolinic acid methyl ester (240 mg) and sodium hydroxide solution (8 mL, 1 mol/L) were added under stirring at room temperature. The reaction system was then reacted for 8 hours at room temperature. After the reaction was completed, the reaction was neutralized with 1 mol/L hydrochloric acid solution. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)amino)picolinic acid. MS m/z(ESI):393.13[M+H] ⁺ .

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and diethylamine (12 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)amino)-N,N-diethylpicolinamide. ¹ H NMR (500 MHz, DMSO) δ 10.19 (s, 1H), 8.41-8.38 (m, 2H), 8.00 (d, J = 9.4 Hz, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.79 (d, J = 9.4 Hz, 1H), 7.73-7.69 (m, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 7.2 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.51 (q, J = 6.8 Hz, 2H), 3.28 (dd, J = 13.9, 7.0 Hz, 2H), 1.21 (t, J = 7.0 Hz, 3H), 1.06 (t, J = 6.9 Hz, 3H).MS m/z(ESI):448.21[M+H] ⁺ .

Example 110. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-N,N-diethylpyridinamide Compound 110

20 mL of 1,4-dioxane was added to a 100 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-amine (300 mg), 6-bromopicolinic acid methyl ester (288 mg), cesium carbonate (1.1 g), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (64 mg) and tetrakistriphenylphosphine palladium (128 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, methyl 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)aminopicolinate. MS m/z (ESI): 406.15 [M+H] ⁺ .

4 mL of methanol was added to a 100 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)aminopicolinic acid methyl ester (240 mg) and sodium hydroxide solution (8 mL, 1 mol/L) were added under stirring at room temperature. The reaction system was then reacted for 8 hours at room temperature. After the reaction was completed, the reaction was neutralized with 1 mol/L hydrochloric acid solution. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid. MS m/z(ESI):392.14[M+H] ⁺ .

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and diethylamine (12 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N,N-diethylpicolinamide. ¹ H NMR (500 MHz, DMSO) δ9.94 (s, 1H), 8.57 (d, J = 7.2 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 7.90 (s, 1H), 7.75-7.70 (m, 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.14 (dd, J = 7.2, 1.8 Hz, 1H), 6.84 (d, J = 7.2 Hz, 1H), 6.69 (s, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.46 (q, J =7.0 Hz, 2H), 3.27 (q, J = 6.9 Hz, 2H), 1.18 (t, J = 7.0 Hz, 3H), 1.07 (t, J = 7.0 Hz, 3H). MS m/z (ESI): 447.21 [M+H] ⁺ .

Example 111. Synthesis of 1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyridin-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one Compound 111

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-amine (50 mg), 1-(6-bromopyridin-2-yl)pyrrolidin-2-one (49 mg), cesium carbonate (181 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakistriphenylphosphine palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one. MS m/z(ESI):431.18[M+H] ⁺ .

Example 112. Synthesis of (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyridin-2-yl)amino)pyridin-2-yl)(pyrrolidin-1-yl)methanone Compound 112

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-amine (50 mg), (6-bromopyridin-2-yl)(pyrrolidin-1-yl)methanone (52 mg), cesium carbonate (181 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakis(triphenylphosphine)palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)amino)pyridin-2-yl)(pyrrolidin-1-yl)methanone. ¹ H NMR (500 MHz, DMSO) δ9.89 (s, 1H), 8.56 (d, J = 7.2 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 1.4 Hz, 1H), 7.74 (dd, J = 8.3, 7.4 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.14 (dd, J = 7.2, 2.1 Hz, 1H), 7.05 (d, J = 6.9 Hz, 1H), 6.70 (s, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.61 (t, J = 6.4 Hz, 2H), 3.51 (t, J = 6.7 Hz, 2H), 1.92-1.82 (m, 4H). MS m/z (ESI): 445.20 [M+H] ⁺ .

Example 113. Synthesis of (6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone Compound 113

20 mL of 1,4-dioxane was added to a 100 mL round-bottom flask, and 5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (300 mg), 6-bromopicolinic acid methyl ester (275 mg), cesium carbonate (1.13 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (67 mg) and tetrakis(triphenylphosphine)palladium (134 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, methyl 6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)aminopicolinate. MS m/z (ESI): 395.13 [M+H] ⁺ .

4 mL of methanol was added to a 100 mL round-bottom flask, and 6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)aminopicolinic acid methyl ester (200 mg) and sodium hydroxide solution (8 mL, 1 mol/L) were added under stirring at room temperature. The reaction system was then reacted for 8 hours at room temperature. After the reaction was completed, the reaction was neutralized with 1 mol/L hydrochloric acid solution. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)picolinic acid. MS m/z(ESI):381.11[M+H] ⁺ .

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)picolinic acid (50 mg), HATU (60 mg), DIPEA (0.046 mL) and 2-methylmorpholine (16 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product (6-(5-(5-fluoro -6-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone. MS m/z(ESI):464.18[M+H] ⁺ .

Example 114. Synthesis of N-(2-(dimethylamino)ethyl)-N-ethyl-6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)picolinamide Compound 114

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)picolinic acid (50 mg), HATU (60 mg), DIPEA (0.046 mL) and N1-ethyl-N2,N2-dimethylethane-1,2-diamine (19 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(2-(dimethylamino)ethyl)-N-ethyl-6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)picolinamide. MS m/z(ESI): 479.23[M+H] ⁺ .

Example 115. Synthesis of tert-butyl 4-(6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridinoyl)piperazine-1-carboxylate Compound 115

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)picolinic acid (50 mg), HATU (60 mg), DIPEA (0.046 mL) and tert-butyl piperazine-1-carboxylate (30 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 4-(6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridinoyl)piperazine-1-carboxylic acid tert-butyl ester. ¹ H NMR (500 MHz, DMSO) δ 10.18 (s, 1H), 9.01 (t, J = 10.2 Hz, 1H), 8.81 (d, J = 1.7 Hz, 1H), 8.37 (dd, J = 11.7, 1.7 Hz, 1H), 7.78 (t, J = 7.9 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 7.3 Hz, 1H), 6.83 (s, 1H), 4.03 (s, 3H), 3.68 (s, 2H), 3.49 (s, 4H), 3.40 (s, 2H), 1.41 (s, 9H). MS m/z (ESI): 549.24 [M+H] ⁺ .

Example 116. Synthesis of (6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(piperazin-1-yl)methanone Compound 116

3 mL of methanol was added to a 100 mL round-bottom flask, and 4-(6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridinoyl)piperazine-1-carboxylic acid tert-butyl ester (30 mg) and 1 mL of hydrochloric acid in ethyl acetate were added under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by vacuum distillation. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The crude product was obtained by vacuum distillation of the organic phase, and the yellow product (6-(5-(5-fluoro-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(piperazine-1-yl)methanone was obtained after silica gel column chromatography. ¹ H NMR (500 MHz, DMSO) δ 10.20 (s, 1H), 9.02 (d, J = 7.2 Hz, 1H), 8.84 (d, J = 1.8 Hz, 1H), 8.41 (dd, J = 11.7, 1.8 Hz, 1H), 7.82-7.74 (m, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.85 (s, 1H), 4.04 (s, 3H), 3.69 (s, 2H), 3.48 (s, 2H), 2.91 (s, 2H), 2.80 (s, 2H). MS m/z (ESI): 449.18 [M+H] ⁺ .

Example 117. Synthesis of 6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N,N-diethylpyridinamide Compound 117

In a 100 mL round-bottom flask, add 20 mL of 1,4-dioxane and add 5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (300 mg), methyl 6-bromopicolinate (232 mg), cesium carbonate (1.11 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57 mg) and tetrakis(triphenylphosphine)palladium (113 mg). The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, the reaction was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)aminopicolinic acid methyl ester. MS m/z (ESI): 443.13 [M+H] ⁺ .

4 mL of methanol was added to a 100 mL round-bottom flask, and 6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)aminopicolinic acid methyl ester (200 mg) and sodium hydroxide solution (8 mL, 1 mol/L) were added under stirring at room temperature. The reaction system was then reacted for 8 hours at room temperature. After the reaction was completed, the reaction was neutralized with 1 mol/L hydrochloric acid solution. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)picolinic acid. MS m/z(ESI):429.11[M+H] ⁺ .

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)picolinic acid (50 mg), HATU (53 mg), DIPEA (0.042 mL) and diethylamine (10 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)-N,N-diethylpicolinamide. ¹ H NMR (500 MHz, DMSO) δ 10.16 (s, 1H), 9.02 (d, J = 7.2 Hz, 1H), 8.88 (d, J = 1.8 Hz, 1H), 8.33 (d, J = 1.3 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.55 (d, J = 7.3 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.50 (s, 0 .25H), 7.36(s, 0.5H), 7.21(s, 0.25H), 6.91(d, J＝7.3Hz, 1H), 6.78(s, 1H), 4.03(s, 3H), 3.49(q, J＝6.9Hz, 2H), 3.28(q, J＝6.8Hz, 2H), 1.19(t, J＝7.0Hz, 3H), 1.08(t, J＝7.0Hz, 3H).MS m/z(ESI): 484.19[M+H] ⁺ .

Example 118. Synthesis of (6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone Compound 118

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)picolinic acid (50 mg), HATU (53 mg), DIPEA (0.042 mL) and 2-methylmorpholine (14 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone. MS m/z(ESI):512.19[M+H] ⁺ .

Example 119. Synthesis of 6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(2-(dimethylamino)ethyl)-N-ethylpicolinamide Compound 119

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)picolinic acid (50 mg), HATU (53 mg), DIPEA (0.042 mL) and N,N-dimethyl-N'-ethylethylenediamine (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N-(2-(dimethylamino)ethyl)-N-ethylpicolinamide. MS m/z(ESI):527.23[M+H] ⁺ .

Example 120. Synthesis of tert-butyl 4-(6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridinoyl)piperazine-1-carboxylate Compound 120

In a 25 mL round-bottom flask, 2 mL of tetrahydrofuran was added, and 6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)picolinic acid (50 mg), HATU (53mg), DIPEA (0.042mL) and tert-butyl piperazine-1-carboxylate (26mg). The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10mL of water. The mixed solution was extracted three times with 20mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20mL of water and 20mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 4-(6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridinoyl)piperazine-1-carboxylic acid tert-butyl ester. ¹ H NMR (500 MHz, DMSO) δ 10.18 (s, 1H), 9.02 (d, J = 7.2 Hz, 1H), 8.88 (d, J = 1.9 Hz, 1H), 8.33 (d, J = 1.7 Hz, 1H), 7.82-7.75 (m, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.49 (s, 0.25H), 7.4 7 (d, J = 8.4 Hz, 1H), 7.34 (s, 0.5H), 7.19 (s, 0.25H), 7.02 (d, J = 7.3 Hz, 1H), 6.83 (s, 1H), 4.02 (s, 3H), 3.67 (s, 2H), 3.49 (d, J = 23.1 Hz, 4H), 3.38 (s, 2H), 1.41 (s, 9H). MS m/z (ESI): 597.24 [M+H] ⁺ .

Example 121. Synthesis of (6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(piperazin-1-yl)methanone Compound 121

Add 3 mL of methanol to a 100 mL round-bottom flask, and add tert-butyl 4-(6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridinoyl)piperazine-1-carboxylate (30 mg) and 1 mL of hydrochloric acid in ethyl acetate under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by distillation under reduced pressure. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product (6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(piperazine-1-yl)methanone. ¹ H NMR (500 MHz, DMSO) δ 10.18 (s, 1H), 9.03 (d, J = 7.3 Hz, 1H), 8.89 (d, J = 2.0 Hz, 1H), 8.34 (s, 1H), 7.80-7.76 (m, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.50 (s, 0.25H), 7.45 (d, J = 8.4 Hz, 1H), 7.35 (s, 0.5H), 7.20 (s, 0.25H), 7.01 (d, J = 7.2 Hz, 1H), 6.84 (s, 1H), 4.03 (s, 3H), 3.72 (s, 2H), 3.51 (s, 2H), 2.95 (s, 2H), 2.84 (s, 2H). MS m/z(ESI):497.19[M+H] ⁺ .

Example 122. Synthesis of tert-butyl 4-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridinoyl)piperazine-1-carboxylate Compound 122

20 mL of 1,4-dioxane was added to a 100 mL round-bottom flask, and 5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (300 mg), 6-bromopicolinic acid methyl ester (231 mg), cesium carbonate (948 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (56 mg) and tetrakis(triphenylphosphine)palladium (112 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, methyl 6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)aminopicolinate. MS m/z(ESI):444.12[M+H] ⁺ .

4 mL of methanol was added to a 100 mL round-bottom flask, and 6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)aminopicolinic acid methyl ester (200 mg) and sodium hydroxide solution (8 mL, 1 mol/L) were added under stirring at room temperature. The reaction system was then reacted for 8 hours at room temperature. After the reaction was completed, the reaction was neutralized with 1 mol/L hydrochloric acid solution. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)picolinic acid. MS m/z(ESI):430.10[M+H] ⁺ .

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)picolinic acid (50 mg), HATU (53 mg), DIPEA (0.042 mL) and tert-butyl piperazine-1-carboxylate (26 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, 4-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridinoyl)piperazine-1-carboxylic acid tert-butyl ester. ¹ H NMR (500 MHz, DMSO) δ 10.20 (s, 1H), 9.23 (d, J = 2.0 Hz, 1H), 9.04 (d, J = 7.3 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 7.81-7.74 (m, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 7.3 Hz, 1H), 6.84 (s, 1H), 4.08 (s, 3H), 3.68 (s, 2H), 3.50 (d, J＝18.9 Hz, 4H), 3.39 (s, 2H), 1.40 (s, 9H). MS m/z (ESI): 599.23 [M+H] ⁺ .

Example 123. Synthesis of (6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)(piperazin-1-yl)methanone Compound 123

Add 3 mL of methanol to a 100 mL round-bottom flask, and add tert-butyl 4-(6-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridinoyl)piperazine-1-carboxylate (30 mg) and 1 mL of hydrochloric acid in ethyl acetate under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by distillation under reduced pressure. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(piperazin-1-yl)methanone. MS m/z(ESI):499.18[M+H] ⁺ .

Example 124. Synthesis of (6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone Compound 124

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)picolinic acid (50 mg), HATU (53 mg), DIPEA (0.042 mL) and 2-methylmorpholine (14 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)(2-methylmorpholinyl)methanone. MS m/z(ESI):514.18[M+H] ⁺ .

Example 125. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N,N-diethyl-3-fluoropyridine-2-amide Compound 125

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 6-bromo-N,N-diethyl-3-fluoropyridine-2-carboxamide (55 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakis(triphenylphosphine)palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N,N-diethyl-3-fluoropyridine-2-amide. ¹ H NMR (500 MHz, DMSO) δ 10.19 (s, 1H), 8.97 (d, J = 7.3 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.75 (t, J = 8.9 Hz, 1H), 7.57-7.52 (m, 2H), 6.68 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.51 (q, J = 7.1 Hz, 2H), 3.21 (q, J = 7.0 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H), 1.07 (t, J = 7.0 Hz, 3H). MS m/z (ESI): 466.20 [M+H] ⁺ .

Example 126. Synthesis of 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)-N,N-diethyl-3-methoxypyridine-2-amide Compound 126

4 mL of 1,4-dioxane was added to a 25 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidine-2-amine (50 mg), 6-bromo-N,N-diethyl-3-methoxypyridine-2-amide (57 mg), cesium carbonate (205 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (11 mg) and tetrakis(triphenylphosphine)palladium (21 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)-N,N-diethyl-3-methoxypyridine-2-amide. ¹ H NMR (500MHz, DMSO) δ9.90 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.53 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 1.5 Hz, 1H), 7.58 (q, J = 9.1 Hz, 2H), 7.49 (d, J = 7.3 Hz, 1H), 6.63 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.78 (s, 3H), 3.48 (q, J = 7.0 Hz, 2H), 3.13 (q, J = 7.0 Hz, 2H), 1.17 (t, J = 7.0 Hz, 3H), 1.03 (t, J = 7.0 Hz, 3H). MS m/z (ESI): 478.22 [M+H] ⁺ .

Example 127. Synthesis of N-(1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)ethyl)-2,6-difluorobenzamide Compound 127

20 mL of 1,4-dioxane was added to a 100 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (200 mg), tert-butyl (1-(6-bromopyridin-2-yl)ethyl)carbamate (244 mg), cesium carbonate (723 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (43 mg) and tetrakistriphenylphosphine palladium (86 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, tert-butyl (1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)ethyl)carbamate. ¹ H NMR (500 MHz, DMSO) δ 9.91 (s, 1H), 8.93 (s, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.04 (s, 1H), 6.79 (d, J = 7.4 Hz, 1H), 4.68-4.59 (m, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 1.40 (s, 9H), 1.39 (s, 3H). MS m/z (ESI): 492.24 [M+H] ⁺ .

3 mL of methanol was added to a 50 mL round-bottom flask, and tert-butyl (1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)ethyl)carbamate (30 mg) and 1 mL of ethyl acetate solution of hydrochloric acid were added under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by vacuum distillation. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The crude product was obtained by vacuum distillation of the organic phase, and the yellow product N-(6-(1-aminoethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-amine was obtained after silica gel column chromatography. MS m/z(ESI):392.18[M+H] ⁺ .

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N-(6-(1-amino)- The reaction system was reacted at 0°C for 1 hour. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)ethyl)-2,6-difluorobenzamide. ¹ H NMR (500 MHz, DMSO) δ 9.99 (s, 1H), 9.27 (d, J = 7.9 Hz, 1H), 8.95 (d, J = 7.5 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.69-7.65 (m, 1H), 7.56-7.49 (m, 2H), 7.24-7.16 (m, 3H), 7.03 (s, 1H), 6.92 (d, J = 7.4 Hz, 1H), 5.14 (p, J = 7.1 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 1.55 (d, J = 7.1 Hz, 3H). MS m/z (ESI): 532.19 [M+H] ⁺ .

Example 128. Synthesis of N-(1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)ethyl)-4-methoxybenzamide Compound 128

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(1-aminoethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 4-methoxybenzoyl chloride (27 mg) and DIPEA (0.044 mL) under stirring at 0°C. The reaction system was continued at 0°C for 1 hour. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(1-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)ethyl)-4-methoxybenzamide. ¹ H NMR (500MHz, DMSO) δ9.98 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.71 (d, J = 7.7 Hz, 1H), 8.56 (d, J = 1.6 Hz, 1H), 8.00 (d, J = 1.5 Hz, 1H), 7.97 (d, J = 8.7 Hz, 2H), 7.62 (t, J = 7.8 Hz, 1H), 7.52 (d, J＝7.3 Hz, 1H), 7.18 (d, J＝8.2 Hz, 1H), 7.09 (s, 1H), 7.00 (d, J＝8.8 Hz, 2H), 6.89 (d, J＝7.4 Hz, 1H), 5.22-5.15 (m, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.78 (s, 3H), 1.60 (d, J＝7.1 Hz, 3H). MS m/z (ESI): 526.22 [M+H] ⁺ .

Example 129. Synthesis of tert-butyl ((6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamate Compound 129

80 mL of 1,4-dioxane was added to a 100 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-amine (1.05 g), tert-butyl ((6-bromopyridin-2-yl)methyl)carbamate (1.2 g), cesium carbonate (4.4 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (224 mg) and tetrakis(triphenylphosphine)palladium (447 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 30 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 30 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 30 mL of water and 30 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, tert-butyl ((6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamate. ¹ H NMR (500 MHz, DMSO) δ 9.96 (s, 1H), 8.94 (d, J = 7.3 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.42 (t, J = 6.1 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.08 (s, 1H), 6.73 (d, J = 7.3 Hz, 1H), 4.22 (d, J = 6.1 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 1.45 (s, 9H). MS m/z (ESI): 478.22 [M+H] ⁺ .

Example 130. Synthesis of N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine Compound 130

15 mL of methanol was added to a 50 mL round-bottom flask, and tert-butyl ((6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamate (1.1 g) and 5 mL of ethyl acetate solution of hydrochloric acid were added under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by vacuum distillation. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The crude product was obtained by vacuum distillation of the organic phase, and the yellow product N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-amine was obtained after silica gel column chromatography. MS m/z(ESI):378.17[M+H] ⁺ .

Example 131. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-phenylpropanamide Compound 131

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 3-phenylpropionic acid (24 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-phenylpropanamide. ¹ H NMR (500MHz, DMSO) δ9.94 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.7 Hz, 1H), 8.44 (t, J = 5.9 Hz, 1H), 7.97 (d, J = 1.7 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.2 6-7.22 (m, 4H), 7.17 (dd, J = 8.2, 4.2 Hz, 2H), 7.03 (s, 1H), 6.59 (d, J = 7.3 Hz, 1H), 4.33 (d, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.88 (s, 3H), 2.91 (t, J = 7.8 Hz, 2H), 2.57-2.53 (m, 2H). MS m/z (ESI): 510.23 [M+H] ⁺ .

Example 132. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(thiophen-2-yl)acetamide Compound 132

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 2-thiopheneacetyl chloride (26 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was continued at 0°C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin ^- 3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(thiophen-2-yl)acetamide. NMR (500MHz, DMSO) δ9.95 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.72 (t, J = 5.9 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 1.7 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.35 (dd, J = 5.1, 0.9 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.02 (s, 1H), 6.99 (d, J = 2.6 Hz, 1H), 6.95 (dd, J = 5.0, 3.5 Hz, 1H), 6.74 (d, J = 7.3 Hz, 1H), 4.36 (d, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.89 (s, 3H), 3.83 (s, 2H). MS m/z (ESI): 502.17 [M+H] ⁺ .

Example 133. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-1-methyl-1H-imidazole-4-carboxamide Compound 133

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 1-methyl-4-imidazolecarboxylic acid (20 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-1-methyl-1H-imidazole-4-carboxamide. ¹ H NMR (500 MHz, DMSO) δ9.93 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.43 (t, J = 6.1 Hz, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.68 (s, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 6.97 (s, 1H), 6.75 (d, J = 7.4 Hz, 1H), 4.50 (d, J = 6.1 Hz, 2H), 3.96 (s, 3H), 3.94 (s, 3H), 3.70 (s, 3H).MS m/z(ESI):486.20[M+H] ⁺ .

Example 134. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(4-fluorophenyl)acetamide Compound 134

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), p-fluorophenylacetyl chloride (28 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(4-fluorophenyl)acetamide. ¹ H NMR (500MHz, DMSO) δ9.94 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.61 (t, J = 5.9 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.36 (dd, J = 8.5, 5.7 Hz, 2H), 7.28 (dd, J = 8.3, 5.8 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.70 (d, J = 7.3 Hz, 1H), 4.34 (d, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.87 (s, 3H), 3.57 (s, 2H). MS m/z (ESI): 514.20 [M+H] ⁺ .

Example 135. Synthesis of tert-butyl (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-ylcarbamate Compound 135

20 mL of 1,4-dioxane was added to a 100 mL round-bottom flask, and 5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (200 mg), (6-bromopyridin-2-yl)carbamic acid tert-butyl ester (222 mg), cesium carbonate (844 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (43 mg) and tetrakis(triphenylphosphine)palladium (86 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a yellow product (tert-butyl (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-ylcarbamate). ¹ H NMR (500MHz, DMSO) δ9.88 (d, J = 14.8 Hz, 2H), 8.90 (d, J = 7.2 Hz, 1H), 8.53 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.66 (s, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 1.51 (s, 9H). MS m/z (ESI): 464.20 [M+H] ⁺ .

Example 136. Synthesis of N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine Compound 136

3 mL of methanol was added to a 50 mL round-bottom flask, and tert-butyl (6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-ylcarbamate (30 mg) and 1 mL of hydrochloric acid in ethyl acetate were added under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by distillation under reduced pressure. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The crude product was obtained by distillation of the organic phase under reduced pressure. The crude product was subjected to silica gel column chromatography to obtain the yellow product N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine. ¹ H NMR (500 MHz, DMSO) δ 9.46 (s, 1H), 8.89 (d, J = 7.2 Hz, 1H), 8.52 (d, J = 1.4 Hz, 1H), 7.96 (d, J = 1.2 Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.30-7.23 (m, 1H), 7.11 (s, 1H), 6.43 (d, J = 7.8 Hz, 1H), 5.95 (d, J = 7.8 Hz, 1H), 5.82 (s, 2H), 3.96 (s, 3H), 3.93 (s, 3H). MS m/z (ESI): 364.15 [M+H] ⁺ .

Example 137. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)benzamide Compound 137

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), benzoyl chloride (24 mg) and DIPEA (0.049 mL) were added under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine. [1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)benzamide. ¹ H NMR (500 MHz, DMSO) δ 10.70 (s, 1H), 10.00 (s, 1H), 8.94 (d, J = 7.3 Hz, 1H), 8.53 (d, J = 1.8 Hz, 1H), 7.99-7.92 (m, 3H), 7.69 (s, 1H), 7.65 (t, J = 4.0 Hz, 2H), 7.62 (d, J = 7.2 Hz, 1H), 7.57 (t, J = 7.4 Hz, 2H), 7.51 (d, J = 7.3 Hz, 1H), 6.86 (p, J = 4.3 Hz, 1H), 3.96 (s, 3H), 3.91 (s, 3H). MS m/z (ESI): 468.18 [M+H] ⁺ .

Example 138. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide Compound 138

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), HATU (65 mg), DIPEA (0.073 mL) and 4-trifluoromethylphenylacetic acid (35 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide. ¹ H NMR (500 MHz, DMSO) δ 10.54 (s, 1H), 9.96 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 7.5 Hz, 2H), 7.57 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 5.5 Hz, 3H), 6.80 (d, J = 7.9 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 2H), 3.93 (s, 3H). MS m/z (ESI): 550.18 [M+H] ⁺ .

Example 139. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)propanamide Compound 139

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), HATU (65 mg), DIPEA (0.073 mL) and 3-[2-(trifluoromethyl)pyridin-5-yl]propionic acid (37 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin- ² -yl)amino)pyridin-2-yl)-3-(6-(trifluoromethyl)pyridin-3-yl)propanamide. NMR (500 MHz, DMSO) δ 10.33 (s, 1H), 9.97 (s, 1H), 8.94 (d, J = 7.3 Hz, 1H), 8.73 (d, J = 1.2 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 8.02 (dd, J = 8.0, 1.5 Hz, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.60-7.54 (m, 2H), 7.54-7.49 (m, 2H), 6.80 (dd, J = 7.0, 1.7 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.09 (t, J = 7.5 Hz, 2H), 2.89 (t, J = 7.5 Hz, 2H). MS m/z(ESI):565.19[M+H] ⁺ .

Example 140. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-2-(6-methoxypyridin-3-yl)acetamide Compound 140

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), HATU (65 mg), DIPEA (0.073 mL) and 6-methoxy-3-pyridineacetic acid (28 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-2-(6-methoxypyridin-3-yl)acetamide. ¹ H NMR (500 MHz, DMSO) δ 10.51 (s, 1H), 9.99 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 2.2 Hz, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.71 (dd, J = 8.5, 2.3 Hz, 1H), 7.61-7.51 (m, 4H), 6.82 (dd, J = 8.2, 3.4 Hz, 2H), 3.97 (s, 3H), 3.94 (s, 3H), 3.84 (s, 3H), 3.78 (s, 2H). MS m/z (ESI): 513.20 [M+H] ⁺ .

Example 141. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)furan-2-carboxamide Compound 141

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), furanoyl chloride (22 mg) and DIPEA (0.049 mL) with stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)furan-2-carboxamide. ¹ H NMR (500 MHz, DMSO) δ 10.36 (s, 1H), 10.00 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 8.02-7.95 (m, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.51 (d, J = 3.5 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.75 (dd, J = 3.4, 1.6 Hz, 1H), 3.97 (s, 3H), 3.94 (s, 3H). MS m/z (ESI): 458.16 [M+H] ⁺ .

Example 142. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)thiophene-2-carboxamide Compound 142

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), 2-thiophenecarbonyl chloride (25 mg) and DIPEA (0.049 mL) with stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)thiophene-2-carboxamide. MS m/z(ESI):474.13[M+H] ⁺ .

Example 143. N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-yl Synthesis of 2-(3-thiophene-1-yl)acetamide Compound 143

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), 2-(thiophene-3-yl)acetyl chloride (27 mg) and DIPEA (0.049 mL) under stirring at 0°C. The reaction system was continued at 0°C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-2-(thiophen-3-yl)acetamide. ¹ H NMR (500 MHz, DMSO) δ 10.43 (s, 1H), 9.95 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.60-7.48 (m, 5H), 7.36 (d, J = 1.9 Hz, 1H), 7.13 (dd, J = 4.9, 1.1 Hz, 1H), 6.80 (dt, J = 10.6, 5.2 Hz, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.82 (s, 2H). MS m/z (ESI): 488.15 [M+H] ⁺ .

Example 144. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide Compound 144

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), 2-(tetrahydro-2H-pyran-4-yl)acetyl chloride (28 mg) and DIPEA (0.049 mL) under stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide. ¹ H NMR (500MHz, DMSO) δ10.23 (s, 1H), 9.92 (s, 1H), 8.94 (d, J＝7.2Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.57 (t, J = 7.1 Hz, 2H), 7.53 (dd, J = 9.4, 7.2 Hz, 2H), 6.76 (dd, J = 7.0, 1.7 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.84 (dd, J = : 11.3, 2.6 Hz, 2H), 3.33 (dd, J = 11.8, 1.7 Hz, 2H), 2.40 (d, J = 7.1 Hz, 2H), 2.04 (dtd, J = 14.8, 7.5, 3.7 Hz, 1H), 1.63 (d, J = 12.8 Hz, 2H), 1.28 (ddd, J = 24.8, 12.3, 4.4 Hz, 2H). MS m/z (ESI): 490.22 [M+H] ⁺ .

Example 145. Synthesis of (S)-tert-butyl 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate Compound 145

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), (S)-2-(carbonyl chloride)pyrrolidine-1-carboxylic acid tert-butyl ester (40 mg) and DIPEA (0.049 mL) with stirring at 0°C. The reaction system was then reacted at 0°C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-tert-butyl 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate. MS m/z(ESI):561.26[M+H] ⁺ .

Example 146. Synthesis of (S)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidine-2-carboxamide Compound 146

Add 3 mL of methanol to a 50 mL round-bottom flask, and add (S)-2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (30 mg) and 1 mL of hydrochloric acid in ethyl acetate under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by distillation under reduced pressure. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively. Then it was dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidine-2-carboxamide. ¹ H NMR (500 MHz, DMSO) δ 10.42 (s, 1H), 10.00 (s, 1H), 8.96 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.57-7.51 (m, 2H), 7.16 (s, 1H), 6.99 (d, J = 8.0 Hz, 1H), 4.08 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.13-3.05 (m, 2H), 2.23 (td, J = 15.5, 7.3 Hz, 1H), 1.94-1.86 (m, 1H), 1.84-1.75 (m, 2H). MS m/z(ESI):461.20[M+H] ⁺ .

Example 147. Synthesis of (S)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)-1-(3,3,3-trifluoropropionyl)pyrrolidine-2-carboxamide Compound 147

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and (S)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidine-2-carboxamide (10 mg), HATU (10 mg), DIPEA (0.008 mL) and trifluoropropionic acid (3 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-1-(3,3,3-trifluoropropionyl)pyrrolidine-2-carboxamide. MS m/z(ESI):571.20[M+H] ⁺ .

Example 148. Synthesis of (S)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)-1-(2-morpholinoethyl)pyrrolidine-2-carboxamide Compound 148

2 mL of N,N-dimethylformamide was added to a 25 mL round-bottom flask, and (S)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidine-2-carboxamide (30 mg), 2-(4-morpholino)ethyl bromide (15 mg) and cesium carbonate (50 mg) were added under stirring at room temperature. The reaction system was heated at 60 °C. The reaction was continued for 14 hours. After the reaction was completed, the reaction was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product (S)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)-1-(2-morpholineethyl)pyrrolidine-2-carboxamide. MS m/z(ESI):574.29[M+H] ⁺ .

Example 149. Synthesis of tert-butyl 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)piperidine-1-carboxylate Compound 149

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), tert-butyl 2-(chlorocarbonyl)piperidine-1-carboxylate (40 mg) and DIPEA (0.049 mL) with stirring at 0°C. The reaction system was then reacted at 0°C for 1 hour. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, tert-butyl 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)piperidine-1-carboxylate. MS m/z(ESI):575.27[M+H] ⁺ .

Example 150. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-2-carboxamide Compound 150

Add 3 mL of methanol to a 50 mL round-bottom flask, and add tert-butyl 2-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)piperidine-1-carboxylate (30 mg) and 1 mL of hydrochloric acid in ethyl acetate under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by distillation under reduced pressure. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then Then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-2-carboxamide. ¹ H NMR (500MHz, DMSO) δ 10.42 (s, 1H), 10.01 (s, 1H), 8.89 (d, J = 7.2 Hz, 1H), 8.47 (d, J = 1.7 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 7.3 Hz, 2H), 7.34 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.77 (d, J = 9.7 Hz, 1H), 3.14 (d, J = 12.7 Hz, 1H), 2.76 (dd, J = 16.9, 7.3 Hz, 1H), 2.06 (d, J = 10.8 Hz, 1H), 1.77 (d, J = 11.8 Hz, 1H), 1.61 (t, J = 11.6 Hz, 1H), 1.50 (qd, J = 23.4, 11.7 Hz, 3H). MS m/z (ESI): 475.22 [M+H] ⁺ .

Example 151. Synthesis of tert-butyl 3-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)piperidine-1-carboxylate Compound 151

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), tert-butyl 3-(chlorocarbonyl)piperidine-1-carboxylate (40 mg) and DIPEA (0.049 mL) with stirring at 0°C. The reaction system was then reacted at 0°C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, tert-butyl 3-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)piperidine-1-carboxylate. MS m/z(ESI):575.27[M+H] ⁺ .

Example 152. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-3-carboxamide Compound 152

3 mL of methanol was added to a 50 mL round-bottom flask, and 3-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (30 mg) and 1 mL of hydrochloric acid in ethyl acetate were added under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by vacuum distillation. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The crude product was obtained by vacuum distillation of the organic phase, and the yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-3-carboxamide was obtained after silica gel column chromatography. ¹ H NMR (500 MHz, DMSO) δ 10.51 (s, 1H), 10.00 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 1.7 Hz, 1H), 7.62-7.51 (m, 4H), 6.80 (d, J = 7.9 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H ), 3.29 (d, J = 10.4 Hz, 2H), 3.21-3.13 (m, 1H), 3.06 (d, J = 10.6 Hz, 1H), 2.98 (t, J = 11.5 Hz, 1H), 2.84 (td, J = 12.1, 3.5 Hz, 1H), 2.14-2.05 (m, 1H), 1.87-1.72 (m, 2H), 1.68-1.57 (m, 1H). MS m/z (ESI): 475.22 [M+H] ⁺ .

Example 153. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide Compound 153

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), tetrahydropyran-4-carbonyl chloride (25 mg) and DIPEA (0.049 mL) under stirring at 0°C. The reaction system was continued at 0°C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)tetrahydro-2H-pyran-4-carboxamide. MS m/z(ESI):476.20[M+H] ⁺ .

Example 154. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)acetamide Compound 154

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), acetyl chloride (13 mg) and DIPEA (0.049 mL) were added under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)acetamide. ¹ H NMR (500 MHz, DMSO) δ 10.30 (s, 1H), 9.95 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.59-7.55 (m, 2H), 7.55-7.51 (m, 2H), 6.77 (dd, J = 9.0, 7.5 Hz, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 2.16 (s, 3H). MS m/z (ESI): 406.16 [M+H] ⁺ .

Example 155. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)propanamide Compound 155

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), propionyl chloride (16 mg) and DIPEA (0.049 mL) were added under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)propionamide. ¹ H NMR (500 MHz, DMSO) δ 10.24 (s, 1H), 9.93 (d, J = 8.7 Hz, 1H), 8.93 (t, J = 7.9 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.60-7.56 (m, 2H), 7.55 (s, 1H), 7.52 (d, J = 7.3 Hz, 1H), 6.80-6.75 (m, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 2.47 (q, J = 7.5 Hz, 2H), 1.12 (t, J = 7.5 Hz, 3H). MS m/z (ESI): 420.18 [M+H] ⁺ .

Example 156. N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridine-2-yl Synthesis of 1-(2-(4-(2-methyl-1-butyl)butanamide compound 156

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), n-butyryl chloride (18 mg) and DIPEA (0.049 mL) were added under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)butanamide. ¹ H NMR (500 MHz, DMSO) δ 10.23 (s, 1H), 9.93 (s, 1H), 8.94 (d, J = 7.3 Hz, 1H), 8.54 (d, J = 1.7 Hz, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.57 (dd, J = 14.3, 7.3 Hz, 3H), 7.52 (d, J = 7.3 Hz, 1H), 6.75 (dt, J = 8.8, 4.4 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 2.42 (t, J = 7.4 Hz, 2H), 1.68-1.60 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). MS m/z (ESI): 434.19 [M+H] ⁺ .

Example 157. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)isobutyramide Compound 157

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), isobutyryl chloride (18 mg) and DIPEA (0.049 mL) were added under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)isobutyramide. ¹ H NMR (500 MHz, DMSO) δ 10.22 (s, 1H), 9.94 (d, J = 10.3 Hz, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.7 Hz, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.62-7.55 (m, 3H), 7.52 (d, J = 7.3 Hz, 1H), 6.77 (t, J = 8.5 Hz, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 2.90-2.80 (m, 1H), 1.14 (d, J = 6.8 Hz, 6H). MS m/z (ESI): 434.19 [M+H] ⁺ .

Example 158. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)pivalamide Compound 158

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), trimethylacetyl chloride (20 mg) and DIPEA (0.049 mL) were added under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)pivalamide after silica gel column chromatography. ¹ H NMR (500 MHz, DMSO) δ 9.88 (s, 1H), 9.35 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.51 (t, J = 7.0 Hz, 2H), 7.43 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 1.29 (s, 9H). MS m/z (ESI): 448.21 [M+H] ⁺ .

Example 159. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)cyclopropanecarboxamide Compound 159

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), cyclopropylcarbonyl chloride (18 mg) and DIPEA (0.049 mL) with stirring at 0°C. The reaction system was then reacted at 0°C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)cyclopropanecarboxamide. ¹ H NMR (500 MHz, DMSO) δ 10.55 (s, 1H), 9.96 (s, 1H), 8.96 (t, J = 8.4 Hz, 1H), 8.55 (d, J = 1.7 Hz, 1H), 7.97 (d, J = 1.7 Hz, 1H), 7.60-7.50 (m, 4H), 6.77 (t, J = 8.9 Hz, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 2.14-2.06 (m, 1H), 0.89-0.80 (m, 4H). MS m/z (ESI): 432.18 [M+H] ⁺ .

Example 160. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)cyclobutanecarboxamide Compound 160

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), cyclobutylcarbonyl chloride (20 mg) and DIPEA (0.049 mL) with stirring at 0°C. The reaction system was reacted at 0°C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)cyclobutanecarboxamide. ¹ H NMR (500MHz, DMSO) δ10.11 (s, 1H), 9.95 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.7 Hz, 1H), 7.96 (d, J = 1.7 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7. 52 (d, J = 7.3 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 3.97 (s, 3H), 3.94 (s, 3H), 3.50-3.42 (m, 1H), 2.27 (dq, J = 17.9, 9.1 Hz, 2H), 2.19-2.11 (m, 2H), 2.02-1.91 (m, 1H), 1.89-1.80 (m, 1H). MS m/z (ESI): 446.19 [M+H] ⁺ .

Example 161. Synthesis of (S)-tert-butyl 2-(6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate Compound 161

20 mL of 1,4-dioxane was added to a 100 mL round-bottom flask, and 5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-amine (200 mg), (6-bromopyridin-2-yl)carbamic acid tert-butyl ester (195 mg), cesium carbonate (635 mg), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (38 mg) and tetrakis(triphenylphosphine)palladium (75 mg) were added respectively under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours, and the reaction was terminated. Afterwards, the reaction was neutralized with 20 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was chromatographed on a silica gel column to obtain a yellow product (6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-ylcarbamic acid tert-butyl ester. MS m/z(ESI):502.18[M+H] ⁺ .

3 mL of methanol was added to a 50 mL round-bottom flask, and tert-butyl (6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-ylcarbamate (30 mg) and 1 mL of hydrochloric acid in ethyl acetate were added under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by vacuum distillation. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The crude product was obtained by vacuum distillation of the organic phase, and the yellow product N2-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)pyridine-2,6-diamine was obtained after silica gel column chromatography. MS m/z(ESI):402.13[M+H] ⁺ .

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N2-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), (S)-2-(chlorocarbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (35 mg) and DIPEA (0.042 mL) were added with stirring at 0°C. The reaction system was then reacted at 0°C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-tert-butyl 2-(6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate. MS m/z(ESI):599.23[M+H] ⁺ .

Example 162. Synthesis of (S)-N-(6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidine-2-carboxamide Compound 162

Add 3 mL of methanol to a 50 mL round-bottom flask, and add (S)-2-(6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (30 mg) and 1 mL of hydrochloric acid in ethyl acetate under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by distillation under reduced pressure. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The crude product was obtained by distillation of the organic phase under reduced pressure, and the crude product was purified by silica gel column chromatography After precipitation, the yellow product (S)-N-(6-(5-(6-methoxy-5-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidine-2-carboxamide was obtained. ¹ H NMR (500 MHz, DMSO) δ 10.45 (s, 1H), 10.07 (s, 1H), 9.26 (s, 1H), 9.05 (d, J = 7.2 Hz, 1H), 8.79 (d, J = 1.7 Hz, 1H), 7.67-7.62 (m, 2H), 7.55 (d, J = 7.8 Hz, 1H), 7.26 (s, 1H), 6.96 (d, J = 8.0 Hz, 1H), 4.09 (s, 4H), 3.10 (t, J = 6.5 Hz, 2H), 2.28-2.21 (m, 1H), 2.02-1.87 (m, 2H), 1.85-1.78 (m, 2H). MS m/z (ESI): 499.18 [M+H] ⁺ .

Example 163. Synthesis of (S)-tert-butyl 2-(6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate Compound 163

20 mL of 1,4-dioxane was added to a 100 mL round-bottom flask, and 5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (200 mg), tert-butyl (6-bromopyridin-2-yl)carbamate (196 mg), cesium carbonate (636 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (38 mg) and tetrakis(triphenylphosphine)palladium (75 mg) were added under stirring at room temperature. The reaction system was reacted at 120°C for 14 hours. After the reaction was completed, 20 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, tert-butyl (6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)carbamate. MS m/z (ESI): 500.19 [M+H] ⁺ .

3 mL of methanol was added to a 50 mL round-bottom flask, and tert-butyl (6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)carbamate (30 mg) and 1 mL of ethyl acetate solution of hydrochloric acid were added under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by vacuum distillation. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The crude product was obtained by vacuum distillation of the organic phase, and the yellow product N2-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine was obtained after silica gel column chromatography. MS m/z(ESI):400.13[M+H] ⁺ .

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N2-(5-(5-(dihydrofuran)) was added under stirring at 0°C. The mixture was added with 1,4-diamino-2,6-diamine (50 mg), (S)-2-(chlorocarbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (35 mg) and DIPEA (0.044 mL). The reaction system was reacted at 0 ° C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product (S)-tert-butyl 2-(6-(5-(5-(difluoromethoxy)-6-methoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)carbamoyl)pyrrolidine-1-carboxylate. MS m/z(ESI):597.24[M+H] ⁺ .

Example 164. Synthesis of N-((6-((5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2,3-dihydrobenzo[B][1,4]dioxin-5-carboxamide Compound 164

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2,3-dihydro-1,4-benzodioxine-5-carboxylic acid (29 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-((6-((5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2,3-dihydrobenzo[B][1,4]dioxin-5-carboxamide. ¹ H NMR (500 MHz, DMSO) δ9.94 (s, 1H), 8.94 (t, J = 6.6 Hz, 2H), 8.55 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.51 (s, 2H), 7.50-7.49 (m, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.02 (s, 1H), 6.92 (d, J = 8.6 Hz, 1H), 6.77 (d, J = 7.4 Hz, 1H), 4.52 (d, J = 5.9 Hz, 2H), 4.27 (dd, J = 11.1, 5.1 Hz, 4H), 3.97 (s, 3H), 3.94 (s, 3H).MS m/z(ESI):540.20[M+H] ⁺ .

Example 165. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)benzo[D][1,3]dioxole-4-carboxamide Compound 165

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and benzo[D][1,3]dioxole-4-carboxylic acid (27 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)benzo[D][1,3]dioxole-4-carboxamide. ¹ H NMR (500 MHz, DMSO) δ9.95 (s, 1H), 9.00 (t, J = 5.9 Hz, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.63-7.57 (m, 2H), 7.52 (dd, J = 8.4, 4.4 Hz, 2H), 7.20 (d, J = 8.2 Hz, 1H), 7.02 (s, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.08 (s, 2H), 4.53 (d, J = 5.9 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H).MS m/z(ESI):526.18[M+H] ⁺ .

Example 166. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)acetamide Compound 166

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-amine (50 mg), acetyl chloride (13 mg) and DIPEA (0.045 mL) were added under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)acetamide. ¹ H NMR (500 MHz, DMSO) δ9.96 (s, 1H), 8.95 (d, J = 7.3 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 8.46 (t, J = 5.9 Hz, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.02 (s, 1H), 6.75 (d, J = 7.3 Hz, 1H), 4.33 (d, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 1.97 (s, 3H). MS m/z (ESI): 420.18 [M+H] ⁺ .

Example 167. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)propanamide Compound 167

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-amine (50 mg), propionyl chloride (15 mg) and DIPEA (0.045 mL) were added under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)propionamide. ¹ H NMR (500 MHz, DMSO) δ9.96 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.5 Hz, 1H), 8.37 (t, J = 5.8 Hz, 1H), 7.99 (d, J = 1.3 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.74 (d, J = 7.3 Hz, 1H), 4.34 (d, J = 5.8 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 2.25 (q, J = 7.6 Hz, 2H), 1.15-1.06 (m, 3H).MS m/z(ESI):434.19[M+H] ⁺ .

Example 168. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)butanamide Compound 168

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), butyryl chloride (17 mg) and DIPEA (0.045 mL) with stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. Distill under reduced pressure The crude product was obtained from the organic phase. The yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)butanamide was obtained after silica gel column chromatography. ¹ H NMR (500MHz, DMSO) δ9.97 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.40 (t, J = 5.9 Hz, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7. 19 (d, J = 8.2 Hz, 1H), 7.02 (s, 1H), 6.74 (d, J = 7.4 Hz, 1H), 4.35 (d, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 2.22 (t, J = 7.4 Hz, 2H), 1.66-1.56 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). MS m/z (ESI): 448.21 [M+H] ⁺ .

Example 169. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)isobutyramide Compound 169

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), isobutyryl chloride (17 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)isobutyramide. MS m/z(ESI):448.21[M+H] ⁺ .

Example 170. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)pivalamide Compound 170

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), pivaloyl chloride (19 mg) and DIPEA (0.045 mL) were added under stirring at 0°C. The reaction system was then reacted at 0°C for 1 hour. After the reaction was completed, The reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was purified by silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)pivalamide. ¹ H NMR (500 MHz, DMSO) δ 9.97 (s, 1H), 8.94 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.12 (t, J = 5.9 Hz, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 7.06 (s, 1H), 6.69 (d, J = 7.4 Hz, 1H), 4.35 (d, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 1.22 (s, 9H). MS m/z (ESI): 462.23 [M+H] ⁺ .

Example 171. Synthesis of Methyl ((6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamate Compound 171

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), methyl chloroformate (15 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was continued at 0°C for 1 hour. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, methyl ((6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamate. ¹ H NMR (500 MHz, DMSO) δ9.96 (s, 1H), 8.94 (d, J = 7.3 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.71 (t, J = 6.1 Hz, 1H), 7.63-7.57 (m, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 7.04 (s, 1H), 6.75 (d, J = 7.3 Hz, 1H), 4.27 (d, J = 6.1 Hz, 2H), 3.96 (s, 3H), 3.92 (d, J = 4.4 Hz, 3H), 3.71-3.61 (m, 3H).MS m/z(ESI):436.17[M+H] ⁺ .

Example 172. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-methoxyacetamide Compound 172

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and methoxyacetic acid (14 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-methoxyacetamide. ¹ H NMR (500 MHz, DMSO) δ9.99 (s, 1H), 8.94 (d, J = 7.3 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 8.37 (t, J = 5.9 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.64-7.57 (m, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.76 (d, J = 7.3 Hz, 1H), 4.41 (d, J = 5.9 Hz, 2H), 3.98 (s, 2H), 3.95 (d, J = 7.2 Hz, 3H), 3.93 (s, 3H), 3.45 (s, 3H).MS m/z(ESI):450.19[M+H] ⁺ .

Example 173. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2,2-difluoroacetamide Compound 173

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and difluoroacetic acid (15 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2,2-difluoroacetamide. ¹ H NMR (500MHz, DMSO) δ10.00 (s, 1H), 9.48 (t, J = 5.9 Hz, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.55 (t, J = 3.8 Hz, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H) ,7.23(d,J＝8.3Hz,1H),7.02(s,1H),6.77(d,J＝7.3Hz,1H),6.49(s,0.25H),6.39(s,0.5H),6.28(s,0.25H),4.44(d,J＝6.0Hz,2H),3.96(s,3H),3.93(d,J＝6.1Hz,3H).MS m/z(ESI):456.16[M+H] ⁺ .

Example 174. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3,3-difluoropropionamide Compound 174

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 3,3-difluoropropionic acid (18 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3,3-difluoropropionamide. ¹ H NMR (500 MHz, DMSO) δ9.97 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.74 (t, J = 5.9 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.76 (d, J = 7.3 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 2.99 (td, J = 17.0, 4.9 Hz, 2H).MS m/z(ESI):470.18[M+H] ⁺ .

Example 175. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-fluoropropanamide Compound 175

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 3-fluoropropionic acid (15 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-fluoropropionamide. MS m/z(ESI):452.18[M+H] ⁺ .

Example 176. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2,2,2-trifluoroacetamide Compound 176

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and trifluoroacetic acid (18 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2,2,2-trifluoroacetamide. ¹ H NMR (500 MHz, DMSO) δ 10.04 (t, J = 5.8 Hz, 1H), 9.99 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.66-7.62 (m, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.03 (s, 1H), 6.75 (d, J = 7.3 Hz, 1H), 4.47 (d, J = 5.7 Hz, 2H), 3.96 (s, 3H), 3.92 (s, 3H). MS m/z (ESI): 474.15 [M+H] ⁺ .

Example 177. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3,3,3-trifluoropropionamide Compound 177

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 3,3,3-trifluoropropionic acid (20 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3,3,3-trifluoropropionamide. ¹ H NMR (500 MHz, DMSO) δ 10.06 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.86 (t, J = 5.8 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.55-7.51 (m, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.00 (s, 1H), 6.78 (d, J = 7.3 Hz, 1H), 4.41 (d, J = 5.8 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.42 (q, J = 11.3 Hz, 2H). MS m/z(ESI): 488.17 [M+H] ⁺ .

Example 178. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(dimethylamino)acetamide Compound 178

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), dimethylglycyl chloride hydrochloride (25 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(dimethylamino)acetamide. ¹ H NMR (500 MHz, DMSO) δ 10.04 (s, 1H), 8.96 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.44 (t, J = 5.6 Hz, 1H), 7.98 (d, J = 1.5 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 7.08 (s, 1H), 6.77 (d, J = 7.3 Hz, 1H), 4.40 (t, J = 9.8 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.03 (s, 2H), 2.35 (s, 6H). MS m/z(ESI):463.22[M+H] ⁺ .

Example 179. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)cyclopropanecarboxamide Compound 179

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), cyclopropylmethyl Acid chloride (17 mg) and DIPEA (0.045 mL). The reaction system was reacted at 0 ° C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product. The crude product was chromatographed on a silica gel column to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)cyclopropanecarboxamide. ¹ H NMR (500 MHz, DMSO) δ9.96 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.62 (t, J = 5.9 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.15 (d, J = 8 .2 Hz, 1H), 7.05 (s, 1H), 6.74 (d, J = 7.3 Hz, 1H), 4.36 (d, J = 6.0 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 1.73-1.67 (m, 1H), 0.82 (dt, J = 7.3, 3.6 Hz, 2H), 0.73 (ddd, J = 10.3, 6.6, 3.4 Hz, 2H). MS m/z (ESI): 446.19 [M+H] ⁺ .

Example 180. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)cyclobutanecarboxamide Compound 180

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), cyclobutylcarbonyl chloride (19 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)cyclobutanecarboxamide. ¹ H NMR (500 MHz, DMSO) δ9.97 (s, 1H), 8.94 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.27 (t, J = 5.9 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H). H), 7.03 (s, 1H), 6.71 (d, J = 7.3 Hz, 1H), 4.33 (d, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.17 (p, J = 8.4 Hz, 1H), 2.30-2.19 (m, 2H), 2.15-2.07 (m, 2H), 1.97-1.84 (m, 1H), 1.84-1.75 (m, 1H). MS m/z (ESI): 460.21 [M+H] ⁺ .

Example 181. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)cyclopentanecarboxamide Compound 181

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), cyclopentylcarbonyl chloride (21 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)cyclopentanecarboxamide. ¹ H NMR (500MHz, DMSO) δ9.97 (s, 1H), 8.94 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 8.38 (t, J = 5.9 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.04 (s, 1H), 6.72 (d, J = 7.3 Hz, 1H), 4.35 (d, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 2.72 (p, J = 8.0 Hz, 1H), 1.90-1.79 (m, 2H), 1.78-1.70 (m, 2H), 1.65 (ddd, J = 16.5, 9.2, 2.8 Hz, 2H), 1.58-1.46 (m, 2H). MS m/z (ESI): 474.23 [M+H] ⁺ .

Example 182. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)cyclohexanecarboxamide Compound 182

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), cyclohexanecarbonyl chloride (23 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)cyclohexanecarboxamide. ¹ H NMR (500 MHz, DMSO) δ9.97 (s, 1H), 8.94 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 8.32 (t, J = 6.0 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.19 (t, J = 9.7 Hz, 1H), 7.04 (d, J = 11.2 Hz, 1H), 6.71 (d, J = 7.4 Hz, 1H), 4.33 ( d, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 2.27 (tt, J = 11.6, 3.4 Hz, 1H), 1.81 (d, J = 11.3 Hz, 2H), 1.72 (dd, J = 9.7, 3.0 Hz, 2H), 1.61 (d, J = 12.1 Hz, 1H), 1.48-1.36 (m, 2H), 1.26 (td, J = 12.1, 5.9 Hz, 2H), 1.15 (ddd, J = 12.6, 8.0, 3.1 Hz, 1H). MS m/z (ESI): 488.24 [M+H] ⁺ .

Example 183. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)tetrahydrofuran-2-carboxamide Compound 183

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), tetrahydrofuran-2-carbonyl chloride (22 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)tetrahydrofuran-2-carboxamide. ¹ H NMR (500 MHz, DMSO) δ 10.00 (s, 1H), 8.94 (d, J = 7.3 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.41-8.34 (m, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.72 (d, J = 7.4 Hz, 1H). z, 1H), 4.41-4.36 (m, 2H), 4.36-4.32 (m, 1H), 4.05 (dd, J=14.4, 6.8 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.84 (dd, J=14.7, 6.9 Hz, 1H), 2.19 (ddd, J=15.1, 12.4, 8.0 Hz, 1H), 1.98 (dt, J=12.5, 6.8 Hz, 1H), 1.92-1.80 (m, 2H). MS m/z (ESI): 476.20 [M+H] ⁺ .

Example 184. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide Compound 184

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), tetrahydropyran-4-carbonyl chloride (24 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was continued at 0°C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)tetrahydro-2H-pyran-4-carboxamide. MS m/z(ESI):490.22[M+H] ⁺ .

Example 185. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide Compound 185

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and tetrahydropyran-4-acetic acid (23 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide. ¹ H NMR (500 MHz, DMSO) δ9.96 (s, 1H), 8.95 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 8.44 (t, J = 5.9 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.02 (s, 1H), 6.74 (d, J = 7.3 Hz, 1H), 4.33 (d, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.83-3.74 (m, 2H), 3.24 (tt, J = 9.5, 4.8 Hz, 2H), 2.16 (t, J = 7.3 Hz, 2H), 2.03-1.91 (m, 1H), 1.62-1.53 (m, 2H). MS m/z (ESI): 504.24 [M+H] ⁺ .

Example 186. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-morpholinoacetamide Compound 186

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 4-morpholineacetic acid (29 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin ^- 3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-morpholineacetamide. NMR (500 MHz, DMSO) δ 10.00 (s, 1H), 8.95 (d, J = 7.3 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.43-8.35 (m, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.07 (s, 1H), 6.75 (d, J = 7.3 Hz, 1H), 4.40 (d, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.93 (d, J = 7.0 Hz, 3H), 3.64-3.57 (m, 4H), 3.05 (d, J = 14.2 Hz, 2H).MS m/z(ESI):505.23[M+H] ⁺ .

Example 187. Synthesis of tert-butyl 3-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)piperidine-1-carboxylate Compound 187

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and N-Boc-3-piperidinic acid (37 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted with 20 mL of ethyl acetate for three times. The organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 3-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester. MS m/z(ESI):589.29[M+H] ⁺ .

Example 188. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)piperidine-3-carboxamide Compound 188

Add 3 mL of methanol to a 50 mL round-bottom flask, and add tert-butyl 3-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)piperidine-1-carboxylate (30 mg) and 1 mL of hydrochloric acid in ethyl acetate under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by distillation under reduced pressure. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a ^yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)piperidine-3-carboxamide. NMR (500 MHz, DMSO) δ9.96 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.61 (t, J = 5.9 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.73 (d, J = 7.3 Hz, 1 H), 4.34 (qd, J = 15.9, 5.9 Hz, 2H), 3.96 (s, 3H), 3.93 (d, J = 8.9 Hz, 3H), 3.12 (dd, J = 12.1, 2.7 Hz, 1H), 2.95 (d, J = 12.2 Hz, 1H), 2.81 (t, J = 11.2 Hz, 1H), 2.68-2.55 (m, 2H), 1.99-1.90 (m, 1H), 1.71-1.59 (m, 2H), 1.58-1.48 (m, 1H). MS m/z (ESI): 489.24 [M+H] ⁺ .

Example 189. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(4-methylpiperazin-1-yl)acetamide Compound 189

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 4-methyl-1-piperazineacetic acid (25 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(4-methylpiperazin-1-yl)acetamide. MS m/z(ESI):518.26[M+H] ⁺ .

Example 190. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-1-methylpiperidine-4-carboxamide Compound 190

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and N-methyl-4-piperidinyl chloride hydrochloride (32 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-1-methylpiperidine-4-carboxamide. ¹ H NMR (500 MHz, DMSO) δ 10.00 (s, 1H), 8.96 (d, J = 7.2 Hz, 1H), 8.67 (t, J = 5.8 Hz, 1H), 8.55 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 1.5 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.01 (s, 1H), 6.73 (d, J = 7.4 Hz, 1H), 4.35 (d, J = 5.8 Hz, 2H), 3.96 (s, 3H), 3.93 (d, J = 9.0 Hz, 3H), 3.29 (d, J = 11.0 Hz, 3H), 2.94-2.75 (m, 2H), 2.62 (s, 3H), 2.03-1.86 (m, 4H). MS m/z (ESI): 503.25 [M+H] ⁺ .

Example 191. Synthesis of tert-butyl 3-((6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)azetidine-1-carboxylate Compound 191

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidine-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 1-Boc-azetidine-3-carboxylic acid (32 mg) were added with stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, tert-butyl 3-((6-((5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)azetidine-1-carboxylate. ¹ H NMR (500 MHz, DMSO) δ9.98 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.62 (t, J = 5.9 Hz, 1H), 8.55 (d, J = 1.7 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.02 (s, 1H), 6.74 (d, J = 7.3 Hz, 1H), 4.39 (s, 2H), 4.07 (d, J = 33.4 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.49-3.42 (m, 1H), 1.33 (s, 8H). MS m/z(ESI):561.26[M+H] ⁺ .

Example 192. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)azetidine-3-carboxamide Compound 192

3 mL of methanol was added to a 50 mL round-bottom flask, and tert-butyl 3-((6-((5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)azetidine-1-carboxylate (30 mg) and 1 mL of ethyl acetate solution of hydrochloric acid were added under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction is completed, the crude product is obtained by vacuum distillation. The reaction is neutralized with saturated NaHCO _3. The mixed solution is extracted three times with 20 mL of ethyl acetate, and the organic phases are combined. The organic phase is washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The organic phase is distilled under reduced pressure to obtain a crude product. The crude product is chromatographed on a silica gel column to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)azetidine-3-carboxamide. ¹ H NMR (500 MHz, DMSO) δ9.99 (s, 1H), 8.96 (d, J = 7.3 Hz, 1H), 8.79 (t, J = 5.9 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 1.7 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.18 (d , J＝8.3 Hz, 1H), 6.99 (s, 1H), 6.77 (d, J＝7.3 Hz, 1H), 4.38 (d, J＝5.9 Hz, 2H), 4.04 (d, J＝2.1 Hz, 2H), 4.02 (d, J＝3.0 Hz, 2H), 3.96 (s, 3H), 3.94 (s, 3H), 3.69 (dd, J＝16.5, 8.2 Hz, 1H). MS m/z (ESI): 461.20 [M+H] ⁺ .

Example 193. Synthesis of tert-butyl 4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)piperidine-1-carboxylate Compound 193

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 1-Boc-4-piperidinic acid (37 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, tert-butyl 4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)piperidine-1-carboxylate. MS m/z(ESI):589.29[M+H] ⁺ .

Example 194. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-(piperidin-1-yl)propanamide Compound 194

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 1-piperidine propionic acid (25 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-(piperidin-1-yl)propanamide. ¹ H NMR (500MHz, DMSO) δ9.94 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.58 (t, J = 5.8 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.19 (d, J＝8.2 Hz, 1H), 7.02 (s, 1H), 6.82 (d, J＝7.4 Hz, 1H), 4.35 (d, J＝5.9 Hz, 2H), 3.96 (s, 3H), 3.94 (s, 3H), 2.66 (s, 2H), 2.44 (d, J＝5.3 Hz, 6H), 1.52-1.45 (m, 4H), 1.35 (d, J＝4.4 Hz, 2H). MS m/z (ESI): 517.27 [M+H] ⁺ .

Example 195. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(pyrrolidin-1-yl)acetamide Compound 195

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-(1-pyrrolidinyl)acetic acid (21 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-( ... pyridin-1-yl)acetamide. ¹ H NMR (500 MHz, DMSO) δ9.99 (s, 1H), 8.94 (d, J = 7.3 Hz, 1H), 8.59-8.53 (m, 2H), 7.98 (d, J = 1.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 7.04 (s, 1H), 6.77 (d, J = 7.3 Hz, 1H), 4.41 (d, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.45 (s, 2H), 2.80 (d, J = 5.4 Hz, 4H), 1.78-1.73 (m, 4H).MS m/z(ESI):489.24[M+H] ⁺ .

Example 196. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)benzamide Compound 196

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), benzoyl chloride (22 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)benzamide. ¹ H NMR (500 MHz, DMSO) δ 9.99 (s, 1H), 9.16 (t, J = 5.9 Hz, 1H), 8.95 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 8.05-7.98 (m, 3H), 7.62 (t, J = 7.8 Hz, 1H), 7.57-7.45 (m, 4H), 7.21 (d, J = 8.2 Hz, 1H), 7.06 (s, 1H), 6.81 (d, J = 7.4 Hz, 1H), 4.57 (d, J = 5.9 Hz, 2H), 3.97 (s, 3H), 3.94 (s, 3H). MS m/z (ESI): 482.19 [M+H] ⁺ .

Example 197. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)thiophene-2-carboxamide Compound 197

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N-(6-(amino)- The reaction system was reacted at 0°C for 1 hour. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product. The crude product was chromatographed on a silica gel column to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)thiophene-2-carboxamide. ¹ H NMR (500 MHz, DMSO) δ 10.00 (s, 1H), 9.21 (t, J = 6.0 Hz, 1H), 8.94 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.97-7.93 (m, 1H), 7.78 (dd, J = 5.0, 0.7 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.18 (dd, J = 4.9, 3.8 Hz, 1H), 7.04 (s, 1H), 6.81 (d, J = 7.4 Hz, 1H), 4.54 (d, J = 6.0 Hz, 2H), 3.97 (s, 3H), 3.95 (s, 3H). MS m/z (ESI): 488.15 [M+H] ⁺ .

Example 198. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)furan-2-carboxamide Compound 198

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), furanoyl chloride (21 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)furan-2-carboxamide. ¹ H NMR (500MHz, DMSO) δ9.99 (s, 1H), 8.98 (t, J = 6.0 Hz, 1H), 8.95 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.90 (t, J = 2.8 Hz, 1H), 7.80 (t, J = 3.9 Hz, 1H), 7.61 (t, J = 3.8 Hz, 1H), 7.90 (t, J = 2.8 Hz, 1H), 7.80 (t, J = 3.8 Hz, 1H), 7.63 (t, J = 3.8 Hz, 1H), 7.90 (t, J = 3 ... .51 (d, J = 7.3 Hz, 1H), 7.22 (t, J = 6.5 Hz, 2H), 7.02 (s, 1H), 6.78 (d, J = 7.4 Hz, 1H), 6.65 (dt, J = 11.6, 5.8 Hz, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.97 (s, 3H), 3.94 (d, J = 8.1 Hz, 3H). MS m/z (ESI): 472.17 [M+H] ⁺ .

Example 199. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)furan-3-carboxamide Compound 199

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 3-furoyl chloride (21 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was continued at 0°C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)furan-3-carboxamide. ¹ H NMR (500MHz, DMSO) δ9.99 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.92-8.85 (m, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.34 (s, 1H), 8.00 (d, J = 1.5 Hz, 1H), 7.76 (d, J = 5.3 Hz, 1H), 7.62 (q, J = 7.7 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.05 (s, 1H), 6.97 (s, 1H), 6.80 (d, J = 7.4 Hz, 1H), 4.52 (d, J = 5.9 Hz, 2H), 3.97 (s, 3H), 3.95 (d, J = 10.0 Hz, 3H). MS m/z (ESI): 472.17 [M+H] ⁺ .

Example 200. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(furan-2-yl)acetamide Compound 200

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-furanacetic acid (20 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(furan-2-yl)acetamide. ¹ H NMR (500 MHz, DMSO) δ 10.00 (s, 1H), 8.96 (d, J = 7.2 Hz, 1H), 8.69 (t, J = : 5.9 Hz, 1H), 8.55 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.57-7.55 (m, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.75 (d, J = 7.3 Hz, 1H), 6.41-6.35 (m, 1H), 6.28 (d, J = 3.1 Hz, 1H), 4.36 (d, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.90 (s, 3H), 3.67 (s, 2H). MS m/z(ESI): 486.19[M+H] ⁺ .

Example 201. Synthesis of ((6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamic acid phenyl ester Compound 201

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), phenyl chloroformate (25 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was continued at 0°C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, phenyl ((6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamate. ¹ H NMR (500 MHz, DMSO) δ 10.04 (s, 1H), 8.96 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 8.41 (t, J = 6.1 Hz, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.35 (t, J = 7.9 Hz, 2H), 7.25-7.15 (m, 5H), 6.84 (d, J = 7.3 Hz, 1H), 4.38 (d, J = 6.1 Hz, 2H), 3.96 (s, 3H), 3.82 (d, J = 10.7 Hz, 3H). MS m/z (ESI): 498.19 [M+H] ⁺ .

Example 202. Synthesis of benzyl ((6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamate Compound 202

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), benzyl chloroformate (27 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product ((6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamic acid benzyl ester. ¹ H NMR (500 MHz, DMSO) δ 9.98 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.54 (dd, J = 6.4, 1.8 Hz, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.87 (t, J = 6.1 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H) ,7.42-7.24(m,5H),7.16(d,J＝8.2Hz,1H),7.08(s,1H),6.76(d,J＝7.3Hz,1H),5.14(d,J＝13.7Hz,2H),4.29(d,J＝6.1Hz,2H),3.96(d,J＝5.4Hz,3H),3.85(d,J＝16.1Hz,3H).MS m/z(ESI):512.20[M+H] ⁺ .

Example 203. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)isonicotinamide Compound 203

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), isonicotinoyl chloride (28 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)isonicotinamide. ¹ H NMR (500 MHz, DMSO) δ9.98 (s, 1H), 9.42 (t, J = 5.9 Hz, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.73 (d, J = 5.9 Hz, 2H), 8.55 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 1.7 Hz, 1H), 7.89-7.87 (m, 2H), 7.61 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.81 (d, J = 7.4 Hz, 1H), 4.58 (d, J = 5.9 Hz, 2H), 3.97 (s, 3H), 3.94 (s, 3H).MS m/z(ESI):483.19[M+H] ⁺ .

Example 204. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)pyridine-2-amide Compound 204

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), pyridine-2-carbonyl chloride (28 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)pyridine-2-amide. ¹ H NMR (500 MHz, DMSO) δ 9.98 (s, 1H), 9.39 (t, J = 5.9 Hz, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.78 (d, J = 4.6 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.02 (dd, J = 7.6, 1.4 Hz, 1H), 7.99 (d d, J = 8.0, 1.7 Hz, 1H), 7.61 (dd, J = 9.8, 5.7 Hz, 2H), 7.52 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.09 (s, 1H), 6.80 (d, J = 7.4 Hz, 1H), 4.61 (d, J = 5.9 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H). MS m/z (ESI): 483.19 [M+H] ⁺ .

Example 205. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-phenylacetamide Compound 205

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), phenylacetyl chloride (25 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-phenylacetamide. ¹ H NMR (500 MHz, DMSO) δ9.93 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.59 (t, J = 6.0 Hz, 1H), 8.54 (d, J = : 1.6 Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.34 (d, J = 7.4 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.22 (d, J = 7.2 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.70 (d, J = 7.4 Hz, 1H), 4.34 (d, J = 5.9 Hz, 2H), 3.95 (s, 3H), 3.86 (s, 3H), 3.58 (s, 2H). MS m/z(ESI): 496.21[M+H] ⁺ .

Example 206. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-(pyridin-4-yl)propanamide Compound 206

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 4-pyridine propionic acid (24 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-(pyridin-4-yl)propanamide. ¹ H NMR (500MHz, DMSO) δ9.96 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.48 (t, J = 5.9 Hz, 1H), 8.41 (d, J = 5.8 Hz, 2H), 7.96 (d, J = 1.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H). z, 1H), 7.25 (d, J = 5.7 Hz, 2H), 7.16 (d, J = 8.2 Hz, 1H), 7.04 (s, 1H), 6.60 (d, J = 7.3 Hz, 1H), 4.33 (d, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.89 (s, 3H), 2.92 (t, J = 7.6 Hz, 2H), 2.59 (t, J = 7.6 Hz, 2H). MS m/z (ESI): 511.22 [M+H] ⁺ .

Example 207. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-(trifluoromethyl)benzamide Compound 207

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 3-(trifluoromethyl)benzoyl chloride (33 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-(trifluoromethyl)benzamide. ¹ H NMR (500MHz, DMSO) δ9.95 (s, 1H), 9.37 (t, J = 5.7 Hz, 1H), 8.93 (d, J = 7.2 Hz, 1H), 8.53 (d, J = 1.4 Hz, 1H), 8.30 (d, J = 6.6 Hz, 2H), 7.97 (d, J = 1.2 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.7 4 (t, J = 7.9 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.83 (d, J = 7.3 Hz, 1H), 4.59 (d, J = 5.7 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H). MS m/z (ESI): 550.18 [M+H] ⁺ .

Example 208. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-4-(trifluoromethyl)benzamide Compound 208

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 4-trifluoromethylbenzoyl chloride (33 mg) and DIPEA (0.045 mL) were added under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxy)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 4-trifluoromethylbenzoyl chloride (33 mg) and DIPEA (0.045 mL). [0063] In some embodiments, the present invention relates to pyridin-3-yl (oxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-4-(trifluoromethyl)benzamide. ¹ H NMR (500 MHz, DMSO) δ9.95 (s, 1H), 9.33 (t, J = 5.9 Hz, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 8.1 Hz, 2H), 7.98 (d, J = 1.7 Hz, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.62 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.05 (s, 1H), 6.82 (d, J = 7.4 Hz, 1H), 4.58 (d, J = 5.9 Hz, 2H), 3.97 (s, 3H), 3.92 (s, 3H).MS m/z(ESI):550.18[M+H] ⁺ .

Example 209. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)pyrimidine-4-carboxamide Compound 209

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 4-pyrimidinecarboxylic acid (20 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)pyrimidine-4-carboxamide. ¹ H NMR (500MHz, DMSO) δ9.99 (s, 1H), 9.62 (t, J = 5.8 Hz, 1H), 9.52 (s, 1H), 9.08 (d, J = 5.0 Hz, 1H), 8.93 (d, J = 7.2 Hz, 1H), 8.53 (d, J = 1.9 Hz, 1H), 8.10 (dd, J = 5.0, 1.3 Hz, 1H), 7.98 ( d, J = 1.8 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.10 (s, 1H), 6.82 (d, J = 7.3 Hz, 1H), 4.63 (d, J = 5.8 Hz, 2H), 3.97 (s, 3H), 3.97 (s, 3H). MS m/z (ESI): 484.18 [M+H] ⁺ .

Example 210. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3,5-dimethoxybenzamide Compound 210

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 3,5-dimethoxybenzoyl chloride (32 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was continued at 0°C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3,5-dimethoxybenzamide. ¹ H NMR (500MHz, DMSO) δ9.97 (s, 1H), 9.10 (t, J = 5.9 Hz, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 1.5 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H) ,7.19(d,J＝8.2Hz,1H),7.13(d,J＝2.1Hz,2H),7.03(s,1H),6.78(d,J＝7.4Hz,1H),6.65(t,J＝2.0Hz,1H),4.53(d,J＝5.8Hz,2H),3.96(s,3H),3.93(s,3H),3.77(s,6H).MS m/z(ESI):542.22[M+H] ⁺ .

Example 211. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2,6-difluorobenzamide Compound 211

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 2,6-difluorobenzoyl chloride (28 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was continued at 0°C for 1 hour. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin ^- 3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2,6-difluorobenzamide. NMR (500 MHz, DMSO) δ 10.00 (s, 1H), 9.36 (t, J = 6.0 Hz, 1H), 8.96 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.53 (dd, J = 10.2, 7.1 Hz, 2H), 7.25 (d, J = 8.3 Hz, 1H), 7.20 (t, J = 8.0 Hz, 2H), 6.99 (s, 1H), 6.85 (d, J = 7.4 Hz, 1H), 4.53 (d, J = 6.0 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H). MS m/z(ESI):518.18[M+H] ⁺ .

Example 212. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2,6-dimethoxybenzamide Compound 212

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 2,6-dimethoxybenzoyl chloride (32 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2,6-dimethoxybenzamide. ¹ H NMR (500MHz, DMSO) δ9.95 (s, 1H), 8.96 (d, J = 7.3 Hz, 1H), 8.64 (t, J = 6.1 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H) ,7.32(t,J＝8.3Hz,1H),7.27(d,J＝8.2Hz,1H),7.05(d,J＝7.4Hz,1H),6.93(s,1H),6.71(d,J＝8.4Hz,2H),4.44(d,J＝6.1Hz,2H),3.96(s,3H),3.93(s,3H),3.79(s,6H).MS m/z(ESI):542.22[M+H] ⁺ .

Example 213. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-methoxybenzamide Compound 213

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), m-methoxybenzoyl chloride (27 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-methoxybenzamide. ¹ H NMR (500MHz, DMSO) δ9.97 (s, 1H), 9.11 (t, J = 5.9 Hz, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 1.7 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.53-7.50 (m, 2H ), 7.39(t, J＝7.9 Hz, 1H), 7.19(d, J＝8.2 Hz, 1H), 7.10(dd, J＝8.2,2.4 Hz, 1H), 7.04(s, 1H), 6.79(d, J＝7.4 Hz, 1H), 4.55(d, J＝5.9 Hz, 2H), 3.96(s, 3H), 3.93(s, 3H), 3.79(d, J＝4.7 Hz, 3H).MS m/z(ESI): 512.20[M+H] ⁺ .

Example 214. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-methoxybenzamide Compound 214

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), o-methoxybenzoyl chloride (27 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-methoxybenzamide. ¹ H NMR (500MHz, DMSO) δ9.97 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.83 (t, J = 5.8 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 7.97 (d, J = 1.7 Hz, 1H), 7.88 (dd, J = 7.7, 1.6 Hz, 1H), 7.63 (t, J = 7.8 Hz , 1H), 7.52-7.46 (m, 2H), 7.18 (dd, J = 10.2, 8.7 Hz, 2H), 7.05 (dd, J = 9.3, 5.5 Hz, 2H), 6.85 (d, J = 7.3 Hz, 1H), 4.59 (d, J = 5.8 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.93 (s, 3H). MS m/z (ESI): 512.20 [M+H] ⁺ .

Example 215. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-4-methoxybenzamide Compound 215

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), p-methoxybenzoyl chloride (27 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-4-methoxybenzamide. ¹ H NMR (500 MHz, DMSO) δ9.97 (s, 1H), 8.96 (dd, J = 9.4, 6.6 Hz, 2H), 8.55 (d, J = 1.5 Hz, 1H), 7.99 (d, J = 1.5 Hz, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.61 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.04 (s, 1H), 7.00 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 7.4 Hz, 1H), 4.53 (d, J = 5.8 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.79 (s, 3H).MS m/z(ESI):512.20[M+H] ⁺ .

Example 216. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(4-methoxyphenyl)acetamide Compound 216

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 4-methoxyphenylacetyl chloride (30 mg) and DIPEA (0.045 mL) were added under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxy)pyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 4-methoxyphenylacetyl chloride (30 mg) and DIPEA (0.045 mL). ^1H NMR (500MHz, DMSO) δ9.93 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.51 (t, J = 5.9 Hz, 1H), 7.98 (d, J = 1.9 Hz, 1H), 7.60-7.56 (m, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.25 (d , J＝8.6 Hz, 2H), 7.16 (d, J＝8.1 Hz, 1H), 7.03 (s, 1H), 6.85 (d, J＝8.6 Hz, 2H), 6.70 (d, J＝7.3 Hz, 1H), 4.33 (d, J＝5.9 Hz, 2H), 3.95 (s, 3H), 3.87 (s, 3H), 3.70 (s, 3H), 3.50 (s, 2H). MS m/z (ESI): 526.22 [M+H] ⁺ .

Example 217. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(3-methoxyphenyl)acetamide Compound 217

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 3-methoxyphenylacetyl chloride (30 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(3-methoxyphenyl)acetamide. ¹ H NMR (500MHz, DMSO) δ9.97 (s, 1H), 8.95 (d, J＝7.2Hz, 1H), 8.66 (t, J＝5.8Hz, 1H), 8.55 (s, 1H), 7.98 (s, 1H), 7.59 (t, J＝7.8Hz, 1H), 7.52 (d, J＝7.2Hz, 1H), 7.20 (dd, J＝14.8, 7 .8Hz, 2H), 7.04(s, 1H), 6.92(d, J＝7.4Hz, 2H), 6.79(d, J＝8.7Hz, 1H), 6.71(d, J＝7.3Hz, 1H), 4.34(d, J＝5.8Hz, 2H), 3.95(s, 3H), 3.87(s, 3H), 3.71(s, 3H), 3.56(s, 2H).MS m/z(ESI): 526.22[M+H] ⁺ .

Example 218. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-4-(trifluoromethoxy)benzamide Compound 218

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 4-(trifluoromethoxy)benzoyl chloride (36 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-4-(trifluoromethoxy)benzamide. ¹ H NMR (500 MHz, DMSO) δ9.96 (s, 1H), 9.26 (t, J = 5.9 Hz, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.7 Hz, 1H), 8.12 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 1.7 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.2 Hz, 1H), 7.05 (s, 1H), 6.82 (d, J = 7.4 Hz, 1H), 4.58 (d, J = 5.9 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H).MS m/z(ESI):566.18[M+H] ⁺ .

Example 219. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(6-methoxypyridin-3-yl)acetamide Compound 219

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 6-methoxy-3-pyridineacetic acid (27 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was a yellow product after silica gel column chromatography. N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(6-methoxypyridin-3-yl)acetamide. ¹ H NMR (500 MHz, DMSO) δ9.96 (s, 1H), 8.95 (d, J＝7.3 Hz, 1H), 8.62 (t, J＝5.9 Hz, 1H), 8.55 (d, J＝1.9 Hz, 1H), 8.08 (d, J＝2.2 Hz, 1H), 7.97 (d, J＝1.9 Hz, 1H), 7.66 (dd, J＝8.5, 2.4 Hz, 1H), 7.61 -7.58 (m, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 7.04 (s, 1H), 6.72 (dd, J = 12.7, 7.9 Hz, 2H), 4.34 (d, J = 5.9 Hz, 2H), 3.95 (s, 3H), 3.87 (s, 3H), 3.80 (s, 3H), 3.53 (s, 2H). MS m/z (ESI): 527.22 [M+H] ⁺ .

Example 220. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-4-methylbenzamide Compound 220

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), p-methylbenzoyl chloride (25 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-4-methylbenzamide. ¹ H NMR (500MHz, DMSO) δ9.97 (s, 1H), 9.02 (t, J = 5.9 Hz, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.61 (t, J = 7.8 Hz, 1H) ,7.52(d,J＝7.3Hz,1H),7.28(d,J＝8.0Hz,2H),7.18(d,J＝8.2Hz,1H),7.04(s,1H),6.78(d,J＝7.4Hz,1H),4.54(d,J＝5.9Hz,2H),3.97(s,3H),3.93(s,3H),2.34(s,3H).MS m/z(ESI):496.21[M+H] ⁺ .

Example 221. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-5-methylnicotinamide Compound 221

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 5-methylnicotinic acid (22 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-5-methylnicotinamide. ¹ H NMR (500 MHz, DMSO) δ9.98 (s, 1H), 9.27 (t, J = 5.9 Hz, 1H), 8.98 (d, J = 1.8 Hz, 1H), 8.93 (d, J = 7.2 Hz, 1H), 8.55-8.52 (m, 2H), 8.11 (s, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.06 (s, 1H), 6.82 (d, J = 7.3 Hz, 1H), 4.57 (d, J = 5.9 Hz, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 2.32 (s, 3H).MS m/z(ESI):497.20[M+H] ⁺ .

Example 222. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-4-ethoxybenzamide Compound 222

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 4-ethoxybenzoyl chloride (30 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-4-ethoxybenzamide. MS m/z(ESI):526.22[M+H] ⁺ .

Example 223. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-4-isopropoxybenzamide Compound 223

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 4-isopropoxybenzoic acid (29 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-4-isopropoxybenzamide. ¹ H NMR (500 MHz, DMSO) δ9.94 (s, 1H), 8.94 (t, J = 6.2 Hz, 2H), 8.55 (d, J = 1.9 Hz, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.61 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.19 (d, J = 7. =8.2 Hz, 1H), 7.05 (s, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 7.4 Hz, 1H), 4.63 (dt, J = 12.0, 6.0 Hz, 1H), 4.54 (d, J = 5.8 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 1.25 (s, 3H), 1.24 (s, 3H). MS m/z (ESI): 540.24 [M+H] ⁺ .

Example 224. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-4-sulfamoylbenzamide Compound 224

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and m-carboxybenzenesulfonamide (32 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction is completed, the reaction system is diluted with 10 mL of water. The mixed solution is extracted three times with 20 mL of ethyl acetate, and the organic phases are combined. The organic phase is washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The organic phase is distilled under reduced pressure to obtain a crude product. The crude product is chromatographed on a silica gel column to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-4-sulfamoylbenzamide. ¹ H NMR (500 MHz, DMSO) δ9.98 (s, 1H), 9.39 (t, J = 5.9 Hz, 1H), 8.96 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 8.40 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.99-7.97 (m, 2H), 7.69 (t, J = 7.8 Hz , 1H), 7.62(t, J＝7.8Hz, 1H), 7.52(d, J＝7.3Hz, 1H), 7.45(s, 2H), 7.23(d, J＝8.2Hz, 1H), 7.02(s, 1H), 6.80(d, J＝7.4Hz, 1H), 4.57(d, J＝5.8Hz, 2H), 3.96(s, 3H), 3.93(s, 3H).MS m/z(ESI): 561.17[M+H] ⁺ .

Example 225. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)azepane-3-carboxamide Compound 225

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidine-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 1-(tert-butoxycarbonyl)azepane-3-carboxylic acid (39 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, tert-butyl 3-((6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)azepane-1-carboxylate. MS m/z(ESI):603.3[M+H] ⁺ .

3 mL of methanol was added to a 50 mL round-bottom flask, and 3-((6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)azepane-1-carboxylic acid tert-butyl ester (30 mg) and 1 mL of hydrochloric acid in ethyl acetate were added under stirring at room temperature. The reaction system was then reacted at room temperature for 24 hours. After the reaction was completed, the crude product was obtained by distillation under reduced pressure. The reaction was neutralized with saturated NaHCO _3. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The crude product was obtained by distillation of the organic phase under reduced pressure, and the crude product was purified by The yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)azepane-3-carboxamide was obtained after silica gel column chromatography. MS m/z(ESI):503.25[M+H] ⁺ .

Example 226. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-(6-(trifluoromethyl)pyridin-3-yl)propanamide Compound 226

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 3-[2-(trifluoromethyl)pyridin-5-yl]propionic acid (35 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-(6-(trifluoromethyl)pyridin-3-yl)propanamide. ¹ H NMR (500MHz, DMSO) δ9.95 (s, 1H), 8.95 (d, J＝7.2Hz, 1H), 8.64 (s, 1H), 8.52 (d, J＝1.8Hz, 1H), 8.48 (t, J＝5.9Hz, 1H), 7.95 (d, J＝1.8Hz, 1H), 7.92 (d, J＝8.9Hz, 1H), 7.75 (d, J＝8.1Hz, 1H), 7. .52 (dd, J = 13.8, 7.6 Hz, 2H), 7.15 (d, J = 8.2 Hz, 1H), 7.02 (s, 1H), 6.55 (d, J = 7.3 Hz, 1H), 4.32 (d, J = 5.9 Hz, 2H), 3.95 (s, 3H), 3.89 (s, 3H), 3.03 (t, J = 7.5 Hz, 2H), 2.63 (t, J = 7.5 Hz, 2H). MS m/z (ESI): 579.21 [M+H] ⁺ .

Example 227. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(2-(trifluoromethoxy)phenyl)acetamide Compound 227

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask and stir at room temperature to add N-(6-(aminomethyl) The mixture was stirred for 2 hours at room temperature. After the reaction, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product. The crude product was chromatographed on a silica gel column to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-(2-(trifluoromethoxy)phenyl)acetamide. ¹ H NMR (500 MHz, DMSO) δ9.97 (s, 1H), 8.95 (d, J = 7.3 Hz, 1H), 8.72 (t, J = 5.9 Hz, 1H), 8.54 (d, J = 1.9 Hz, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.64-7.60 (m, 1H), 7.52 (d, J = 7.3 Hz, 2H), 7.3 8 (dd, J = 9.1, 4.5 Hz, 1H), 7.33 (d, J = 7.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 1H), 7.05 (s, 1H), 6.77 (d, J = 7.3 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 3.96 (s, 3H), 3.88 (s, 3H), 3.72 (s, 2H). MS m/z (ESI): 580.19 [M+H] ⁺ .

Example 228. Synthesis of 4-(difluoromethoxy)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)benzamide Compound 228

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 4-(difluoromethoxy)benzoic acid (30 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 4-(difluoromethoxy)-N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)benzamide. MS m/z(ESI):548.19[M+H] ⁺ .

Example 229. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-fluorobenzamide Compound 229

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), o-fluorobenzoyl chloride (25 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-2-fluorobenzamide. ¹ H NMR (500 MHz, DMSO) δ9.96 (s, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.90 (dd, J = 6.6, 4.6 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.77 (td, J = 7.5, 1.6 Hz, 1H), 7.64 (t , J＝7.8 Hz, 1H), 7.57-7.50 (m, 2H), 7.32 (d, J＝8.6 Hz, 1H), 7.23 (d, J＝8.2 Hz, 1H), 7.03 (s, 1H), 6.84 (d, J＝7.3 Hz, 1H), 4.56 (d, J＝5.9 Hz, 2H), 3.97 (s, 3H), 3.92 (s, 3H). MS m/z (ESI): 500.18 [M+H] ⁺ .

Example 230. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-4-fluorobenzamide Compound 230

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), p-fluorobenzoyl chloride (25 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-4-fluorobenzamide. ¹ H NMR (500MHz, DMSO) δ9.94 (s, 1H), 9.12 (t, J＝5.9Hz, 1H), 8.94 (d, J＝7.2Hz, 1H), : 8.54 (d, J = 1.8 Hz, 1H), 8.04 (dd, J = 8.7, 5.6 Hz, 2H), 7.98 (d, J = 1.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.30 (t, J = 8.8 Hz, 2H), 7.20 (d, J = 8.2 Hz, 1H), 7.02 (s, 1H), 6.79 (d, J = 7.4 Hz, 1H), 4.55 (d, J = 5.9 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H). MS m/z (ESI): 500.18 [M+H] ⁺ .

Example 231. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-fluorobenzamide Compound 231

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), m-fluorobenzoyl chloride (25 mg) and DIPEA (0.045 mL) with stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)-3-fluorobenzamide. ¹ H NMR (500MHz, DMSO) δ9.95 (s, 1H), 9.21 (t, J = 5.9 Hz, 1H), 8.94 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 9.8 Hz, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.56-7.50 (m, 2H), 7.38 (td, J = 8.5, 2.4 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.03 (s, 1H), 6.80 (d, J = 7.4 Hz, 1H), 4.56 (d, J = 5.9 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H). MS m/z (ESI): 500.18 [M+H] ⁺ .

Example 232. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)furan-2-carboxamide Compound 232

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), furanoyl chloride (22 mg) and DIPEA (0.049 mL) with stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)furan-2-carboxamide. ¹ H NMR (500 MHz, DMSO) δ 10.35 (s, 1H), 9.99 (s, 1H), 8.95 (d, J = 7.2 Hz, 1H), 8.55 (d, J = 1.8 Hz, 1H), 8.02-7.95 (m, 2H), 7.64 (t, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.51 (dd, J = 11.0, 5.4 Hz, 2H), 6.89 (d, J = 8.0 Hz, 1H), 6.74 (dd, J = 3.4, 1.7 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H). MS m/z (ESI): 458.46 [M+H] ⁺ .

Example 233. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)propanamide Compound 233

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), propionyl chloride (16 mg) and DIPEA (0.049 mL) were added under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)propionamide. ¹ H NMR (500 MHz, DMSO) δ 10.24 (s, 1H), 9.94 (s, 1H), 8.93 (t, J = 7.7 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 7.60-7.56 (m, 2H), 7.55 (s, 1H), 7.52 (d, J = 7.3 Hz, 1H), 6.80-6.75 (m, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 2.47 (q, J = 7.5 Hz, 2H), 1.12 (t, J = 7.5 Hz, 3H). MS m/z (ESI): 420.45 [M+H] ⁺ .

Example 234. Synthesis of tert-butyl 4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)piperazine-1-carboxylate Compound 234

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), 4-BOC-1-piperazinecarbonyl chloride (40 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was reacted for 1 hour at 0°C. After the reaction was completed, 10 mL of water was used to neutralize the reaction. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, 4-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)piperazine-1-carboxylic acid tert-butyl ester. ¹ H NMR (500 MHz, DMSO) δ9.91 (s, 1H), 8.93 (d, J = 7.2 Hz, 1H), 8.54 (d, J = 1.8 Hz, 1H), 7.98 (d, J = 1.7 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.17 (t, J = 5.7 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.05 (s, 1H), 6.74 (d, J = 7.4 Hz, 1H), 4.32 (d, J = 5.6 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.40-3.37 (m, 4H), 3.32 (s, 4H), 1.35 (s, 9H).MS m/z(ESI):589.66[M+H] ⁺ .

Example 235. Synthesis of N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)benzamide Compound 235

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N-(6-(aminomethyl)pyridin-2-yl)-5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-amine (50 mg), benzoyl chloride (22 mg) and DIPEA (0.045 mL) under stirring at 0°C. The reaction system was allowed to react for 1 hour at 0°C. After the reaction was completed, the reaction was neutralized with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product, N-(6-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)methyl)benzamide. ¹ H NMR (500MHz, DMSO) δ9.98 (s, 1H), 9.13 (t, J = 5.9 Hz, 1H), 8.94 (d, J = 7.3 Hz, 1H), 8.55 (d, J = 1.9 Hz, 1H), 8.01-7.97 (m, 3H), 7.62 (t, J = 7.8 Hz, 1H), 7.56-7.47 (m, 4H), 7.21 (d, J = 8.2 Hz, 1H), 7.05 (s, 1H), 6.81 (d, J = 7.4 Hz, 1H), 4.57 (d, J = 5.9 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H). MS m/z (ESI): 482.52 [M+H] ⁺ .

Example 236. Synthesis of N-(6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidine-2-carboxamide Compound 236

3 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and proline (20 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-(6-((5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)pyrrolidine-2-carboxamide. MS m/z(ESI):461.51[M+H] ⁺ .

Example 237. Synthesis of N-(6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-2-carboxamide Compound 237

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-piperidinic acid (21 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-2-carboxamide. MS m/z(ESI):475.33[M+H] ⁺ .

Example 238. Synthesis of N-(6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-4-carboxamide Compound 238

Add 3 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add N2-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)pyridine-2,6-diamine (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 4-piperidinic acid (21 mg) under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-4-carboxamide. MS m/z(ESI):475.33[M+H] ⁺ .

Example 239. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-N-methylpicolinamide Compound 239

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and methylamine (5 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N-methylpicolinamide. MS m/z(ESI):405.44[M+H] ⁺ .

Example 240. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-N,N-dimethylpicolinamide Compound 240

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and dimethylamine (7 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N,N-dimethylpicolinamide. MS m/z(ESI):419.47[M+H] ⁺ .

Example 241. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-N-(2-(dimethylamino)ethyl)-N-methylpicolinamide Compound 241

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and N,N,N'-trimethylethylenediamine (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)amino)-N-(2-(dimethylamino)ethyl)-N-methylpicolinamide. MS m/z(ESI): 476.56[M+H] ⁺ .

Example 242. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-N-isobutylpicolinamide Compound 242

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and isobutylamine (12 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N-isobutylpicolinamide. MS m/z(ESI):447.52[M+H] ⁺ .

Example 243. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-N-propylpicolinamide Compound 243

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and n-propylamine (10 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N-propylpicolinamide. MS m/z(ESI):433.49[M+H] ⁺ .

Example 244. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-N-isopropylpicolinamide Compound 244

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and isopropylamine (10 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N-isopropylpicolinamide. MS m/z(ESI):433.49[M+H] ⁺ .

Example 245. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-N-neopentylpicolinamide Compound 245

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and tert-pentylamine (14 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N-neopentylpicolinamide. MS m/z(ESI):461.55[M+H] ⁺ .

Example 246. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-N,N-diisopropylpicolinamide Compound 246

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and diisopropylamine (16 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N,N-diisopropylpicolinamide. MS m/z(ESI):475.57[M+H] ⁺ .

Example 247. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-N,N-dipropylpicolinamide Compound 247

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and di-n-propylamine (16 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N,N-dipropylpicolinamide. MS m/z(ESI):475.57[M+H] ⁺ .

Example 248. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N-(2,2,2-trifluoroethyl)picolinamide Compound 248

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2,2,2-trifluoroethylamine (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N-(2,2,2-trifluoroethyl)picolinamide. MS m/z(ESI): 473.44[M+H] ⁺ .

Example 249. Synthesis of N-(2,2-difluoroethyl)-6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)picolinamide Compound 249

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2,2-difluoroethylamine (13 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(2,2-difluoroethyl)-6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinamide. MS m/z(ESI): 455.45[M+H] ⁺ .

Example 250. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N-(2-fluoroethyl)picolinamide Compound 250

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-fluoroethylamine hydrochloride (16 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N-(2-fluoroethyl)picolinamide. MS m/z(ESI):437.46[M+H] ⁺ .

Example 251. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-N-(2-hydroxy-2-methylpropyl)picolinamide Compound 251

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 1-amino-2-methyl-2-propanol (15 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazol[1,5-A]pyridin-2-yl)amino)-N-(2-hydroxy-2-methylpropyl)picolinamide. MS m/z(ESI): 463.52[M+H] ⁺ .

Example 252. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide Compound 252

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-amino-3-methyl-1-butanol (17 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide. MS m/z(ESI):477.55[M+H] ⁺ .

Example 253. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N-(2-methoxyethyl)picolinamide Compound 253

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-methoxyethylamine (12 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N-(2-methoxyethyl)picolinamide. MS m/z(ESI):449.49[M+H] ⁺ .

Example 254. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N-(2-ethoxyethyl)picolinamide 254

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-ethoxyethylamine (15 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N-(2-ethoxyethyl)picolinamide. MS m/z(ESI):463.52[M+H] ⁺ .

Example 255. Synthesis of N-cyclopropyl-6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)picolinamide Compound 255

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and cyclopropylamine (10 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-cyclopropyl-6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinamide. MS m/z(ESI):431.48[M+H] ⁺ .

Example 256. Synthesis of N-(2-(cyclopropylmethoxy)ethyl)-6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)picolinamide Compound 256

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-(cyclopropylmethoxy)ethane-1-amine (18 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(2-(cyclopropylmethoxy)ethyl)-6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinamide. MS m/z(ESI): 489.56[M+H] ⁺ .

Example 257. Synthesis of 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-a]pyridin-2-yl)amino)-N-ethylpicolinamide Compound 257

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and ethylamine (7 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((5-(5,6-dimethoxypyridin-3-yl)pyrazolo[1,5-A]pyridin-2-yl)amino)-N-ethylpicolinamide. MS m/z(ESI):419.47[M+H] ⁺ .

Example 258. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-ethylpicolinamide Compound 258

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and ethylamine (7 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-ethylpicolinamide. MS m/z (ESI): 420.45 [M+H] ⁺ .

Example 259. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-methylpicolinamide Compound 259

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and methylamine (5 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-methylpicolinamide. MS m/z (ESI): 406.43 [M+H] ⁺ .

Example 260. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N,N-dimethylpicolinamide Compound 260

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and dimethylamine (7 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N,N-dimethylpicolinamide. MS m/z(ESI):420.45[M+H] ⁺ .

Example 261. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-isobutylpicolinamide Compound 261

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and isobutylamine (12 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-isobutylpicolinamide. MS m/z (ESI): 448.51 [M+H] ⁺ .

Example 262. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-propylpicolinamide Compound 262

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and n-propylamine (10 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazol[1,5-A]pyridin-2-yl)amino)-N-propylpicolinamide. MS m/z (ESI): 434.48 [M+H] ⁺ .

Example 263. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-isopropylpicolinamide Compound 263

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and isopropylamine (10 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-isopropylpicolinamide. MS m/z(ESI): 434.48[M+H] ⁺ .

Example 264. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-neopentylpicolinamide Compound 264

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and tert-amylamine (14 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazol[1,5-A]pyridin-2-yl)amino)-N-neopentylpicolinamide. MS m/z (ESI): 462.53 [M+H] ⁺ .

Example 265. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N,N-diisopropylpicolinamide Compound 265

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and diisopropylamine (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N,N-diisopropylpicolinamide. MS m/z(ESI):476.56[M+H] ⁺ .

Example 266. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N,N-dipropylpicolinamide Compound 266

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and di-n-propylamine (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N,N-dipropylpicolinamide. MS m/z(ESI):476.56[M+H] ⁺ .

Example 267. Synthesis of N-(2,2-difluoroethyl)-6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)picolinamide Compound 267

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2,2-difluoroethylamine (13 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(2,2-difluoroethyl)-6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)picolinamide. MS m/z(ESI): 456.43[M+H] ⁺ .

Example 268. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2,2,2-trifluoroethyl)picolinamide Compound 268

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2,2,2-trifluoroethylamine (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2,2,2-trifluoroethyl)picolinamide. MS m/z(ESI):474.42[M+H] ⁺ .

Example 269. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2-fluoroethyl)picolinamide Compound 269

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-fluoroethylamine hydrochloride (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain a yellow product 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2-fluoroethyl)picolinamide. MS m/z(ESI):438.44[M+H] ⁺

Example 270. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2-hydroxy-2-methylpropyl)picolinamide Compound 270

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 1-amino-2-methyl-2-propanol (15 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2-hydroxy-2-methylpropyl)picolinamide. MS m/z(ESI):464.51[M+H] ⁺ .

Example 271. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide Compound 271

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-amino-3-methyl-1-butanol (15 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide. MS m/z(ESI):478.53[M+H] ⁺ .

Example 272. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2-methoxyethyl)picolinamide Compound 272

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-methoxyethylamine (12 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazol[1,5-A]pyridin-2-yl)amino)-N-(2-methoxyethyl)picolinamide. MS m/z (ESI): 450.48 [M+H] ⁺ .

Example 273. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2-ethoxyethyl)picolinamide Compound 273

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-ethoxyethylamine (15 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2-ethoxyethyl)picolinamide. MS m/z(ESI):464.51[M+H] ⁺ .

Example 274. Synthesis of N-cyclopropyl-6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)picolinamide Compound 274

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and cyclopropylamine (10 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-cyclopropyl-6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)picolinamide. MS m/z(ESI): 432.46[M+H] ⁺ .

Example 275. Synthesis of N-(2-(cyclopropylmethoxy)ethyl)-6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)picolinamide Compound 275

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-(cyclopropylmethoxy)ethane-1-amine (18 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(2-(cyclopropylmethoxy)ethyl)-6-((6-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)picolinamide. MS m/z(ESI): 490.54[M+H] ⁺ .

Example 276. Synthesis of 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-ethylpicolinamide Compound 276

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and ethylamine (7 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazol[1,5-A]pyridin-2-yl)amino)-N-ethylpicolinamide. MS m/z (ESI): 420.45 [M+H] ⁺ .

Example 277. Synthesis of 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-methylpicolinamide Compound 277

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and methylamine (5 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-methylpicolinamide. MS m/z(ESI): 406.43[M+H] ⁺ .

Example 278. Synthesis of 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N,N-dimethylpicolinamide Compound 278

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and dimethylamine (7 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N,N-dimethylpicolinamide. MS m/z(ESI):420.45[M+H] ⁺ .

Example 279. Synthesis of 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-isobutylpicolinamide Compound 279

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and isobutylamine (12 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-isobutylpicolinamide. MS m/z (ESI): 448.51 [M+H] ⁺ .

Example 280. Synthesis of 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-propylpicolinamide Compound 280

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and n-propylamine (10 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction is completed, the reaction system is diluted with 10 mL of water. The mixed solution is extracted three times with 20 mL of ethyl acetate, and the organic phases are combined. The organic phase is washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried with anhydrous Na ₂ SO _4. The organic phase is distilled under reduced pressure to obtain a crude product, and the crude product is chromatographed on a silica gel column to obtain a yellow product 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazol[1,5-A]pyridin-2-yl)amino)-N-propylpicolinamide. MS m/z(ESI):434.48[M+H] ⁺ .

Example 281. Synthesis of 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-isopropylpicolinamide Compound 281

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and isopropylamine (10 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-isopropylpicolinamide. MS m/z (ESI): 434.48 [M+H] ⁺ .

Example 282. Synthesis of 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-neopentylpicolinamide Compound 282

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and tert-pentylamine (14 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO _4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((7-(5,6- (2-(2-(dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-neopentylpicolinamide. MS m/z (ESI): 462.53 [M+H] ⁺ .

Example 283. Synthesis of 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N,N-diisopropylpicolinamide Compound 283

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and diisopropylamine (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N,N-diisopropylpicolinamide. MS m/z(ESI):476.56[M+H] ⁺ .

Example 284. Synthesis of 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N,N-dipropylpicolinamide Compound 284

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and di-n-propylamine (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N,N-dipropylpicolinamide. MS m/z(ESI):476.56[M+H] ⁺ .

Example 285. Synthesis of N-(2,2-difluoroethyl)-6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)picolinamide Compound 285

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2,2-difluoroethylamine (13 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(2,2-difluoroethyl)-6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)picolinamide. MS m/z(ESI): 456.43[M+H] ⁺ .

Example 286. Synthesis of 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2,2,2-trifluoroethyl)picolinamide Compound 286

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2,2,2-trifluoroethylamine (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2,2,2-trifluoroethyl)picolinamide. MS m/z(ESI):474.42[M+H] ⁺ .

Example 287. Synthesis of 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2-fluoroethyl)picolinamide Compound 287

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-fluoroethylamine hydrochloride (16 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2-fluoroethyl)picolinamide. MS m/z(ESI): 438.44[M+H] ⁺ .

Example 288. Synthesis of 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2-hydroxy-2-methylpropyl)picolinamide Compound 288

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 1-amino-2-methyl-2-propanol (15 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2-hydroxy-2-methylpropyl)picolinamide. MS m/z(ESI):464.51[M+H] ⁺ .

Example 289. Synthesis of 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide Compound 289

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-amino-3-methyl-1-butanol (15 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide. MS m/z(ESI):478.53[M+H] ⁺ .

Example 290. Synthesis of 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2-methoxyethyl)picolinamide Compound 290

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-methoxyethylamine (12 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2-methoxyethyl)picolinamide. MS m/z(ESI):450.48[M+H] ⁺ .

Example 291. Synthesis of 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)-N-(2-ethoxyethyl)picolinamide Compound 291

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-ethoxyethylamine (15 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazol[1,5-A]pyridin-2-yl)amino)-N-(2-ethoxyethyl)picolinamide. MS m/z(ESI):464.51[M+H] ⁺ .

Example 292. Synthesis of N-cyclopropyl-6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)picolinamide Compound 292

Add 2 mL of tetrahydrofuran to a 25 mL round-bottom flask, and add 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and cyclopropylamine (10 mg) respectively under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-cyclopropyl-6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)picolinamide. MS m/z(ESI): 432.46[M+H] ⁺ .

Example 293. Synthesis of N-(2-(cyclopropylmethoxy)ethyl)-6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)amino)picolinamide Compound 293

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-(7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolyl[1,5-A]pyridin-2-yl)amino)picolinic acid (50 mg), HATU (61 mg), DIPEA (0.045 mL) and 2-(cyclopropylmethoxy)ethane-1-amine (18 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na ₂ SO ₄ . The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(2-(cyclopropylmethoxy)ethyl)-6-((7-(5,6-dimethoxypyridin-3-yl)-[1,2,4]triazolo[1,5-A]pyridin-2-yl)amino)picolinamide. MS m/z(ESI): 490.54[M+H] ⁺ .

Example 294. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-ethylpicolinamide Compound 294

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and ethylamine (7 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-ethylpicolinamide. MS m/z(ESI):420.45[M+H] ⁺ .

Example 295. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-methylpicolinamide Compound 295

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and methylamine (5 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-methylpicolinamide. MS m/z(ESI):406.42[M+H] ⁺ .

Example 296. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N,N-dimethylpicolinamide Compound 296

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and dimethylamine (7 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N,N-dimethylpicolinamide. MS m/z(ESI):420.45[M+H] ⁺ .

Example 297. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-(2-(dimethylamino)ethyl)-N-methylpicolinamide Compound 297

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazine-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and N,N,N'-trimethylethylenediamine (15 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-(2-(dimethylamino)ethyl)-N-methylpicolinamide. MS m/z(ESI):477.54[M+H] ⁺ .

Example 298. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-isobutylpicolinamide Compound 298

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and isobutylamine (11 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-isobutylpicolinamide. MS m/z(ESI):448.50[M+H] ⁺ .

Example 299. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-propylpicolinamide Compound 299

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and n-propylamine (9 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-propylpicolinamide. MS m/z(ESI):434.47[M+H] ⁺ .

Example 300. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-isopropylpicolinamide Compound 300

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and isopropylamine (9 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-isopropylpicolinamide. MS m/z(ESI):434.47[M+H] ⁺ .

Example 301. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-neopentylpicolinamide Compound 301

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and tert-pentylamine (13 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-neopentylpicolinamide. MS m/z(ESI):462.53[M+H] ⁺ .

Example 302. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N,N-diisopropylpicolinamide

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and diisopropylamine (15 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N,N-diisopropylpicolinamide. MS m/z(ESI):476.55[M+H] ⁺ .

Example 303. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N,N-dipropylpicolinamide Compound 303

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and di-n-propylamine (15 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N,N-dipropylpicolinamide. MS m/z(ESI):476.55[M+H] ⁺ .

Example 304. Synthesis of N-(2,2-difluoroethyl)-6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinamide Compound 304

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazine-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and 2,2-difluoroethylamine (12 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(2,2-difluoroethyl)-6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinamide. MS m/z(ESI): 456.43[M+H] ⁺ .

Example 305. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-(2,2,2-trifluoroethyl)picolinamide Compound 305

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazine-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and 2,2,2-trifluoroethylamine (15 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-(2,2,2-trifluoroethyl)picolinamide. MS m/z(ESI):474.42[M+H] ⁺ .

Example 306. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-(2-fluoroethyl)picolinamide Compound 306

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and 2-fluoroethylamine hydrochloride (15 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-(2-fluoroethyl)picolinamide. MS m/z(ESI):438.44[M+H] ⁺ .

Example 307. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-(2-hydroxy-2-methylpropyl)picolinamide Compound 307

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and 1-amino-2-methyl-2-propanol (13 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-(2-hydroxy-2-methylpropyl)picolinamide. MS m/z(ESI):464.50[M+H] ⁺ .

Example 308. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide Compound 308

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazine-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and 2-amino-3-methyl-1-butanol (15 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-(1-hydroxy-3-methylbutan-2-yl)picolinamide. MS m/z(ESI):478.53[M+H] ⁺ .

Example 309. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-(2-methoxyethyl)picolinamide Compound 309

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and 2-methoxyethylamine (11 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-(2-methoxyethyl)picolinamide. MS m/z(ESI):450.47[M+H] ⁺ .

Example 310. Synthesis of 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-(2-ethoxyethyl)picolinamide Compound 310

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and 2-ethoxyethylamine (13 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)-N-(2-ethoxyethyl)picolinamide. MS m/z(ESI):464.50[M+H] ⁺ .

Example 311. Synthesis of N-cyclopropyl-6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinamide Compound 311

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and cyclopropylamine (8 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phases were washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography to obtain a yellow product N-cyclopropyl-6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinamide. MS m/z(ESI):432.46[M+H] ⁺ .

Example 312. Synthesis of N-(2-(cyclopropylmethoxy)ethyl)-6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinamide Compound 312

2 mL of tetrahydrofuran was added to a 25 mL round-bottom flask, and 6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazine-2-yl)amino)picolinic acid (50 mg), HATU (57 mg), DIPEA (0.043 mL) and 2-(cyclopropylmethoxy)ethane-1-amine (17 mg) were added under stirring at room temperature. The reaction system was reacted at room temperature for 2 hours. After the reaction was completed, the reaction system was diluted with 10 mL of water. The mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed with 20 mL of water and 20 mL of saturated NaCl, respectively, and then dried over anhydrous Na2SO4. The organic phase was distilled under reduced pressure to obtain a crude product, which was chromatographed on a silica gel column to obtain a yellow product, N-(2-(cyclopropylmethoxy)ethyl)-6-((6-(5,6-dimethoxypyridin-3-yl)imidazo[1,2-B]pyridazin-2-yl)amino)picolinamide. MS m/z(ESI):490.54[M+H] ⁺ .

Example 313. In vitro inhibitory activity (enzyme activity) assay

In vitro enzyme activity assay was used to determine the IC ₅₀ value of the compound against PI3K family type I kinase (PI3Kγ, stock concentration 5.9 mM). Protein kinase PI3Kγ was purchased from Invitrogen (USA); substrates PIP2:3PS, PI and ADP-Glo assay The kit was purchased from Promega (USA). 5.4 μL of protein kinase PI3Kγ diluted to a certain concentration using the protein diluent in the kit (final concentration was 1 ng/μL) was taken and mixed with 1 μL of the compound diluted in a gradient manner (using the reaction buffer in the kit as solvent dilution), and incubated at room temperature for 1 hour (the final concentrations of the compounds were 10 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, and 0.001 μM, respectively); the substrate (final concentration of the substrate was 0.01 mg/mL) was added and mixed, and the mixed system was reacted at room temperature for 1 hour; finally, 8 μL of detection reagent was added, incubated at 25°C for 40 minutes, and the fluorescence value was read using the MD SpectraMax I3X microplate reader (Molecular Devices, USA). The specific steps refer to the instructions of the PI3Kγ protease activity kit. Prism 8.0 (GraphPad Software, San Diego, CA) was used to plot the fluorescence values and calculate the IC ₅₀ value of the control compound IPI549 (purchased from MCE, China) against the tested protein kinase PI3Kγ, as shown in the following table.

Industrial Applicability

The present invention provides a PI3Kγ kinase inhibitor, which can be used to treat cancer, inflammatory diseases or autoimmune diseases. Therefore, the present invention is suitable for industrial application.

Although the present invention is described in detail herein, the present invention is not limited thereto. Those skilled in the art may make modifications based on the principles of the present invention. Therefore, all modifications made in accordance with the principles of the present invention should be understood to fall within the scope of protection of the present invention.

Claims

A PI3Kγ kinase inhibitor, which is a compound of formula (I) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug thereof,

in,

represents a fused heteroaryl group having 2 or 3 nitrogen atoms selected from:

X is selected from CH or N;

R 1 is selected from C1-6 alkoxy, halogen, C1-6 haloalkyl, or C1-6 haloalkoxy;

R2 is selected from H, Heteroaryl, heteroarylC1-6alkyl, C2-6dialkylaminosulfonyl, or dihydropyran-4-yl;

R3 is selected from H, halogen, or C1-6 alkoxy;

m, n and p are each 0 or 1;

R4 and R5 are each independently selected from H, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C3-6 cycloalkylC1-6 hydroxyalkyl, C1-6 alkoxyC1-6 alkyl, C3-6 cycloalkylC1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, C1-6 aminoalkyl optionally substituted with an amino protecting group, C3-6 cycloalkyl, 4-8 membered heterocyclyl, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl, or heteroarylaminoC1-6 alkyl,

or R 4 , R 5 together with the N to which they are attached form a 4-8 membered heterocyclic group;

R6 and R7 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy C1-6 alkyl, C2-6 dialkylamino C1-6 alkyl, amino protecting group, aminoacyl C1-6 alkyl, C1-6 alkylaminoacyl C1-6 alkyl, or 4-8 membered heterocyclyl C1-6 alkyl,

or R 6 , R 7 together with the N to which they are attached form a 4-8 membered heterocyclic group;

R 8 is selected from C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, phenyl, phenoxy, phenylC1-6 alkyl, phenylC1-6 alkoxy, heteroaryl, heteroarylC1-6 alkyl, 4-8 membered heterocyclyl, or 4-8 membered heterocyclylC1-6 alkyl;

R 9 is selected from H or methyl;

R 10 is selected from 1-methyl-pyrrolidin-3-yl, tetrahydrofuran-3-yl, or pyrrolidin-2-one-5-ylmethyl;

wherein the above-mentioned C3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, and heteroaryl are each optionally substituted by 1-3 substituents independently selected from the following: hydroxy, oxo, aminoacyl, sulfamoyl, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino protecting group, amino optionally substituted by amino protecting group, C2-6 dialkylamino, C2-6 alkanoyl, C2-6 haloalkanoyl, C1-6 alkylsulfonyl, 4-8 membered heterocyclyl, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl, heteroarylC1-6 alkylaminoacyl, or C1-6 alkoxyC1-6 alkylaminoacyl, or two adjacent substituents together form a 4-6 membered fused heterocyclyl.
The PI3Kγ kinase inhibitor according to claim 1, which is a compound of formula (II) or a pharmaceutically acceptable salt, solvate, polymorph, ester, acid, isomer, metabolite or prodrug thereof,

in,

R 1 is selected from C1-6 alkoxy, halogen, C1-6 haloalkyl, or C1-6 haloalkoxy;

R2 is selected from H, Heteroaryl, heteroarylC1-6alkyl, C2-6dialkylaminosulfonyl, or dihydropyran-4-yl;

R3 is selected from H, halogen, or C1-6 alkoxy;

m, n and p are each 0 or 1;

R4 and R5 are each independently selected from H, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C3-6 cycloalkylC1-6 hydroxyalkyl, C1-6 alkoxyC1-6 alkyl, C3-6 cycloalkylC1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, C1-6 aminoalkyl optionally substituted with an amino protecting group, C3-6 cycloalkyl, 4-8 membered heterocyclyl, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl, or heteroarylaminoC1-6 alkyl,

or R 4 , R 5 together with the N to which they are attached form a 4-8 membered heterocyclic group;

R6 and R7 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy C1-6 alkyl, C2-6 dialkylamino C1-6 alkyl, amino protecting group, aminoacyl C1-6 alkyl, C1-6 alkylaminoacyl C1-6 alkyl, or 4-8 membered heterocyclyl C1-6 alkyl,

or R 6 , R 7 together with the N to which they are attached form a 4-8 membered heterocyclic group;

R 8 is selected from C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, phenyl, phenoxy, phenylC1-6 alkyl, phenylC1-6 alkoxy, heteroaryl, heteroarylC1-6 alkyl, 4-8 membered heterocyclyl, or 4-8 membered heterocyclylC1-6 alkyl;

R 9 is selected from H or methyl;

R 10 is selected from 1-methyl-pyrrolidin-3-yl, tetrahydrofuran-3-yl, or pyrrolidin-2-one-5-ylmethyl;

wherein the above-mentioned C3-6 cycloalkyl, 4-8 membered heterocyclyl, phenyl, and heteroaryl are each optionally substituted by 1-3 substituents independently selected from the following: hydroxy, oxo, aminoacyl, sulfamoyl, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino protecting group, amino optionally substituted by amino protecting group, C2-6 dialkylamino, C2-6 alkanoyl, C2-6 haloalkanoyl, C1-6 alkylsulfonyl, 4-8 membered heterocyclyl, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl, heteroarylC1-6 alkylaminoacyl, or C1-6 alkoxyC1-6 alkylaminoacyl, or two adjacent substituents together form a 4-6 membered fused heterocyclyl.
The PI3Kγ kinase inhibitor according to claim 1 or 2, wherein

The heterocyclic group is selected from azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, imidazolinyl, dioxolanyl, or dioxanyl;

The heteroaryl group is selected from pyrazolyl, pyridyl, imidazolyl, isoxazolyl, triazolyl, thienyl, furanyl, or pyrimidinyl;

The amino protecting group is selected from tert-butyloxycarbonyl, pivaloyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, or trifluoroacetyl.
The PI3Kγ kinase inhibitor according to any one of claims 1 to 3, wherein R 1 is selected from methoxy, fluorine, trifluoromethyl, or difluoromethoxy; more preferably methoxy.
The PI3Kγ kinase inhibitor according to any one of claims 1 to 4, wherein R 3 is selected from H, fluorine, or methyl Oxy group; more preferably H.
The PI3Kγ kinase inhibitor according to any one of claims 1 to 5, wherein R 2 is selected from Heteroaryl optionally substituted by 1-3 independently selected Ra, preferably pyrazolyl or pyridinyl; heteroaryl C1-6 alkyl optionally substituted by 1-3 independently selected Ra, preferably imidazolylmethyl; C2-6 dialkylaminosulfonyl, preferably diethylaminosulfonyl; or dihydropyran-4-yl;

R2 is more preferably selected from Pyrazol-4-yl optionally substituted by 1-3 independently R a; or imidazol-1-ylmethyl optionally substituted by 1-3 independently R a;

Wherein, each Ra is independently selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, 4-8 membered heterocyclyl; more preferably, each Ra is independently selected from methyl, ethyl, isopropyl, difluoromethyl, 2-hydroxy-2-methylpropyl, tetrahydropyran-4-yl, morpholin-4-yl; most preferably, each Ra is independently selected from methyl, or 2-hydroxy-2-methylpropyl.
The PI3Kγ kinase inhibitor according to any one of claims 1 to 5, wherein R2 is

wherein m is 0 or 1, more preferably 0;

R4 and R5 are each independently selected from H, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C3-6 cycloalkylC1-6 hydroxyalkyl, C1-6 alkoxyC1-6 alkyl, C3-6 cycloalkylC1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, C1-6 aminoalkyl optionally substituted with an amino protecting group, C3-6 cycloalkyl optionally substituted with 1-3 independently Rb, 4-8 membered heterocyclyl optionally substituted with 1-3 independently Rb, 4-8 membered heterocyclylC1-6 alkyl, heteroaryl optionally substituted with 1-3 independently Rb, heteroarylaminoC1-6 alkyl, or R4 , R5 together with the N to which they are attached form a 4-8 membered heterocyclyl optionally substituted with 1-3 independently Rb; more preferably, R4 and R5 are each independently selected from H, C1-6 alkyl, C ...3-6 cycloalkyl, C1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 5 are each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hydroxyethyl, 2-hydroxy-2-methylpropyl, 1-hydroxy-3-methylbutan-2-yl, 2,2,2,-trifluoroethyl, 2,2-difluoroethyl, 2-fluoroethyl, 1-cyclopropyl-2-hydroxyethyl, methoxyethyl, ethoxyethyl, 2-(cyclopropylmethoxy)ethyl, dimethylaminoethyl, Boc-aminoethyl, optionally 1-3 R4 and R5 are substituted with 1-3 Rb independently, cyclopropyl, cyclopentyl or cyclohexyl, pyrrolidinyl or tetrahydropyranyl, morpholinoethyl, isoxazolyl or pyridinyl, or pyridinylaminoethyl, or R4 , R5 and the N to which they are attached form pyrrolidinyl, piperazinyl, morpholino, piperidinyl, or 1,4-diazepanyl optionally substituted with 1-3 Rb independently; most preferably, ... R 4 and R 5 are each independently selected from H, methyl, ethyl, propyl, isopropyl, hydroxyethyl, 2-hydroxy-2-methylpropyl, 2-fluoroethyl, methoxyethyl, dimethylaminoethyl, Boc-aminoethyl, cyclopentyl optionally substituted with 1-3 R b independently, pyrrolidin-3-yl optionally substituted with 1-3 R b independently, 2-morpholinoethyl, or pyridin-2-ylaminoethyl, or R 4 , R 5 together with the N to which they are attached form pyrrolidin-1-yl, piperazin-1-yl, morpholin-4-yl, or piperidin-1-yl optionally substituted with 1-3 R b independently;

Each Rb is independently selected from hydroxy, oxo, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C2-6 dialkylamino, C2-6 alkanoyl, C1-6 alkylsulfonyl, an amino protecting group, a 4-8 membered heterocyclyl, or a heteroaryl; more preferably, each Rb is independently selected from hydroxy, oxo, fluoro, methyl, ethyl, isopropyl, isobutyl, hydroxymethyl, ethoxy, dimethylamino, acetyl, ethylsulfonyl, Boc, pyrrolidinyl, morpholinyl, or pyridinyl; most preferably, each Rb is independently selected from hydroxy, oxo, methyl, ethyl, isopropyl, isobutyl, hydroxymethyl, dimethylamino, acetyl, ethylsulfonyl, pyrrolidin-1-yl, or pyridin-2-yl.
The PI3Kγ kinase inhibitor according to any one of claims 1 to 5, wherein R2 is

Where p is 0 or 1;

R 6 and R 7 are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, an amino protecting group, aminoacylC1-6 alkyl, C1-6 alkylaminoacylC1-6 alkyl, or a 4-8 membered heterocyclylC1-6 alkyl, or R 6 , R 7 together with the N to which they are attached form a 4-8 membered heterocyclyl optionally substituted by 1-3 independently R c; more preferably, R 6 and R 7 are each independently selected from H, ethyl, propyl, isopropyl, 2-fluoroethyl, 2,2-difluoroethyl, methoxyethyl, methoxypropyl, ethoxyethyl, dimethylaminoethyl, Boc, aminoacylmethyl, methylaminoacylmethyl, or 2-morpholinoethyl, or R 6 , R R 6 and R 7 together with the N to which they are attached form a pyrrolidinyl, piperidinyl, or imidazolinyl optionally substituted by 1-3 independently R c ; most preferably, R 6 and R 7 are each independently selected from H, ethyl, isopropyl, 2-fluoroethyl, methoxyethyl, methoxypropyl, ethoxyethyl, Boc, or 2-morpholinoethyl, or R 6 , R 7 together with the N to which they are attached form a pyrrolidin-1-yl, or imidazolin-1-yl optionally substituted by 1-3 independently R c ;

Each Rc is independently selected from hydroxy, oxo, aminoacyl, halogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 dialkylamino, amino optionally substituted with an amino protecting group, heteroaryl C1-6 alkylaminoacyl, or C1-6 alkoxy C1-6 alkylaminoacyl; more preferably, each Rc is independently selected from hydroxy, oxo, aminoacyl, fluorine, methyl, difluoromethyl, dimethylamino, Boc-amino, amino, 1,2,4-triazolylethylaminoacyl, or methoxyethylaminoacyl; most preferably, each Rc is independently selected from oxo, aminoacyl, methyl, dimethylamino, Boc-amino, 1,2,4-triazol-1-ylethylaminoacyl, or methoxyethylaminoacyl.
The PI3Kγ kinase inhibitor according to any one of claims 1 to 5, wherein R2 is

wherein n is 0 or 1, more preferably 1;

R 9 is selected from H or methyl; preferably, R 9 is H;

R is selected from C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkoxyC1-6 alkyl, C2-6 dialkylaminoC1-6 alkyl, phenyl optionally substituted by 1-3 Rd independently, phenoxy, phenylC1-6 alkyl optionally substituted by 1-3 Rd independently, phenylC1-6 alkoxy, heteroaryl optionally substituted by 1-3 Rd independently, heteroarylC1-6 alkyl optionally substituted by 1-3 Rd independently, 4-8 membered heterocyclyl optionally substituted by 1-3 Rd independently, or 4-8 membered heterocyclylC1-6 alkyl optionally substituted by 1-3 Rd independently; preferably, R 8 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, trifluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, methoxy, methoxymethyl, dimethylaminomethyl, phenyl optionally substituted by 1-3 Rd independently, phenoxy, benzyl or phenethyl optionally substituted by 1-3 Rd independently, phenylmethoxy, heteroaryl optionally substituted by 1-3 Rd independently selected from thienyl, furanyl, pyridyl, pyrimidinyl, or imidazolyl, any is a heteroarylC1-6 alkyl group optionally substituted by 1-3 independently Rd selected from thienylmethyl, furanylmethyl, pyridinylmethyl, or pyridinylethyl, a heterocyclyl group optionally substituted by 1-3 independently Rd selected from pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, azetidinyl, or azepanyl, or a heterocyclylC1-6 alkyl group optionally substituted by 1-3 independently Rd selected from tetrahydropyranylmethyl, morpholinylmethyl, piperazinylmethyl, piperidinylethyl, or pyrrolidinylmethyl; most preferably, R 8 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, methoxy, methoxymethyl, dimethylaminomethyl, phenyl optionally substituted by 1-3 independently Rd, phenoxy, phenylmethoxy, heteroaryl optionally substituted by 1-3 independently Rd selected from thien-2-yl, furan-2-yl, furan-3-yl, pyrimidin-4-yl, or imidazol-4-yl, heteroarylC1-6alkyl optionally substituted by 1-3 Rd independently selected from thien-3-ylmethyl or furan-2-ylmethyl, heterocyclyl optionally substituted by 1-3 Rd independently selected from pyrrolidin-2-yl, piperidin-3-yl, piperidin-4-yl, or azetidin-3-yl, or heterocyclylC1-6alkyl optionally substituted by 1-3 Rd independently selected from tetrahydropyran-4-ylmethyl, morpholin-4-ylmethyl, or piperazin-1-ylmethyl;

Each Rd is independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, amino protecting group, C2-6 haloalkanoyl, sulfamoyl, or 4-8 membered heterocyclic C1-6 alkyl, or two adjacent Rd together form a 4-6 membered fused heterocyclic group; preferably, each Rd is independently selected from fluorine, methyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, Boc, trifluoropropionyl, sulfamoyl, or morpholinoethyl, or two adjacent Rd together form a dioxolanyl or dioxanyl; more preferably, each Rd is independently selected from methyl, methoxy, Boc, sulfamoyl, or morpholinoethyl.
The PI3Kγ kinase inhibitor according to claim 1, which is selected from the following compounds or pharmaceutically acceptable salts, solvates, polymorphs, esters, acids, isomers, metabolites or prodrugs thereof:
A pharmaceutical composition comprising the PI3Kγ kinase inhibitor according to any one of claims 1 to 10, and a pharmaceutically acceptable carrier or excipient.
The PI3Kγ kinase inhibitor according to any one of claims 1 to 10, for use in treating a PI3Kγ-mediated disease selected from cancer, inflammatory diseases or autoimmune diseases.
The use of a PI3Kγ kinase inhibitor as claimed in claim 12, wherein the cancer is selected from a solid tumor or a blood cancer, and the solid tumor is preferably selected from: head and neck cancer, nasal cancer, paranasal sinus cancer, nasopharyngeal cancer, oral cancer, oropharyngeal cancer, laryngeal cancer, hypopharyngeal cancer, salivary gland cancer, paraganglioma, pancreatic cancer, gastric cancer, gastrointestinal cancer, skin cancer, esophageal cancer, uterine cancer, endometrial cancer, liver cancer, hepatocellular carcinoma, bile duct cancer, bone cancer, gastrointestinal cancer, intestinal cancer, colon cancer, rectal cancer, ovarian cancer, prostate cancer, breast cancer, central nervous system tumors, brain cancer, lung cancer, melanoma, glioblastoma, renal cell carcinoma, thyroid cancer, sarcoma, cervical cancer, vulvar cancer, esophageal cancer, adrenal cancer, kidney cancer, urinary system cancer, medulloblastoma, basal cell carcinoma, glioma, testicular cancer, bladder cancer, neuroectodermal tumor, epithelial cancer, squamous cell carcinoma, bronchial cancer, neuroendocrine carcinoma, carcinoid tumor, or diffuse giant cell tumor, or metastatic lesions thereof; the blood cancer is preferably selected from: acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, myeloproliferative disorder, mast cell cancer, Hodgkin's disease, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, I human lymphotropic viral leukemia/lymphoma, AIDS-related lymphoma, adult T-cell lymphoma, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphocytic leukemia, chronic lymphocytic leukemia, or multiple myeloma.
The use of a PI3Kγ kinase inhibitor as claimed in claim 12, wherein the inflammatory disease or autoimmune disease is selected from one or more of the following: asthma, emphysema, allergy, dermatitis, arthritis, psoriasis, lupus erythematosus, graft-versus-host disease, inflammatory bowel disease, eczema, scleroderma, Crohn's disease or multiple sclerosis.