WO2023227125A1

WO2023227125A1 - New fused-heterocyclic compound as cdk inhibitor and use thereof

Info

Publication number: WO2023227125A1
Application number: PCT/CN2023/096666
Authority: WO
Inventors: 张龙; 牛张明
Original assignee: 杭州德睿智药科技有限公司
Priority date: 2022-05-26
Filing date: 2023-05-26
Publication date: 2023-11-30

Abstract

Disclosed in the present invention is a new fused-heterocyclic compound having target inhibitory activity for CDKs, and specifically disclosed is a compound having a structure as represented by formula (I) as a target inhibitor for CDKs or a pharmaceutically acceptable salt, a solvate, a hydrate, an isotope substitute or an isomer thereof.

Description

New heterocyclic compounds as CDKs inhibitors and their applications

The present invention requires the following:

Submitted to the State Intellectual Property Office of China on May 26, 2022, the patent application number is 2022105893943, entitled "New heterocyclic compounds as CDKs inhibitors and their applications" and the priority of the earlier application;

Submitted to the State Intellectual Property Office of China on July 26, 2022, the patent application number is 2022108953999, entitled "New heterocyclic compounds as CDKs inhibitors and their applications" and the priority of the earlier application;

Submitted to the State Intellectual Property Office of China on October 11, 2022, the patent application number is 2022112429830, entitled "New heterocyclic compounds as CDKs inhibitors and their applications" and the priority of the earlier application;

Submitted to the State Intellectual Property Office of China on November 9, 2022, the patent application number is 2022114010056, entitled "New heterocyclic compounds as CDKs inhibitors and their applications" and the priority of the earlier application;

The entirety of said prior application is incorporated into this application by reference.

Technical field

The invention belongs to the field of medicinal chemistry, and specifically includes the disclosure of novel heterocyclic compounds with CDKs target inhibitory activity, compositions containing such compounds, and the application of such compounds in the preparation of treatments or preventions related to CDKs targets. Methods of medicine for diseases.

Background technique

Cyclin-dependent kinases (CDKs) belong to the serine/threonine protein kinase family. 21 types of CDKs have been discovered so far. The activation of most CDKs must bind to cyclins to form active heterodimer complexes. This active dimer complex can phosphorylate the corresponding substrate, thereby driving various processes of the cell cycle, thereby regulating cell growth and proliferation. Among all CDKs, CDK1/2/4/6 mainly function by regulating the cell cycle, while CDK7/8/9/10/11 can also participate in cell cycle and transcriptional regulation to exert biological functions.

Studies have shown that the occurrence and development of many malignant tumors are related to cell cycle disorders, of which excessive activation of CDK is one of the most important reasons. CDK plays an important role in the proliferation and apoptosis of tumor cells. Therefore, selective inhibition of CDK can play a positive therapeutic role in the treatment of tumors. Currently, CDK4/6-targeting inhibitors palbociclib, ribociclib, abeciclib, and dalsilide are on the market, and have shown excellent efficacy in the treatment of breast cancer. As an important member of the CDK family, CDK7 mainly forms the CDK-activated kinase complex (CAK) with cyclin H (cyclin H) and MAT1. On the one hand, the CAK complex can phosphorylate other cell cycle kinases and promote the normal progression of the cell cycle. On the other hand, the CAK complex can phosphorylate RNA polymerase II and participate in the transcriptional regulation of related genes.

Studies have shown that CDK7 is overexpressed in many malignant tumors such as liver cancer, gastric cancer, cervical cancer, breast cancer, pancreatic cancer, colorectal cancer, neuroblastoma, prostate cancer, non-small cell lung cancer, and acute myeloid leukemia. , and has a certain correlation with aggressive clinical pathology and poor prognosis. Since members of the entire CDK family have high homology, and their mechanisms are also different in different types of tumors, non-selective CDK7 inhibitors have certain adverse effects due to off-target effects in clinical trials. reaction. Currently, there are no selective CDK7 inhibitors on the market. A large number of preclinical and clinical trials have shown that highly selective CDK7 inhibitors have great potential therapeutic value in a variety of refractory tumors.

Technical effect

The inventor unexpectedly discovered that some of the new heterocyclic compounds of the formula (I) of the present invention not only have significant CDK7 inhibitory activity, but also have better inhibitory activity than clinical reference compounds with known structures such as THZ2, Samuraciclib, CYC-202, etc. With higher activity, better selectivity, pharmacokinetics and bioavailability, it is expected to have better human PK characteristics and efficacy, and is more suitable for development as a candidate drug for the prevention or treatment of CDKs targets. Diseases related to points or signaling pathways.

Contents of the invention

The object of the present invention is to provide a compound represented by formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof,

in,

Ring A, Ring C and Ring D are each independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, Alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

Ring B is arbitrarily independently non-existent or a monocyclic or polycyclic structure with 3 to 18 carbon atoms. The monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, and a heterocyclic ring. , paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

X ₁ , X ₂ , X ₃ , and X ₄ are each independently selected from -C(R _d1 )– or -N-;

L ₁ , L ₂ and L ₃ are each independently selected from the group consisting of absence, single bond, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 ) (R _d2 )O-, -C(＝O)N(R _d3 )-, -N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )-, -S(＝O) ₂ N(R _d3 )-, -N(R _d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)- , -C(=O)-, -C(=S)-, -S(=O)–, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )O-, -C(R _d1 )(R _d2 )C (＝O)N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(＝ NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )S(=O) ₂ N(R _d3 )-, -N(R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)O-, -OC(=O)C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)-, -C( R _d1 )(R _d2 )C(=S)-, -S(=O)C(R _d1 )(R _d2 )– or -C(R _d1 )(R _d2 )S(=O) ₂ -;

Each R ₁ may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , -COOH or selected from C _1-10 alkyl, C _2-10 alkene base, C _2-10 alkynyl or C _1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C _2-10 heteroalkyl group, C _3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _{3- 10-} cycloalkyl-substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R ₁ carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C _1-10 alkyl, C _2-10 Alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, C _3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, _C _{1-10 alkyl substituted by C 3-10} cycloalkyl or C _3-10 heterocycloalkyl, C _2-10 substituted by C _3-10 cycloalkyl Heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, CN ;

Each R ₂ may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _{3- 10-} cycloalkyl-substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R ₁ carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C _1-10 alkyl, C _2-10 alkenyl, C _{2- 10} alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, C _3-10 saturated or partially saturated heterocycloalkyl, aryl, Heteroaryl, _C _1-10 alkyl substituted by C 3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _2-10 heteroalkyl substituted by C _3-10 cycloalkyl, C _{3 -10} heterocyclyl, C _1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, CN;

Each R ₃ may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group or C _1-10 alkoxy group, C _{2 -10} heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _3-10 cycloalkyl or C _{3 -10} heterocycloalkyl substituted C _1-10 alkyl, C _2-10 heteroalkyl substituted with C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl Or carboxyl substitute; or any two R ₁ and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic ring Structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, and The ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; the C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group or C _1-10 alkoxy group , C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, C _3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C _3-10 cycloalkyl base or C _1-10 alkyl substituted by C _3-10 heterocycloalkyl, C _2-10 heteroalkyl substituted by C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl The carboxyl group or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, CN;

Each R _d1 , R _d2 and R _d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _{2 -10} alkynyl, C _1-10 alkylamino, N, N-di(C _1-10 alkyl) amino, C _1-10 alkyloxy, C _1-10 alkyl acyl, C _1-10 alkyl baseoxy group, C _1-10 alkylsulfonyl group, C _1-10 alkylsulfinyl group, C _3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C _3-10 cycloalkoxy group , C _3-10 cycloalkyloyl, C _3-10 cycloalkoxyacetyl, C _3-10 cycloalkylsulfonyl and C _3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF _3. C _1-6 alkyl, C _1-6 alkoxy, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , oxygen, and saturated or partially saturated C _3-6 cycloalkyl is substituted, and C _1-6 alkyl and C _1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ and saturated or partially saturated C _3-6 cycloalkyl groups are substituted; or any two R _d1 , R _d2 or R _d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ ;

Said hetero represents any atom or group independently selected from O, N, S, S=O, S(=O) ₂ , P and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4.

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (1-I),

in,

Ring A and ring C are each independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, Heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

L ₁ , L ₂ and L ₃ are each independently selected from the group consisting of absence, single bond, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 ) (R _d2 )O-, -C(＝O)N(R _d3 )-, -N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )-, -S(＝O) ₂ N(R _d3 )-, -N(R _d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)- , -C(=O)-, -C(=S)-, -S(=O)–, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )O-, -C(R _d1 )(R _d2 )C(＝O)N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C (R _d1 )(R _d2 )C(=NR _d3 )-,-C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-,-C(R _d1 )(R _d2 )S(=O) ₂ N(R _d3 )-, -N(R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 ) (R _d2 )-, -C(R _d1 )(R _d2 )C(＝O)O-, -OC(＝O)C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(＝O)-, -C(R _d1 )(R _d2 )C(＝S)-, -S(＝O)C(R _d1 )(R _d2 )–or -C(R _d1 )(R _d2 )S(＝O) ₂ -;

Each R ₃ may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group or C _1-10 alkoxy group, C _{2 -10} heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _3-10 cycloalkyl or C _{3 -10} heterocycloalkyl substituted C _1-10 alkyl, C _2-10 heteroalkyl substituted with C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R ₁ and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heterocyclic Aromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The above-mentioned C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkane base, C _3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl _, C 1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _3-10 cycloalkyl substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkylcarboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen , OCH ₃ , carboxyl, OH, CN substituent substitution;

Each R _d1 , R _d2 and R _d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _{2 -10} alkynyl, C _1-10 alkylamino, N, N-di(C _1-10 alkyl) amino, C _1-10 alkyloxy, C _1-10 alkyl acyl, C _1-10 alkyl baseoxy group, C _1-10 alkylsulfonyl group, C _1-10 alkylsulfinyl group, C _3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C _3-10 cycloalkoxy group , C _3-10 cycloalkyloyl, C _3-10 cycloalkoxyacetyl, C _3-10 cycloalkylsulfonyl and C _3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF _3. C _1-6 alkyl, C _1-6 alkoxy, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , oxygen, and saturated or partially saturated C _3-6 cycloalkyl is substituted, and C _1-6 alkyl and C _1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ and saturated or partially saturated C _3-6 cycloalkyl groups are substituted; or any two R _d1 , R _d2 or R _d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ ;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (1-IA),

in,

Ring B is arbitrarily independently a monocyclic or polycyclic structure with 3 to 18 carbon atoms. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, paracyclic ring, Spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

L ₁ and L ₂ are each independently selected from a single bond, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )O- , -C(＝O)N(R _d3 )-, -N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )-, -S (＝O) ₂ N(R _d3 )-, -N(R _d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O )-, -C(＝S)-, -S(＝O)–, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 ) C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )O-, -C(R _d1 )(R _d2 )C(＝O)N( R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(=NR _d3 )-,- C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )S(＝O) ₂ N(R _d3 )-, -N (R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C (＝O)O-, -OC(＝O)C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(＝O)-, -C(R _d1 )(R _d2 )C(=S)-, -S(=O)C(R _d1 )(R _d2 )– or -C(R _d1 )(R _d2 )S(=O) ₂ -;

L ₃ is independently selected from -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )O-, -C(=O) N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )-, -S(＝O) ₂ N(R _d3 )-, -C( ＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R _d1 )(R _d2 )C( R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )O -, -C(R _d1 )(R _d2 )C(＝O)N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-, -C(R _d1 ) (R _d2 )S(=O) ₂ N(R _d3 )-, -N(R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(＝O)O-, -OC(＝O)C(R _d1 )(R _d2 )-, -C(R _d1 )( R _d2 )C(＝O)-, -C(R _d1 )(R _d2 )C(＝S)-, -S(＝O)C(R _d1 )(R _d2 )–or -C(R _d1 ) (R _d2 )S(=O) ₂ -;

Each R ₂ may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _{3- 10} cycloalkyl substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; or any The two R _1s and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C _1-10 alkane Base, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, C _3-10 saturated Or partially saturated heterocycloalkyl, aryl, heteroaryl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _3-10 cycloalkyl The substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl carboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH , CN substituent substitution;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (1-IB),

in,

Each R ₁ may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , -COOH or selected from C _1-10 alkyl, C _2-10 alkene base, C _2-10 alkynyl or C _1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C _2-10 heteroalkyl group, C _3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _{3- 10} cycloalkyl substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R ₁ carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C _1-10 alkyl, C _2-10 Alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, C _3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, _C _{1-10 alkyl substituted by C 3-10} cycloalkyl or C _3-10 heterocycloalkyl, C _2-10 substituted by C _3-10 cycloalkyl Heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, CN ;

Each R _d1 , R _d2 and R _d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _{2 -10} alkynyl, C _1-10 alkylamino, N, N-di(C _1-10 alkyl) amino, C _1-10 alkyloxy, C _1-10 alkyl acyl, C _1-10 alkyl baseoxy group, C _1-10 alkylsulfonyl group, C _1-10 alkylsulfinyl group, C _3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C _3-10 cycloalkoxy group , C _3-10 cycloalkyloyl, C _3-10 cycloalkoxyacetyl, C _3-10 cycloalkylsulfonyl and C _3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl groups are optionally substituted by 1 to more selected from hydrogen, deuterium, Halogen, -CN, -OH, CF ₃ , C _1-6 alkyl, C _1-6 alkoxy, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , Oxygen group, and saturated or partially saturated C _3-6 cycloalkyl group are substituted, and C _1-6 alkyl group and C _1-6 alkoxy group are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxygen substitution, CN, CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ and saturated or partially saturated C _3-6 cycloalkyl groups; or any two R _d1 , R _d2 or R _d3 may be attached to it The carbons together form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure. ; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkyl, aromatic The base and heteroaryl are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF ₃ , OH, OCH ₃ and OCH ₂ CH ₃ ;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (1-IC),

in,

X ₁ and X ₀ are each independently selected from -CH– or -N-;

Ring C is arbitrarily independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms. The monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, and a polycyclic ring. Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

L ₁ and L ₃ are each independently selected from the group consisting of absence, single bond, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )O-, -C(＝O)N(R _d3 )-, -N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )- , -S(＝O) ₂ N(R _d3 )-, -N(R _d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C (＝O)-, -C(＝S)-, -S(＝O)–, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )( R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _{d2 )C(R d1} ₎ (R _d2 )O-, -C(R _d1 )(R _d2 )C(＝O )N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(＝NR _d3 ) -, -C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )S(＝O) ₂ N(R _d3 )- , -N(R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)O-, -OC(=O)C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)-, -C(R _d1 ) (R _d2 )C(=S)-, -S(=O)C(R _d1 )(R _d2 )– or -C(R _d1 )(R _d2 )S(=O) ₂ -;

Each R ₂ may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _{3- 10} cycloalkyl substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R ₁ carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms or heteroatom-containing groups such as C=O, S=O, S(=O) ₂ , etc.; wherein the C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, C _3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C _3-10 cycloalkyl or C _3-10 heterocycloalkyl Substituted C _1-10 alkyl, C _2-10 heteroalkyl substituted by C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkylcarboxyl or carboxyl substitutes are optionally preferably Substituted with 1 to more substituents selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, and CN;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (1-ID),

in,

L ₁ , L ₂ and L ₃ are each independently selected from the group consisting of absence, single bond, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 ) (R _d2 )O-, -C(=O)N(R _d3 )-, -N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )-, -S(＝O) ₂ N(R _d3 )-, -N (R _d3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)-, -C(=S)-, -S( ＝O)–, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -C( R _d1 )(R _d2 )C(R _d1 )(R _d2 )O-, -C(R _d1 )(R _d2 )C(＝O)N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 ) C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )S(＝O) ₂ N(R _d3 )-, -N(R _d3 )C(R _d1 )(R _d2 )- , -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)O-, -OC(=O)C (R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)-, -C(R _d1 )(R _d2 )C(=S)-, -S(=O) C(R _d1 )(R _d2 )–or-C(R _d1 )(R _d2 )S(=O) ₂ -;

Each R ₂ may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _{3- 10} cycloalkyl substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R ₁ carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C _1-10 alkyl, C _2-10 alkenyl, C _{2- 10} alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, C _3-10 saturated or partially saturated heterocycloalkyl, aryl, Heteroaryl, _C _1-10 alkyl substituted by C 3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _2-10 heteroalkyl substituted by C _3-10 cycloalkyl, C _{3 -10} heterocyclyl, C _1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, CN;

Each R ₃ may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group or C _1-10 alkoxy group, C _{2 -10} heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _3-10 cycloalkyl or C _{3 -10} heterocycloalkyl substituted C _1-10 alkyl, C _2-10 heteroalkyl substituted with C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R ₁ and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heterocyclic Aromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The above-mentioned C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkane base, C _3-10 _saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _3-10 cycloalkyl substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkylcarboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen , OCH ₃ , carboxyl, OH, CN substituent substitution;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (1-IE),

in,

X ₀ is independently selected from -CH– or -N-;

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

L ₁ and L ₃ are each independently selected from the group consisting of absence, single bond, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )O-, -C(＝O)N(R _d3 )-, -N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )- , -S(＝O) ₂ N(R _d3 )-, -N(R _d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C (＝O)-, -C(＝S)-, -S(＝O)–, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )( R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )O-, -C(R _d1 )(R _d2 )C(＝O )N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(＝NR _d3 ) -, -C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )S(＝O) ₂ N(R _d3 )- , -N(R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)O-, -OC(=O)C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)-, -C(R _d1 ) (R _d2 )C(=S)-, -S(=O)C(R _d1 )(R _d2 )– or -C(R _d1 )(R _d2 )S(=O) ₂ -;

Each R ₂ may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _{3- 10} cycloalkyl substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R ₁ carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms or heteroatom-containing groups such as C=O, S=O, S(=O) ₂ , etc.; wherein the C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, C _3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C _3-10 cycloalkyl or C _3-10 heterocycloalkyl Substituted C _1-10 alkyl, substituted by C _3-10 cycloalkyl C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkylcarboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, CN Substituted with substituents;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

In certain aspects of the present invention, the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (1-IF),

in,

X ₀ and X are independently selected from -CH- or -N-;

L ₁ and L ₃ are each independently selected from the group consisting of absence, single bond, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )O-, -C(＝O)N(R _d3 )-, -N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )- , -S(＝O) ₂ N(R _d3 )-, -N(R _d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C (＝O)-, -C(＝S)-, -S(＝O)–, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )( R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _{d2 )C(R d1} ₎ (R _d2 )O-, -C(R _d1 )(R _d2 )C(＝O )N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(＝NR _d3 ) -, -C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )S(＝O) ₂ N(R _d3 )- , -N(R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)O-, -OC(=O)C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)-, -C(R _d1 ) (R _d2 )C(=S)-, -S(=O)C(R _d1 )(R _d2 )– or -C(R _d1 )(R _d2 )S(=O) ₂ -; and when L ₁ When it does not exist or is a single bond, L ₃ is not NH;

Each R ₁ may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , -COOH or selected from C _1-10 alkyl, C _2-10 alkene base, C _2-10 alkynyl or C _1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C _2-10 heteroalkyl group, C _3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _{3- 10} cycloalkyl substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; or any The two R _1s and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl , C _3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _3-10 cycloalkyl substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkylcarboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, CN substituent substitution;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1 and 2.

In some aspects of the present invention, the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (2-I),

in,

X is arbitrarily independently selected from N or CR;

Ring A and ring C are each independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be any is selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the aliphatic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated ethylenic bonds;

Ring B is arbitrarily independently selected from monocyclic or polycyclic structures that do not exist or have 3 to 18 carbon atoms. The monocyclic or polycyclic structures can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

L ₁ and L ₂ are each independently selected from the group consisting of absence, single bond, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )O-, -C(＝O)N(R _d3 )-, -N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )- , -S(＝O) ₂ N(R _d3 )-, -N(R _d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C (＝O)-, -C(＝S)-, -S(＝O)–, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )( R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )O-, -C(R _d1 )(R _d2 )C(＝O )N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(＝NR _d3 ) -, -C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )S(＝O) ₂ N(R _d3 )- , -N(R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)O-, -OC(=O)C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)-, -C(R _d1 ) (R _d2 )C(=S)-, -S(=O)C(R _d1 )(R _d2 )– or -C(R _d1 )(R _d2 )S(=O) ₂ -;

R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , -COOH, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _{1 -10} alkoxy;

Each R ₁ may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , -COOH, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C _3-10 saturated _or partially saturated heterocyclyl, C 1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _3-10 ring Alkyl-substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R ₁ together with the carbon atoms connected to the ring form 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the The alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C _1-10 alkyl group and C _2-10 alkenyl group , C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, C _3-10 saturated or partially saturated heterocycloalkyl , aryl, heteroaryl, _C 1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _2-10 heteroalkyl substituted by C _3-10 cycloalkyl The base, C _3-10 heterocyclyl, C _1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, CN;

Each R ₂ may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide base, N,N-dimethylbutenamide group, C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group or C _1-10 alkoxy group, C _2-10 heteroalkyl group , C _3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _3-10 cycloalkyl or C _3-10 heterocycloalkyl C _1-10 alkyl substituted by C 3-10 cycloalkyl, C _{2-10 heteroalkyl substituted by C 3-10} _cycloalkyl , C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; Or any two R ₁ and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, and aliphatic rings. , heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C _{1- 10} alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, C _{3- 10} saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _3-10 ring The alkyl-substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl carboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen, OCH ₃ , carboxyl , OH, CN substituent substitution;

Each R ₃ may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group or C _1-10 alkoxy group, C _{2 -10} heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _3-10 cycloalkyl or C _{3 -10} heterocycloalkyl substituted C _1-10 alkyl, C _2-10 heteroalkyl substituted with C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R ₁ and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heterocyclic Aromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The above-mentioned C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group or C _{1-10 alkoxy group, C 2-10} _heteroalkyl group, C _3-10 saturated or partially saturated cycloalkane base, C _3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl _, C 1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _3-10 cycloalkyl substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkylcarboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen , OCH ₃ , carboxyl, OH, CN substituent substitution;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (2-IC),

in,

X ₁ and X ₀ are each independently selected from -CR– or -N-;

L ₁ and L ₂ are each independently selected from the group consisting of absence, single bond, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )O-, -C(＝O)N(R _d3 )-, -N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )- , -S(＝O) ₂ N(R _d3 )-, -N(R _d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C (＝O)-, -C(＝S)-, -S(＝O)–, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )( R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _{d2 )C(R d1} ₎ (R _d2 )O-, -C(R _d1 )(R _d2 )C(＝O )N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(＝NR _d3 ) -, -C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )S(＝O) ₂ N(R _d3 )- , -N(R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)O-, -OC(=O)C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)-, -C(R _d1 ) (R _d2 )C(=S)-, -S(=O)C(R _d1 )(R _d2 )– or -C(R _d1 )(R _d2 )S(=O) ₂ -;

Each R may be the same or different and independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , -COOH, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy;

Each R ₃ may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group or C _1-10 alkoxy group, C _{2 -10} heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _3-10 cycloalkyl or C _{3 -10} heterocycloalkyl substituted C _1-10 alkyl, C _2-10 heteroalkyl substituted with C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R ₁ and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heterocyclic Aromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The above-mentioned C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group or C _{1-10 alkoxy group, C 2-10} _heteroalkyl group, C _3-10 saturated or partially saturated cycloalkane base, C _3-10 _saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _3-10 cycloalkyl substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkylcarboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen , OCH ₃ , carboxyl, OH, CN substituent substitution;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (2-ID),

in,

X, X ₁ and X ₀ are each independently selected from -CR– or -N-;

L ₁ is independently selected from the group consisting of absence, single bond, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )O-, -C(＝O)N(R _d3 )-, -N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )-, -S( ＝O) ₂ N(R _d3 )-, -N(R _d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O) -, -C(＝S)-, -S(＝O)–, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )C (R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )O-, -C(R _d1 )(R _d2 )C(＝O)N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(＝NR _d3 )-, -C (R _d1 )(R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )S(＝O) ₂ N(R _d3 )-, -N( R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C( ＝O)O-, -OC(＝O)C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(＝O)-, -C(R _d1 )(R _d2 ) C(=S)-, -S(=O)C(R _d1 )(R _d2 )– or -C(R _d1 )(R _d2 )S(=O) ₂ -;

Each R ₀ may be the same or different and is independently selected from hydrogen, deuterium, halogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, or C _1-10 alkoxy; and The hydrogen of R ₀ is preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, CN, -N(R _d1 )(R _d2 );

Each R ₂ may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoroxy, Alkylsulfonyl, -COOH, acrylamide, N,N-dimethylcrotonamide, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkyl Oxygen, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _3-10 ring Alkyl or C _1-10 alkyl substituted by C _3-10 heterocycloalkyl, C _2-10 heteroalkyl substituted by C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 Alkyl-substituted carboxyl or carboxyl substitute; or any two R ₁ and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be selected arbitrarily From aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated Ethylenic bond; wherein the C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or Partially saturated cycloalkyl, C _3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C _1- substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl ₁₀ alkyl, C _2-10 heteroalkyl substituted by C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl carboxyl or carboxyl substitute is optionally preferably selected from 1 to more H, deuterium, halogen, OCH ₃ , carboxyl, OH, CN substituent substitution;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (2-IE),

in,

X ₀ is independently selected from -CR– or -N-;

L ₁ and L ₃ are each independently selected from the group consisting of absence, single bond, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )O-, -C(＝O)N(R _d3 )-, -N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )- , -S(＝O) ₂ N(R _d3 )-, -N(R _d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C (＝O)-, -C(＝S)-, -S(＝O)–, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )( R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _{d2 )C(R d1} ₎ (R _d2 )O-, -C(R _d1 )(R _d2 )C(＝O )N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(＝NR _d3 ) -, -C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )S(=O) ₂ N(R _d3 )- , -N(R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)O-, -OC(=O)C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)-, -C(R _d1 ) (R _d2 )C(=S)-, -S(=O)C(R _d1 )(R _d2 )–or -C(R _d1 )(R _d2 )S(=O) ₂ -;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

In some aspects of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (2-IF),

X ₀ is independently selected from -CR– or -N-;

L ₁ and L ₃ are each independently selected from the group consisting of absence, single bond, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )O-, -C(＝O)N(R _d3 )-, -N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )- , -S(＝O) ₂ N(R _d3 )-, -N(R _d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C (＝O)-, -C(＝S)-, -S(＝O)–, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )( R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )O-, -C(R _d1 )(R _d2 )C(＝O )N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(＝NR _d3 ) -, -C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )S(=O) ₂ N(R _d3 )- , -N(R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)O-, -OC(=O)C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)-, -C(R _d1 ) (R _d2 )C(=S)-, -S(=O)C(R _d1 )(R _d2 )– or -C(R _d1 )(R _d2 )S(=O) ₂ -;

Each R _d1 , R _d2 and R _d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _{2 -10} alkynyl, C _1-10 alkylamino, N, N-di(C _1-10 alkyl) amino, C _1-10 alkyloxy, C _1-10 alkyl acyl, C _1-10 alkyl Oxygen group, C _1-10 alkylsulfonyl group, C _1-10 alkylsulfinyl group, C _3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C _3-10 cycloalkyl group Oxygen, C _3-10 cycloalkyloyl, C _3-10 cycloalkoxyacetyl, C _3-10 cycloalkylsulfonyl and C _3-10 cycloalkylsulfinyl, aryl, heteroaryl ; And the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl groups are optionally substituted by 1 to more selected from hydrogen, deuterium, halogen, -CN, -OH , CF ₃ , C _1-6 alkyl, C _1-6 alkoxy, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , oxygen, and saturated or partially Saturated C _3-6 cycloalkyl is substituted, and C _1-6 alkyl and C _1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF ₃ , Group substitution of OH, OCH ₃ , OCH ₂ CH ₃ and saturated or partially saturated C _3-6 cycloalkyl; or any two R _d1 , R _d2 or R _d3 can together with their attached carbons form a 3-18 member Monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the aliphatic ring , heterocyclic, paracyclic, spirocyclic or bridged ring structures may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups are optional Ground is substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ ;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1 and 2.

In certain aspects of the present invention, the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (II),

in,

Ring A' is arbitrarily independently selected from

Ring B' is arbitrarily independently selected from

Q, L and Z are arbitrarily independently selected from S, O, NR _d3 or C(R ₂ ) ₂ ;

Each X, X ₀ , X ₁ or X ₂ may be the same or different and independently selected from N or CR ₂ ;

Y is independently selected from -O-, -S-, -NR _d3 -, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )( R _d2 )O-, -C(=O)N(R _d3 )-, -C(=NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )-, -S(=O ) ₂ N(R _d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )O-, -C(R _d1 )(R _d2 )C(＝O)N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 ) (R _d2 )-, -C(R _d1 )(R _d2 )S(＝O) ₂ N(R _d3 )-, -N(R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)O-, -OC(=O)C(R _d1 )( R _d2 )-, -C(R _d1 )(R _d2 )C(=O)-, -C(R _d1 )(R _d2 )C(=S)-, -S(=O)C(R _d1 ) (R _d2 )–or-C(R _d1 )(R _d2 )S(=O) ₂ -;

Each R ₁ ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , -COOH, C _1-10 alkyl, C _2-10 alkenyl , C _2-10 alkynyl or C _1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _3-10 Cycloalkyl-substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R ₁ ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R ₁ ' is optionally preferably 1 Substituted with at least a plurality of substituents selected from H, deuterium, halogen, alkyl, OCH ₃ , haloalkyl, carboxyl, OH, and CN;

R ₂ ' and R ₃ ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-dimethylbutylamido, C _1-10 alkyl, C _1-10 haloalkyl, C _1-10 deuterated alkyl, C _2-10 alkenyl, C _1-10 alkoxy, C _1-10 haloalkoxy, C _1-10 deuterated alkoxy, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _{3- 10} saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl _or _R ₂ _' _{_} _{_} and R ₃ ' and the carbon atoms connected to the ring together form a 4-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optional Optimally substituted by 1 to more substituents selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, and CN;

R ₄ is independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C _3-10 saturated _or partially saturated heterocyclyl, C 1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _3-10 ring Alkyl-substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; more Further, the hydrogen on R ₄ is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH ₃ , haloalkyl, carboxyl, OH, and CN;

Each Ra, _Rb , _Rd1 _, _Rd2 and _Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C _1-10 alkyl, C _{2- 10} alkenyl, C _2-10 alkynyl, C _1-10 alkylamino, N, N-bis (C _1-10 alkyl) amino, C _1-10 alkyloxy, C _1-10 alkyl acyl , C _1-10 alkyloxy group, C _1-10 alkylsulfonyl group, C _1-10 alkylsulfinyl group, C _3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C _{3 -10} cycloalkoxy, C _3-10 cycloalkyloyl, C _3-10 cycloalkoxyacetyl, C _3-10 cycloalkylsulfonyl and C _3-10 cycloalkylsulfinyl, aryl , heteroaryl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by 1 to more selected from hydrogen, deuterium, halogen, - CN, -OH, CF ₃ , C _1-6 alkyl group, C _1-6 alkoxy group, -NH ₂ , -NHC _1-6 alkyl group, -N(C _1-6 alkyl) ₂ , oxy group, And saturated or partially saturated C _3-6 cycloalkyl substituted, and C _1-6 alkyl and C _1-6 alkoxy are optionally further selected from 1 to more hydrogen, deuterium, halogen, oxo, CN , CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ and saturated or partially saturated C _3-6 cycloalkyl groups are substituted; or any two R _a , R _b , R _d1 , R _d2 or R _d3 can be Together with its attached carbon, it forms a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or Bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkane Aryl, aryl, heteroaryl are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ ;

The heterodyne represents any atom or group independently selected from O, N, S, S=O, S(=O) ₂ , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily chosen from an integer among 0, 1, 2, 3 and 4.

In certain aspects of the present invention, the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (3-I),

in,

Can be a double bond or a single bond;

when When it is a double bond, X is independently selected from N or CR; when When it is a single bond, X is independently selected from NR _d3 or C(R) ₂ ;

R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , -COOH, C _1-10 alkyl, C _1-10 haloalkyl, C _1-10 deuterated alkyl, C _2-10 alkenyl, C _1-10 haloalkoxy, C _1-10 deuterated alkoxy, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy;

Each R ₁ ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , -COOH, C _1-10 alkyl, C _2-10 alkenyl , C _2-10 alkynyl or C _1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _3-10 Cycloalkyl-substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R ₁ ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C _1-10 alkyl, C _2-10 Alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, C _3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, _C _{1-10 alkyl substituted by C 3-10} cycloalkyl or C _3-10 heterocycloalkyl, C _2-10 substituted by C _3-10 cycloalkyl Heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, CN ;

R ₄ is independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C _3-10 saturated _or partially saturated heterocyclyl, C 1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _3-10 ring Alkyl-substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group or C _1-10 alkoxy group, C _2-10 heteroalkyl group, C _3-10 saturated or partially saturated ring Alkyl, C _3-10 _saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, The C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl carboxyl or carboxyl substitute substituted by C _3-10 cycloalkyl is optionally preferably 1 to more selected from H, deuterium, Substituted by halogen, alkyl, OCH ₃ , carboxyl, OH, CN substituents;

Each R _d1 , R _d2 and R _d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C _1-10 Alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkylamino, N, N-bis (C _1-10 alkyl) amino, C _1-10 alkyloxy, C _1-10 alkyl acyl, C _1-10 alkyloxy, C _1-10 alkylsulfonyl, C _1-10 alkylsulfinyl, C _3-10 cycloalkylamino, C3-10 heterocycle Alkylamino, C _3-10 cycloalkoxy, C _3-10 cycloalkyloyl, C _3-10 cycloalkoxyacetyl, C _3-10 cycloalkylsulfonyl and C _3-10 cycloalkyl Sulfinyl, aryl, heteroaryl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally replaced by 1 to more hydrogen , deuterium, halogen, -CN, -OH, CF ₃ , C _1-6 alkyl, C _1-6 alkoxy, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl ) ₂ , oxygen, and saturated or partially saturated C _3-6 cycloalkyl substituted, and C _1-6 alkyl and C _1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, Halogen, oxo, CN, CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ and saturated or partially saturated C _3-6 cycloalkyl group substitution; or any two R _d1 , R _d2 or R _d3 can be Together with its attached carbon, it forms a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or Bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkane Base, aryl, heteroaryl are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ ;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IA),

in,

X is arbitrarily independently selected from NR _d3 or C(R) ₂ ;

Y is independently selected from -O-, -S-, -NR _d3 -, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )( R _d2 )O-, -C(=O)N(R _d3 )-, -C(=NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )-, -S(=O ) ₂ N(R _d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )O-, -C(R _d1 )(R _d2 )C(=O)N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 ) (R _d2 )-, -C(R _d1 )(R _d2 )S(＝O) ₂ N(R _d3 )-, -N(R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)O-, -OC(=O)C(R _d1 )( R _d2 )-, -C(R _d1 )(R _d2 )C(=O)-, -C(R _d1 )(R _d2 )C(=S)-, -S(=O)C(R _d1 ) (R _d2 )–or-C(R _d1 )(R _d2 )S(=O) ₂ -;

R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , -COOH, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _{1 -10} haloalkyl, C _1-10 deuterated alkyl, C _2-10 alkenyl, C _1-10 alkoxy, C _1-10 haloalkoxy, C _1-10 deuterated alkoxy;

R ₂ ' and R ₃ ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-Dimethylcrotonyl, C _1-10 alkyl, C _1-10 haloalkyl, C _1-10 deuterated alkyl, C _2-10 alkenyl, C _1-10 alkoxy, C _1-10 haloalkoxy, C _1-10 deuterated alkoxy, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _{3- 10} saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl _1-10 Alkyl, C _2-10 heteroalkyl substituted by C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; or R ₂ ' and R ₃ 'Together with the carbon atoms connected to the ring, they form a 4-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, alicyclic rings, heterocyclic rings, and Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optionally preferably Substituted with 1 to more substituents selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, and CN;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IB),

in,

X is arbitrarily independently selected from N or CR;

Each R ₁ ' may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , -COOH, C _1-10 Alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C _2-10 heteroalkyl, C _3-10 saturated Or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _1- substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl ₁₀ alkyl, C _2-10 heteroalkyl substituted by C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R ₁ 'Together with the carbon atoms connected to the ring, they form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, and Ring, spiro ring or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C _{1 -10} alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, C _{3 -10} saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _3-10 The cycloalkyl substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl carboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen, OCH ₃ , Carboxyl, OH, CN substituents are substituted;

The heterogeneous representative represents any atom or group independently selected from O, N, S, S=O, S(=O) ₂ , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IC),

in,

X is arbitrarily independently selected from N or CR;

R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , -COOH, C _1-10 alkyl, C _1-10 haloalkyl, C _1-10 deuterated alkyl, C _2-10 alkenyl, C _1-10 alkoxy, C _1-10 haloalkoxy, C _1-10 deuterated alkoxy, C _2-10 alkenyl, C _2-10 alkynyl;

R ₂ ' and R ₃ ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-Dimethylcrotonyl, C _1-10 alkyl, C _1-10 haloalkyl, C _1-10 deuterated alkyl, C _2-10 alkenyl, C _1-10 alkoxy, C _1-10 haloalkoxy, C _1-10 deuterated alkoxy, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _{3- 10} saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl _or _R ₂ _' _{_} _{_} and R ₃ ' and the carbon atoms connected to the ring together form a 4-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optional Optimally substituted by 1 to more substituents selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, and CN;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily chosen from an integer among 0, 1, 2, 3 and 4.

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-ID),

in,

X is arbitrarily independently selected from N or CR;

Y and Z are independently selected from -O-, -S-, -NR _d3 -, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )O-, -C(＝O)N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )-, -S( ＝O) ₂ N(R _d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O) –, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 ) (R _d2 )C(R _d1 )(R _d2 )O-, -C(R _d1 )(R _d2 )C(=O)N(R _d3 )-, -C(R _d1 )(R _d2 )C( R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(=NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )S(=O) ₂ N(R _d3 )-, -N(R _d3 )C(R _d1 )(R _d2 )-, -OC (R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)O-, -OC(=O)C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)-, -C(R _d1 )(R _d2 )C(=S)-, -S(=O)C(R _d1 )(R _d2 )–or-C(R _d1 )(R _d2 )S(=O) ₂ -;

Each R _a and R _b may be the same or different, and are independently selected from hydrogen, deuterium, halogen, -CN, C _1-10 alkyl, C _1-10 haloalkyl, C _1-10 deuterated alkyl, C _2-10 alkenyl, C _1-10 alkoxy, C _1-10 haloalkoxy, C _1-10 deuterated alkoxy, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 Alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _3-10 Cycloalkyl or C _3-10 heterocycloalkyl substituted C _1-10 alkyl, C _2-10 heteroalkyl substituted by C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _{1- 10} alkyl-substituted carboxyl or carboxyl substitute; or R _a and R _b together with the carbon atoms connected to the ring form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be optional Selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the aliphatic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more different Saturated olefinic bonds; and the cyclic structure is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, and CN;

Each R _d1 , R _d2 and R _d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _{2 -10} alkynyl, C _1-10 alkylamino, N, N-di(C _1-10 alkyl) amino, C _1-10 alkyloxy, C _1-10 alkyl acyl, C _1-10 alkyl baseoxy group, C _1-10 alkylsulfonyl group, C _1-10 alkylsulfinyl group, C _3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C _3-10 cycloalkoxy group , C _3-10 cycloalkyloyl, C _3-10 cycloalkoxyacetyl, C _3-10 cycloalkylsulfonyl and C _3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF _3. C _1-6 alkyl, C _1-6 alkoxy, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , oxygen, and saturated or partially saturated C _3-6 cycloalkyl is substituted, and C _1-6 alkyl and C _1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxygen substitution, CN, CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ and saturated or partially saturated C _3-6 cycloalkyl groups; or any two R _d1 , R _d2 or R _d3 may be attached to it The carbons together form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure. ; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkyl, aromatic The base and heteroaryl are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF ₃ , OH, OCH ₃ and OCH ₂ CH ₃ ;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IE),

in,

R _a and R _b may be the same or different, and are independently selected from hydrogen, deuterium, halogen, -CN, C _1-10 alkyl, C _1-10 haloalkyl, C _1-10 deuterated alkyl, C _{2- 10} alkenyl, C _1-10 alkoxy, C _1-10 haloalkoxy, C _1-10 deuterated alkoxy, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy Base, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _3-10 cycloalkyl base or C _1-10 alkyl substituted by C _3-10 heterocycloalkyl, C _2-10 heteroalkyl substituted by C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl carboxyl or carboxyl substitute; or R _a and R _b together with the carbon atoms connected to the ring form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be arbitrarily selected from Aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefins bond; and the cyclic structure is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, CN; or R _a and R _b are connected to it on the ring The carbon atoms come together to form a carbonyl group or C=NR _d3 structure;

R ₂ ' and R ₃ ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-Dimethylcrotonyl, C _1-10 alkyl, C _1-10 haloalkyl, C _1-10 deuterated alkyl, C _2-10 alkenyl, C _1-10 alkoxy, C _1-10 haloalkoxy, C _1-10 deuterated alkoxy, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _{3- 10} Saturated or partially filled and cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl base, C _2-10 heteroalkyl substituted by C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; or R ₂ ' and R ₃ ' The carbon atoms connected to the ring together form a 4-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, and a paracyclic ring. , spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optionally preferably 1 Substituted with multiple substituents selected from H, deuterium, halogen, OCH ₃ , carboxyl, OH, and CN;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

In some aspects of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IF),

X is independently selected from -CR– or -N-;

L is independently selected from the group consisting of absence, single bond, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )O-, - C(＝O)N(R _d3 )-, -N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )-, -S(＝ O) ₂ N(R _d3 )-, -N(R _d3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)- , -C(=S)-, -S(=O)–, -S(=O) ₂ –, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC( R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )O-, -C(R _d1 )(R _d2 ) C(＝O)N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C( ＝NR _d3 )-,-C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-,-C(R _d1 )(R _d2 )S(＝O) ₂ N( R _d3 )-, -N(R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(＝O)O-, -OC(＝O)C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(＝O)-, -C (R _d1 )(R _d2 )C(=S)-, -S(=O)C(R _d1 )(R _d2 )– or -C(R _d1 )(R _d2 )S(=O) ₂ -;

Y and Z are independently selected from -O-, -S-, -NR _d3 -, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )O-, -C(＝O)N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )-, -S( ＝O) ₂ N(R _d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O) –, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 ) (R _d2 )C(R _d1 )(R _d2 )O-, -C(R _d1 )(R _d2 )C(＝O)N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(＝NR _d3 )-, -C(R _d1 ) (R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )S(＝O) ₂ N(R _d3 )-, -N(R _d3 )C (R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(＝O)O -, -OC(=O)C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)-, -C(R _d1 )(R _d2 )C(=S )-, -S(＝O)C(R _d1 )(R _d2 )– or -C(R _d1 )(R _d2 )S(＝O) ₂ -;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

In certain aspects of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IG),

X is independently selected from -CR– or -N-;

R _a and R _b are independently selected from C _1-10 alkyl, C _1-10 haloalkyl, C _1-10 deuterated alkyl, C _2-10 alkenyl, C _1-10 alkoxy, C _{1- 10} haloalkoxy, C _1-10 deuterated alkoxy, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl , aryl, heteroaryl, C _3-10 saturated _or partially saturated heterocyclyl, C 1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _{3 -10} cycloalkyl substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; or the carbon to which R _a and R _b are attached to the ring The atoms together form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure. ; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optionally preferably 1 to more selected from H, deuterium , halogen, OCH ₃ , carboxyl, OH, CN substituent substitution;

R ₄ is independently selected from C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C _3-10 saturated _or partially saturated heterocyclyl, C 1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _3-10 ring Alkyl-substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _6-20 spirocyclyl, C _7-20 bridged cyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic The ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group or C _1-10 alkoxy group, C _{2 -10} heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, C _3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C _3-10 cycloalkyl or C C _1-10 alkyl substituted by _3-10 heterocycloalkyl, C _2-10 heteroalkyl substituted by C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkylcarboxyl or carboxyl The substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH ₃ , carboxyl, OH, and CN;

Each R _d1 , R _d2 and R _d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _{2 -10} alkynyl, C _1-10 alkylamino, N, N-di(C _1-10 alkyl) amino, C _1-10 alkyloxy, C _1-10 alkyl acyl, C _1-10 alkyl baseoxy group, C _1-10 alkylsulfonyl group, C _1-10 alkylsulfinyl group, C _3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C _3-10 cycloalkoxy group , C _3-10 cycloalkyloyl, C _3-10 cycloalkoxyacetyl, C _3-10 cycloalkylsulfonyl and C _3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF _3. C _1-6 alkyl, C _1-6 alkoxy, -NH ₂ , -NHC _1-6 alkyl, -N(C _1-6 alkyl) ₂ , oxygen, and saturated or partially saturated C _3-6 cycloalkyl is substituted, and C _1-6 alkyl and C _1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ and saturated or partially saturated C _3-6 cycloalkyl groups are substituted; or any two R _d1 , R _d2 or R _d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic rings, Heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to multiple heteroatoms; wherein, the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF ₃ , OH, OCH _3. Group substitution of OCH ₂ CH ₃ ;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

In some aspects of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-IH),

in,

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

In some aspects of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (3-II),

in,

Any independently selected from single or double bonds;

X and X ₁ are arbitrarily independently selected from N or CR;

X ₂ , X ₃ and X ₄ are arbitrarily independently selected from N, N(R _d3 ), C(R _d1 )(R _d2 ) or CR;

L ₃ is independently selected from -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )O-, -C(=O) N(R _d3 )-, -C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )-, -S(＝O) ₂ N(R _d3 )-, -C( ＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R _d1 )(R _d2 )C( R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )O -, -C(R _d1 )(R _d2 )C(＝O)N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-, -C(R _d1 ) (R _d2 )S(=O) ₂ N(R _d3 )-, -N(R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(＝O)O-, -OC(＝O)C( R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(=O)-, -C(R _d1 )(R _d2 )C(=S)-, -S(=O)C (R _d1 )(R _d2 )–or -C(R _d1 )(R _d2 )S(=O) ₂ -;

Each R ₂ may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide base, N,N-dimethylbutenamide group, C _1-10 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group or C _1-10 alkoxy group, C _2-10 heteroalkyl group , C _3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _3-10 cycloalkyl or C _3-10 heterocycloalkyl C _1-10 alkyl substituted by C 3-10 cycloalkyl, C _{2-10 heteroalkyl substituted by C 3-10} _cycloalkyl , C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; Or any two R ₁ and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, and aliphatic rings. , heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C _{1- 10} alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, C _{3- 10} saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _3-10 ring The alkyl substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl carboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen, OCH ₃ , carboxyl , OH, CN substituent substitution;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1 and 2.

In certain aspects of the present invention, the compound or its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution has the structure of formula (4-I),

in,

Ring A' is arbitrarily independently selected from

Ring B' is arbitrarily independently selected from

Q and Z are arbitrarily independently selected from S, O, NR _d3 or C(R ₂ ) ₂ ;

Each R ₂ ' may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryloxy, alkylsulfonyl, -COOH, Acrylamide group, N,N-dimethylbutylene amide group, C _1-10 alkyl group, C _1-10 haloalkyl group, C _1-10 deuterated alkyl group base, C _2-10 alkenyl, C _1-10 alkoxy, C _1-10 haloalkoxy, C _1-10 deuterated alkoxy, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C C 1-10 alkyl substituted by _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _2-10 heteroalkyl _substituted by C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; further, the hydrogen on R ₂ ' is optionally preferably 1 to more selected from H, deuterium, halogen, alkyl, OCH ₃ , haloalkyl, carboxyl, Substituted by OH and CN substituents;

Each Ra, _Rb , _Rd1 _, _Rd2 and _Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C _1-10 alkyl, C _{2- 10} alkenyl, C _2-10 alkynyl, C _1-10 alkylamino, N, N-bis (C _1-10 alkyl) amino, C _1-10 alkyloxy, C _1-10 alkyl acyl , C _1-10 alkyloxy group, C _1-10 alkylsulfonyl group, C _1-10 alkylsulfinyl group, C _3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C _{3 -10} cycloalkoxy, C _3-10 cycloalkyloyl, C _3-10 cycloalkoxyacetyl, C _3-10 cycloalkylsulfonyl and C _3-10 cycloalkylsulfinyl, aryl , heteroaryl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by 1 to more selected from hydrogen, deuterium, halogen, - CN, -OH, CF ₃ , C _1-6 alkyl group, C _1-6 alkoxy group, -NH ₂ , -NHC _1-6 alkyl group, -N(C _1-6 alkyl) ₂ , oxygen group, And saturated or partially saturated C _3-6 cycloalkyl substituted, and C _1-6 alkyl and C _1-6 alkoxy are optionally further selected from 1 to more hydrogen, deuterium, halogen, oxo, CN , CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ and saturated or partially saturated C _3-6 cycloalkyl groups are substituted; or any two R _a , R _b , R _d1 , R _d2 or R _d3 can be Together with its attached carbon, it forms a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or Bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkane Base, aryl, heteroaryl are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF ₃ , OH, OCH ₃ , OCH ₂ CH ₃ ;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (4-IA),

in,

Q is arbitrarily independently selected from S, O, NR _d3 or C(R ₂ ') ₂ ;

X, X ₀ and X ₁ are independently selected from N or CR ₂ ';

Each R ₁ ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , -COOH, C _1-10 alkyl, C _2-10 alkenyl , C _2-10 alkynyl or C _1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl, C _3-10 Cycloalkyl-substituted C _2-10 heteroalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R ₁ ' carbon atoms connected to it on the ring Together they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from aromatic rings, Heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to multiple heteroatoms; further, the hydrogen on R ₁ ' is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH ₃ , haloalkyl, carboxyl, OH, and CN;

Each R ₂ ' may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryloxy, alkylsulfonyl, -COOH, Acrylamide group, N,N-dimethylbutyrylamide group, C _1-10 alkyl group, C _1-10 haloalkyl group, C _1-10 deuterated alkyl group, C _2-10 alkenyl group, C _1-10 Alkoxy, C _1-10 haloalkoxy, C _1-10 deuterated alkoxy, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl base, C _3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _3-10 cycloalkyl or C _3-10 heterocycle Alkyl-substituted C _1-10 alkyl, C _2-10 heteroalkyl substituted by C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute ;Furthermore, the hydrogen on R ₂ ' is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH ₃ , haloalkyl, carboxyl, OH, and CN;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (4-IB),

in,

Each R ₁ ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , -COOH, C _1-10 alkyl, C _2-10 alkenyl , C _2-10 alkynyl or C _1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C _2-10 heteroalkyl, C _3-10 saturated or partially saturated and cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _1-10 alkyl substituted by C _3-10 cycloalkyl or C _3-10 heterocycloalkyl base, C _2-10 heteroalkyl substituted by C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R ₁ ' The carbon atoms connected on the ring together form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, Spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, on R ₁ ' Hydrogen is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH ₃ , haloalkyl, carboxyl, OH, and CN;

Each R ₂ ' may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryloxy, alkylsulfonyl, -COOH, Acrylamide group, N,N-dimethylbutyrylamide group, C _1-10 alkyl group, C _1-10 haloalkyl group, C _1-10 deuterated alkyl group, C _2-10 alkenyl group, C _1-10 Alkoxy, C _1-10 haloalkoxy, C _1-10 deuterated alkoxy, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _2-10 heteroalkyl base, C _3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _3-10 cycloalkyl or C _3-10 heterocycle Alkyl-substituted C _1-10 alkyl, C _2-10 heteroalkyl substituted by C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl or carboxyl substitute ;Furthermore, the hydrogen on R ₂ ' is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH ₃ , haloalkyl, carboxyl, OH, CN;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (4-IC),

in,

Q is arbitrarily independently selected from S, O, NR _d3 or C(R ₂ ') ₂ ;

X, X ₀ , X ₁ and X ₂ are independently selected from N or CR ₂ ';

Y is independently selected from -O-, -S-, -NR _d3 -, -C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -C(R _d1 )( R _d2 )O-, -C(=O)N(R _d3 )-, -C(=NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )-, -S(=O ) ₂ N(R _d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )C(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )O-, -C(R _d1 )(R _d2 )C(＝O)N(R _d3 )-, -C(R _d1 )(R _d2 )C(R _d1 )(R _d2 )N(R _d3 )-, -C(R _d1 )(R _d2 )C(＝NR _d3 )-, -C(R _d1 )(R _d2 )N(R _d3 )C(R _d1 )(R _d2 )-, -C(R _d1 ) (R _d2 )S(=O) ₂ N(R _d3 )-, -N(R _d3 )C(R _d1 )(R _d2 )-, -OC(R _d1 )(R _d2 )-, -SC(R _d1 )(R _d2 )-, -C(R _d1 )(R _d2 )C(＝O)O-, -OC(＝O)C(R _d1 )(R _d2 )-, -C(R _d1 )( R _d2 )C(＝O)-, -C(R _d1 )(R _d2 )C(＝S)-, -S(＝O)C(R _d1 )(R _d2 )–or -C(R _d1 ) (R _d2 )S(=O) ₂ -;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (4-ID),

in,

X ₀ and X ₁ are independently selected from N or CR ₂ ';

Each R ₂ ' or R ₃ ' may be the same or different, and are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryloxy, alkylsulfonyl , -COOH, acrylamide group, N,N-dimethylbutyrylamide group, C _1-10 alkyl group, C _1-10 haloalkyl group, C _1-10 deuterated alkyl group, C _2-10 alkenyl group, C _1-10 alkoxy, C _1-10 haloalkoxy, C _1-10 deuterated alkoxy, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _{2 -10} heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _3-10 cycloalkyl or C _{3 -10} heterocycloalkyl substituted C _1-10 alkyl, C _2-10 heteroalkyl substituted with C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl Or a carboxyl substitute; further, the hydrogen on R ₂ ' is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH ₃ , haloalkyl, carboxyl, OH, CN;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

In one aspect of the present invention, the compound or its pharmaceutically acceptable salt, isotope substitution or isomer thereof has the structure of formula (4-IE),

in,

Each X ₀ and X ₁ may be the same or different and independently selected from N or CR ₂ ';

Each R ₂ ' or R ₃ ' may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH ₂ , dialkylphosphoryloxy, alkylsulfonyl , -COOH, acrylamide group, N,N-dimethylbutyrylamide group, C _1-10 alkyl group, C _1-10 haloalkyl group, C _1-10 deuterated alkyl group, C _2-10 alkenyl group, C _1-10 alkoxy, C _1-10 haloalkoxy, C _1-10 deuterated alkoxy, C _2-10 alkenyl, C _2-10 alkynyl or C _1-10 alkoxy, C _{2 -10} heteroalkyl, C _3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C _3-10 saturated or partially saturated heterocyclyl, C _3-10 cycloalkyl or C _{3 -10} heterocycloalkyl substituted C _1-10 alkyl, C _2-10 heteroalkyl substituted with C _3-10 cycloalkyl, C _3-10 heterocyclyl, C _1-10 alkyl substituted carboxyl Or a carboxyl substitute; further, the hydrogen on R ₂ ' is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH ₃ , haloalkyl, carboxyl, OH, CN;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily chosen from an integer among 0, 1, 2, 3 and 4.

In certain embodiments, R ₂ or R ₂ ' is preferably selected from hydrogen, deuterium, halogen, -CN, dialkylphosphoroxy, alkylsulfonyl, -COOH, C _1-10 alkyl, C _{1- 10} haloalkyl, C _1-10 deuterated alkyl, C _1-10 alkoxy, C _1-10 haloalkoxy, C _1-10 deuterated alkoxy; further, R ₂ or R ₂ ' Hydrogen is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH ₃ , haloalkyl, carboxyl, OH, CN.

In one aspect of the present invention, the above-mentioned compound or its pharmaceutically acceptable salt, solvate, hydrate, isotopic substitution or isomer thereof is selected from compounds with structures as listed in the embodiments of the present invention.

The present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer and isotope substitution. kind.

According to an embodiment of the invention, the pharmaceutical composition is formulated for administration by a route selected from: oral, injectable, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, Intramuscular, intravenous, intradermal, intrathecal and epidural.

According to an embodiment of the present invention, the pharmaceutical composition is preferably administered orally.

The oral dosage form is not particularly limited, and any oral dosage form well known in the art can be used, preferably including tablets, capsules, suspensions or oral solutions and other oral dosage forms known in the art. When used as an oral dosage form, the dosage standard used is, for example, 1-1500 mg/day.

According to embodiments of the present invention, the pharmaceutical composition may further include pharmaceutically acceptable auxiliary materials, which are selected from at least one of the following auxiliary materials including but not limited to: fillers, disintegrants, binders, lubricants , surfactants, flavoring agents, wetting agents, pH regulators, solubilizers or co-solvents, and osmotic pressure regulators. Those skilled in the art can easily determine how to select the corresponding excipients and their corresponding dosage according to the needs of the specific dosage form.

According to embodiments of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

Another object of the present invention is to provide the above compounds in the preparation of drugs for preventing and/or treating diseases related to CDKs targets, including tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, psoriasis) and other diseases. use.

The present invention also provides the compound represented by formula (I), its pharmaceutically acceptable salts, solvates, enantiomers and isotope substitutions, as well as the pharmaceutical composition for preventing and/or treating CDKs. Use in diseases related to signaling pathways. The diseases related to the CDKs signaling pathway have the definitions described above.

The present invention also provides a method for preventing and/or treating diseases related to the CDKs signaling pathway, which includes administering to the patient a preventive or therapeutically effective amount of the compound represented by formula (I), its pharmaceutically acceptable salts, solvates, At least one of enantiomers and isotopic substitutions, or a prophylactically or therapeutically effective amount of the above-mentioned pharmaceutical composition is administered to the patient. The diseases related to the CDKs signaling pathway have the definitions described above.

In some embodiments, the patient is a mammal, preferably a human.

Definition and Description:

C _1-10 is selected from C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ and C ₁₀ ; C _2-10 is selected from C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ and C ₁₀ ; C _3-10 is selected from C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ and C ₁₀ ;

The term "alkyl" as used herein refers to a straight or branched chain monovalent hydrocarbon group. Non-limiting examples include methyl, ethyl, propyl, butyl, 2-methyl-propyl, 1,1-dimethylethyl, pentyl and hexyl.

As used herein, the term "alkylene" refers to a straight or branched chain divalent hydrocarbon group of the formula -( _CH2 ) _n- . Non-limiting examples include ethylene and propylene.

The term "1 to more" used herein refers to more than 1, such as 1, 2, 3, 4, 5 or more.

The term "aliphatic ring", "carbocycle(yl)" or "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group. The carbocyclic ring may contain 3 to 20 carbon atoms, preferably 3 to 20 carbon atoms. 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more preferably 3 to 6 carbon atoms. The carbocycle may be monocyclic or polycyclic, it may be a saturated cycloalkyl group or it may optionally contain one, two or more double and/or triple bonds on its ring, thereby forming a so-called Cycloalkenyl or cycloalkynyl. When a carbocyclic ring has multiple rings, these rings can form spiro, fused, and bridged ring structures. For example, non-limiting examples of monocyclic carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyltri Alkenyl, cyclooctyl, cyclooctatetraenyl, etc.; non-limiting examples of polycyclic carbocycles include decalinyl or isobornyl.

The term "aryl" or "aromatic ring" refers to: It should be understood that it preferably represents a monovalent aromatic or partially aromatic monocyclic or bicyclic ring (such as fused ring, bridged ring, spiro ring) with 6 to 20 carbon atoms. ) or a tricyclic hydrocarbon ring, which may be a single aromatic ring or a polyaromatic ring fused together, preferably "C _6-14 aryl". The term "C _6-14 aryl" is understood to mean preferably a monovalent or partially aromatic monocyclic, bicyclic or Tricyclic hydrocarbon rings ("C _6-14 aryl"), especially rings with 6 carbon atoms ("C ₆ aryl"), such as phenyl; or biphenyl, or with 9 carbon atoms a ring ("C ₉ aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C ₁₀ aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, Either a ring with 13 carbon atoms ("C ₁₃ aryl"), such as fluorenyl, or a ring with 14 carbon atoms ("C ₁₄ aryl"), such as anthracenyl. When the C _6-20 aryl group is substituted, it may be mono- or poly-substituted. Moreover, there is no restriction on the substitution position, for example, it may be ortho, para or meta substitution.

The term "spiro ring" refers to a ring system in which two rings share one ring atom, which may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.

The term "cyclic ring" refers to a ring system in which two rings share two ring-forming atoms, which may contain aliphatic rings, heterocyclic rings, aromatic rings or heteroaromatic rings as mentioned above. The term "bridged ring" refers to a ring system in which two rings share more than three ring-forming atoms, which may contain aliphatic rings, heterocyclic rings, aromatic rings or heteroaromatic rings as mentioned above.

The term "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which Ring atoms are heteroatoms or atomic groups selected from N, O, NH, S, S(O) or S(O) ₂ , but do not include the ring part of -OO-, -OS- or -SS-, and the remaining rings The atom is carbon. Preferably it contains 3 to 12 ring atoms, of which 1-4 are heteroatoms (eg 1, 2, 3 and 4); more preferably it contains 3 to 6 ring atoms (eg 3, 4, 5, 6). The heterocyclyl group may be attached to the remainder of the molecule through any one of the carbon atoms or nitrogen atom, if present, or oxygen or sulfur atom (particularly in the case of an onium salt). The heterocyclyl group may include fused or bridged rings and/or spirocyclic rings. Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl , dihydropyrazolyl, dihydropyrrolyl, dioxolyl, tetrahydropyranyl, pyrrolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithiophenyl Alkyl group, trithialkyl group, homopiperazinyl group, diazepanyl group, etc., preferably piperidinyl group and pyrrolidinyl group. Polycyclic heterocyclyl groups include spirocyclic, fused-ring and bridged-ring heterocyclyl groups, and may also be benzo-fused heterocyclyl groups such as dihydroisoquinolinyl groups. The heterocyclyl group may be bicyclic, and non-limiting examples thereof include hexahydrocyclopenta[c]pyrrole-2(1H)-yl, hexahydropyrrolo[1,2-a]pyrazine-2(1H) )-base. Heterocyclyl may also be partially unsaturated, i.e. it may contain one or more double bonds, non-limiting examples of which include dihydrofuryl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl , 4H-[1,3,4]thiadiazinyl, 4,5-dihydroxazolyl or 4H-[1,4]thiazinyl.

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

The term "heteroaryl/heteroaryl ring" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 20 ring atoms, where the heteroatoms are selected from oxygen, sulfur, nitrogen and phosphorus. The heteroaryl group is preferably 5 to 10 yuan (for example, 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan. Non-limiting examples of heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, tris Azolyl, thiadiazolyl, thi-4H-pyrazolyl, etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzo Imidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives , such as quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolinyl, purinyl, etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazoline base, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and/or phenoxazinyl, etc.

The heteroaryl/heteroaryl ring may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one, two or more groups independently selected from the group consisting of: alkyl, alkenyl Base, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, Heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.

Unless otherwise stated, heterocyclyl, heteroaryl or heteroaromatic ring includes all possible isomeric forms thereof, such as positional isomers thereof. Therefore, for some illustrative non-limiting examples, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12 may be included Forms in which -, if present, are substituted at one, two or more positions or bonded to other groups, including pyridin-2-yl, pyridinylene-2-yl, pyridin-3-yl, Pyridin-3-yl, pyridin-4-yl, and pyridin-4-yl; thienyl or thienylene includes thiophene-2-yl, thiophene-2-yl, thiophene-3-yl, and thiophene-3 - base; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared from a compound having specific substituents found in the present invention and a relatively non-toxic acid or base. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, including acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , as well as salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.

Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound. The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

"Pharmaceutically acceptable salts" as used herein belong to derivatives of the compounds of the present invention, wherein the parent compound is modified by salt formation with an acid or salt with a base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid radicals such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts such as Na salt, potassium salt, amine salt, quaternary ammonium salt of the parent compound, etc. Conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids, inorganic bases and organic bases, the inorganic acid or organic acid being selected from 2-acetoxybenzoic acid, 2-hydroxyethyl sulfonate Acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, Carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucose heptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, Hydroxy, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methane sulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid , polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, tartaric acid and p-toluenesulfonic acid. The base and organic base are selected from Na, potassium, magnesium, calcium, etc. or amine, diethylamine, triethylamine, ethanolamine, etc.

The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

In addition to salt forms, the compounds provided by the invention also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to transform into the compounds of the present invention. In addition, prodrugs can be converted to compounds of the invention by chemical or biochemical methods in the in vivo environment.

Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms. In general, solvated and unsolvated forms are equivalent to each other and are included within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous forms.

As used herein, the term "solvate" refers to an association of one or more solvent molecules with a compound of the invention. Solvents that form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. Therefore, the term "hydrate" refers to an association of solvent molecules that is water.

Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the invention.

The illustrations of racemic, ambiscalemic and scalemic or enantiopure compounds in this article are from Maehr, J. Chem. Ed. 1985, 62: 114-120. 1985, 62: 114-120. Unless otherwise stated, wedge-shaped bonds and dashed-line bonds represent the absolute configuration of a stereocenter. When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of this invention.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.

The optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereomeric salts are formed with a suitable optically active acid or base, and then the diastereomeric salts are formed by step-by-step procedures well known in the art. Diastereomers are resolved by crystallization or chromatography, and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally combined with chemical derivatization methods (e.g., generation of amino groups from amines). formate).

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium ( ³ H), iodine-125 ( ¹²⁵ I), or C-14 ( ¹⁴ C). All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These matrices include suspending agents, viscosifiers, transdermal penetration enhancers, etc. Their preparations are well known to those skilled in the field of cosmetics or topical medicine. For additional information on vectors, please refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. Thus, for example, if a group is substituted by 0-2 R, then said group may optionally be substituted by up to two R's, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.

When a substituent's bond can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When an enumerated substituent does not indicate through which atom it is bonded to a compound included but not specifically mentioned in the general chemical formula, such substituent may be bonded through any atom thereof. Combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.

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

The invention is now further described by way of examples. The examples given below are for illustrative purposes only and do not limit the scope of the invention. The compounds of the present invention can be prepared by many methods known in the art of organic synthesis. Embodiments of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the field of organic synthetic chemistry, or by improved methods based on them. Preferred methods include, but are not limited to, the methods described below.

Unless otherwise specified, all solvents used in the present invention are commercially available and can be used without further purification. The reaction is usually carried out under an inert atmosphere of nitrogen using anhydrous solvents. NMR spectra were measured on a Bruker-Avance-400 (400 MHz) spectrometer, and chemical shifts were reported in delta (ppm). Mass spectrometry uses Agilent 1200 series (plus 6110/and 1956A) LC/MS or Shimadzu MS (DAD: SPD-M20A (LC)) and Shimadzu Micromass 2020 detector. The mass spectrometer is equipped with an electrospray ion source (ESI) operating in positive and negative modes.

The present invention uses the following abbreviations: aq represents water; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; Cbz represents benzyloxycarbonyl, an amine protecting group; Boc represents tert-butyloxycarbonyl, an amine protecting group; HOAc represents acetic acid; NaBH(OAc) ₃ represents triacetoxyboration Sodium; rt represents room temperature; THF represents tetrahydrofuran; Boc ₂ O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; Pd(dppf)Cl ₂ represents [1,1'- Bis(diphenylphosphino)ferrocene]palladium(II) dichloride; POCl ₃ represents phosphorus oxychloride; NaH represents sodium hydride; LAH represents lithium aluminum hydride; Pd(OAc) ₂ represents palladium(II) ethane acid salt; Pd ₂ (dba) ₃ represents tris (dibenzylidene acetone) dipalladium; Pd (PPh ₃ ) ₄ represents tetrakis (triphenylphosphine) palladium; Et ₃ SiH represents triethylsilane; PPh ₃ represents triethylsilane Phenylphosphine; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethyl; MeSO ₃ H represents methanesulfonic acid; , 6'-triisopropylbiphenyl;Lawson's reagent represents 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphane-2,4- Disulfide; NBS represents N-bromosuccinimide; t-BuOK represents potassium tert-butoxide; DIPEA is diisopropylethylamine; SOCl ₂ is thionyl chloride; CS2 is carbon disulfide; TsOH is 4-toluenesulfonate Acid; MTBE is tert-butyl methyl ether; i-PrOH is 2-propanol; DAST is diethylaminosulfur trifluoride; DIAD is diisopropyl azodicarboxylate; DEAD is diethyl azodicarboxylate; DBAD is Di-tert-butyl azodicarboxylate; TES is triethylsilane; LDA is lithium diisopropylamide; NBS is N-bromosuccinimide; NIS is N-iodosuccinimide; NCS is N -Chlorosuccinimide; DMP is DMP reagent; DMF-DMA is 1,1-dimethoxy-N,N-dimethylmethylamine; TMP is 2,2,6,6-tetramethylpiperdine Ridine; NMO is N-methylmorpholine N-oxide; TBSC1 is tert-butyldimethylsilyl chloride; SEMC1 is 2-(trimethylsilyl)ethoxymethyl chloride; NFSI is N-fluorobenzene Sulfonamide; AIBN is azobisisobutyronitrile; EDCI is l-ethyl-3-(3-dimethylaminopropyl)carbodiimide; HOBT is hydroxybenzotriazole; TBAF is tetra-n-butyl fluoride ammonium; HATU is l-[bis(dimethylamino)methylene]-lH-l, 2,3-triazolyl[4,5-b]pyridinium trioxide hexafluorophosphate; Xphos is 2-di Cyclohexylphosphine-2', 4', 6'-triisopropylbiphenyl; cataCXium A is n-butyl-bis(1-adamantyl)phosphorus; DPPP is 1,3-bis(diphenylphosphine) Propane; DPPF is 1,1'-bis(diphenylphosphino)ferrocene; HMTA is 1,3,5,7-tetraazaadamantane; PMBC1 is p-methoxybenzyl chloride; HEPES is 4 -(2-Hydroxyethyl)-1-piperazineethanesulfonic acid; EGTA is ethylene glycol bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid.

Compounds can be named manually or using For naming, if purchased commercially, you can also use the supplier's catalog name. TLC or LC-MS is usually used to determine whether the reaction is complete.

Detailed ways

In order to illustrate the present invention in more detail, the following examples are given, but the scope of the present invention is not limited thereto.

Example 1, 3-acrylamide-N-(3-((2-(((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-8-isopropylpyrazole [ Synthesis of 2,2,2-trifluoroacetate (compound 1) of 1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide:

1), 8-isopropyl-2-(methylthio)-N-(3-nitrobenzyl)pyrazole[1,5-a][1,3,5]triazine-4-amine synthesis:

Dissolve 4-chloro-8-isopropyl-2-(methylthio)pyrazole[1,5-a][1,3,5]triazine (500.0mg, 2.06mmol), 3-nitro A mixed solution (10.0 mL) of benzylamine (376.8 mg, 2.48 mmol) and N,N-diisopropylethylamine (799.6 mg, 6.20 mmol) in isopropyl alcohol was heated to 80°C and stirred for 2 hours. After cooling, the resulting mixture was concentrated in vacuo to remove the solvent and purified using C18 column chromatography (mobile phase: acetonitrile and water (containing 0.1% ammonia), gradient: 5%-95%) to obtain 8-isopropyl-2-(methylthio) )-N-(3-nitrobenzyl)pyrazole[1,5-a][1,3,5]triazin-4-amine (650 mg, 1.82 mmol, yield: 88%).

LC-MS m/z:359[M+H] ⁺ .

2), 8-isopropyl-2-(methanesulfonyl)-N-(3-nitrobenzyl)pyrazole[1,5-a][1,3,5]triazine-4-amine synthesis:

Dissolve 8-isopropyl-2-(methylthio)-N-(3-nitrobenzyl)pyrazole[1,5-a][1,3,5]triazine-4-amine ( 650.0 mg, 1.82 mmol) and m-chloroperbenzoic acid (1837 mg, 9.08 mmol, purity: 85%) in toluene solution (15.0 mL) were stirred and reacted at room temperature overnight. At the end of the reaction, the resulting mixture was concentrated in vacuo to remove the solvent and purified using C18 column chromatography (mobile phase: acetonitrile containing 0.1% formic acid and water containing 0.1% formic acid, gradient: 5%-95%) to obtain 8-isopropyl-2- (Methanesulfonyl)-N-(3-nitrobenzyl)pyrazole[1,5-a][1,3,5]triazine-4-amine (400mg, 1.02mmol, yield: 56%) . LC-MS: m/z=391[M+H] ⁺ .

3), (3R,4R)-3-hydroxy-4-((8-isopropyl-4-((3-nitrobenzyl)amino)pyrazole[1,5-a][1,3, 5] Synthesis of triazin-2-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester:

Dissolve 8-isopropyl-2-(methanesulfonyl)-N-(3-nitrobenzyl)pyrazole[1,5-a][1,3,5]triazine-4-amine ( 400.0 mg, 1.02 mmol) and (3R, 4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (283.1 mg, 1.23 mmol) in dioxane (10.0 mL) The solution was heated to 140°C and reacted overnight. After cooling, the resulting mixture was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain (3R, 4R)-3-hydroxy-4-( (8-isopropyl-4-((3-nitrobenzyl)amino)pyrazole[1,5-a][1,3,5]triazin-2-yl)amino)methyl)piperidine -1-tert-butylcarboxylate (300 mg, 0.56 mmol, yield: 55%). LC-MS: m/z=541[M+H] ⁺ .

4), (3R, 4R)-4-((4-((3-aminobenzyl)amino)-8-isopropylpyrazole[1,5-a][1,3,5]triazine- Synthesis of 2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

At room temperature, (3R, 4R)-3-hydroxy-4-((8-isopropyl-4-((3-nitrobenzyl)amino)amino)pyrazole [1,5-a][ 1,3,5]triazin-2-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (300.0 mg, 0.56 mmol) and iron powder (155.6 mg, 2.78 mmol) in ethanol (4 mL) Saturated ammonium chloride solution (1 mL) was added dropwise to the solution. After the dropwise addition is completed, the temperature is raised to 70°C and the reaction is carried out for 2 hours. After cooling, the reaction solution was directly filtered through diatomaceous earth, and the filter cake was washed three times with methanol (3×10 mL). The resulting filtrate was concentrated in vacuo to remove the solvent and purified using C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain the target compound (3R, 4R)-4-((4-( (3-Aminobenzyl)amino)-8-isopropylpyrazole[1,5-a][1,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine- 1-tert-butylcarboxylate (120 mg, 0.24 mmol, yield: 42%). LC-MS: m/z=511[M+H] ⁺ .

5), (3R, 4R)-4-((4-((3-(3-acrylamidebenzamide)benzyl)amino)-8-isopropylpyrazole[1,5-a][1 Synthesis of tert-butyl ester of ,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate:

Dissolve (3R, 4R)-4-((4-((3-aminobenzyl)amino)-8-isopropylpyrazole[1,5-a][1,3,5]triazine- 2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (120.0mg, 0.24mmol), 3-acrylamide benzoic acid (53.9mg, 0.28mmol), N,N,N ',N'-Tetramethylchloroformamidine hexafluorophosphate (134.4mg, 0.48mmol) and N-methylimidazole (78.7mg, 0.96mmol) were mixed in N,N-dimethylformamide (5.0mL) The solution was stirred and reacted at 30°C for 2 hours. The reaction is completed, and the reaction solution is directly purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain (3R, 4R)-4-((4-((3-( 3-Acrylamidebenzamide)benzyl)amino)-8-isopropylpyrazole[1,5-a][1,3,5]triazin-2-yl)amino)methyl)-3- Hydroxypiperidine-1-carboxylic acid tert-butyl ester (60 mg, 0.09 mmol, yield: 36%). LC-MS: m/z=684[M+H] ⁺ .

6), 3-Acrylamide-N-(3-((2-(((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-8-isopropylpyrazole[1 ,Synthesis of 2,2,2-trifluoroacetate (compound 1) of ,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide:

There is (3R, 4R)-4-((4-((3-(3-acrylamidebenzamide)benzyl)amino)-8-isopropylpyrazole[1,5-a][1 ,3,5]Triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (60mg, 0.09mmol) in dichloromethane (3mL), add triazine dropwise Fluoroacetic acid (1mL), react at room temperature for 2 hours. At the end of the reaction, the reaction solution was concentrated in vacuo to remove the solvent and purified using C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain the target compound 3-acrylamide-N-(3-( (2-((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-8-isopropylpyrazole[1,5-a][1,3,5]triazine- Trifluoroacetate of 4-yl)amino)methyl)phenyl)benzamide (26.5 mg, 0.038 mmol, yield: 42%). LC-MS: m/z=584[M+H] ⁺ .

¹ H NMR (400MHz, MeOD_d ₄ ): 8.39 (s, 1H), 7.93 (d, J = 2.4Hz, 2H), 7.67-7.61 (m, 2H), 7.48 (t, J = 8Hz, 2H), 7.38 (t,J＝8Hz,1H),7.23(d,J＝8Hz,1H),6.46-6.38(m,2H),5.82(d,J＝8Hz,1H),4.86(s,2H),3.83( s,1H),3.64(s,2H),3.07-3.00(m,1H),2.86(t,J＝8Hz,1H),2.73(t,J＝8Hz,1H),1.98-1.94(m,2H ), 1.45 (s, 1H), 1.29 (d, J = 4Hz, 6H), 1.14 (s, 2H).

Example 2, 3-acrylamido-N-(3-((3R,4R)-3-hydroxypiperidin-4-yl)methylamino)-8-isopropylpyrazole [1,5-a Synthesis of ][1,3,5]triazin-4-yl)amino)phenyl)benzamide (compound 2):

1), 8-isopropyl-2-(methylthio)-N-(3-nitrophenyl)pyrazole[1,5-a][1,3,5]triazine-4-amine synthesis:

Dissolve 4-chloro-8-isopropyl-2-(methylthio)pyrazole[1,5-a][1,3,5]triazine (1g, 4.13mmol) and 3-nitroaniline (742 mg, 5.37 mmol) and N, N-diisopropylethylamine (1.6 g, 12.39 mmol) in acetonitrile mixed solution (20.0 mL), heated to 80°C, and reacted for 4 hours. cool down Afterwards, water (40 mL) was added to the reaction solution, and extracted three times with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain the target compound 8-isopropyl-2-(methylthio)-N-(3- Nitrophenyl)pyrazole [1,5-a][1,3,5]triazin-4-amine (1.2g, 3.48mmol, yield: 84%). LC-MS: m/z=345[M+H] ⁺ .

2), 8-isopropyl-2-(methanesulfonyl)-N-(3-nitrophenyl)pyrazole[1,5-a][1,3,5]triazine-4-amine synthesis:

Dissolve 8-isopropyl-2-(methylthio)-N-(3-nitrophenyl)pyrazole[1,5-a][1,3,5]triazin-4-amine ( 1g, 2.91mmol)) and m-chloroperoxybenzoic acid (885mg, 4.36mmol, purity: 85%) in dichloromethane solution (15.0mL), stir at room temperature, and react for 2 hours. At the end of the reaction, the resulting mixture was concentrated in vacuo to remove the solvent to obtain a crude product, which was directly used in the next reaction. LC-MS: m/z=377[M+H] ⁺ .

3), (3R, 4R)-3-hydroxy-4-((8-isopropyl-4-((3-nitrophenyl)amino)pyrazole[1,5-a][1,3, 5] Synthesis of triazin-2-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester:

Dissolve 8-isopropyl-2-(methanesulfonyl)-N-(3-nitrophenyl)pyrazole[1,5-a][1,3,5]triazine-4-amine ( 800mg, 2.12mmol) and (3R, 4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (587mg, 2.55mmol) dioxane solution (10.0mL) was heated to 100 ℃, react overnight. After cooling, add water (20 mL) to the reaction system, and extract with ethyl acetate three times (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain the target compound (3R, 4R)-3-hydroxy-4-((8-isopropyl) -4-((3-nitrophenyl)amino)pyrazole[1,5-a][1,3,5]triazin-2-yl)amino)methyl)piperidine-1-carboxylic acid tert. Butyl ester (600 mg, 1.13 mmol, yield: 53%). LC-MS: m/z=527 [M+H] ⁺ .

4), (3R, 4R)-4-((4-((3-aminophenyl)amino)-8-isopropylpyrazole[1,5-a][1,3,5]triazine- Synthesis of 2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

At room temperature, (3R, 4R)-3-hydroxy-4-((8-isopropyl-4-((3-nitrophenyl)amino)pyrazole[1,5-a][ 1,3,5]triazin-2-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (50mg, 0.095mmol) and iron powder Fe (26.7mg, 0.047mmol) in ethanol (2mL) Saturated ammonium chloride solution (0.5 mL) was added dropwise to the solution. After the dropwise addition is completed, the temperature is raised to 70°C and the reaction is carried out for 2 hours. After cooling, the reaction solution was directly filtered through diatomaceous earth, and the filter cake was washed three times with methanol (10 mL × 3). The obtained filtrate was concentrated in vacuo to remove the solvent to obtain the target compound (3R, 4R)-4-((4-((3-aminophenyl)amino)-8-isopropylpyrazole [1,5-a][1 ,3,5]Triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30.0 mg, 0.06 mmol, yield: 63%). LC-MS: m/z=497[M+H] ⁺ .

5), (3R, 4R)-4-((4-((3-(3-acrylamidebenzamide)phenyl)amino)-8-isopropylpyrazole[1,5-a][1 Synthesis of tert-butyl ester of ,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate:

There is (3R, 4R)-4-((4-((3-aminophenyl)amino)-8-isopropylpyrazole[1,5-a][1,3,5]triazine- N,N-dimethyl of 2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.40 mmol) and 3-acrylamide benzoic acid (116 mg, 0.60 mmol) Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (201mg, 0.53mmol) and N,N to the formamide (3mL) solution. -Diisopropylethylamine (69 mg, 0.53 mmol), react at room temperature for 2 hours under nitrogen protection. After the reaction was completed, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate three times (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain (3R, 4R)-4-((4-((3-(3-acrylamide) Benzamide)phenyl)amino)-8-isopropylpyrazole[1,5-a][1,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine- 1-tert-butylcarboxylate (130 mg, 0.19 mmol, yield: 48%). LC-MS: m/z=670[M+H] ⁺ .

6), 3-Acrylamide-N-(3-((3R,4R)-3-hydroxypiperidin-4-yl)methylamino)-8-isopropylpyrazole[1,5-a] Synthesis of [1,3,5]triazin-4-yl)amino)phenyl)benzamide (compound 2):

There is (3R, 4R)-4-((4-((3-(3-acrylamidebenzamide)phenyl)amino)-8-isopropylpyrazole[1,5-a][1 ,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (60mg, 0.089mmol) in dichloromethane (1.5mL), add dropwise Trifluoroacetic acid (0.3 mL), react at room temperature for 1 hour. At the end of the reaction, the reaction solution was concentrated in vacuo to remove the solvent and purified using C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain 3-acrylamido-N-(3-(( 3R, 4R)-3-hydroxypiperidin-4-yl)methylamino)-8-isopropylpyrazole[1,5-a][1,3,5]triazin-4-yl)amino) Phenyl)benzamide (compound 2) (40 mg, 0.07 mmol, yield: 78%).

LC-MS: m/z=570[M+H] ⁺ ;

1H NMR(400MHz,MeOD)δ8.40(m,3H),8.23(s,1H),7.70(s,1H),7.60(d,J＝8.0Hz,2H),7.41(t,J＝7.7Hz ,2H),7.31(m,2H),6.36(dt,J＝21.3,12.3Hz,2H),5.73(d,J＝9.2Hz,1H),3.78(m,2H),3.54(m,2H) ,3.38(sm1H),3.03(m,1H),2.93(m,1H),2.70(m 1H),1.93(d,J＝8.7Hz,1H),1.73(m,1H),1.57(m,1H ),1.20(d,J＝6.8Hz,6H).

Example 3, 3-acrylamide-N-(3-((5-((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazole [1 Synthesis of ,5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide (compound 3):

1), Synthesis of 5-chloro-3-isopropyl-N-(3-nitrobenzyl)pyrazole[1,5-a]pyrimidine-7-amine:

Dissolve 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (300.0mg, 1.30mmol), 3-nitrobenzylamine (218mg, 1.43mmol) and triethyl A solution of amine (144 mg, 1.43 mmol) in isopropyl alcohol (4.0 mL) was heated to 80°C and reacted for 2 hours. After cooling, the resulting mixture was concentrated in vacuo to remove the solvent and purified using C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain 5-chloro-3-isopropyl-N-( 3-nitrobenzyl)pyrazole[1,5-a]pyrimidin-7-amine (250 mg, 0.72 mmol, yield 56%). LC-MS: m/z＝345.8[M+H] ⁺ .

2) Synthesis of (5-chloro-3-isopropylpyrazole[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester:

Dissolve 5-chloro-3-isopropyl-N-(3-nitrobenzyl)pyrazole[1,5-a]pyrimidin-7-amine (250.0mg, 0.72mmol), di-tert-butyldi A solution of carbonate (205 mg, 0.94 mmol), 4-dimethylaminopyridine (40 mg, 0.33 mmol) and triethylamine (146 mg, 1.45 mmol) in tetrahydrofuran (2.0 mL) was heated to 50°C and reacted overnight. The resulting mixture was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain ((5-chloro-3-isopropylpyrazole [1, 5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (158 mg, 0.35 mmol, yield: 49%). LC-MS: m/z=446 [M+H] ⁺ .

3), (3R, 4R)-4-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidine-5 Synthesis of -(base)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (5-chloro-3-ethylpyrazol[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (50.0mg, 0.11mmol), (3R , 4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylic acid butyl ester (31 mg, 0.13 mmol), (SP-4-1)-[1,3-bis[2,6- Bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (8.4 mg, 0.01mmol), a solution of cesium carbonate (110mg, 0.34mmol) in dioxane (2mL) was heated to 90°C, and the reaction was carried out overnight. After cooling, the resulting mixture was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and 0.1% ammonia in water, gradient: 5%-95%) to obtain the target compound (3R, 4R)-4-((7- ((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine- 1-Carboxylic acid tert-butyl ester (38.8 mg, 0.06 mmol, yield: 54%). LC-MS: m/z=640[M+H] ⁺ .

4), (3R, 4R)-4-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidine-5- Synthesis of tert-butyl (base)amino)methyl)-3-hydroxypiperidine-1-carboxylate:

There is (3R, 4R)-4-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidine-5 in solution -Amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (38.8 mg, 0.06 mmol) and iron powder (17 mg, 0.3 mmol) in ethanol (2 mL) were added dropwise to a solution of saturated chlorine Ammonium solution (0.5 mL). After the dropwise addition is completed, the temperature is raised to 70°C and the reaction is carried out for 2 hours. After cooling, the reaction solution was directly filtered through diatomaceous earth, and the filter cake was washed three times with methanol (10 mL × 3). The obtained filtrate was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and 0.1% ammonia in water, gradient: 5%-95%) to obtain the target compound (3R, 4R)-4-((7-((3 -Aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid Tert-butyl ester (30 mg, 0.05 mmol, yield: 81%). LC-MS: m/z=610[M+H] ⁺ .

5), (3R, 4R)-4-((7-((3-(3-acrylamidebenzamido)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazole[1 ,5-a] Synthesis of pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (3R, 4R)-4-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidine-5- (hydroxy)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30.0mg, 0.05mmol), 3-acrylamide benzoic acid (12mg, 0.06mmol) N,N-dimethylformate Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (28mg, 0.07mmol) and N,N- Diisopropylethylamine (19 mg, 0.15 mmol), raise the temperature to 30°C, and react for 2 hours. The reaction solution was filtered and purified by C18 column chromatography (mobile phase: acetonitrile and 0.1% ammonia water, gradient: 5%-95%) to obtain the target compound (3R, 4R)-4-((7-((3-(3- Acrylamide benzamido)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine -1-tert-butylcarboxylate (30 mg, 0.039 mmol, yield: 78%). LC-MS: m/z=783[M+H] ⁺ .

6), 3-Acrylamide-N-(3-((5-((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazole[1, Synthesis of 5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide:

(3R, 4R)-4-((7-((3-(3-acrylamidebenzamido)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazole[1 ,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30mg, 0.039mmol) in dichloromethane (3mL), add trifluoroethylene dropwise Acetic acid (1mL), react at room temperature for 2 hours. At the end of the reaction, the reaction solution was concentrated in vacuo to remove the solvent and purified using C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain the target compound 3-acrylamide-N-(3-( (5-((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidin-7-yl)amino)methyl )phenyl)benzamide (compound 3) (15.08 mg, 0.026 mmol, yield: 66%). LC-MS: m/z=583[M+H] ⁺ .

¹ H NMR (400MHz, MeOD): δ8.37(s,1H),7.89(s,2H),7.77–7.54(m,2H),7.51-7.40(m,3H),7.22(d,J＝7.4 Hz,1H),6.58–6.32(m,2H),5.82(dd,J＝9.4,2.1Hz,1H),5.45(s,1H),4.74(s,2H),3.97–3.43(m,5H) ,3.43–3.25(m,1H),3.09–2.96(m,1H),2.84(dt,J＝22.7,10.6Hz,1H),2.02(d,J＝12.1Hz,1H),1.84(s,1H ), 1.52 (d, J = 11.7Hz, 1H), 1.30 (d, J = 6.9Hz, 6H).

Example 4, (R)-3-acrylamido-N-(3-((3-isopropyl-5-(piperidin-3-oxy))pyrazole[1,5-a]pyrimidine-7 Synthesis of -base)amino)phenyl)benzamide (compound 4):

1), Synthesis of 5-chloro-3-isopropyl-N-(3-nitrophenyl)pyrazole[1,5-a]pyrimidine-7-amine:

At 0°C, add sodium hydride (160 mg, 3.93 mmol, purity: 60%) to a solution of N, N-dimethylformamide (4 mL) dissolved in 3-nitroaniline (180 mg, 1.31 mmol). in kerosene), stir and react at 0°C for 0.5 hours. Then, 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (300 mg, 1.31 mmol) was added, the temperature was raised to 90°C, and the reaction was carried out for 16 hours. After the reaction is completed, cool to room temperature and add methanol (2 mL) to obtain a mixed solution that is filtered and directly purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain the target compound 5- Chloro-3-isopropyl-N-(3-nitrophenyl)pyrazole[1,5-a]pyrimidin-7-amine (380 mg, 1.14 mmol, yield: 87%). LC-MS: m/z=332[M+H] ⁺ .

2) Synthesis of (5-chloro-3-isopropylpyrazole[1,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamic acid tert-butyl ester:

In solution were 5-chloro-3-isopropyl-N-(3-nitrophenyl)pyrazole[1,5-a]pyrimidin-7-amine (300 mg, 0.90 mmol) and di-tert-butyl dicarbonate. 4-Dimethylaminopyridine (254 mg, 2.08 mmol) was added to a solution of ester (300 mg, 1.37 mmol) in tetrahydrofuran (2.0 mL), and the reaction was stirred at room temperature for 4 hours. At the end of the reaction, the mixture was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain the target compound 5-chloro-3-isopropylpyrazole [ 1,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamic acid tert-butyl ester (320 mg, 0.74 mmol, yield: 82%). LC-MS: m/z=432 [M+ H] ⁺ .

3), (R)-3-((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidin-5-yl Synthesis of )oxy)piperidine-1-carboxylic acid tert-butyl ester:

At 0°C, sodium hydride ( 60 mg, 1.52 mmol, purity 60% dispersed in kerosene), return to room temperature and stir for 30 minutes. Then, at room temperature, 5-chloro-3-isopropylpyrazole[1,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamic acid tert-butyl ester (220 mg, 0.51 mmol) was added. ) tetrahydrofuran solution (2 mL), continue stirring at room temperature for 4 hours. After the reaction is completed, a small amount of methanol is added to the reaction system to quench the sodium hydrogen, and then the reaction solution is filtered and purified through C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) Obtain the target compound (R)-3-((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidin-5-yl )oxy)piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.13 mmol, yield: 26.3%). LC-MS: m/z=597[M+H] ⁺ .

4), (R)-3-((7-((3-Aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidin-5-yl) Synthesis of tert-butyloxy)piperidine-1-carboxylate:

In solution, there is (R)-3-((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidin-5-yl )oxy)piperidine-1-carboxylic acid tert-butyl ester (120 mg, 0.20 mmol) and iron powder (57 mg, 1.0 mmol) were added dropwise to a solution of ethanol (4 mL). A saturated ammonium chloride solution (1 mL) was added dropwise. The temperature was raised to 70°C, and the reaction was stirred for 2 hours. After cooling, the reaction solution was directly filtered through diatomaceous earth, and the filter cake was washed three times with methanol (10 mL × 3). The obtained filtrate was concentrated in vacuo to remove the solvent and purified using C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain (R)-3-((7-((3-aminobenzene) (tert-butoxycarbonyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.17 mmol, Yield: 85%). LC-MS: m/z=567[M+H] ⁺ .

5), (R)-3-((7-((3-(3-acrylamidebenzamido)phenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazole[1,5 -Synthesis of tert-butyl a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate:

Dissolved (R)-3-((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidin-5-yl) 2- (7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (100mg, 0.26mmol) and N,N-diisopropylethylamine (34mg, 0.26mmol), react at room temperature for 3 hours under nitrogen protection. The reaction solution was filtered and purified through C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain (R)-3-((7-((3-(3-acrylamide benzene) Carboxamido)phenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazole[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester ( 30 mg, 0.04 mmol, yield: 23%). LC-MS: m/z=740[M+H] ⁺ .

6), (R)-3-acrylamide-N-(3-((3-isopropyl-5-(piperidin-3-oxy)pyrazole[1,5-a]pyrimidine-7- Synthesis of base)amino)phenyl)benzamide:

(R)-3-((7-((3-(3-acrylamidebenzamido)phenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazole[1,5 -To a solution of a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.054 mmol) in dichloromethane (2.0 mL), trifluoroacetic acid (0.5 mL) was added, and the reaction was stirred at room temperature. 1 hour. At the end of the reaction, the reaction solution was concentrated in vacuo to remove the solvent and purified by C18 column chromatography (mobile phase: acetonitrile and water containing 0.1% ammonia, gradient: 5%-95%) to obtain (R)-3-acrylamido-N-( 3-((3-isopropyl-5-(piperidin-3-oxy)pyrazole[1,5-a]pyrimidin-7-yl)amino)phenyl)benzamide (Compound 4) (20 mg , 0.037mmol, yield: 68%). LC-MS: m/z=540[M+H] ⁺ ; 1H NMR (400MHz, DMSO) δ10.47 (s, 1H), 10.42 (s, 1H), 8.20 (s, 1H), 7.94 (d, J＝11.5Hz,2H),7.87(s,1H),7.73–7.62(m,2H),7.50(t,J＝7.9Hz,1H),7.42(t,J＝7.9Hz,1H),7.16( d,J＝8.1Hz,1H),6.47(dd,J＝16.8,9.8Hz,1H),6.30(d,J＝16.7Hz,1H),5.79(d,J＝10.3Hz,1H),5.66( s,1H),5.07(s,1H),3.19(d,J＝9.7Hz,1H), 3.07(d,J＝7.2Hz,1H),2.79(m,1H),2.73(m,1H),2.66(m,J＝12.9Hz,1H),2.01(s,1H),1.76–1.44(m ,4H),1.32(d,J＝6.8Hz,6H).

Example 5, (R)-3-acrylamido-N-(3-(((3-isopropyl-5-(piperidin-3-yloxy))pyrazolo[1,5-a] Synthesis of pyrimidin-7-yl)amino)methyl)phenyl)benzamide (compound 5):

1), (R)-3-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 Synthesis of -yl)oxy)piperidine-1-carboxylic acid tert-butyl ester:

Dissolve nickel dichloride 1,2-dimethoxyethane (10.99mg, 0.050mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (13.42mg, 0.050mmol) in acetonitrile (4 mL) solution, stir at room temperature for 1 minute. Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (445 mg, 1.0 mmol) , (3S)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (603mg, 3mmol), quinuclidine (11mg, 0.10mmol), potassium carbonate (138mg, 1mmol) and bis[2-(2,4 -Difluorophenyl)-5-trifluoromethylpyridine][2-2'-bi(4-tert-butylpyridine)]iridium bis(hexafluorophosphate) salt (14 mg, 0.010 mmol) in acetonitrile (4 mL) The solution was stirred at room temperature for 1 minute. Then add the first reaction solution to the second reaction solution. The resulting mixed reaction liquid was stirred under the protection of nitrogen gas and room temperature under 455nm blue LED light irradiation for 16 hours. The obtained mixed reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: elution with pure water containing 0.1% NH ₄ OH) to obtain (R)-3-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino) )-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (210 mg, yield: 34.4%), LC-MS m /z:611[M+H] ⁺ ;

2), (R)-3-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Synthesis of tert-butyl)piperidine-1-carboxylate:

Dissolve (R)-3-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 A solution of tert-butyl-yl)oxy)piperidine-1-carboxylate (61 mg, 0.1 mmol) and iron (28 mg, 0.5 mmol) in saturated ammonium chloride (0.5 mL) and ethanol (2 mL) was heated to 70°C and stirred. 2 hours. After cooling, the resulting mixed reaction was filtered, and the filter cake was washed with dichloromethane (3×10 ml). The filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was directly used in the next step without further purification. LC-MS m/z: 581[M+H] ⁺ ;

3), (R)-3-((7-((3-(3-acrylamidobenzoylamino)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[ Synthesis of 1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester:

Dissolve (R)-3-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- tert-butyl)piperidine-1-carboxylate (82 mg, 0.141 mmol), 3-acrylamidobenzoic acid (32 mg, 0.169 mmol), 2-(7-azobenzotriazole)- N,N-dimethylmethane of N,N,N',N'-tetramethylurea hexafluorophosphate (80mg, 0.211mmol) and N,N-diisopropylethylamine (55mg, 0.423mmol) A solution of amide (2 mL) was stirred at room temperature for 4 hours. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 to 90% elution) to obtain (R)-3-((7-((3-(3-acrylamidobenzoylamino)benzyl) (tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (26 mg, collected Rate: 24.4%), LC-MS m/z: 754[M+H] ⁺ ;

4), (R)-3-acrylamido-N-(3-(((3-isopropyl-5-(piperidin-3-yloxy))pyrazolo[1,5-a]pyrimidine Synthesis of -7-yl)amino)methyl)phenyl)benzamide:

There is (R)-3-((7-((3-(3-acrylamidobenzoylamino)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[ To a solution of tert-butyl 1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (26 mg, 0.034 mmol) in dichloromethane (1.5 mL), add 2,2,2 dropwise ,-trifluoroacetic acid (0.5 mL). The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography to obtain (R)-3-acrylamido-N-(3-(((3-isopropyl-5-(piperidin-3-yloxy)pyrazolo) [1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide (2.05 mg, yield: 10.8%), LC-MS m/z: 554[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d ₄ ): δ8.24 (s, 1H), 7.80 (d, J = 4.0Hz, 2H), 7.71 (d, J = 8.0Hz, 1H), 7.61 (dd, J ＝20.0,8.0Hz,2H),7.47(t,J＝8.0Hz,1H),7.36(t,J＝7.8Hz,1H),7.19(d,J＝7.4Hz,1H),6.51–6.34(m ,2H),5.81(dd,J＝9.2,2.4Hz,1H),5.47(d,J＝7.2Hz,2H),4.64(s,2H),3.52(t,J＝14.8Hz,1H),3.37 (s,1H),3.33(s,1H),3.25(s,1H),3.09(dd,J＝13.6,7.2Hz,2H),2.16–1.74(m,4H),1.32(d,J＝6.8 Hz,6H)

Example 6, (R)-3-acrylamido-N-(3-((8-isopropyl-2-(piperidin-3-ylmethoxy)pyrazolo[1,5-a Synthesis of ][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide (compound 6):

1), 8-isopropyl-2-(methylthio)-N-(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazine-4-amine Synthesis:

Dissolve 4-chloro-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1.08g, 4.46mmol), (3- A solution of nitrophenyl)methylamine (1.08g, 5.36mmol) and N,N-diisopropylethylamine (1.70g, 13.18mmol) in isopropyl alcohol (15mL) was heated to 80°C and stirred overnight. After cooling, the obtained mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). Combined organic phases Wash with saturated brine (1×100 mL), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 5-95% elution) to obtain 8-isopropyl-2-(methylthio)-N-(3-nitrobenzyl)pyrazole And [1,5-a][1,3,5]triazin-4-amine (1.19g, yield: 74.2%). LC-MS: m/z=359[M+H] ⁺ ;

2), 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazine-4- Synthesis of amines:

Dissolve 8-isopropyl-2-(methylthio)-N-(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1.18g, 3.30mmol) and m-chloroperbenzoic acid (1.14g, 6.59mmol) in dichloromethane (12mL) were stirred at room temperature overnight. The obtained mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 5-95% elution) to obtain 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrobenzyl)pyridine Azolo[1,5-a][1,3,5]triazin-4-amine (1.16g, yield: 90.2%), LC-MS m/z: 391[M+H] ⁺ ;

3), (R)-3-(((8-isopropyl-4-((3-nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5]triazine Synthesis of -2-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester:

At room temperature, (R)-3-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (306 mg, 1.42 mmol) and potassium dimethylamine (550 mg, 2.76 mmol, 0.5 mol) were dissolved. To a solution of N,N-dimethylformamide (3 mL) in toluene solution), add 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrobenzyl)pyrazolo[1 ,5-a][1,3,5]triazin-4-amine (185 mg, 0.47 mmol). The resulting mixed reaction solution was heated to 60°C and stirred overnight. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 10-95%) to obtain (R)-3-(((8-isopropyl-4-((3- Nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (108 mg, Yield: 43.4%), LC-MS m/z: 526[M+H] ⁺ ;

4), (R)-3-((((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine Synthesis of -2-yl)oxy)methyl tert-butyl)piperidine-1-carboxylic acid tert-butyl ester:

Dissolve (R)-3-(((8-isopropyl-4-((3-nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5]triazine -2-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (108 mg, 0.21 mmol), iron (54 mg, 0.97 mmol) in aqueous ammonium chloride (0.5 mL) and ethanol (2.0 mL) The solution was heated to 70°C and stirred for 8 hours. After cooling, the mixed reaction solution was filtered, and the filter cake was washed with methanol (3×10 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which could be used directly in the next step without further purification. LC-MS m/z:496[M+H] ⁺ ;

5), (R)-3-((((4-((3-(3-acrylamidobenzoylamino)benzyl)amino)-8-isopropylpyrazolo[1,5-a Synthesis of [1,3,5]triazin-2-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester:

Dissolve (R)-3-((((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine -2-yl)oxy)methyl tert-butyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.20 mmol), 3-(prop-2-enamido)benzamide (46 mg, 0.24 mmol) ), N,N-dimethylformamide of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (113 mg, 0.40 mmol) and 1-methylimidazole (66 mg, 0.80 mmol) (1.2mL) solution was heated to 60°C and stirred overnight. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was passed through C18 column chromatography (acetonitrile: pure water containing 0.1% NH 4HCO 3 = 5-95% elution) Purification gave (R)-3-((((4-((3-(3-acrylamidobenzoylamino)benzyl)amino)-8-isopropylpyrazolo[1,5-a] [1,3,5]Triazin-2-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (74.2 mg, yield: 55.0%), LC-MS m/z: 669[ M+H] ⁺ ;

6), (R)-3-Acrylamide-N-(3-(((8-isopropyl-2-(piperidin-3-ylmethoxy)pyrazolo[1,5-a] Synthesis of [1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide:

Dissolve (R)-3-((((4-((3-(3-acrylamidobenzoylamino)benzyl)amino)-8-isopropylpyrazolo[1,5-a ][1,3,5]triazin-2-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.10 mmol) and 2,2,2-trifluoroacetic acid (0.1 mL ) in dichloromethane (0.3 mL), stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95 % elution) purification gave (R)-3-acrylamido-N-(3-((8-isopropyl-2-(piperidin-3-ylmethoxy)pyrazolo[1,5 -a][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide (45 mg, yield: 75.6%), LC-MS m/z: 569 [M+H ] ⁺ ;

1H NMR(400MHz,MeOD-d4)δ8.55(s,1H),8.34(s,1H),7.81(s,1H),7.67(d,J＝6.9Hz,1H),7.49(s,1H) ,7.44–7.34(m,2H),7.20(d,J＝7.3Hz,2H),4.69(s,1H),4.58(d,J＝10.8Hz,1H),4.35(s,1H),4.22( s,1H),3.68(t,J＝12.9Hz,2H),3.45(d,J＝13.5Hz,1H),3.19–3.16(m,1H),3.14–2.99(m,4H),2.44(s ,1H),2.07(d,J＝7.3Hz,1H),1.98(d,J＝13.6Hz,2H),1.56–1.42(m,1H),1.34(d,J＝6.8Hz,6H).

Example 7, (S)-3-acrylamido-N-(3-((8-isopropyl-2-(piperidin-3-ylmethoxy)pyrazolo[1,5-a Synthesis of ][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide (compound 7):

1), (S)-3-(((8-isopropyl-4-((3-nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5]triazine Synthesis of -2-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester:

At room temperature, (S)-3-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (446 mg, 2.07 mmol) and potassium dimethylamine (550 mg, 2.76 mmol, 0.5 mol) were dissolved. To a solution of N,N-dimethylformamide (3 mL) in toluene solution), add 8-isopropyl-2-(methylsulfonate Acyl)-N-(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (270 mg, 0.69 mmol). The resulting mixed reaction solution was heated to 60°C and stirred overnight. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 10-95%) elution) to obtain (S)-3-(((8-isopropyl-4-((3- Nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (72 mg, Yield: 19.7%), LC-MS m/z: 526[M+H] ⁺ ;

2), (S)-3-((((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine Synthesis of -2-yl)oxy)methyl tert-butyl)piperidine-1-carboxylic acid tert-butyl ester:

Dissolve (S)-3-(((8-isopropyl-4-((3-nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5]triazine -2-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (76 mg, 0.14 mmol), iron (39 mg, 0.70 mmol), ammonium chloride (38 mg, 0.70 mmol), ethanol (0.40 mL) The mixed solution with water (0.1 mL) was heated to 70°C and stirred for 2 hours. After cooling, the mixed reaction solution was filtered, and the filter cake was washed with methanol (3×10 mL). The filtrate was collected and concentrated under reduced pressure to obtain crude product (55 mg). LC-MS m/z:496[M+H] ⁺ ;

3), (S)-3-((((4-((3-(3-acrylamidobenzoylamino)benzyl)amino)-8-isopropylpyrazolo[1,5-a Synthesis of [1,3,5]triazin-2-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester:

Dissolve (S)-3-((((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine -2-yl)oxy)methyl tert-butyl)piperidine-1-carboxylic acid tert-butyl ester (55 mg, 0.11 mmol), 3-(prop-2-enamido)benzamide (25 mg, 0.13 mmol) ), N,N-dimethylformamide of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (62mg, 0.22mmol) and 1-methylimidazole (36mg, 0.44mmol) (0.5mL) solution was heated to 60°C and stirred overnight. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was eluted by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 10-95% ) was purified to obtain ((S)-3-((((4-((3-(3-acrylamidobenzoylamino)benzyl)amino)-8-isopropylpyrazolo[1,5- a][1,3,5]triazin-2-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (45 mg, yield: 60.6%), LC-MS m/z: 669 [M+H] ⁺ ;

4), (S)-3-Acrylamide-N-(3-((8-isopropyl-2-(piperidin-3-ylmethoxy)pyrazolo[1,5-a] Synthesis of [1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide:

Dissolve (S)-3-((((4-((3-(3-acrylamidobenzoylamino)benzyl)amino)-8-isopropylpyrazolo[1,5-a ][1,3,5]triazin-2-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (46 mg, 0.10 mmol) and 2,2,2-trifluoroacetic acid (0.1 mL ) in dichloromethane (0.3 mL), stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 10-95 % elution) purification gave (S)-3-acrylamido-N-(3-((8-isopropyl-2-(piperidin-3-ylmethoxy)pyrazolo[1,5 -a][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide (33 mg, yield: 84.4%), LC-MS m/z: 569[M+H ] ⁺ ;

1H NMR (400MHz, MeOD-d4): δ8.31(s,1H),7.92(s,1H),7.86(s,1H),7.64(d,J＝5.0Hz,2H),7.49(dd,J ＝19.7,7.9Hz,2H),7.35(d,J＝7.7Hz,1H),7.21(d,J＝7.6Hz,1H),6.50–6.35(m,2H),5.81(d,J＝9.3Hz ,1H),4.80(s,2H),4.46–4.41(m,1H),4.33–4.25(m,1H),3.49(d,J＝9.9Hz,1H),3.34(s,1H),3.08( dd,J＝19.6,12.4Hz,1H),2.87(t,J＝11.7Hz,2H),2.27(s,1H),1.92(s,2H),1.74(s,1H),1.45(d,J ＝13.4Hz,1H),1.29(dd,J＝6.9,1.3Hz,6H).

Example 8, (S)-3-acrylamido-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino))-3-isopropylpyrazole Synthesis of [1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide (compound 8):

1) Synthesis of (S)-(6,6-dimethylpiperidin-3-yl)carbamic acid tert-butyl ester:

At -10°C, add tetrahydrofuran (94.0 mL) in batches to a solution of (S)-(6-oxopiperidin-3-yl)carbamic acid tert-butyl ester (2.0g, 9.33mmol). Zirconium chloride (5.22g, 22.4mmol). The obtained mixed reaction liquid was stirred at -10°C for 30 minutes, and then methylmagnesium bromide (3M, 46.7 mmol) was added dropwise to the above reaction liquid. The resulting mixed reaction solution was stirred at room temperature for 16 hours. At 0°C, the mixed reaction solution was added to aqueous sodium hydroxide solution (content: 30%, 200 mL), filtered, and the aqueous phase was extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 20-25%) to obtain (S)-(6,6-dimethylpiperidin-3-yl)carbamic acid tert-butyl ester (1.0g, yield : 47%), LC-MS m/z: 229[M+H] ⁺ ;

2), Synthesis of (S)-6,6-dimethylpiperidin-3-amine:

To a solution of (S)-(6,6-dimethylpiperidin-3-yl)carbamic acid tert-butyl ester (500mg, 2.19mmol) dissolved in dichloromethane (5mL) at 0°C, add 2,2,2-Trifluoroacetic acid (2.5 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which could be directly used in the next step without further purification. LC-MS m/z: 129 [M+H] ⁺ ;

3), Synthesis of 3-isopropylpyrazolo[1,5-a]pyrimidine-5,7(4H, 6H)-dione:

Dissolve 4-(prop-2-yl)-1H-pyrazol-5-amine (25g, 199.73mmol) and dimethyl malonate (26.39g, 199.73mmol) in sodium methoxide/methanol (90mL/210mL ) solution was heated to 60°C and stirred for 16 hours. After cooling, the mixed reaction solution precipitated a solid, filtered, and washed with methanol (3×80 mL). The solid was collected and dried under vacuum to obtain a crude product, LC-M: m/z: 194 [M+H] ⁺ ;

4), Synthesis of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine:

Dissolve 3-isopropylpyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (155g, 802mmol) and N,N-dimethylaniline (116.6g, 962mmol) ), the reaction solution of phosphorus oxychloride (800 mL) was heated to 110°C and stirred for 16 hours. After cooling, the obtained mixed reaction solution was quenched with sodium bicarbonate (700 mL) at 0°C, and extracted with ethyl acetate (6 × 1 L). The combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (39g, yield: 21%), LC-MS m/z 230[M+H] ⁺ ;

5), Synthesis of 5-chloro-3-isopropyl-N-(3-nitrobenzyl)pyrazolo[1,5-a]pyrimidine-7-amine:

At room temperature, 5,7-dichloro-3-(prop-2-yl)pyrazolo[1,5-a]pyrimidine (4g, 17.38mmol) and (3-nitrophenyl) were dissolved in the solution. To a solution of methylamine (3.97g, 26.07mmol) in isopropyl alcohol (200mL), N,N-diisopropylethylamine (6.74g, 52.14mmol) was added. The resulting mixed reaction solution was heated to 80°C and stirred overnight. After cooling, the mixed reaction solution produced a precipitate, which was filtered and washed with methanol (3 × 20 mL). Collect the solid and vacuum dry 5-chloro-3-isopropyl-N-(3-nitrobenzyl)pyrazolo[1,5-a]pyrimidin-7-amine (3.70g, yield: 41%), LC-MS m/z:346[M+H] ⁺ ;

6) Synthesis of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamate:

At room temperature, 5-chloro-3-isopropyl-N-(3-nitrobenzyl)pyrazolo[1,5-a]pyrimidin-7-amine (3.7g, 10.70mmol) was dissolved in To the tetrahydrofuran (200 mL) solution, add di-tert-butyl dicarbonate (4.67g, 21.4mmol), N,N-diisopropylethylamine (4.15g, 32.10mmol) and 4-dimethylaminopyridine (0.13g , 1.07mmol). The obtained mixed reaction liquid was heated to 60° C. and stirred for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% ammonium bicarbonate = 10 to 95%) to obtain (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidine-7 -(3-nitrobenzyl)carbamic acid tert-butyl ester (3.0g, yield: 62%), LC-MS m/z: 446[M+H] ⁺ ;

7), (S)-(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) Synthesis of (3-nitrobenzyl)carbamic acid tert-butyl ester:

At room temperature, dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (3g, 6.73 mmol) and 6,6-dimethylpiperidin-3-amine (3.45g, 26.92mmol) in 1,4-dioxane (200mL), add cesium carbonate (6.58g, 20.19mmol) and ( SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2 -Ylidene]dichloro(2-methyl Pyridine)palladium (0.57g, 0.67mmol). The resulting mixed reaction solution was heated to 100°C and stirred overnight under the protection of argon gas. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% TFA = 10 to 70%) to obtain (S)-(5-((6,6-dimethylpiperidin-3-yl)amino) )-tert-butyl 3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamate (1.50g, yield: 41%), LC-MS m/z:538[M+H] ⁺ ;

8), (S)-5-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Synthesis of tert-butyl (amino)-2,2-tert-butyldimethylpiperidine-1-carboxylate:

Dissolved (S)-(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) (3-nitrobenzyl)carbamate tert-butyl ester (1.5g, 2.79mmol), N,N-diisopropylethylamine (1.08g, 8.37mmol) and di-tert-butyl dicarbonate (1.52g, 6.97 mmol) in dichloromethane (200 mL) was heated to 60°C and stirred for 2 hours. After cooling, the filtrate of the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: (0.1% NH ₄ HCO ₃ in pure water = 10 to 95%)) to obtain (S)-5-((7-((tert-butoxycarbonyl)(3-nitrile) ((benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-tert-butyldimethylpiperidine-1-carboxylic acid tert-butyl Ester (1.2g, yield: 67%) and recovery of (S)-(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1, 5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (600 mg). LC-MS m/z: 638[M+H] ⁺ ;

9), (S)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Synthesis of tert-butyl (amino)-2,2-tert-butyldimethylpiperidine-1-carboxylate:

Dissolve (S)-5-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- amino)-2,2-tert-butyldimethylpiperidine-1-carboxylic acid tert-butyl ester (1.2g, 1.88mmol), iron (0.52g, 9.40mmol) and ammonium chloride (0.50g, 9.40 mmol) of ethanol (160 mL) and water (40 mL) was heated to 70°C and stirred for 2 hours. After cooling, the obtained mixed reaction liquid was filtered, and the filter cake was washed with methanol (3×30 mL). The filtrate was collected and concentrated under reduced pressure to obtain (S)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine -5-yl)amino)-2,2-tert-butyldimethylpiperidine-1-carboxylic acid tert-butyl ester (700 mg, yield: 61%), LC-MS m/z: 608 [M+H ] ⁺ ;

10), (S)-5-((7-((3-(3-Acrylamidobenzoylamino)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1 Synthesis of 5-a]pyrimidin-5-yl)amino tert-butyl)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester:

Solution (S)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl )Amino)-2,2-tert-butyldimethylpiperidine-1-carboxylate (700mg, 1.15mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt A solution of acid salt (264.5 mg, 1.38 mmol), 4-dimethylaminopyridine (28.10 mg, 0.23 mmol) and 3-acrylamidobenzoic acid (262.4 mg, 1.38 mmol) in dichloromethane (100 mL) was heated. Stir overnight at 50°C. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: purification containing 0.1% ammonium bicarbonate = 10 to 95%) to obtain (S)-5-((7-((3-(3-acrylamidobenzoyl) Amino)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)aminotert-butyl)-2,2-dimethylpiperidine -1-tert-butylcarboxylate (400mg, yield: 44%), LC-MS m/z: 781[M+H] ⁺ ;

11), (S)-3-acrylamido-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino))-3-isopropylpyrazolo Synthesis of [1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide:

(S)-5-((7-((3-(3-Acrylamidobenzoylamino)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1 ,5-a]pyrimidin-5-yl)amino tert-butyl)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.51 mmol) in dichloromethane (6 mL), 2,2,2-trifluoroacetic acid (3 mL) was added, and the resulting mixed reaction solution was stirred at room temperature for 0.5 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: purification containing 0.1% ammonium bicarbonate = 10~95%) to obtain (S)-3-acrylamido-N-(3-(((5-((6 ,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide (223mg , Yield: 75%), LC-MS m/z: 581[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4) δ8.53(s,1H),8.23(s,1H),7.81–7.70(m,2H),7.70–7.62(m,2H),7.59(d,J＝ 8.0Hz,1H),7.47(t,J＝8.0Hz,1H),7.36(t,J＝8.0Hz,1H),7.20(d,J＝7.6Hz,1H),6.49–6.39(m,2H) ,5.80(dd,J＝9.4,2.4Hz,1H),5.22(s,1H),4.58(s,2H),4.20–4.10(m,1H),3.51(dd,J＝12.4,4.2Hz,1H ),3.20–3.02(m,2H),1.99(s,1H),1.93–1.69(m,3H),1.38(d,J＝64Hz,6H),1.30(dd,J＝6.8,3.2Hz,6H ).

Example 9, (1s,4s)-4-acrylamido-N-(3-(2-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)- Synthesis of 5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-6-yl)cyclohexane-1-carboxamide (compound 9):

1), Synthesis of 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-nitro-1H-indole:

Dissolve 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.33g, 6.17mmol) and aluminum trichloride (2.2g, 16.5mmol) in 1,2-dichloroethane (10mL) The solution was heated to 80°C and stirred for 1 hour under an argon atmosphere. At room temperature, a solution of 1,2-dichloroethane (5 mL) dissolved in 6-nitro-1H-indole (3.0 g, 18.52 mmol) was added dropwise to the above reaction solution. The resulting mixed reaction solution was stirred at 80°C overnight. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified through a C18 column (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 15-35%) to obtain 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)- 6-nitro-1H-indole (500mg, yield: 24%), LC-MS m/z: 343[M+H] ⁺ ;

2), (3R, 4R)-3-hydroxy-4-(((4-(6-nitro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl) Synthesis of amino)methyl)piperidine-1-carboxylic acid tert-butyl ester:

Dissolve 3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-6-nitro-1H-indole (500mg, 1.46mmol), (3R, 4R)-4-( A solution of aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (404 mg, 1.76 mmol) and N,N-diisopropylethylamine (472 mg, 3.66 mmol) in isopropyl alcohol (5 mL), Heat to 100°C and stir overnight. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified through a C18 column (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 30-80%) to obtain (3R, 4R)-3-hydroxy-4-(((4-(6-nitrile) Tert-butyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)piperidine-1-carboxylate (700 mg, yield: 89%) , LC-MS m/z: 537[M+H] ⁺ ;

3), (3R, 4R)-4-(((4-(6-amino-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl) Synthesis of -3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (3R, 4R)-3-hydroxy-4-(((4-(6-nitro-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl) Amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (500mg, 0.93mmol) and iron (261mg, 0.3mmol) in ethanol (4mL) and ammonium chloride aqueous solution (1mL), heated for 70 under nitrogen protection °C and stirred for 1.5 hours. After cooling. The mixed reaction solution was filtered, and the filter cake was washed with methanol (3×15 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which could be directly used in the next step without further purification, LC-MS: m/z=507.1[M+H] ⁺ ;

4), (3R, 4R)-4-(((4-(6-((1s,4s)-4-acrylamidocyclohexane-1-carboxamido))-1H-indol-3-yl Synthesis of )-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

Will dissolve (3R, 4R)-4-(((4-(6-amino-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl) -3-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.40 mmol), (1s, 4s)-4-acrylamidocyclohexane-1-carboxylic acid (93.4 mg, 0.47 mmol), HATU ( 225.4 mg, 0.59 mmol) and N,N-diisopropylethylamine (153 mg, 1.19 mmol) in N,N-dimethylformamide (2 mL) were stirred at room temperature for 2 hours. The mixed reaction solution was purified through a C18 column (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 30-55%) to obtain (3R, 4R)-4-(((4-(6-((( 1s, 4s)-4-acrylamidocyclohexane-1-carboxamido)-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl) -3-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (50 mg, yield: 18.5%), LC-MS m/z: 686.0 [M+H] ⁺ ;

5), (1s, 4s)-4-acrylamido-N-(3-(2-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-5 Synthesis of -(trifluoromethyl)pyrimidin-4-yl)-1H-indol-6-yl)cyclohexane-1-carboxamide

(3R, 4R)-4-(((4-(6-((1s,4s)-4-acrylamidocyclohexane-1-carboxamido))-1H-indol-3-yl )-5-(Trifluoromethyl)pyrimidin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.07 mmol) in dichloromethane (0.6 mL) 2,2,2-trifluoroacetic acid (0.2 mL) was added dropwise. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95%) to obtain (1s, 4s)-4-acrylamide-N-(3-(2-( ((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indol-6-yl) ring Hexane-1-carboxamide (2.48 mg, yield: 6.0%), LC-MS m/z: 586 [M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.51(s,2H),7.92(s,1H),7.81(s,1H),7.21(s,1H),6.37(q,J＝12.0,8.0 Hz,1H),6.23(dd,J＝16.8,1.6Hz,1H),5.65(dd,J＝10.0,8.0Hz,1H),4.05(s,1H),3.778(s,1H),3.65-3.59 (m,2H),3.01-2.65(m,2H),2.54(s,1H),2.13-2.03(m,1H),2.01-1.83(m,6H),1.83-1.67(m,5H),1.66 -1.53(m,1H).

Example 10, (S)-3-acrylamido-N-(3-((5-((6,6-dimethylpiperidin-3-yl)amino))-3-isopropylpyrazolo Synthesis of [1,5-a]pyrimidin-7-yl)amino)phenyl)benzamide (compound 10):

1) Synthesis of tert-butyl (3-aminophenyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate:

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamic acid tert-butyl ester (70 mg, 0.16 mmol) and iron (45.5 mg, 0.81 mmol) ammonium chloride aqueous solution (0.5 mL) and ethanol (2.0 mL) were heated at 70°C and stirred for 2 hours. After cooling, the mixed reaction solution was filtered, and the filter cake was washed with methanol (3×10 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was directly used in the next step without further purification. LC-MS m/z: 402[M+H] ⁺ ;

2), (3-(3-Acrylamidobenzamido)phenyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl Synthesis of esters:

Dissolve (3-aminophenyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (70mg, 0.17mmol), 3- Acrylamide benzoic acid (40.0 mg, 0.21 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (97.0 mg, 0.26 mmol) and a solution of N,N-diisopropylethylamine (65.8 mg, 0.51 mmol) in N,N-dimethylformamide (1.5 mL) at room temperature overnight. The residue was purified by C18 column (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) 3-(3-acrylamidobenzamido)phenyl) (5-chloro- 3-Isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (60 mg, yield: 60%), LC-MS m/z: 575[M+H] ⁺ ;

3), (S)-(3-(3-acrylamidobenzamido)phenyl)(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropyl Synthesis of pyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester:

Dissolve tert-butyl (3-(3-acrylamidobenzoylamino)phenyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate Ester (60.0mg, 0.11mmol), (S)-6,6-dimethylpiperidin-3-amine (33.4mg, 0.26mmol), (SP-4-1)-[1,3-bis[2 ,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium ( 8.4 mg, 0.01 mmol) and cesium carbonate (179 mg, 0.55 mmol) in 1,4-dioxane (2 mL), under argon protection, heated to 100°C and stirred overnight. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (S)-(3-(3-acrylamidobenzamido)benzene tert-butyl)(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (30mg, yield: 43%), LC-MS m/z: 667[M+H] ⁺ ;

3), (S)-3-acrylamido-N-(3-((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[ Synthesis of 1,5-a]pyrimidin-7-yl)amino)phenyl)benzamide:

At room temperature, (S)-(3-(3-acrylamidobenzamido)phenyl)(5-((6,6-dimethylpiperidin-3-yl)amino) -To a solution of tert-butyl 3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (30.0mg, 0.045mmol) in dichloromethane (1.2mL), add 2,2 dropwise ,2,-trifluoroacetic acid (0.4mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (S)-3-acrylamido-N-(3-((5 -((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)benzamide ( 8.1mg, yield: 31.8%), LC-MS m/z: 567[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.30 (s, 1H), 8.02 (s, 1H), 7.74 (d, J = 8.0Hz, 2H), 7.68 (d, J = 8.0Hz, 1H) ,7.50(t,J＝8.0Hz,1H),7.45-7.38(m,1H),7.15(d,J＝8.0Hz,1H),6.50-6.38(m,2H),5.88(s,1H), 5.81(dd,J＝8.0,4.0Hz,1H),4.17(s,1H),3.55-3.51(m,1H),3.15-3.08(m,2H),2.03-2.01(m,2H),1.99- 1.74(m,3H),1.38(s,6H),1.34(s,3H),1.32(s,3H).

Example 11, (R)-3-acrylamido-N-(3-((3-isopropyl-5-(piperidin-3-oxy))pyrazole[1,5-a]pyrimidine-7 Synthesis of -base)amino)phenyl)benzamide (compound 4):

1), Synthesis of 7-bromo-3-nitro-1H-indole:

At 0°C, add benzoyl chloride (890mg) dropwise to a solution of 7-bromo-1H-indole (1.0g mg, 5.28mmol), silver nitrate (986.60mg, 5.81mmol) and acetonitrile (5mL). , 6.34mmol). The resulting mixed reaction solution was stirred at 0°C for 45 minutes. The mixed reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 1% formic acid in pure water = 25%-75% elution) to obtain 7-bromo-3-nitro-1H-indole (400 mg, yield: 38.55%). LC-MS m/z:239[MH] ^- .

2) Synthesis of dimethyl (3-nitro-1H-indol-7-yl)phosphine oxide:

Dissolve 7-bromo-3-nitro-1H-indole (300mg, 1.24mmol), dimethylphosphine oxide (242mg, 3.1mmol), potassium phosphate (395mg, 1.86mmol), palladium acetate (27.8mg, A solution of N,N-dimethylformamide (5 mL) of Xantphos (143.5 mg, 0.25 mmol) and Xantphos (0.12 mmol) was heated to 150°C and stirred for 2 hours under _N2 protection. The obtained mixed reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10%-50% elution) to obtain dimethyl (3-nitro-1H-indol-7-yl) phosphine oxide (150 mg, yield :50%), LC-MS m/z: 237[MH] ^-

3) Synthesis of (7-(dimethylphosphoryl)-1H-indol-3-yl)carbamic acid tert-butyl ester:

Dimethyl (3-nitro-1H-indol-7-yl)phosphine oxide (400 mg, 1.68 mmol), palladium on carbon (80 mg) and di-tert-butyl dicarbonate (550 mg, 2.52 mmol) were dissolved in methanol. (4 mL) solution, stirred at room temperature for 16 hours under hydrogen atmosphere. The obtained mixed reaction liquid was filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10-30%) to obtain (7-(dimethylphosphoryl)-1H-indol-3-yl)carbamic acid tert-butyl ester (300 mg, Yield: 58%), LC-MS m/z: 309[M+H] ⁺ ;

4), Synthesis of (3-amino-1H-indol-7-yl)dimethylphosphine oxide:

Dissolve (7-(dimethylphosphoryl)-1H-indol-3-yl)carbamic acid tert-butyl ester (200 mg, 0.65 mmol) in dichloromethane (1.5 mL) and 2,2,2-tris Fluoroacetic acid (0.5 mL) solution, stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step without further purification. LC-MS m/z: 209 [M+H] ⁺ ;

5) Synthesis of dimethyl (3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-1H-indol-7-yl)phosphine oxide:

Dissolve (3-amino-1H-indol-7-yl)dimethylphosphine oxide (180mg, 0.86mmol), 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (216.3 mg, 0.95 mmol) and N,N-diisopropylethylamine (333 mg, 2.58 mmol) in isopropyl alcohol (2 mL), heated to 60°C and stirred for 4 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 40%-70% elution) to obtain dimethyl (3-((2-(methylthio)-5-(trifluoromethyl)pyrimidine) -4-yl)amino)-1H-indol-7-yl)phosphine oxide (100 mg, yield: 29%), LC-MS m/z: 401 [M+H] ⁺ ;

6), dimethyl (3-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-1H-indol-7-yl)phosphine oxide synthesis:

Dissolve dimethyl (3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-1H-indol-7-yl)phosphine oxide (40 mg, 0.10 mmol) and potassium peroxymonosulfonate (123 mg, 0.20 mmol) in tetrahydrofuran (1 mL) and water (1 mL) were stirred at room temperature under nitrogen protection for 0.5 hours. The mixed reaction solution was concentrated under reduced pressure and the crude product was used directly in the next step without further purification. LC-MS m/z: 417[M+H] ⁺ ;

7), (S)-(3-((2-((6,6-dimethylpiperidin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)- Synthesis of 1H-indol-7-yl)dimethylphosphine oxide:

Dimethyl (3-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-1H-indol-7-yl)phosphine oxide (20 mg, 0.048mmol), (S)-6,6-dimethylpiperidin-3-amine (12.3mg, 0.096mmol) and N,N-isopropylethylamine (18.6mg, 0.14mmol) in tetrahydrofuran (1mL) The solution was stirred at room temperature for 0.5 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: 0.1% NH ₄ HCO ₃ in pure water = 20 to 70% elution) to obtain (S)-(3-((2-((6,6-dimethylpiperdine) ((ridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-1H-indol-7-yl)dimethylphosphine oxide (8 mg, 34.7%), LC-MS m/z:481[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD) δ8.10 (s, 1H), 7.65 (d, J = 7.2Hz, 1H), 7.55 (s, 1H), 7.43 (dd, J = 14, 7.2Hz, 1H), 7.20(td,J＝7.6,2.4Hz,1H),3.79-3.41(m,1H),2.99-2.65(m,1H),2.57(s,1H),1.90(t,J＝13.6Hz,6H) ,1.75-1.67(m,1H),1.48-1.40(m,2H),1.19-1.00(m,7H).

Example 12, N-(1-(6-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)methyl)amino)-3-isopropylpyrazole Synthesis of [1,5-a]pyrimidin-7-yl)amino)methyl)pyridin-2-yl)-1H-pyrazol-4-yl)acrylamide (compound 12):

1), Synthesis of ((6-bromopyridin-2-yl)methyl)carbamic acid tert-butyl ester:

Dissolve (6-bromopyridin-2-yl)methanamine (2.00g, 10.7mmol), triethylamine (3.25g, 32.1mmol) and di-tert-butyl dicarbonate (2.8g, 12.84mmol) in tetrahydrofuran ( 20 mL) solution was stirred at room temperature for 1 hour. After cooling, the obtained mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with saturated brine (1×100 mL) and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=0~50%) to obtain ((6-bromopyridin-2-yl)methyl)carbamic acid tert-butyl ester (1.56g, yield: 50%) , LC-MS m/z:288[M+H] ⁺ ;

2) Synthesis of ((6-(4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)methyl)carbamic acid tert-butyl ester:

Under nitrogen protection, dissolve ((6-bromopyridin-2-yl)methyl)carbamic acid tert-butyl ester (1.00g, 3.5mmol) and 4-nitro-1H-pyrazole (0.47g, 4.2mmol) , a solution of cesium carbonate (3.42g, 10.5mmol) and copper iodide (190mg, 1.05mmol) in N,N-dimethylformamide (6mL) was heated to 80°C and stirred for 4h. After cooling, the obtained mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with saturated brine (1×100 mL) and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 to 24%) to obtain ((6-(4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)methyl)amino Tert-butyl formate (0.6g, yield: 54%), LC-MS m/z: 320[M+H] ⁺ ;

3), Synthesis of (6-(4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)methanamine:

Dissolve (6-(4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)methyl)carbamic acid tert-butyl ester (0.29 mg, 0.91 mmol) in dichloromethane and 2,2 , 2-trifluoroacetic acid (5mL:v/v=4:1) mixed solution was stirred at room temperature for 1 hour. The obtained mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step of the reaction without further purification. LC-MS m/z: 220 [M+H] ⁺ ;

4), 5-chloro-3-isopropyl-N-((6-(4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)methyl)pyrazolo[1,5 Synthesis of -a]pyrimidine-7-amine:

Dissolve (6-(4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)methanamine (0.43g, 1.53mmol) and 5,7-dichloro-3-isopropylpyra A solution of azozo[1,5-a] (0.28g, 1.22mmol) and N,N-diisopropylethylamine (0.59g, 4.59mmol) in isopropyl alcohol (4.0mL) was heated to 60°C and stirred overnight. After cooling, the resulting reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×30 mL) and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 to 20%) to obtain 5-chloro-3-isopropyl-N-((6-(4-nitro-1H-pyrazole- 1-yl)pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.35g, yield: 69%), LC-MS m/z: 413[M+ H] ⁺ ;

5), (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)((6-(4-nitro-1H-pyrazol-1-yl)pyridine- Synthesis of 2-yl)methyl)carbamic acid tert-butyl ester:

The dissolved 5-chloro-3-isopropyl-N-((6-(4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)methyl)pyrazolo[1,5 -a]pyrimidin-7-amine (82 mg, 0.20 mmol), di-tert-butyl dicarbonate (52 mg, 0.24 mmol), 4-dimethylaminopyridine (2.40 mg, 0.02 mmol) and triethylamine (70 mg, 0.69 mmol) in tetrahydrofuran (0.80 mL) was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×30 mL) and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 to 20%) to obtain (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) (( 6-(4-Nitro-1H-pyrazol-1-yl)pyridin-2-yl)methyl)carbamic acid tert-butyl ester (68 mg, yield: 67%), LC-MS m/z 513 [M +H] ⁺ ;

6), (3R, 4R)-4-(((7-((tert-butoxycarbonyl))((6-(4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)methyl Synthesis of tert-butyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate :

Dissolve 5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)((6-(4-nitro-1H-pyrazol-1-yl)pyridine-2 -tert-butyl)methyl)carbamate (1.7g, 3.2mmol), (3R, 4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.81g, 3.52mmol), A solution of Pd ₂ (dba) ₃ (0.30g, 0.32mmol) and Xantphos (786mg, 1.36mmol) in N,N-dimethylformamide (17mL) was heated to 90°C and stirred for 16 hours under nitrogen protection. After cooling, the resulting mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×30 mL) and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=0~5%) to obtain (3R, 4R)-4-(((7-((tert-butoxycarbonyl)((6-(4) -nitro-1H-pyrazol-1-yl)pyridin-2-yl)methyl)aminotert-butyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino )Methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (277 mg, yield: 12%), LC-MS m/z: 776 [M+H] ⁺ ;

7), (3R, 4R)-4-(((7-((3-(4-amino-1H-pyrazol-1-yl)benzyl)(tert-butoxycarbonyl)amino)-3-iso Synthesis of propylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (3R, 4R)-4-(((7-((tert-butoxycarbonyl))((6-(4-nitro-1H-pyrazol-1-yl)pyridin-2-yl)methyl (yl)amino tert-butyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.10 g, 0.14 mmol) and iron (0.04 g, 0.70 mmol) in ammonium chloride aqueous solution (1 mL) and ethanol (4 mL) were heated to 80° C. and stirred for 2 hours. After cooling, the resulting reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was directly used in the next step without further processing.

8), (3R, 4R)-4-(((7-(((6-(4-acrylamido-1H-pyrazol-1-yl)pyridin-2-yl)methyl)(tert-butoxy Synthesis of tert-butyl (carbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate:

A solution of prop-2-enoyl chloride (21 mg, 0.23 mmol) and triethylamine (58 mg, 0.57 mmol) dissolved in dichloromethane (1.3 mL) was stirred at 0°C for 0.01 h. Then (3R, 4R)-4-(((7-((3-(4-amino-1H-pyrazol-1-yl)benzyl)(tert-butoxycarbonyl)amino) -3-Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (128 mg, 0.19 mmol) dichloro The methane solution was added dropwise to the above reaction solution, and the resulting mixed reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure. Purification by silica gel column chromatography (methanol: dichloromethane=0~10%) gave (3R, 4R)-4-(((7-((((6-(4-acrylamido-1H-pyrazole- 1-yl)pyridin-2-yl)methyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)- 3-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (41 mg, yield: 30%), LC-MS m/z: 731 [M+H] ⁺ ;

9), N-(1-(6-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)methyl)amino)-3-isopropylpyrazolo Synthesis of [1,5-a]pyrimidin-7-yl)amino)methyl)pyridin-2-yl)-1H-pyrazol-4-yl)acrylamide:

To a solution of 2,2,2-trifluoroacetic acid (47mg, 0.41mmol) in dichloromethane (0.1mL), add (3R,4R)-4-(((7-(((6-(4- Acrylamide-1H-pyrazol-1-yl)pyridin-2-yl)methyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 -(yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.041 mmol). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column (acetonitrile: pure water containing 0.1% NH ₃ H ₂ O = 5-95%) to obtain N-(1-(6-(((5-((((3R, 4R )-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)pyridin-2-yl) -1H-pyrazol-4-yl)acrylamide (10 mg, yield: 46%), LC-MS m/z: 531[M+H] ⁺ ; ¹ H NMR (400MHz, MeOH-d4): δ ( 8.93,1H),7.93-7.90(m,3H),7.78(s,1H),7.34(d,J＝8.0Hz,1H),6.39(d,J＝4.0Hz,1H),6.38(s,1H ),5.80(dd,J＝8.0,4.0Hz,1H),5.58(s,1H),3.59–3.50(m,4H),3.12–3.05(m,1H),2.86–2.80(m,1H), 2.70–2.65(m,1H),2.0(d,J＝8.0Hz,1H),1.79(s,1H),1.54(s,1H),1.32(d,J＝8.0Hz,3H),1.30(d ,J＝8.0Hz,3H).

Example 13, N-(1-(3-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)methyl)amino)-3-isopropylpyrazole Synthesis of [1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-1H-pyrazol-4-yl)acrylamide (compound 13):

1), Synthesis of (3-(4-nitro-1H-pyrazol-1-yl)benzyl)carbamic acid tert-butyl ester:

Under room temperature and nitrogen conditions, (3-bromobenzyl)carbamic acid tert-butyl ester (2g, 6.99mmol), 4-nitro-1H-pyrazole (0.95g, 8.39mmol), and cesium carbonate (6.83 g, 20.95mmol) and copper iodide (0.40g, 2.10mmol) in N,N-dimethylformamide (20mL), add trans-N,N'-dimethyl-1,2-cyclo Hexamethylenediamine (0.30g, 2.1mmol). The obtained mixed reaction liquid was heated to 100°C and stirred for 16 hours under nitrogen protection. After cooling, the obtained mixed reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 25%-75% elution) to obtain (1.2g, 54%), LC-MS m/z: 319[M+H] ⁺ ;

2), Synthesis of 3-(4-nitro-1H-pyrazol-1-yl)phenyl)methanamine:

Dissolve (3-(4-nitro-1H-pyrazol-1-yl)benzyl)carbamic acid tert-butyl ester (800 mg, 2.50 mmol) in dichloromethane (3 mL) and 2,2,2-tris The mixed solution of fluoroacetic acid (1 mL) was stirred at room temperature for 2 hours. The obtained mixed reaction solution was concentrated under reduced pressure and the crude product was directly used in the next step without further purification. LC-MS m/z: 219[M+H] ⁺ ;

3), 5-chloro-3-isopropyl-N-(3-(4-nitro-1H-pyrazol-1-yl)benzyl)pyrazolo[1,5-a]pyrimidine-7- Synthesis of amines:

Dissolve (3-(4-nitro-1H-pyrazol-1-yl)phenyl)methanamine (400mg, 1.83mmol), 5,7-dichloro-3-isopropylpyrazolo[1 A solution of 5-a]pyrimidine (456 mg, 2.0 mmol) and N, N-diisopropylethylamine (1349 mg, 10.45 mmol) in isopropyl alcohol (5 mL) was heated to 60°C and stirred for 16 hours. The resulting mixture was concentrated in vacuo. Purified by silica gel column chromatography (ethyl acetate: petroleum ether = 15%-50% elution) to obtain 5-chloro-3-isopropyl-N-(3-(4-nitro-1H-pyrazole-1) -yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (350mg, yield: 46.5%), LC-MS m/z: 412[M+H] ⁺ ;

4), (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) (3-(4-nitro-1H-pyrazol-1-yl)benzyl) Synthesis of tert-butyl carbamate:

The dissolved 5-chloro-3-isopropyl-N-(3-(4-nitro-1H-pyrazol-1-yl)benzyl)pyrazolo[1,5-a]pyrimidine-7- Amine (300 mg, 0.73 mmol), N,N-diisopropylethylamine (141 mg, 1.09 mmol), 4-dimethylaminopyridine (268 mg, 2.19 mmol) and di-tert-butyl dicarbonate (16 mg, 0.073 mmol) A solution of tetrahydrofuran (5 mL) was stirred at room temperature for 4 hours. The obtained reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10%-60% elution) to obtain (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl )(3-(4-nitro-1H-pyrazol-1-yl)benzyl)carbamic acid tert-butyl ester (260 mg, yield: 69.7%), LC-MS m/z: 512[M+H] ⁺ ;

5), (3-(4-amino-1H-pyrazol-1-yl)benzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino Synthesis of tert-butyl formate:

Dissolved (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(4-nitro-1H-pyrazol-1-yl)benzyl) A solution of tert-butyl carbamate (300 mg, 0.59 mmol), ammonium chloride (158 mg, 2.95 mmol) and iron (165 mg, 2.95 mmol) in ethanol (2 mL) and water (0.2 mL) was heated at 80°C and stirred for 4 hours. The obtained mixed reaction liquid was filtered, and the filter cake was washed with methanol. The collected filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with methanol: dichloromethane = 0-10%) to obtain (3-(4-amino-1H-pyrazol-1-yl)benzyl)(5-chloro-3- Isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (160 mg, 56.7%), LC-MS m/z: 482[M+H] ⁺ ;

6), (3-(4-Acrylamido-1H-pyrazol-1-yl)benzyl) (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl )Synthesis of tert-butyl carbamate:

Dissolve (3-(4-amino-1H-pyrazol-1-yl)benzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino A mixed solution of tert-butyl formate (260 mg, 0.54 mmol), acryloyl chloride (59 mg, 0.65 mmol) and sodium bicarbonate (68 mg, 0.81 mmol) in tetrahydrofuran (1 mL) and water (1 mL) was stirred at room temperature for 4 hours. The obtained reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20%-50% elution) to obtain (3-(4-acrylamido-1H-pyrazol-1-yl)benzyl)(5- Chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (150 mg, yield: 52%), LC-MS m/z: 536 [M+H ] ⁺ ;

7), (3R, 4R)-4-(((7-((3-(4-acrylamido-1H-pyrazol-1-yl)benzyl)(tert-butoxycarbonyl)amino)-3 Synthesis of -isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

At room temperature, (3-(4-acrylamido-1H-pyrazol-1-yl)benzyl)(5-chloro-3-isopropylpyrazolo[1,5-a] Pyrimidin-7-yl)carbamic acid tert-butyl ester (50mg, 0.093mmol), (3R, 4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (26mg, 0.11mmol) ) and (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H- To a solution of imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (7.81 mg, 0.0093 mmol) in 1,4-dioxane (1 mL) was added cesium carbonate (91 mg, 0.28 mmol). Under the protection of nitrogen gas, the mixed reaction mixture was heated to 90°C and stirred for 4 hours. After cooling, the obtained mixed reaction solution was diluted with water (5 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: 0.1% NH ₄ HCO ₃ in pure water = 20 to 70% elution) to obtain (3R, 4R)-4-(((7-((3-(4-propene) Amido-1H-pyrazol-1-yl)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl )-3-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (30 mg, yield: 44%), LC-MS m/z: 730 [M+H] ⁺ ;

8), N-(1-(3-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)methyl)amino)-3-isopropylpyrazolo Synthesis of [1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-1H-pyrazol-4-yl)acrylamide:

Dissolve (3R, 4R)-4-(((7-((3-(4-acrylamido-1H-pyrazol-1-yl)benzyl)(tert-butoxycarbonyl)amino)-3 -Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.041 mmol) in dichloromethane ( A mixed solution of 0.9 mL) and 2,2,2,-trifluoroacetic acid (0.3 mL) was stirred at room temperature for 2 hours. The resulting reaction mixture was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 20 to 70% elution) to obtain N-(1-(3-(((5-((((3R, 4R )-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-1H- Pyrazol-4-yl)acrylamide (5 mg, yield: 23%), LC-MS m/z: 530[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD) δ8.54 (s, 1H), 7.77 (d, J = 6Hz, 2H), 7.69–7.63 (m, 2H), 7.47 (t, J = 8Hz, 1H), 7.36 ( d,J＝7.6Hz,1H),6.36(s,2H),5.80(s,1H),5.18(s,1H),4.63(d,J＝4.4Hz,2H),3.98(d,J＝14Hz ,1H),3.47(s,1H),3.15(d,J＝14.4Hz,2H),3.02-2.93(m,2H),2.76(t,J＝11.2Hz,1H),1.88(d,J＝ 12Hz, 1H), 1.64 (s, 2H), 1.28 (t, J = 7.2Hz, 7H).

Example 14, (1s,4s)-4-acrylamido-N-(3-(((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl) Synthesis of amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)cyclohexane-1-carboxamide (compound 14):

1), (3R, 4R)-4-(((7-((3-((1s,4s)-4-acrylamidocyclohexane-1-carboxamido)benzyl)(tert-butoxy) Synthesis of tert-butyl carbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate:

Dissolve (3R, 4R)-4-((((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-5-yl)amino)methyl tert-butyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.08 mmol), (1s, 4s)-4-acrylamidocyclohexane- 1-carboxylic acid (19 mg, 0.1 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (46 mg, 0.12 mmol) and A solution of N,N-diisopropylethylamine (31 mg, 0.24 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature overnight. The mixed reaction solution was directly passed through C18 column chromatography (acetonitrile: containing 0.1% formic acid (3R, 4R)-4-(((7-((3-((1s,4s))-4-acrylamidocyclohexane-1-carboxamide)) yl)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1- Tert-butyl carboxylate (25 mg, yield: 38.6%), LC-MS m/z: 789 [M+H] ⁺ ;

2), (1s,4s)-4-acrylamido-N-(3-(((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)methyl)amino Synthesis of )-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)cyclohexane-1-carboxamide:

To the solution is (3R, 4R)-4-(((7-((3-((1s,4s)-4-acrylamidocyclohexane-1-carboxamido)benzyl)(tert-butoxy) Carbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (25 mg, 0.03 mmol ) in dichloromethane (0.9 mL), 2,2,2-trifluoroacetic acid (0.3 mL) was added dropwise. The obtained mixed reaction liquid was stirred at room temperature for 1 hour, and then the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95% elution) to obtain (1s, 4s)-4-acrylamido-N-(3-((5 -(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino )Methyl)phenyl)cyclohexane-1-carboxamide (16mg, yield: 86%), LC-MS m/z: 589[M+H] ⁺ ; ¹ H NMR (400MHz, MeOD-d4) :δ7.74(s,1H),7.65(s,1H),7.48(d,J＝8.0Hz,1H),7.30(t,J＝8.0Hz,1H),7.25(d,J＝8.0Hz, 1H),6.35(dd,J＝8.0,4.0Hz,1H),6.21(d,J＝8.0Hz,1H),5.69(dd,J＝10.4,2.4Hz,1H),5.20(s,1H), 4.55(s,2H),4.02(s,1H),3.96(d,J＝8.0Hz,1H),3.53-3.48(m,1H),3.40-3.97(m,1H),3.25-3.20(d, J＝8.0Hz,1H),3.12-3.09(m,1H),3.04-2.96(m,1H),2.68(t,J＝8.0Hz,1H),2.46(s,1H),1.92-1.80(m ,5H),1.75-1.64(m,6H),1.30-1.25(m,1H),1.23(s,3H),1.16(s,3H).

Example 15, (S)-N-(1-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino))-3-isopropylpyrazolo[1 Synthesis of ,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-1H-pyrazol-4-yl)acrylamide (compound 15):

1), (S)-(3-(4-acrylamido-1H-pyrazol-1-yl)benzyl)(5-((6,6-dimethylpiperidin-3-yl)amino) Synthesis of -3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester:

At room temperature, (3-(4-acrylamido-1H-pyrazol-1-yl)benzyl)(5-chloro-3-isopropylpyrazolo[1,5-a] Pyrimidin-7-yl)carbamic acid tert-butyl ester (30 mg, 0.056 mmol), (S)-6,6-dimethylpiperidin-3-amine (15 mg, 0.11 mmol) and cesium carbonate (55 mg, 0.17 mmol) To a solution of 1,4-dioxane (1mL), add (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4, 5-Dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (4.70 mg, 0.0056 mmol). The resulting mixed reaction liquid was heated to 90°C and stirred for 4 hours under the protection of nitrogen gas. After cooling, the obtained mixed reaction solution was diluted with water (5 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 20 to 70% elution) to obtain (S)-(3-(4-acrylamido-1H-pyrazole-1) -yl)benzyl)(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino Tert-butyl formate (15 mg, yield: 42.7%), LC-MS m/z: 628[M+H] ⁺ ;

2), (S)-N-(1-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino))-3-isopropylpyrazolo[1, Synthesis of 5-a]pyrimidin-7-yl)amino)methyl)phenyl)-1H-pyrazol-4-yl)acrylamide:

Dissolved (S)-(3-(4-acrylamido-1H-pyrazol-1-yl)benzyl)(5-((6,6-dimethylpiperidin-3-yl)amino) -tert-butyl 3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (20 mg, 0.032 mmol) in dichloromethane (0.3 mL) and 2,2,2-trifluoro The mixed solution of acetic acid (0.1 mL) was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was eluted and purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 25-70%) to obtain (S)-N-(1-(3-(((5-((6 ,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-1H-pyrazole -4-yl)acrylamide (7mg, yield: 41%), LC-MS: m/z: 528[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD) δ8.53 (s, 1H), 7.79 (s, 1H), 7.77 (s, 1H), 7.63 (d, J = 12.4Hz, 2H), 7.47 (t, J = 8Hz ,1H),7.36(d,J＝7.6Hz,1H),6.39–6.36(m,2H),5.78(dd,J＝8.0,4.0Hz,1H),5.19(s,1H),4.62(s, 2H),3.87(s,1H),3.13-3.03(m,2H),2.72(s,1H),1.88(s,1H),1.61(s,2H),1.51(s,1H),1.30(d ,J＝2Hz,3H),1.28(d,J＝2.4Hz,3H),1.18(s,6H)

Example 16, (S)-N-(3-((2-((6,6-dimethylpiperidin-3-yl)amino)-8-isopropylpyrazolo[1,5-a Synthesis of ][1,3,5]triazin-4-yl)amino)phenyl)acrylamide (compound 16):

1), 8-isopropyl-2-(methylthio)-N-(3-nitrophenyl)pyrazolo[1,5-a][1,3,5]triazine-4-amine Synthesis:

To a solution of 3-nitroaniline (684 mg, 4.96 mmol) dissolved in tetrahydrofuran (5 mL) at 0°C, sodium hydride (298 mg, 12.40 mmol) was added in batches, and the resulting mixed reaction solution was stirred at room temperature for 30 minutes. A solution of 4-chloro-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1 g, 4.13 mmol) in tetrahydrofuran (5 mL) was then Add dropwise to the above reaction solution. The resulting mixed reaction solution was heated to 90°C and stirred for 2 hours. After cooling, the resulting mixed reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and reduced pressure. concentrate. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain 8-isopropyl-2-(methylthio)-N- (3-nitrophenyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (800 mg, yield: 56.1%), LC-MS m/z: 345[ M+H] ⁺ ;

2), 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrophenyl)pyrazolo[1,5-a][1,3,5]triazine-4- Synthesis of amines:

8-Isopropyl-2-(methylthio)-N-(3-nitrophenyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine will be dissolved (370 mg, 1.0 mmol) and m-chloroperoxybenzoic acid (355 mg, 2.07 mmol) in dichloromethane (5 mL), stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain 8-isopropyl-2-(methylsulfonyl)-N -(3-nitrophenyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (340 mg, yield: 84.4%), LC-MS m/z: 377 [M+H] ⁺ ;

3), (S)-N ² -(6,6-dimethylpiperidin-3-yl)-8-isopropyl-N4-(3-nitrophenyl)pyrazolo[1,5- Synthesis of a][1,3,5]triazine-2,4-diamine:

At room temperature, 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrophenyl)pyrazolo[1,5-a][1,3,5]tri To a solution of oxazine-4-amine (320 mg, 0.851 mmol) and (S)-6,6-dimethylpiperidin-3-amine (131 mg, 1.02 mmol) in isopropyl alcohol (4 mL), add N,N- Diisopropylethylamine (329 mg, 2.55 mmol). The resulting mixed reaction solution was heated to 90°C and stirred for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (S)-N ² -(6,6-dimethylpiperidine) -3-yl)-8-isopropyl-N ⁴ -(3-nitrophenyl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine ( 200mg, yield: 55.4%), LC-MS m/z: 425[M+H] ⁺ ;

4), (S)-5-((8-isopropyl-4-((3-nitrophenyl)amino)pyrazolo[1,5-a][1,3,5]triazine- Synthesis of tert-butyl 2-yl)amino)-2,2-dimethylpiperidine-1-carboxylate:

At room temperature, (S)-N ² -(6,6-dimethylpiperidin-3-yl)-8-isopropyl-N ⁴ -(3-nitrophenyl)pyrazolo was dissolved in the solution. To a solution of [1,5-A][1,3,5]triazine-2,4-diamine (100 mg, 0.236 mmol) and triethylamine (72 mg, 0.708 mmol) in tetrahydrofuran (2 mL), dicarbonic acid was added Di-tert-butyl ester (103 mg, 0.472 mmol) and 4-dimethylaminopyridine (14.4 mg, 0.118 mmol). The resulting mixed reaction solution was heated to 50°C and stirred for 2 hours. After cooling, water (50 mL) was added to the obtained mixed reaction liquid, and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (S)-5-((8-isopropyl-4- ((3-nitrophenyl)amino)pyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)-2,2-dimethylpiperidine-1- Tert-butyl carboxylate (70 mg, yield: 56.6%), LC-MS m/z: 525[M+H] ⁺ ;

5), (S)-5-((4-((3-aminophenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2 Synthesis of -(yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (S)-5-((8-isopropyl-4-((3-nitrophenyl)amino)pyrazolo[1,5-a][1,3,5]triazine- 2-yl)Amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.095 mmol) and iron (16.0 mg, 0.286 mmol) in ethanol (2 mL) and ammonium chloride Aqueous solution (0.5 mL). The resulting mixed reaction solution was heated to 70°C and stirred for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (S)-5-((4-((3-amino Phenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)-2,2-dimethylpiperidine-1- Tert-butyl carboxylate (40 mg, yield: 84.9%), LC-MS m/z: 495 [M+H] ⁺ ;

6), (S)-5-((4-((3-acrylamidophenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine Synthesis of -2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester:

At room temperature, (S)-5-((4-((3-aminophenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5] is dissolved into the solution Triazin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.061 mmol) and triethylamine (37 mg, 0.364 mmol) in dichloromethane (2 mL) To the solution, acryloyl chloride (16 mg, 0.182 mmol) was added. The resulting mixed reaction solution was stirred at room temperature for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (S)-5-((4-((3-acrylamide) Phenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)-2,2-dimethylpiperidine-1- Tert-butyl carboxylate (30 mg, yield: 90.1%), LC-MS m/z: 549[M+H] ⁺ ;

7), (S)-N-(3-((2-((6,6-dimethylpiperidin-3-yl)amino)-8-isopropylpyrazolo[1,5-a] Synthesis of [1,3,5]triazin-4-yl)amino)phenyl)acrylamide:

Dissolve (S)-5-((4-((3-acrylamidophenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine -2-yl)amino)-2,2- A solution of dimethylpiperidine-1-carboxylic acid tert-butyl ester (25 mg, 0.046 mmol) in dichloromethane (1.5 mL) and 2,2,2-trifluoroacetic acid (0.5 mL) was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (S)-N-(3-((2-((6, 6-dimethylpiperidin-3-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)phenyl)propylene Amide (10 mg, yield: 48.9%), LC-MS m/z: 449[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.55(s,1H),7.78(s,1H),7.43-7.34(m,2H),7.24(s,1H),6.53-6.35(m,2H ),5.84-5.81(m,1H),4.31(s,1H),3.49-3.45(m,1H),3.15-3.01(m,2H),2.05-2.02(m,1H),1.90-1.76(m ,3H),1.39(d,J＝6.0Hz,6H),1.31(d,J＝7.2Hz,6H).

Example 17, (R)-N-(3-((2-((6,6-dimethylpiperidin-3-yl)oxy)-8-isopropylpyrazolo[1,5- Synthesis of a][1,3,5]triazin-4-yl)amino)phenyl)acrylamide (compound 17):

1), N ¹ -(8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)benzene-1,3- Synthesis of diamines:

8-Isopropyl-2-(methylthio)-N-(3-nitrophenyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine will be dissolved (300 mg, 0.872 mmol) and iron (195 mg, 3.49 mmol) in ethanol (4 mL) and ammonium chloride aqueous solution (1 mL) were heated at 70°C and stirred for 2 hours. After cooling, the obtained mixed reaction liquid was added with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: water, pure water containing 0.1% formic acid = 25%-65% elution) to give N ¹ -(8-isopropyl-2-(methylthio)) Pyrazolo[1,5-a][1,3,5]triazin-4-yl)benzene-1,3-diamine (200 mg, yield: 73.0%), LC-MS m/z: 315 [M+H] ⁺ ;

2), N-(3-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)benzene Synthesis of acrylamide:

At room temperature, N ¹ -(8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)benzene- A solution of 1,3-diamine (200mg, 0.637mmol) and triethylamine (193mg, 1.91mmol) in acetonitrile (2mL) was added with 2,4,6-tripropyl-1,3,5,2,4, 6-trioxytriphosphate-2,4,6-trioxide (486 mg, 0.764 mmol, 50% mass fraction in ethyl acetate solution). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The mixed reaction solution was diluted with water (100 mL), and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% FA: pure water containing 0.1% FA formic acid = 25%-65% elution) to obtain N-(3-((8-isopropyl-2- (Methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)phenyl)acrylamide (165 mg, yield: 70.4%), LC-MS m /z：369[M+H] ⁺ ;

3), N-(3-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino) Synthesis of phenyl)acrylamide:

Dissolve N-(3-((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)benzene A solution of acrylamide (80 mg, 0.217 mmol) and m-chloroperoxybenzoic acid (75 mg, 0.435 mmol) in dichloromethane (2 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% FA: pure water containing 0.1% formic acid = 25%-65% elution) to obtain N-(3-((8-isopropyl-2-() Methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)phenyl)acrylamide (40 mg, yield: 46.0%), LC-MS m /z:401[M+H] ⁺ ;

4), (R)-5-((4-((3-Acrylamidophenyl)(tert-butoxycarbonyl)amino)-8-isopropylpyrazolo[1,5-a][1 Synthesis of tert-butyl ester of ,3,5]triazin-2-yl)oxy)-2,2-dimethylpiperidine-1-carboxylate:

At 0°C, add (R)-5-hydroxy-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (17 mg, 0.075 mmol) in tetrahydrofuran (1 mL) in batches. Sodium hydride (3.00 mg, 0.125 mmol) was added. The resulting mixed reaction solution was stirred at room temperature for 30 minutes. Then N-(3-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)benzene A solution of acrylamide (25.0 mg, 0.063 mmol) in tetrahydrofuran (1 mL) was added dropwise to the above mixed reaction solution. The resulting mixed reaction solution was stirred at room temperature for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (R)-5-((4-((3-acrylamide) phenyl)(tert-butoxycarbonyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)-2,2 - Dimethylpiperidine-1-carboxylic acid tert-butyl ester (22 mg, yield: 54.2%), LC-MS m/z: 650 [M+H] ⁺ ;

5), (R)-N-(3-((2-((6,6-dimethylpiperidin-3-yl)oxy)-8-isopropylpyrazolo[1,5-a Synthesis of ][1,3,5]triazin-4-yl)amino)phenyl)acrylamide:

At room temperature, (R)-5-((4-((3-acrylamidophenyl)(tert-butoxycarbonyl)amino)-8-isopropylpyrazolo[1,5- a][1,3,5]Triazin-2-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (22 mg, 0.034 mmol) in dichloromethane (1 mL) To the solution, 2,2,2-trifluoroacetic acid (0.3 mL) was added. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water (30 mL) and mixed with Extract with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (R)-N-(3-((2-((6 ,6-dimethylpiperidin-3-yl)oxy)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)phenyl ) Acrylamide (10 mg, yield: 53.7%), LC-MS: m/z: 550[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.36(s,1H),7.93(s,1H),7.41-7.38(m,3H),6.51-6.37(m,2H),5.80-5.78(m ,1H),5.18(s,1H),3.20-3.16(m,1H),3.13-3.08(m,1H),3.03-2.97(m,1H),2.09-2.04(m,1H),1.97-1.91 (m,1H),1.78-1.72(m,1H),1.53-1.46(m,1H),1.33(d,J＝7.2Hz,6H),1.19(d,J＝12.4Hz,6H).

Example 18, (R)-3-acrylamido-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino))-3-isopropylpyrazole Synthesis of [1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide (compound 18):

1) Synthesis of (R)-(6,6-dimethylpiperidin-3-yl)carbamic acid tert-butyl ester:

At -10°C, to a solution of (R)-(6-oxopiperidin-3-yl)carbamic acid tert-butyl ester (2.0g, 9.33mmol) in tetrahydrofuran (94.0mL) was added in batches. Zirconium chloride (5.22g, 22.4mmol). The obtained mixed reaction liquid was stirred at -10°C for 30 minutes, and then methylmagnesium bromide (3M, 46.7 mmol) was added dropwise to the above reaction liquid. The resulting mixed reaction solution was stirred at room temperature for 16 hours. At 0°C, the mixed reaction solution was added to aqueous sodium hydroxide solution (content: 30%, 200 mL), filtered, and the aqueous phase was extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 20-25%) to obtain (R)-(6,6-dimethylpiperidin-3-yl)carbamic acid tert-butyl ester (1.0g, yield : 47%), LC-MS m/z: 229[M+H] ⁺ ;

2), Synthesis of (R)-6,6-dimethylpiperidin-3-amine:

To a solution of (R)-(6,6-dimethylpiperidin-3-yl)carbamic acid tert-butyl ester (500 mg, 2.19 mmol) dissolved in dichloromethane (5 mL) at 0°C, 2,2,2-Trifluoroacetic acid (2.5 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which could be directly used in the next step without further purification. LC-MS m/z: 129 [M+H] ⁺ ;

3), (R)-(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) Synthesis of (3-nitrobenzyl)carbamic acid tert-butyl ester:

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (300mg, 0.67mmol), ( R)-6,6-dimethylpiperidin-3-amine (216mg, 1.69mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl) )phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (57 mg, 0.07 mmol) and cesium carbonate (1089 mg, 3.35 mmol) in 1,4-dioxane (4 mL), heated to 100°C and stirred overnight under argon protection. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ H ₂ O = 5-95% elution) to obtain (R)-(5-((6,6-dimethylpiperidine-3) -(yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (70 mg, yield: 19.3%), LC-MS m/z:538[M+H] ⁺ ;

4), (R)-5-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Synthesis of tert-butyl (amino)-2,2-tert-butyldimethylpiperidine-1-carboxylate:

Dissolved (R)-(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) (3-nitrobenzyl)carbamic acid tert-butyl ester (70 mg, 0.13 mmol), di-tert-butyl dicarbonate (34 mg, 0.16 mmol) and N,N-diisopropylethylamine (50 mg, 0.39 mmol) The dichloromethane (2 mL) solution was heated to 60°C and stirred for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (R)-5-((7-((tert-butoxycarbonyl)(3) -nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-tert-butyldimethylpiperidine-1-carboxylic acid Tert-butyl ester (30 mg, yield: 36.1%), LC-MS m/z: 638[M+H] ⁺ ;

5), (R)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Synthesis of tert-butyl (amino)-2,2-tert-butyldimethylpiperidine-1-carboxylate:

Dissolve (R)-5-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Amino)-2,2-tert-butyldimethylpiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.047 mmol) and iron (13.2 mg, 0.24 mmol) in aqueous ammonium chloride solution (0.2 mL) and The ethanol (0.8 mL) solution was heated to 70°C and stirred for 2 hours. After cooling, the obtained mixed reaction liquid was filtered, and the filter cake was washed with methanol (3×10 mL). The collected filtrate was concentrated under reduced pressure to obtain a crude product, which could be used directly in the next step without further purification. LC-MS m/z: 608[M+H] ⁺ ;

6), (R)-5-((7-((3-(3-acrylamidobenzoylamino)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[ Synthesis of 1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (R)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- amino)-2,2-tert-butyldimethylpiperidine-1-carboxylic acid tert-butyl ester (30mg, 0.05mmol), 3-acrylamidobenzoic acid (11.3mg, 0.06mmol), 2-( 7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (28.5mg, 0.075mmol) and N,N-diisopropylethylamine (19.4mg , 0.15 mmol) in N,N-dimethylformamide (1.5 mL), stirred at room temperature overnight. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (R)-5-((7-((3-(3-acrylamide) Benzoylamino)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethyl Piperidine-1-carboxylic acid tert-butyl ester (20 mg, yield: 52%), LC-MS m/z: 781 [M+H] ⁺ ;

7), (R)-3-acrylamido-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino))-3-isopropylpyrazolo [1,5-a]pyrimidin-7-yl)amino Synthesis of methyl)phenyl)benzamide:

There is (R)-5-((7-((3-(3-acrylamidobenzoylamino)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[ 1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (20.0 mg, 0.026 mmol) was dropped into a solution of dichloromethane (1.2 mL) Add 2,2,2-trifluoroacetic acid (0.4 mL). The resulting mixed reaction solution was stirred at room temperature for 30 minutes. The obtained reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (R)-3-acrylamido-N-(3-(((( 5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl) Benzamide (7.8mg, yield: 52.4%), LC-MS m/z: 581[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.19 (s, 1H), 7.76 (s, 2H), 7.64–7.62 (m, 3H), 7.47 (t, J = 8.0Hz, 1H), 7.36 ( t,J＝8.0Hz,1H),7.21(d,J＝4.0Hz,1H),6.49–6.41(m,2H),5.80(d,J＝8.0Hz,1H),5.21(s,1H), 4.58(s,2H),3.93(s,1H),3.29(s,1H),3.08–3.05(m,1H),2.81(s,1H),1.93–1.89(m,1H),1.70–1.55( m,3H),1.33–1.22(m,12H).

Example 19, (R)-3-acrylamido-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)oxy))-3-isopropylpyra Synthesis of azozo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide (compound 19):

1), (R)-5-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Synthesis of tert-butyl)oxy)-2,2-tert-butyldimethylpiperidine-1-carboxylate:

At room temperature, dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (120 mg, 0.27 mmol) and (R)-5-hydroxy-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (74 mg, 0.32 mmol) in toluene solution (2 mL), add tris(dibenzylidene Acetone) palladium (25 mg, 0.03 mmol), (R)-1-[(SP)-2-(dicyclohexylphosphine)ferrocenyl]ethyldi-tert-butylphosphine (30 mg, 0.05 mmol) and cesium carbonate (264mg, 0.81mmol). The resulting mixed reaction solution was heated in microwave at 140°C and stirred for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (R)-5-((7-((tert-butoxycarbonyl)) (3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2,2-tert-butyldimethylpiperidine-1 -tert-butyl carboxylate (130 mg, yield: 75.6%), LC-MS m/z: 639 [M+H] ⁺ ;

2), (R)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Synthesis of tert-butyl)oxy)-2,2-dimethylpiperidine-1-carboxylate:

(R)-5-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- (130 mg, 0.2 mmol) and iron (57 mg, 1.02 mmol) in ethanol (2 mL), add chlorine Ammonium chloride aqueous solution (30 mg, 0.61 mmol). The mixed reaction solution was heated to 70°C and stirred for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (R)-5-((7-((3-amino Benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2,2-dimethylpiperidine-1- Tert-butyl carboxylate (110 mg, yield: 88.7%), LC-MS m/z: 609[M+H] ⁺ ;

3), (R)-5-((7-((3-(3-acrylamidobenzoylamino)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[ Synthesis of 1,5-a]pyrimidin-5-yl)oxytert-butyl)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester:

At room temperature, (R)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a ]pyrimidin-5-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.08 mmol) and 3-acrylamidobenzoic acid (19 mg, 0.10 mmol) in acetonitrile (1 mL) solution, 1-methylimidazole (27 mg, 0.33 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (46 mg, 0.16 mmol) were added. The resulting mixed reaction solution was stirred at room temperature for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (R)-5-((7-((3-(3- Acrylamidobenzoylamino)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxytert-butyl)-2 , 2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (35 mg, yield: 54.5%), LC-MS m/z: 782[M+H] ⁺ ;

4), (R)-3-acrylamido-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)oxy))-3-isopropylpyrazole Synthesis of [1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide:

Dissolve (R)-5-((7-((3-(3-acrylamidobenzoylamino)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[ 1,5-a]pyrimidin-5-yl)oxytert-butyl)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (35 mg, 0.04 mmol) in dichloromethane (3 mL) and A solution of 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 8 hours. Water (20 mL) was added to the mixed reaction solution, and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (R)-3-acrylamido-N-(3-(( (5-((6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)benzene base) benzamide (20 mg, yield: 76.8%), LC-MS: m/z: 582 [M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d ₄ ): δ8.210 (s, 1H), 7.788-7.727 (m, 3H), 7.625 (t, J = 8.8Hz, 2H), 7.465 (t, J = 7.6Hz ,1H),7.367(t,J＝7.6Hz,1H),7.198(d,J＝7.6Hz,1H),6.484-6.369(m,2H),5.818-5.789(m,1H),5.446(s, 1H),5.333(s,1H),4.638(s,2H),3.478-3.394(m,2H),3.129-3.060(m,1H),2.025(m,2H),1.903-1.877(m,1H) ,1.626-1.589(m,1H),1.341-1.313(m,12H).

Example 20, (S)-N-(3-(((2-((6,6-dimethylpiperidin-3-yl)amino))-8-isopropylpyrazolo[1,5- Synthesis of a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acrylamide (compound 20):

1), (S)-N ² -(6,6-dimethylpiperidin-3-yl)-8-isopropyl-N ⁴ -(3-nitrobenzyl)pyrazolo[1,5 Synthesis of -a][1,3,5]triazine-2,4-diamine:

At room temperature, 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]tri To a solution of oxazine-4-amine (300 mg, 0.77 mmol) in 1,4-dioxane (5.0 mL), (S)-6,6-dimethylpiperidin-3-amine (295 mg, 2.31mmol) and cesium fluoride (702mg, 4.62mmol). The obtained mixed reaction liquid was heated to 100°C and stirred for 8 hours. After cooling, the mixed reaction solution was diluted with water (50 mL), extracted with ethyl acetate (3×50 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with ethyl acetate: petroleum ether = 15-25%) to obtain (S)-N ² -(6,6-dimethylpiperidin-3-yl)-8-isopropyl Base-N ⁴ -(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (220 mg, yield: 65.3%), LC -MS m/z: 439[M+H] ⁺ ;

2), (S)-5-((8-isopropyl-4-((3-nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5]triazine- Synthesis of tert-butyl 2-yl)amino)-2,2-dimethylpiperidine-1-carboxylate:

At room temperature, (S)-N ² -(6,6-dimethylpiperidin-3-yl)-8-isopropyl-N ⁴ -(3-nitrobenzyl)pyrazolo was dissolved in To a solution of [1,5-a][1,3,5]triazine-2,4-diamine (220 mg, 0.5 mmol) in dichloromethane (3.0 mL), di-tert-butyl dicarbonate ( 164 mg, 0.75 mmol) and N,N-diisopropylethylamine (194 mg, 1.5 mmol) and 4-dimethylaminopyridine (6.1 mg, 0.05 mmol). The resulting mixed reaction solution was stirred at room temperature for 8 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10-20% elution) to obtain (S)-5-((8-isopropyl-4-((3-nitrobenzyl)amino) Pyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (90 mg, yield: 33.3%), LC-MS m/z 539[M+H] ⁺ ;

3), (S)-5-((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2 Synthesis of -(yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester:

At room temperature, (S)-5-((8-isopropyl-4-((3-nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5 ]Triazin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (90 mg, 0.167 mmol) in ethanol (3.0 mL) and aqueous ammonium chloride solution (1.0 mL) To the solution, zinc (55 mg, 0.84 mmol) was added in portions. The resulting mixed reaction solution was stirred at room temperature for 8 hours. The mixed reaction solution was filtered, the filtrate was extracted with ethyl acetate (3×5 mL), and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 30-50% elution) to obtain (S)-5-((4-((3-aminobenzyl)amino)-8-isopropylpyra) Azolo[1,5-a][1,3,5]triazin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (80 mg, yield: 94.1 %), LC-MS m/z: 509[M+H] ⁺ ;

4), (S)-5-((4-((3-Acrylamidobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine Synthesis of -2-yl)amino)-2,2-dimethylpiperidine-1-carboxylate tert-butyl ester:

At 0℃, (S)-5-((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3, 5] Triazin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.157 mmol) in dichloromethane (3.0 mL), add propylene in batches Acid chloride (17 mg, 0.188 mmol) and triethylamine (48 mg, 0.47 mmol). The resulting mixed reaction solution was stirred at room temperature for 4 hours. The obtained mixed reaction solution was diluted with water (20 mL), extracted with ethyl acetate (3×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-45% elution) to obtain (S)-5-((4-((3-acrylamidobenzyl)amino)-8-isopropyl) pyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylate tert-butyl ester (60 mg, collected Rate: 67.8%), LC-MS m/z: 563[M+H] ⁺ ;

5), (S)-N-(3-(((2-((6,6-dimethylpiperidin-3-yl)amino)-8-isopropylpyrazolo[1,5-a Synthesis of ][1,3,5]triazin-4-yl)amino)methyl)phenyl)acrylamide:

In solution, (S)-5-((4-((3-acrylamidobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine To a solution of -2-yl)amino)-2,2-dimethylpiperidine-1-carboxylate tert-butyl ester (60 mg, 0.107 mmol) in dichloromethane (3.0 mL), add 2,2, 2-Trifluoroacetic acid (1.0 mL). The resulting mixed reaction solution was stirred at room temperature for 4 hours. The obtained mixed reaction liquid was collected under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3·H 2O = 5-95% elution) to obtain (S)-N-(3-(((2-((6,6- Dimethylpiperidin-3-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl) Acrylamide (2.1 mg, yield: 4.3%), LC-MS m/z: 463[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.72 (s, 1H), 7.66 (s, 1H), 7.51 (d, J = 7.5Hz, 1H), 7.29 (t, J = 7.8Hz, 1H) ,7.14(d,J＝7.5Hz,1H),6.29–6.45(m,2H),5.74(dd,J＝9.5,2.0Hz,1H),4.73(s,2H),3.95–3.82(m,1H ),2.90-3.15(m,2H),2.62–2.74(m,1H),1.80–1.92(m,1H),1.52–1.68(m,2H),1.41–1.53(m,1H),1.26(d ,J＝6.9Hz,6H),1.15(d,J＝5.2Hz,6H).

Example 21, 3-acrylamido-N-(3-((5-((6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1, Synthesis of 5-a]pyrimidin-7-yl)amino)phenyl)benzamide (compound 21):

1), Synthesis of 5-chloro-3-isopropyl-N-(3-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7-amine:

Dissolve 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (300mg, 1.30mmol), 3-nitroaniline (216mg, 1.57mmol) and N,N-di A solution of isopropylethylamine (503 mg, 3.90 mmol) in isopropyl alcohol (4.0 mL) was heated to 70° C. and stirred for 16 hours. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile:water=5-95% elution) 5-chloro-3-isopropyl-N-(3-nitrophenyl)pyrazolo[1,5-a]pyrimidine -7-amine (260 mg, yield: 60%), LC-MS m/z: 332[M+H] ⁺ ;

2), 5-((3-isopropyl-7-((3-nitrophenyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2,2- Synthesis of dimethylpiperidine-1-carboxylic acid tert-butyl ester:

Dissolve 5-chloro-3-isopropyl-N-(3-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7-amine (150 mg, 0.45 mmol), 5-hydroxy-2 , tert-butyl 2-dimethylpiperidine-1-carboxylate (259mg, 1.13mmol), tris(dibenzylideneacetone)palladium (42mg, 0.05mmol), (R)-(-)-1-[ (S)-2-(dicyclohexylphosphine)ferrocene]ethyl di-tert-butylphosphine (50 mg, 0.09 mmol) and cesium carbonate (443 mg, 1.36 mmol) in toluene (5.0 mL) The solution was heated under argon gas at 140°C in the microwave and stirred for 2 hours. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 5-95% elution) to obtain 5-((3-isopropyl-7-((3-nitrophenyl)amino)pyrazolo[1, 5-a]pyrimidin-5-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (108 mg, yield: 45.3%), LC-MS m/z: 525[ M+H] ⁺ ;

3), 5-((7-((3-aminophenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2,2-di Synthesis of methylpiperidine-1-carboxylic acid tert-butyl ester:

The dissolved 5-((3-isopropyl-7-((3-nitrophenyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2,2- A solution of dimethylpiperidine-1-carboxylic acid tert-butyl ester (108 mg, 0.21 mmol) and palladium on carbon (21 mg) in methanol (5 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. After cooling, the mixed reaction solution was filtered, and the filter cake was washed with methanol (3×10 mL). The filtrate was collected and concentrated under reduced pressure to obtain 5-((7-((3-aminophenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2, 2-Dimethylpiperidine-1-carboxylic acid tert-butyl ester (95 mg, yield: 93.3%), LC-MS m/z: 495 [M+H] ⁺ ;

4), 5-((7-((3-(3-Acrylamidobenzamido)phenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl Synthesis of )oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester:

The dissolved 5-((7-((3-aminophenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2,2-di Methylpiperidine-1-carboxylic acid tert-butyl ester (95mg, 0.19mmol), 3-acrylamidobenzoic acid (55mg, 0.29mmol), N,N,N',N'-tetramethylchloroformamidine A solution of fluorophosphate (108 mg, 0.38 mmol) and N-methylimidazole (63 mg, 0.77 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 16 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: water = 5-95% elution) to obtain 5-((7-((3-(3-acrylamidobenzoylamino)phenyl)amino)- 3-Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (70 mg, yield: 55. %), LC-MS m/z: 668[M+H] ⁺ ;

5), 3-Acrylamide-N-(3-((5-((6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5 Synthesis of -a]pyrimidin-7-yl)amino)phenyl)benzamide:

There is 5-((7-((3-(3-acrylamidobenzoylamino)phenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl in solution )oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.10 mmol) in dichloromethane (3 mL), 2,2,2-trifluoroacetic acid ( 1mL). The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 5-95% elution) to obtain 3- Acrylamide-N-(3-((5-((6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidine- 7-yl)amino)phenyl)benzamide (40 mg, yield: 67.2%), LC-MS m/z: 568[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD) δ8.31 (s, 1H), 8.03 (s, 1H), 7.86 (s, 1H), 7.74 (d, J = 7.2Hz, 1H), 7.69 (d, J = 7.2 Hz,1H),7.53–7.43(m,3H),7.20(s,1H),6.44(d,J＝13.2Hz,2H),6.00(s,1H),5.81(d,J＝8.8Hz,1H ),5.43(s,1H),3.48(s,1H),3.39(s,1H),3.13(s,1H),2.08(s,2H),1.92(s,1H),1.66(s,1H) ,1.40–1.33(m,12H).

Example 22, N-(3-(((3-isopropyl-5-(piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl) Synthesis of phenyl)acrylamide (compound 22):

1) Synthesis of tert-butyl (3-aminobenzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate:

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (800mg, 1.79mmol), iron A mixed solution of ethanol (10 mL) solution and water (1 mL) of ammonium chloride (500 mg, 8.95 mmol) and ammonium chloride (478 mg, 8.95 mmol) was heated to 80°C and stirred for 4 hours. The obtained mixed reaction liquid was filtered, and the filter cake was washed with methanol (10 mL×3). The filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-10% elution) to obtain (3-aminobenzyl)(5-chloro-3-isopropylpyrazolo[1,5-a] Pyrimidin-7-yl)carbamic acid tert-butyl ester (550 mg, yield: 74%), LC-MS: m/z: 416 [M+H] ⁺ ;

2) Synthesis of tert-butyl (3-aminobenzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate:

Dissolve (3-aminobenzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (400 mg, 0.96 mmol), acryloyl chloride A mixed solution of sodium bicarbonate (105 mg, 1.15 mmol) and sodium bicarbonate (121 mg, 1.44 mmol) in tetrahydrofuran (2 mL) and water (2 mL) was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 15-40% elution) to obtain (3-aminobenzyl)(5-chloro-3-isopropylpyrazolo[1,5-a ]pyrimidin-7-yl)carbamate tert-butyl ester (260 mg, yield: 57.5%), LC-MS m/z: 470 [M+H] ⁺ ;

3), 4-((7-((3-Acrylamidobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino )Synthesis of piperidine-1-carboxylic acid tert-butyl ester:

At room temperature, tert-butyl (3-acrylamidobenzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (50 mg , 0.11mmol), 4-aminopiperidine-1-tert-butyl ester (26.44mg, 0.13mmol) and cesium carbonate (108mg, 0.33mmol) in 1,4-dioxane (1mL), add (SP -4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2- Yethylene]dichloro(2-methylpyridine)palladium (9.24 mg, 0.011 mmol). The resulting mixed reaction liquid was heated to 90°C and stirred for 4 hours under the protection of nitrogen gas. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-60% elution) to obtain 4-((7-((3-acrylamidobenzyl)(tert-butoxycarbonyl)amino)-3 -Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (30 mg, yield: 44.5%), LC-MS m/z: 634 [M+H] ⁺ ;LC-MS m/z:634[M+H] ⁺ ;

4), N-(3-(((3-isopropyl-5-(piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)benzene Synthesis of acrylamide:

The dissolved 4-((7-((3-acrylamidobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino ) The reaction mixture of tert-butyl piperidine-1-carboxylate (30 mg, 0.047 mmol) in dichloromethane (0.6 mL) and 2,2,2-trifluoroacetic acid (0.2 mL) was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH4HCO3 = 20~70% elution) to obtain N-(3-(((3-isopropyl-5-(piperidin-4-yl) Amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (9 mg, yield: 43.9%), LC-MS m/z: 434 [M+H ] ⁺ ;

¹ H NMR (400MHz, MeOD) δ7.92(d,J＝5.6Hz,2H),7.44–7.35(m,2H),7.20(d,J＝7.6Hz,1H),6.47–6.34(m,2H ),5.79(d,J＝9.6Hz,1H),5.37(s,1H),4.75(s,2H),3.96(s,1H),3.46(d,J＝13.2Hz,2H),3.17(t ,J＝10.8Hz,3H),2.16(d,J＝12Hz,2H),1.82–1.74(m,2H),1.31(d,J＝6.8Hz,6H).

Example 23, N-(3-(((3-isopropyl-5-(piperidin-4-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl Synthesis of )phenyl)acrylamide (compound 23):

1), 4-((7-((3-Acrylamidobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy Synthesis of piperidine-1-carboxylic acid tert-butyl ester:

Dissolve (3-acrylamidobenzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (50 mg, 0.11mmol), a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (27mg, 0.13mmol) and cesium carbonate (108mg, 0.33mmol) in 1,4-dioxane (1mL) was added (SP- 4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene methyl]dichloro(2-methylpyridine)palladium (9.24 mg, 0.011 mmol). The obtained mixed reaction liquid was heated to 90°C and stirred for 4 hours under nitrogen protection. After cooling, the mixed reaction liquid was diluted with water (5 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 4HCO 3 = 20 to 70% elution) to obtain 4-((7-((3-acrylamidobenzyl))(tert-butoxycarbonyl) )Amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (30 mg, yield: 44.4%), LC- MS m/z: 635[M+H] ⁺ ;

2), N-(3-(((3-isopropyl-5-(piperidin-4-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl) Synthesis of phenyl)acrylamide:

Will dissolve 4-((7-((3-acrylamidobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxygen A mixed solution of piperidine-1-carboxylic acid tert-butyl ester (25 mg, 0.039 mmol) in dichloromethane (0.3 mL) and 2,2,2-trifluoroacetic acid (0.1 mL) was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing H 0.1% NH ₄ HCO ₃ = 20 to 70% elution) to obtain N-(3-(((3-isopropyl-5-(piperidine) -4-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (6 mg, yield: 35%), LC-MS m/z: 435[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD) δ7.92(d,J＝5.6Hz,2H),7.44–7.35(m,2H),7.20(d,J＝7.6Hz,1H),6.47–6.34(m,2H ),5.79(d,J＝9.6Hz,1H),5.37(s,1H),4.75(s,2H),3.96(s,1H),3.46(d,J＝13.2Hz,2H),3.17(t ,J＝10.8Hz,3H),2.16(d,J＝12.2Hz,2H),1.82–1.74(m,2H),1.31(d,J＝6.8Hz,6H).

Example 24, 3-(2-fluoroacrylamido)-N-(3-(((2-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)methyl)amino Synthesis of )-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide (compound 24):

1), (3R, 4R)-4-(((4-((3-(3-(2-fluoroacrylamido)benzamido)benzyl)amino)-8-isopropylpyrazolo Synthesis of [1,5-a][1,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

At room temperature, (3R, 4R)-4-(((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3 ,5]triazin-2-yl)amino tert-butyl)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.078 mmol) and 3-(2-fluoroacrylamido)benzene To a solution of formic acid (20 mg, 0.094 mmol) in N,N-dimethylformamide (2 mL), add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (36 mg, 0.094 mmol) and N,N-diisopropylethylamine (31 mg, 0.235 mmol). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The mixed reaction solution was diluted with water (50 mL) and ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% FA: pure water containing 0.1% FA = 25%-65% elution) to obtain (3R, 4R)-4-(((4-((3 -(3-(2-fluoroacrylamido)benzamido)benzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2- (Basic) amino) methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30 mg, yield: 54.6%), LC-MS m/z: 702 [M+H] ⁺ ;

2), 3-(2-fluoroacrylamido)-N-(3-(((2-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino) Synthesis of -8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide:

Dissolve (3R, 4R)-4-(((4-((3-(3-(2-fluoroacrylamido)benzamido)benzyl)amino)-8-isopropylpyrazolo [1,5-a][1,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.043 mmol) in dichloromethane (1.2 mL) solution, 2,2,2-trifluoroacetic acid (0.4 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The mixed reaction was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain 3-(2-fluoroacrylamido)-N-(3-( ((2-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3 ,5]triazin-4-yl)amino)methyl)phenyl)benzamide (15mg, yield: 58.3%), LC-MS m/z: 602[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.18–8.17(m,1H),7.84–7.81(m,1H),7.77(s,1H),7.71–7.69(m,2H),7.61(d ,J＝7.6Hz,1H),7.49(t,J＝8.0Hz,1H),7.34(t,J＝8.0Hz,1H),7.20–7.18(m,1H),5.75(dd,J＝86.4, 3.2Hz,1H),5.33(dd,J＝15.2,3.6Hz,1H),4.76(s,2H),3.90–3.81(m,1H),3.35–3.41(m,2H),3.09–3.06(m ,1H),3.03–2.96(m,2H),2.55–2.47(m,1H),2.41–2.36(m,1H),1.70–1.67(m,1H),1.56–1.51(m,2H),1.28 –1.25(m,6H).

Example 25, 3-(2-fluoroacrylamido)-N-(3-(((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)methyl)amino Synthesis of )-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide (compound 25):

1), (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-(3-(2-fluoroacrylamido)benzoylamino)benzyl)amino)-3 Synthesis of -isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (3R, 4R)-4-((((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-5-yl)amino)methyl tert-butyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (90 mg, 0.14 mmol) in 3-(2-fluoroacrylamido)benzoic acid (37 mg, 0.17mmol) and N,N-dimethyl of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (78mg, 0.28mmol) and 1-methylimidazole (46mg, 0.56mmol) Formamide (2mL) solution was stirred at room temperature overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 4HCO 3 = 5-95% elution) (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-(3-(2-fluoroacrylamido)benzoylamino)benzyl)amino)-3-isopropylpyrazole And[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (45 mg, yield: 38.0%), LC-MS m/z: 801[M+H] ⁺ ;

2), 3-(2-fluoroacrylamido)-N-(3-(((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino) Synthesis of -3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide:

In solution, there is (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-(3-(2-fluoroacrylamido)benzoylamino)benzyl)amino)-3 -Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (45 mg, 0.06 mmol) in dichloromethane ( 0.9 mL) solution, 2,2,2-trifluoroacetic acid (0.3 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 0.5 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95% elution) to obtain 3-(2-fluoroacrylamido)-N-(3-(((5- (((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino) Methyl)phenyl)benzamide (26.5mg, yield: 78.7%), LC-MS m/z: 601[M+H] ⁺ ; ¹ H NMR (400MHz, MeOD-d4): δ8.19 ( s,1H),7.75(d,J＝8.0Hz,1H),7.69(s,1H),7.66(d,J＝8.0Hz,1H),7.64(s,1H),7.49(s,1H), 7.45(s,1H),7.36(s,1H),7.21(s,1H),5.73(d,J＝8.0Hz,1H),5.39(dd,J＝8.0,4.0Hz,1H),5.28(s ,1H),4.58(s,2H),4.28(s,1H),3.31(s,1H),3.18-2.96(m,3H),2.78-2.56(m,2H),2.60-2.39(m, 1H),1.78-1.66(m,1H),1.63-1.49(m,2H),1.38(s,3H),1.29(s,3H).

Example 26, 2-fluoro-N-(3-(((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropyl Synthesis of pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (compound 26):

1), (3R, 4R)-4-((((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Synthesis of pyrimidin-5-yl)amino)methyltert-butyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (3R, 4R)-4-((((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a ]pyrimidin-5-yl)amino)methyltert-butyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.47 mmol) and palladium on carbon (250 mg) in methanol (3 mL), hydrogen protection and stirred at room temperature for 1 hour. The resulting mixed reaction solution was filtered, and the filter cake was washed with methanol (3 × 10 mL). The collected filtrate was concentrated under reduced pressure to obtain a crude product, which could be used directly in the next step without further purification. LC-MS m /z：610[M+H] ⁺ ;

2), (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[ Synthesis of 1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (3R, 4R)-4-((((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-5-yl)amino)methyltert-butyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (230 mg, 0.38 mmol), 2-fluoroprop-2-enoic acid (51.3 mg, 0.57 mmol) ), 1-methyl-1H-imidazole (124.8mg, 1.52mmol) and N,N-di-tetramethylchloroformamidine hexafluorophosphate (213mg, 0.76mmol) The methylformamide (2.5 mL) solution was stirred at room temperature for 3 hours. The resulting mixed reaction solution was purified through a C18 column (acetonitrile: 0.1% NH ₃ ·H ₂ O in pure water = 5-95%) to obtain (3R, 4R)- 4-(((7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 -(yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (150 mg, yield: 58%), LC-MS m/z: 682 [M+H] ⁺ ;

3), 2-fluoro-N-(3-(((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyra Synthesis of azozo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide:

Dissolve (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[ 1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.22 mmol) in hydrochloric acid (1.5 mL, 4 M The 1,4-dioxane solution) solution) was stirred at room temperature for 1 hour. The resulting mixed reaction was concentrated under reduced pressure. The residue was purified through a C18 column (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95%) to obtain 2-fluoro-N-(3-(((5-(((((3R, 4R )-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide ( 50mg, yield: 47%), LC-MS m/z: 482[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.67(d,J＝8.0Hz,2H),7.59(d,J＝8.0Hz,1H),7.34(t,J＝7.6Hz,1H),7.21 (d,J＝7.6Hz,1H),5.69(dd,J＝46.4,3.2Hz,1H),5.28(dd,J＝15.2,3.2Hz,1H),5.17(s,1H),4.55(s, 2H),3.94(d,J＝13.6Hz,1H),3.28-3.22(m,1H),3.14–2.95(m,4H),2.62-2.52(m,1H),2.43(t,J＝11.2Hz ,1H),1.67(d,J＝10.4Hz,1H),1.52–1.39(m,2H),1.28(dd,J＝9.4,6.8Hz,6H).

Example 27, 4), (E)-4-(dimethylamino)-N-(3-((((((((3R,4R)-3-hydroxypiperidin-4-yl)methyl Synthesis of )amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)but-2-enamide (compound 27):

1), (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a Synthesis of ]pyrimidin-5-yl)amino)methyltert-butyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

Dissolve N-(5-chloro-3-(prop-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)-N-[(3-nitrophenyl)methyl] Tert-butyl carbamate (500mg, 1.12mmol), (3R, 4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (280mg, 1.23mmol), (SP-4 -1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene ] A solution of dichloro(2-methylpyridine)palladium (94 mg, 0.11 mmol) and cesium carbonate (1.09 g, 3.36 mmol) in 1,4 dioxane (6 mL), under argon protection, heated to 90°C and stirred 4 Hour. After cooling. The obtained mixed reaction liquid was collected under reduced pressure. The residue was purified using a C18 column (acetonitrile: pure water containing 0.1% NH ₃ .H ₂ O = 5-95%) to obtain (3R, 4R)-4-(((7-((tert-butoxycarbonyl)() 3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyltert-butyl)-3-hydroxypiperidine-1-carboxylic acid Tert-butyl ester (500mg, yield: 70%), LC-MS m/z: 640[M+H] ⁺ ;

2), (3R, 4R)-4-((((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Synthesis of pyrimidin-5-yl)amino)methyltert-butyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (3R, 4R)-4-((((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a ]pyrimidin-5-yl)amino)methyltert-butyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (500 mg, 0.78 mmol) and palladium on carbon (415 mg) in methanol (5 mL), protected by hydrogen , and stirred at room temperature for 2 hours. The resulting mixed reaction solution was filtered, and the filter cake was washed with methanol (3 × 10 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which could be used directly in the next step without further purification. LC-MS m /z:610[M+H] ⁺ ;

3), (3R, 4R)-4-(((7-((tert-butoxycarbonyl))(3-((E)-4-(dimethylamino)but-2-enamido)benzyl Synthesis of )amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (3R, 4R)-4-{[(7-{[(3-aminophenyl)methyl][(tert-butoxy)carbonyl]amino}-3-(prop-2-yl)pyridine Azolo[1,5-A]pyrimidin-5-yl)amino]methyl}-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (350 mg, 0.57 mmol), (2E)-4-(dimethyl A solution of amino)but-2-enoic acid (88.4 mg, 0.68 mmol), triethylamine (288.4 mg, 2.85 mmol) and _T3P (362.7 mg, 1.14 mmol) in acetonitrile (4 mL) was stirred at room temperature for 16 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified through a C18 column (acetonitrile: water containing 0.1% NH ₃ H ₂ O = 5-95%) to obtain (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3- ((E)-4-(dimethylamino)but-2-enamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino) Methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (200 mg, yield: 48%), LC-MS m/z: 721 [M+H] ⁺ ;

4), (E)-4-(dimethylamino)-N-(3-((((((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)- Synthesis of 3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)but-2-enamide:

There is (3R, 4R)-4-(((7-((tert-butoxycarbonyl))(3-((E)-4-(dimethylamino)but-2-enamido)benzyl) in solution) )amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.055mmol) To a solution of dichloromethane (1 mL), 2,2,2-trifluoroacetic acid (0.1 mL) was added dropwise. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified through a C18 column (acetonitrile: water containing 0.1% NH ₃ ·H ₂ O = 5-95%) to obtain (E)-4-(dimethylamino)-N-(3-((((((( (((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl) Phenyl)but-2-enamide (9 mg, yield: 31%), LC-MS m/z: 521 [M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d ₄ ): δ7.67 (d, J = 4.2 Hz, 2H), 7.54 (d, J = 8.3 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.16(d,J＝7.6Hz,1H),6.90–6.81(m,1H),6.35(d,J＝15.2Hz,1H),5.17(s,1H),3.96(d,J＝15.7Hz,1H ),3.49(d,J＝6.4Hz,3H),3.36(dd,J＝12.4,4.2Hz,2H),3.17(d,J＝13.7Hz,1H),3.00(ddd,J＝32.5,19.4, 9.7Hz,2H),2.78(t,J＝11.2Hz,1H),2.54(s,6H),1.94–1.86(m,2H),1.64(d,J＝20.5Hz,2H),1.28(t, J＝7.4Hz,7H).

Example 28, (S, E)-4-(dimethylamino)-N-(3-(5-(6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyra Synthesis of azozo[1,5-a]pyrimidin-7-yl)amino)phenyl)but-2-enamide (compound 28):

1) Synthesis of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamate:

At 0°C, 5-chloro-3-isopropyl-N-(3-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.4g, 1.21mmol ), a solution of triethylamine (0.37g, 3.63mmol) and 4-dimethylaminopyridine (0.03g, 0.24mmol) in tetrahydrofuran (4.0mL), batchwise Di-tert-butyl dicarbonate (0.32g, 1.45mmol) was added. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50%) to obtain (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) (3 -Nitrophenyl)carbamate tert-butyl ester (0.51g, yield: 97%), LC-MS m/z: 431[M+H] ⁺ ;

2), (S)-(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) Synthesis of (3-nitrophenyl)carbamic acid tert-butyl ester:

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamic acid tert-butyl ester (0.297g, 0.69mmol) and (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole- 2-ylidene]dichloro(2-methylpyridine)palladium (0.058g, 0.069mmol), cesium carbonate (0.67g, 2.07mmol) and (S)-6,6-dimethylpiperidin-3-amine (0.097g, 0.76mmol) in 1,4-dioxane (2.3mL), under nitrogen protection, heated to 100°C and stirred for 16 hours. The resulting mixed reaction liquid was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (pure water containing 0.1% formic acid: acetonitrile = 59:41) to obtain (S)-(5-((6,6-dimethylpiperidin-3-yl)amino)- 3-Isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamic acid tert-butyl ester (0.22g, yield: 61%), LC-MS m/ z: 524[M+H] ⁺ ;

3), (S)-5-((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Synthesis of tert-butyl (amino)-2,2-tert-butyldimethylpiperidine-1-carboxylate:

At 0°C, (S)-(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a] is dissolved in tert-butylpyrimidin-7-yl)(3-nitrophenyl)carbamate (0.256g, 0.49mmol), triethylamine (0.15g, 1.47mmol) and 4-dimethylaminopyridine (0.006g, 0.049 mmol) in tetrahydrofuran (2.5 mL), add di-tert-butyl dicarbonate (0.13 g, 0.59 mmol). The resulting mixed reaction liquid was stirred for 1 hour. The obtained mixed reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 to 10%) to obtain (S)-5-((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3 -Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-tert-butyldimethylpiperidine-1-carboxylic acid tert-butyl ester (0.066g, yield: 21%), LC-MS m/z: 624[M+H] ⁺ ;

4), (S)-5-((7-((3-Aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Synthesis of tert-butyl (amino)-2,2-dimethylpiperidine-1-carboxylate:

Dissolve (S)-5-((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Amino)-2,2-tert-butyldimethylpiperidine-1-carboxylic acid tert-butyl ester (0.066g, 0.11mmol) and iron (0.031g, 0.55mmol) in aqueous ammonium chloride solution (1.5mL) The solution was heated to 70°C and ethanol (6 mL) and stirred for 2 hours. After cooling, filter the reaction solution, collect the filtrate and concentrate the crude product under reduced pressure, which can be used directly in the next step without further purification. LC-MS m/z: 594[M+H] ⁺ ;

5), (S, E)-5-((7-((tert-butoxycarbonyl)(3-(4-(dimethylamino)but-2-enamido)phenyl)amino)-3- Isopropylpyrazole Synthesis of tert-butyl[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylate:

Dissolve (S)-5-((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- (E)Amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (0.05g, 0.084mmol), (E)-4-(dimethylamino)but-2-enoic acid (13mg, 0.10mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (0.047g, 0.17mmol) and NMI (0.028g, 0.34mmol) in acetonitrile (0.5mL) at room temperature Stir for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (methanol: dichloromethane=0~10%) to obtain (S, E)-5-((7-((tert-butoxycarbonyl)(3-(4-(di) Methylamino)but-2-enamido)phenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine -1-tert-butylcarboxylate (0.037g, yield: 62%), LC-MS m/z: 705[M+H] ⁺ ;

6), (S, E)-4-(dimethylamino)-N-(3-(5-(6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazole Synthesis of [1,5-a]pyrimidin-7-yl)amino)phenyl)but-2-enamide:

Dissolve (S,E)-5-((7-((tert-butoxycarbonyl)(3-(4-(dimethylamino)but-2-enamido)phenyl)amino)-3 -Isopropylpyrazolo[1,5-A]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (5 mg, 0.071 mmol) and 2,2 , a solution of 2-trifluoroacetic acid (0.2 mL) in dichloromethane (0.8 mL) was stirred at room temperature for 1 hour. The filtrate of the mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel preparative thin layer chromatography (methanol: dichloromethane=0-10%) to obtain (S, E)-4-(dimethylamino)-N-(3-(5-(6,6 -Dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)but-2-enamide (2 mg, collected Rate: 56%), LC-MS m/z: 505[M+H] ⁺ ;

¹ H NMR (400MHz, MeOH-d4): δ7.95 (s, 1H), 7.72 (s, 1H), 7.40 (t, J = 8.0Hz, 1H), 7.30 (d, J = 8.0Hz, 1H) ,7.14(d,J＝8.0Hz,1H),6.94–6.86(m,1H),6.43(d,J＝15.3Hz,1H),5.81(s,1H),4.26–4.17(m,1H), 3.65–3.56(m,3H),3.22–3.10(m,3H),2.63(s,6H),2.08–2.01(m,1H),1.95–1.89(m,1H),1.85–1.75(m,2H ), 1.42 (d, J = 4.0Hz, 6H), 1.33 (dd, J = 6.8, 2.4Hz, 6H).

Example 29, 3-acrylamido-N-(3-((5-((6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1, Synthesis of 5-a]pyrimidin-7-yl)amino)phenyl)benzamide enantiomers (compounds 29A and 29B):

3-Acrylamido-N-(3-((5-((6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a ]pyrimidin-7-yl)amino)phenyl)benzamide (100 mg, 0.18 mmol) (Example 21) by preparative supercritical fluid chromatography (system: Waters SFC 150; column: 250*25mm 10μm; mobile phase A: Supercritical CO ₂ ; mobile phase B: MeOH (+0.5% 7.0mol/LAmmonia in MEOH), A:B=70:30; detection wavelength: 214nm; flow rate: 100mL/min; column Temperature: room temperature; column pressure: 100 bar; injection volume: 2.0mL) was separated and purified to obtain 3-acrylamido-N-(3-((5-((6,6-dimethylpiperidin-3-yl)oxy)-3-iso Propylpyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)benzamide 2 enantiomers (31 mg, yield: 31.0%), LC-MS m/z: 568[ M+H] ⁺ ; 29A: ¹ H NMR (400MHz, MeOD-d ₄ ): δ8.30 (s, 1H), 8.02 (s, 1H), 7.86 (s, 1H), 7.74 (d, J = 8.4 Hz,1H),7.68(d,J＝7.6Hz,1H),7.53–7.43(m,3H),7.20(d,J＝6.8Hz,1H),6.54–6.34(m,2H),6.00(s ,1H),5.81(dd,J＝9.2,2.8Hz,1H),5.42(s,1H),3.50–3.48(m,1H),3.39–3.37(m,1H),3.13(d,J＝6.8 Hz,1H),2.07(s,2H),1.93(s,1H),1.64(d,J＝14.4Hz,1H),1.39–1.33(m,12H).29B: ¹ H NMR(400MHz,MeOD) δ8.31(s,1H),8.03(s,1H),7.86(s,1H),7.73(d,J＝7.2Hz,1H),7.68(d,J＝8.0Hz,1H),7.49(dd ,J＝16.0,7.2Hz,3H),7.20(s,1H),6.50–6.36(m,2H),6.00(s,1H),5.81(d,J＝9.2Hz,1H),5.43(s, 1H),3.49(s,1H),3.40–3.39(m,1H),3.13(s,1H),2.09(s,2H),1.92(s,1H),1.66(s,1H),1.39–1.33 (m,12H).

Example 30, N-(3-(((5-((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino)-3-isopropyl Synthesis of pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (compound 30):

1) Synthesis of (3R, 4R)-4-((dibenzylamino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.25g, 1.08mmol) in N,N-dimethylformamide (3mL) solution, (bromomethyl)benzene (0.55g, 3.24mmol) and potassium carbonate (0.77g, 5.40mmol) were added. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The residue was purified by C18 column chromatography (acetonitrile and water = 0-60%) to obtain (3R, 4R)-4-((dibenzylamino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl Ester (0.25g, yield: 56%), LC-MS m/z: 411[M+H] ⁺ , LC-MS m/z: 411[M+H] ⁺ ;

2) Synthesis of (3R, 4R)-4-((dibenzylamino)methyl)piperidin-3-ol:

A solution of (3R, 4R)-4-((dibenzylamino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.25g, 0.61mmol) and dichloromethane (3mL) was dissolved 2,2,2-Trifluoroacetic acid (1 mL) was added. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which could be directly used in the next step without further purification. LC-MS m/z: 311[M+H] ⁺ ;

3) Synthesis of (3R, 4R)-4-((dibenzylamino)methyl)-1-methylpiperidin-3-ol:

Dissolve (3R, 4R)-4-((dibenzylamino)methyl)piperidin-3-ol (0.2g, 0.64mmol), sodium triacetoxyborohydride (0.40g, 1.92mmol) and A solution of formaldehyde (0.02 g, 0.67 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 1 hour. The residue was purified by C18 column chromatography (acetonitrile: water = 0-60%) to obtain (3R, 4R)-4-((dibenzylamino)methyl)-1-methylpiperidin-3-ol (0.15 g, yield: 72%), LC-MS m/z: 325[M+H] ⁺ ;

4), Synthesis of (3R, 4R)-4-(aminomethyl)-1-methylpiperidin-3-ol:

Dissolve (3R, 4R)-4-((dibenzylamino)methyl)-1-methylpiperidin-3-ol (0.15g, 0.46mmol) and palladium on carbon (0.05g) in methanol (3mL ) solution, stir for 1 hour under a hydrogen atmosphere. The resulting mixed reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure to obtain a crude product, which could be directly used in the next step without further purification. LC-MS m/z: 145[M+H] ⁺ ;

Dissolve 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (0.15g, 0.65mmol) and (3-nitrophenyl)methylamine (0.099g, 0.65mmol) ) and a solution of N,N-diisopropylethylamine (0.21g, 1.63mmol) in isopropyl alcohol (2mL), heated to 80°C and stirred for 2 hours. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50%) to obtain 5-chloro-3-isopropyl-N-(3-nitrobenzyl)pyrazolo[1,5-a ] Pyrimidine-7-amine (0.2g, yield: 90%), LC-MS: m/z: 346[M+H] ⁺ ;

5-Chloro-3-isopropyl-N-(3-nitrobenzyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.2g, 0.59mmol), di-tert-butyl dicarbonate (0.19g, 0.87mmol), 4-dimethylaminopyridine (0.01g, 0.06mmol) and triethylamine (0.178g, 1.77mmol) in dichloromethane (3mL) were stirred at room temperature for 1 hour. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-20%) to obtain (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) (3 -Nitrobenzyl)carbamic acid tert-butyl ester (0.2g, yield: 76%), LC-MS m/z: 446[M+H] ⁺ ;

7), (5-(((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5 Synthesis of -a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester:

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (50mg, 0.11mmol), ( 3R, 4R)-4-(aminomethyl)-1-methylpiperidin-3-ol (48 mg, 0.33 mmol), (1,3-bis(2,6-diisopropylphenyl)imidazole A solution of (3-chloropyridyl)palladium(II) dichloride (15 mg, 0.022 mmol) and cesium carbonate (110 mg, 0.33 mmol) in 1,4-dioxane (3 mL), Under nitrogen protection, heat to 100°C and stir for 2 hours. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50%)) to obtain (5-((((((3R, 4R)-3-hydroxy-1-methylpiperidine-4- methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (40 mg, yield: 65% ), LC-MS m/z:554[M+H] ⁺ ;

8), (3-aminobenzyl)(5-((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino)-3-isopropylpyra Synthesis of tert-butyl azolo[1,5-a]pyrimidin-7-yl)carbamate:

The dissolved 5-(((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5- a] A solution of tert-butylpyrimidin-7-yl)(3-nitrobenzyl)carbamate (40 mg, 0.072 mmol) and iron (20 mg, 0.36 mmol) in ethanol (0.8 mL) and aqueous ammonium chloride (0.2 mL) The solution was heated to 80°C and stirred for 2 hours. After cooling, the resulting mixed reaction solution was concentrated under reduced pressure. The residue was filtered, and the filter cake was washed with methanol. The collected filtrate was concentrated under reduced pressure to obtain (3-aminobenzyl)(5-((( ((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino Tert-butyl formate (37 mg, yield: 98%), LC-MS m/z: 524[M+H] ⁺ ;

9), (3-acrylamidobenzyl)(5-(((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino)-3-iso Synthesis of propylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester:

At 0°C, dissolve (3-aminobenzyl)(5-((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino)- 3-Isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (20 mg, 0.038 mmol) and triethylamine (12 mg, 0.11 mmol) in dichloromethane (1 mL), Propan-2-enoyl chloride (3.4 mg, 0.038 mmol) was added. The resulting mixed reaction liquid was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was passed through silica gel column chromatography (ethyl acetate:petroleum ether=0- 50%) was purified to obtain (3-acrylamidobenzyl)(5-(((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino)-3 -Isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate tert-butyl ester (12 mg, yield: 54%), LC-MS m/z: 578[M+H] ⁺ ;

10), N-(3-(((5-((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino)-3-isopropylpyra Synthesis of azozo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide:

(3-Acrylamidobenzyl)(5-(((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino)-3-iso To a solution of propylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (12 mg, 0.02 mmol) in dichloromethane (0.6 mL), add 2,2,2-Trifluoroacetic acid (0.2 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water=0-95%) to obtain N-(3-(((5-(((((3R,4R))-3-hydroxy-1-methylpiperidine-4 -yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (1 mg, yield: 10%), LC-MS:m/z:478[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.64 (s, 1H), 7.63–7.54 (m, 2H), 7.32 (t, J = 7.8Hz, 1H), 7.16 (d, J = 7.9Hz, 1H),6.48–6.28(m,2H),5.74(dd,J＝9.4,2.5Hz,1H),5.16(s,1H),4.56(d,J＝11.0Hz,4H),3.90(s,1H ),3.02(ddd,J＝28.5,21.8,10.8Hz,3H),2.80(d,J＝10.0Hz,1H),2.24(s,3H),1.96(d,J＝9.7Hz,1H),1.88 (t,J＝10.6Hz,1H),1.64(d,J＝12.5Hz,1H),1.50(d,J＝12.5Hz,1H),1.30–1.24(m,5H).

Example 31, (R)-N-(4-chloro-3-((((2-((6,6-dimethylpiperidin-3-yl)oxy))-8-isopropylpyrazole Synthesis of [1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-2-fluoroacrylamide (compound 31):

1), N-(2-chloro-5-nitrobenzyl)-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine -Synthesis of 4-amine:

4-Chloro-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1g, 4.13mmol), (2-chloro A solution of -5-nitrophenyl)methanamine (0.92g, 4.95mmol) and N,N-diisopropylethylamine (1.59g, 12.39mmol) in isopropyl alcohol (20mL) was heated at 70°C and stirred for 8 hours. After cooling, the obtained mixed reaction solution was diluted with water (40 mL), and extracted with ethyl acetate (3×200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%-100%) to obtain N-(2-chloro-5-nitrobenzyl)-8-isopropyl-2-(methylthio) Pyrazolo[1,5-a][1,3,5]triazin-4-amine (0.85g, yield: 52.5%), LC-MS m/z: 393[M+H] ⁺ ;

2), N-(2-chloro-5-nitrobenzyl)-8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]tri Synthesis of oxazin-4-amine:

Dissolve N-(2-chloro-5-nitrobenzyl)-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine -A solution of 4-amine (0.8g, 2.04mmol) and m-chloroperoxybenzoic acid (1.40g, 8.16mmol) in isopropanol (10mL) was heated at 70°C and stirred for 8 hours. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%-100% elution) to obtain N-(2-chloro-5-nitrobenzyl)-8-isopropyl-2-(methyl) Sulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (0.4g, yield: 46.2%), LC-MS m/z: 425[M+H] ⁺ ;

3), N-(5-amino-2-chlorobenzyl)-8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine -Synthesis of 4-amine:

Dissolve N-(2-chloro-5-nitrobenzyl)-8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]tri A solution of oxazin-4-amine (0.4g, 0.94mmol) and iron (0.26g, 4.71mmol) in ethanol (4mL) and ammonium chloride aqueous solution (1mL) was heated at 70°C and stirred for 4 hours. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%-100% elution) to obtain N-(5-amino-2-chlorobenzyl)-8-isopropyl-2-(methylsulfonate) Acyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (0.2g, yield: 53.8%), LC-MS m/z: 395[M+H] ⁺ ;

4), (R)-5-((4-((5-amino-2-chlorobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5] Synthesis of triazin-2-yl)oxytert-butyl)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (R)-5-hydroxy-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.61 mmol) into N, N-dimethylformamide at 0°C. (3 mL) solution was added in portions with sodium hydride (60 mg, 1.52 mmol, content: 60%). The resulting mixed reaction solution was stirred at 0°C for 30 minutes. N-(5-amino-2-chlorobenzyl)-8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine-4 -Amine (200 mg, 0.51 mmol) was added to the above reaction solution. The resulting mixed reaction solution was stirred at room temperature for 8 hours. The obtained mixed reaction solution was diluted with water (40 mL), and extracted with ethyl acetate (3×200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0%-100% elution) to obtain (R)-5-((4-((5-amino-2-chlorobenzyl)amino)- 8-isopropylpyrazolo[1,5-a][1,3,5triazin-2-yl)oxytert-butyl)-2,2-dimethylpiperidine-1-carboxylic acid Tert-butyl ester (100 mg, yield: 36.2%), LC-MS m/z: 544[M+H] ⁺

5), (R)-N-(4-chloro-3-((((2-((6,6-dimethylpiperidin-3-yl)oxy))-8-isopropylpyrazolo Synthesis of [1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-2-fluoroacrylamide:

Dissolve (R)-5-((4-((5-amino-2-chlorobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5] Mixture of triazin-2-yl)oxy)-2,2-dimethylpiperidine-1-carboxylate (0.10g, 0.18mmol), N,N-diisopropylethylamine (87mg, 0.67 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (0.17g, 0.45mmol) and 2-fluoroacrylic acid (24mg, 0.27 mmol) in dichloromethane (2 mL) and stirred at room temperature for 8 hours. The obtained mixed reaction solution was diluted with water (5 mL), and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in dichloromethane (1.5 mL) solution, and 2,2,2-trifluoroacetic acid (0.5 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (R)-N-(4-chloro-3-((((2- ((6,6-dimethylpiperidin-3-yl)oxy)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino )Methyl)phenyl)-2-fluoroacrylamide (50mg, yield: 53%), LC-MS m/z: 516[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d ₄ ): δ8.53 (s, 1H), 7.88 (s, 1H), 7.73 (s, 1H), 7.68 (d, J = 8.0Hz, 1H), 7.41 (d ,J＝8.0Hz,1H),5.66(d,J＝48.0Hz,1H),5.27(d,J＝16.0Hz,1H),5.13(s,2H),3.31(s,1H),3.30(s ,1H),3.13-3.07(m,1H),1.97(s,2H),1.81(s,1H),1.53(s,1H),1.31(d,J＝8.0Hz,6H),1.27(d, J＝4.0Hz,6H).

Example 32, 2-fluoro-N-(3-(((5-(((((3R,4R)-3-fluoropiperidin-4-yl)methyl)methyl)amino)-3-isopropyl Synthesis of pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (compound 32):

1), (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a ]pyrimidin-5-yl)amino) Synthesis of methyl tert-butyl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (225mg, 0.50mmol), ( 3R, 4R)-3-fluoro-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.60 mmol), cesium carbonate (0.49 g, 1.5 mmol) and (SP-4-1) -[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro (2-methylpyridine)palladium (42 mg, 0.050 mmol) in 1,4-dioxane (1 mL) was heated to 100°C and stirred for 16 hours under argon protection. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 15-30%) to obtain (3R, 4R)-4-((((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)) -3-Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl tert-butyl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (190 mg, yield: 58.7%), LC-MS m/z: 642[M+H] ⁺ ;

2), (3R, 4R)-4-(((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine Synthesis of -5-yl)amino)methyltert-butyl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (3R, 4R)-4-((((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a ]pyrimidin-5-yl)amino)methyl tert-butyl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (180 mg, 0.28 mmol) and iron (78 mg, 1.4 mmol) in ethanol (0.8 mL) and Ammonium chloride aqueous solution (0.2 mL) was heated to 70°C and stirred for 2 hours. The mixed reaction solution was filtered, the filter cake was washed with methanol (10 mL), the filtrate was collected and concentrated under reduced pressure to obtain (3R, 4R)-4-(((7-( (3-Aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyltert-butyl)-3-fluoro Piperidine-1-carboxylic acid tert-butyl ester (163 mg, yield: 94.9%), LC-MS m/z: 612 [M+H] ⁺ ;

3), (3R, 4R)-4-((((7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo Synthesis of [1,5-a]pyrimidin-5-yl)amino)methyl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (3R, 4R)-4-(((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine -5-yl)amino)methyltert-butyl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.049mmol) and 2-fluoroprop-2-enamide (5.2 mg, 0.059mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (11.27 mg, 0.059mmol) and 4-dimethylaminopyridine (1.20 mg, 0.0098mmol). A solution of methyl chloride (1 mL) was stirred at 25°C for 16 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 60-80% elution) to obtain (3R, 4R)-4-((((7-((tert-butoxycarbonyl))(3-(2-fluoropropene) Amino)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester ( 17mg, yield: 50.7%), LC-MS m/z:684[M+H] ⁺ ;

4), 2-fluoro-N-(3-(((5-(((((3R,4R)-3-fluoropiperidin-4-yl)methyl)methyl)amino)-3-isopropylpyra Synthesis of azozo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide:

Dissolve (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo A solution of [1,5-a]pyrimidin-5-yl)amino)methyl)-3-fluoropiperidine-1-carboxylic acid tert-butyl ester (17 mg, 0.025 mmol) in dichloromethane (0.9 mL) and 2, 2,2-Trifluoroacetic acid (0.3 mL) solution was stirred at 25°C for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 15-30% elution) to obtain 2 -Fluoro-N-(3-(((5-(((((3R,4R)-3-fluoropiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1 ,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (8 mg, yield: 66.7%), LC-MS m/z: 484[M+H] ⁺ ;

1H NMR (400MHz, MeOD-d ₄ ): δ7.68 (s, 1H), 7.63 (s, 1H), 7.59 (d, J = 8.4Hz, 1H), 7.34 (t, J = 8.0Hz, 1H) ,7.21(d,J＝8.0Hz,1H),5.69(dd,J＝46.4,3.4Hz,1H),5.28(dd,J＝15.2,3.4Hz,1H),5.19(s,1H),4.56( s,2H),4.29(dtd,J＝48.8,9.0,4.5Hz,1H),3.65(dd,J＝14.0,4.4Hz,1H),3.27(s,2H),3.20(ddd,J＝12.4, 7.9,4.4Hz,1H),3.07(dt,J＝14.0,6.9Hz,1H),2.89(dd,J＝12.8,3.5Hz,1H),2.58–2.42(m,2H),1.94–1.81(m ,2H),1.29(d,J＝6.8Hz,6H).

Example 33, (R)-3-acrylamido-N-(3-(((5-((1-(2-hydroxyethyl)piperidin-3-yl)oxy))-3-isopropyl Synthesis of pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide (compound 33):

At 0°C, add (R)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (452 mg, 2.24 mmol) in 1,6-dioxane (10 mL) in batches. Sodium hydride (180 mg, 4.5 mmol, mass dispersion: 60%). The resulting mixed reaction liquid was stirred for 0.5 hours. Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (200 mg, 0.44 mmol) at room temperature. Add batches into the above reaction solution. The resulting mixed reaction solution was stirred at room temperature for 2 hours. At 0°C, the mixed reaction solution was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-80% elution) to obtain (R)-3-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)) Amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (109 mg, yield: 39.7%), LC-MS m/z: 611[M+H] ⁺ ;

2), (R)-3-isopropyl-N-(3-nitrobenzyl)-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidine-7- Synthesis of amines:

At room temperature, (R)-3-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a ]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol) in dichloromethane (1.5 mL), 2,2,2-trifluoroacetic acid (0.5 mL), and the resulting mixed reaction solution was stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step without further purification. LC-MS m/z: 411[M+H] ⁺ ;

3), (R)-2-(3-((3-isopropyl-7-((3-nitrobenzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)oxy Synthesis of piperidin-1-yl)ethane-1-ol:

At room temperature, (R)-3-isopropyl-N-(3-nitrobenzyl)-5-(piperidin-3-yloxy)pyrazolo[1,5-a] was dissolved in To a solution of pyrimidin-7-amine (100 mg, 0.24 mmol) in acetonitrile (2 mL), potassium carbonate (168 mg, 1.21 mmol) was added in portions. The resulting mixed reaction liquid was stirred for 0.5 hours. Then 2-bromoethyl-1-ol (50 mg, 0.40 mmol) was added to the above reaction solution. The resulting mixed reaction solution was heated to 50°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95% elution) to obtain (R)-2-(3-((3-isopropyl-7-(( 3-nitrobenzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidin-1-yl)ethan-1-ol (68 mg, yield: 61.4%) , LC-MS m/z: 455[M+H] ⁺ ;

4), (R)-2-(3-((7-((3-aminobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy )Synthesis of piperidin-1-yl)ethane-1-ol:

Dissolve (R)-2-(3-((3-isopropyl-7-((3-nitrobenzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)oxygen A solution of piperidin-1-yl)ethane-1-ol (30 mg, 0.034 mmol), iron (19 mg, 0.33 mmol) in ethanol (0.8 mL) and ammonium chloride aqueous solution (0.2 mL) was heated to 70°C and stirred for 1 Hour. The mixed reaction solution was filtered, and the filter cake was washed with methanol (3×10 mL). The filtrate was collected and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95% elution) to obtain (R)-2-(3-((7-((3-aminobenzyl)) Amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidin-1-yl)ethane-1-ol (20 mg, yield: 71.4%), LC-MS m/z: 425[M+H] ⁺ ;

5), (R)-3-acrylamido-N-(3-(((5-((1-(2-hydroxyethyl)piperidin-3-yl)oxy))-3-isopropyl Synthesis of pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide:

The dissolved (R)-2-(3-((7-((3-aminobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy group )piperidin-1-yl)ethane-1-ol (20 mg, 0.04mmol), 3-acrylamidobenzoic acid (12mg, 0.06mmol), 2-(7-azobenzotriazole)-N , N,N-dimethylformamide of N,N',N'-tetramethylurea hexafluorophosphate (27mg, 0.07mmol) and N,N-diisopropylethylamine (18mg, 0.13mmol) (1.5 mL) solution and stirred at room temperature overnight. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-60% elution) to obtain (R)-3-acrylamido-N-(3-(((5-( (1-(2-hydroxyethyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl) Benzamide (2.14mg, yield: 7.6%), LC-MS m/z: 598[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d ₄ ): δ8.14 (s, 1H), 7.80 (d, J = 7.6Hz, 1H), 7.75 (s, 1H), 7.72-7.66 (m, 2H), 7.66 -7.61(m,1H),7.45(t,J＝8.0Hz,1H),7.36(t,J＝8.0Hz,1H),7.19(d,J＝7.2Hz,1H),6.48-6.36(m, 2H),5.79((dd,J＝8.8Hz,2.4Hz,1H),5.35(s,1H),5.23–5.15(m,1H),4.60(s,2H),3.65(t,J＝6.4Hz ,2H),3.13–3.03(m,2H),2.75–2.65(m,1H),2.56(s,2H),2.47–2.26(m,2H),2.06–1.95(m,1H),1.89–1.78 (m,1H),1.72–1.61(m,1H),1.61–1.50(m,1H),1.33(s,3H),1.31(s,3H).

Example 34, (R)-N-(3-(((5-((1-(2-hydroxyethyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1 Synthesis of ,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (compound 34):

The dissolved (R)-2-(3-((7-((3-aminobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy group )piperidin-1-yl)ethane-1-ol (50 mg, 0.12 mmol), acrylic acid (10 mg, 0.13 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt A solution of the acid salt (27 mg, 0.14 mmol) and 4-dimethylaminopyridine (3 mg, 0.024 mmol) in dichloromethane (2 mL) was stirred at room temperature overnight. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 4HCO 3 = 5-60% elution) to obtain (R)-N-(3-(((5-((1-(2-hydroxy Ethyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (2.2 mg, Yield: 4.0%), LC-MS m/z: 479[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.76 (s, 1H), 7.60 (d, J = 11.2Hz, 2H), 7.32 (t, J = 7.6Hz, 1H), 7.14 (d, J = 7.6Hz,1H),6.44-6.29(m,2H),5.73(dd,J＝2.4Hz,9.6Hz,1H),5.34(s,1H),5.26(s,1H),4.58(d,J＝ 8.8Hz,2H),3.69((t,J＝6.0Hz,2H),3.19-3.04(m,2H),2.79(s,1H),2.69(s,2H),2.45(s,2H),2.04 –1.95(m,1H),1.92–1.83(m,1H),1.75-1.61(m,2H),1.33(s,3H),1.32(s,3H).

Example 35, (R)-3-(2-fluoroacrylamido)-N-(3-(((5-((1-(2-hydroxyethyl)piperidin-3-yl)oxy)) Synthesis of -3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)benzamide (compound 35):

The dissolved (R)-2-(3-((7-((3-aminobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy group )piperidin-1-yl)ethan-1-ol (50 mg, 0.12 mmol), 3-(2-fluoroacrylamido)benzoic acid (32 mg, 0.15 mmol), 2-(7-azobenzotris) N,N-tetramethylurea hexafluorophosphate (68 mg, 0.18 mmol) and N,N-diisopropylethylamine (46 mg, 0.36 mmol) A solution of dimethylformamide (1.5 mL) was stirred at room temperature overnight. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (R)-3-(2-fluoroacrylamido)-N-(3 -(((5-((1-(2-hydroxyethyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino )Methyl)phenyl)benzamide (20mg, yield: 27.8%), LC-MS m/z: 616[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.15 (s, 1H), 7.84 (d, J = 8.0Hz, 1H), 7.76 (s, 1H), 7.70–7.67 (m, 3H), 7.49 ( t,J＝8.0Hz,1H),7.37(t,J＝8.0Hz,1H),7.20(d,J＝8.0Hz,1H),5.75(dd,J＝48.0,4.0Hz,1H),5.35– 5.30(m,2H),5.21(s,1H),4.61(s,2H),3.66(t,J＝4.0Hz,2H),3.12–3.07(m,2H),2.68(s,1H),2.57 (s,2H),2.36(s,2H),2.00(s,1H),1.82(s,1H),1.68-1.50(m,2H),1.33(s,3H),1.31(s,3H).

Example 36, (R)-2-fluoro-N-(3-(((5-((1-(2-hydroxyethyl)piperidin-3-yl)oxy))-3-isopropylpyra Synthesis of azozo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (compound 36):

The dissolved (R)-2-(3-((7-((3-aminobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy group )piperidin-1-yl)ethane-1-ol (20 mg, 0.047mmol), 2-fluoroacrylic acid (4.2 mg, 0.047mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbon A solution of diimine hydrochloride (9.0 mg, 0.047 mmol) and 4-dimethylaminopyridine (0.48 mg, 0.004 mmol) in dichloromethane (1.0 mL) was stirred at room temperature overnight. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH3.H2O = 5-95% elution) to obtain (R)-2-fluoro-N-(3-(((5-((1- (2-Hydroxyethyl)piperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide ( 5mg, yield: 21.4%), LC-MS m/z: 497[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.75 (s, 1H), 7.65 (s, 1H), 7.62 (d, J = 8.0Hz, 1H), 7.35 (t, J = 8.0Hz, 1H) ,7.20(d,J＝8.0Hz,1H),5.69(dd,J＝48.0,4.0Hz,1H),5.33(s,1H),5.30(dd,J＝16.0,12.0Hz,1H),5.25- 5.20(m,1H),4.59(s,2H),3.25-3.06(m,2H),3.66(d,J＝4.0Hz,2H),2.68(s,1H),2.57(s,2H),2.50 -2.30(m,2H),2.00(s,1H),1.67(s,1H),1.65-1.50(m,2H),1.33(s,3H),1.31(s,3H).

Example 37, N-(3-(((2-(4-aminopiperidin-1-yl))-8-isopropylpyrazolo[1,5-a][1,3,5]triazine Synthesis of -4-yl)amino)methyl)phenyl)-2-fluoroacrylamide (compound 37):

Dissolve 4-chloro-8-isopropyl-2-(methylthio)pyrazolo[1,5-A][1,3,5]triazine (500.0mg, 2.07mmol), (3- A solution of nitrophenyl)methylamine (471 mg, 3.10 mmol) and N,N-diisopropylethylamine (800 mg, 6.20 mmol) in isopropyl alcohol (10.0 mL) was heated to 70°C and stirred for 2 hours. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified through a C18 column (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95%) to obtain 8-isopropyl-2-(methylthio)-N-(3-nitrobenzyl) Pyrazolo[1,5-a][1,3,5]triazin-4-amine (262 mg, yield: 35.4%), LC-MS m/z: 359[M+H] ⁺ ;

2), 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazine-4- Synthesis of amines

Dissolve 8-isopropyl-2-(methylthio)-N-(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (164 mg, 0.46 mmol) and m-chloroperoxybenzoic acid (237 mg, 1.37 mmol) in dichloromethane (10 mL) was stirred at room temperature for 0.5 h. The obtained mixed reaction liquid was concentrated under reduced pressure to obtain crude product. The crude product was used directly in the next step without further purification. LC-MS m/z:391[M+H] ⁺ ;

3), (1-(8-isopropyl-4-((3-nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5]triazin-2-yl) Synthesis of piperidin-4-yl)carbamic acid tert-butyl ester:

Dissolve 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazine-4- A solution of amine (178 mg, 0.46 mmol), piperidin-4-ylcarbamate tert-butyl ester (137 mg, 0.68 mmol) and triethylamine (138 mg, 1.37 mmol) in isopropyl alcohol (10.0 mL) was heated to 90°C and stirred for 2 hours. . After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column (acetonitrile: water = 5-95%) to obtain (1-(8-isopropyl-4-((3-nitrobenzyl)amino)pyrazolo[1,5-a ][1,3,5]triazin-2-yl)piperidin-4-yl)carbamic acid tert-butyl ester (120 mg, yield: 51.5%), LC-MS m/z: 511[M+H] ⁺ ;

4), (1-(4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)piper Synthesis of tert-butyl carbamate:

Dissolved (1-(8-isopropyl-4-((3-nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5]triazin-2-yl) A solution of piperidin-4-yl)carbamic acid tert-butyl ester (120 mg, 0.23 mmol) and palladium on carbon (24 mg) in methanol (5 mL) was stirred at room temperature for 2 hours under hydrogen. After cooling, the mixed reaction solution was filtered, and the filter cake was washed with methanol (3×10 mL). The filtrate was collected and concentrated under reduced pressure to obtain (1-(4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2- (yl)piperidin-4-yl)carbamic acid tert-butyl ester (95 mg, yield: 84%), LC-MS m/z: 481 [M+H] ⁺ ;

5), (1-(4-((3-(2-fluoroacrylamido)benzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]tri Synthesis of tert-butyl azine-2-yl)piperidin-4-yl)carbamate:

Dissolve (1-(4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)piper tert-butyl(din-4-yl)carbamate (90mg, 0.19mmol), 2-fluoroacrylic acid (25mg, 0.28mmol), 2-(7-azobenzotriazole)-N,N,N', A solution of N'-tetramethylurea hexafluorophosphate (107 mg, 0.28 mmol) and N,N-diisopropylethylamine (72 mg, 0.56 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature. 4 hours. The residue was purified through a C18 column (acetonitrile: water = 5-95% elution) to obtain (1-(4-((3-(2-fluoroacrylamido)benzyl)amino)-8-isopropylpyrazole) And[1,5-a][1,3,5]triazin-2-yl)piperidin-4-yl)carbamic acid tert-butyl ester (60 mg, yield: 58%), LC-MS m/z :553[M+H] ⁺ ;

6), N-(3-(((2-(4-aminopiperidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine- Synthesis of 4-yl)amino)methyl)phenyl)-2-fluoroacrylamide:

In solution, there is ((1-(4-((3-(2-fluoroacrylamido)benzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5] To a solution of triazin-2-yl)piperidin-4-yl)carbamic acid tert-butyl ester (60 mg, 0.11 mmol) in dichloromethane (3 mL), 2,2,2-trifluoroacetic acid (1 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The residue was purified through a C18 column (acetonitrile: pure water containing 0.05% NH ₃ ·H ₂ O = 5-95%) to obtain N-(3-( ((2-(4-Aminopiperidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl) Phenyl)-2-fluoroacrylamide (41.4 mg, yield: 84%), LC-MS m/z: 453 [M+H] ⁺ ;

¹ H NMR (400MHz, MeOD) δ7.71 (s, 1H), 7.66 (s, 1H), 7.55 (d, J = 7.0Hz, 1H), 7.31 (t, J = 7.8Hz, 1H), 7.22 ( d,J＝7.2Hz,1H),5.69(dd,J＝46.6,3.4Hz,1H),5.28(dd,J＝15.2,3.6Hz,1H),4.71(s,2H),3.39(s,1H ),3.04–2.97(m,1H),2.90(t,J＝11.6Hz,3H),1.84(d,J＝10.8Hz,2H),1.29(s,2H),1.27(d,J＝6.8Hz ,6H).

Example 38, (S)-7-(dimethylphosphoryl)-3-(5-(dimethylphosphoryl)-2-((6,6-dimethylpiperidin-3-yl)amino Synthesis of )pyrimidin-4-yl)-1H-indole-6-nitrile (compound 38):

1), Synthesis of 7-bromo-3-(5-bromo-2-chloropyrimidin-4-yl)-1H-indole-6-nitrile:

Dissolve 5-bromo-2,4-dichloropyrimidine (1g, 4.39mmol), 7-bromo-1H-indole-6-nitrile (1.07g, 4.83mmol), trifluoromethanesulfonic acid (0.66g, 4.39 mmol) of 1,1,1,3,3,3-hexafluoro-2-propanol (15 mL) was heated at 60°C and stirred for 24 hours. The obtained mixed reaction liquid was filtered, the filter cake was washed with 1,1,1,3,3,3-hexafluoro-2-propanol (3×10 mL), and the solid was collected to obtain 7-bromo-3-(5-bromo- 2-Chloropyrimidin-4-yl)-1H-indole-6-carbonitrile (500mg, crude product), used directly in the next step without further purification, LC-MS m/z: 409[M+H] ^- ;

2), (S)-7-bromo-3-(5-bromo-2-((6,6-dimethylpiperidin-3-yl)amino)pyrimidin-4-yl)-1H-indole- Synthesis of 6-nitrile:

Dissolve 7-bromo-3-(5-bromo-2-chloropyrimidin-4-yl)-1H-indole-6-nitrile (183 mg, 0.488 mmol), (S)-6,6-dimethyl A solution of piperidin-3-amine (15 6 mg, 1.22 mmol) and potassium fluoride (85 mg, 1.46 mmol) in dimethyl sulfoxide (2.5 mL) was heated to 100°C and stirred for 16 hours. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% FA = 5-95% elution) to obtain (S)-7-bromo-3-(5-bromo-2-((6,6-di Methylpiperidin-3-yl)amino)pyrimidin-4-yl)-1H-indole-6-nitrile (180 mg, yield: 73.5%), LC-MS m/z: 503 [M+H] ⁺ ;

3), (S)-7-(dimethylphosphoryl)-3-(5-(dimethylphosphoryl)-2-((6,6-dimethylpiperidin-3-yl)amino) Synthesis of pyrimidin-4-yl)-1H-indole-6-nitrile:

Dissolve (S)-7-bromo-3-(5-bromo-2-((6,6-dimethylpiperidin-3-yl)amino)pyrimidin-4-yl)-1H-indole- 6-nitrile (100 mg, 0.199 mmol), dimethylphosphine oxide (38 mg, 0.487 mmol), Pd(OAc) ₂ (3 mg, 0.01 mmol), Xantphos (12 mg, 0.02 mmol) and potassium phosphate (46 mg, 0.219 mmol) A solution of N,N-dimethylformamide (3 mL) was heated in the microwave at 150°C under nitrogen protection and stirred for 1 hour. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% FA = 5-95% elution) to obtain (S)-7-(dimethylphosphoryl)-3-(5-(dimethylphosphoryl) Acyl)-2-((6,6-dimethylpiperidin-3-yl)amino)pyrimidin-4-yl)-1H-indole-6-nitrile (75 mg, yield: 75.8%), LC- MS m/z:499[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d ₄ ): δ8.78 (d, J = 28.8Hz, 1H), 8.55 (d, J = 52.8Hz, 2H), 7.65 (s, 1H), 4.08-4.01 (m ,1H),3.11(s,1H),2.84(t,J＝8.4Hz,1H),2.13(d,J＝13.6Hz,6H),1.97(s,1H),1.79(s,1H),1.64 (dd,J＝13.2,4.8Hz,7H),1.53(d,J＝13.2Hz,1H),1.20(d,J＝12.4Hz,6H).

Example 39, (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5- Synthesis of a]pyrimidin-7-yl)amino)methyl)phenyl)butan-2-amide (compound 39):

1), (S)-5-((7-((3-(but-2-ynylamido)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1, Synthesis of 5-a]pyrimidin-5-yl)tert-butylamino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (S)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- (170mg, 0.280mmol) and 2-(7-azobenzotriazole)-N,N, N',N'-tetramethylurea hexafluorophosphate (160mg, 0.420mmol) and N,N-diisopropylethylamine (109mg, 0.840mmol) and butan-2-ynoic acid (31mg, 0.364mmol) A solution of N,N-dimethylformamide (2.5 mL) was stirred at room temperature for 16 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step without further purification. LC-MS m/z: 674[M+H] ⁺ ;

2), (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a Synthesis of ]pyrimidin-7-yl)amino)methyl)phenyl)butan-2-amide:

The dissolved (S)-5-((7-((3-(but-2-ynynylamido)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1, 5-a]pyrimidin-5-yl)tert-butylamino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.045 mmol) and 2,2,2-trifluoroacetic acid ( 1 mL) in dichloromethane (4 mL) and stirred at room temperature for 3 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with acetonitrile and water) to give (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino))-3 -Isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)butan-2-amide (7 mg, yield: 33.1%), LC-MS m/z: 474[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.66 (s, 1H), 7.62 (s, 1H), 7.42 (d, J = 12.0Hz, 1H), 7.30 (t, J = 12.0Hz, 1H) ,7.13(d,J＝8.0Hz,1H),5.21(s,1H),4.53(s,2H),4.15(dd,J＝8.4,4.4Hz,1H),3.32(dd,J＝12.4,4.0 Hz,1H),3.18–3.04(m,2H),2.01(s,3H),1.98–1.70(m,4H),1.41(d,J＝8.0Hz,6H),1.30(dd,J＝6.8, 2.4Hz,6H).

Example 40, (S)-2-chloro-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino))-3-isopropylpyrazolo[ Synthesis of 1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acetamide (compound 40):

1), (S)-5-((7-((tert-butoxycarbonyl)(3-(2-chloroacetamido)benzyl)amino)-3-isopropylpyrazolo[1,5- Synthesis of a]pyrimidin-5-yl)amino tert-butyl)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester:

At 0°C, dissolve (S)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5- To a solution of a]pyrimidin-5-yl)amino)-2,2-tert-butyldimethylpiperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.065 mmol) in dichloromethane (1.5 mL), add tris Ethylamine (20mg, 0.20mmol), kept at 0°C and stirred for 30 minutes, then 2-chloroacetyl chloride (11.0mg, 0.10mmol) of dichloromethane (0.5 mL) solution was added dropwise to the above reaction solution. The resulting mixed reaction solution was stirred at room temperature overnight. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified through a C18 column (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95%) to obtain (S)-5-((7-((tert-butoxycarbonyl)(3-(2- Chloroacetamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)aminotert-butyl)-2,2-dimethylpiperidine-1-carboxy Tert-butyl acid ester (32 mg, yield: 71.%), LC-MS m/z 684[M+H] ⁺ ;

2), (S)-2-chloro-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1 ,Synthesis of 5-a]pyrimidin-7-yl)amino)methyl)phenyl)acetamide:

(S)-5-((7-((tert-butoxycarbonyl)(3-(2-chloroacetylamino)benzyl)amino)-3-isopropylpyrazolo[1,5- a] Pyrimidin-5-yl)amino tert-butyl)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (32 mg, 0.05 mmol) in dichloromethane (0.9 mL), add dropwise 2,2,2,-Trifluoroacetic acid (0.3 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95% elution) to obtain (S)-2-chloro-N-(3-(((5-((6 ,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acetamide (5 mg, Yield: 22%), LC-MS m/z: 484[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.73(d,J＝12.0Hz,2H),7.41(d,J＝8.0Hz,1H),7.34(t,J＝8.0Hz,1H),7.19 (d,J＝8.0Hz,1H),5.23(s,1H),4.60(s,2H),4.18(s,2H),3.53–3.47(m,2H),3.18–3.06(m,2H), 2.05–1.87(m,2H),1.82–1.77(m,2H),1.43(s,3H),1.41(s,3H),1.31(d,3H),1.29(d,3H).

Example 41, (S)-2-chloro-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino))-3-isopropylpyrazolo[ Synthesis of 1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (compound 41):

1), (S)-5-((7-((tert-butoxycarbonyl)(3-(2-chloroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1,5 Synthesis of -a]pyrimidin-5-yl)amino tert-butyl)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (S)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- (hydroxy)amino)-2,2-tert-butyldimethylpiperidine-1-carboxylic acid methyl ester (20mg, 0.03mmol), 2-chloroacrylic acid (6mg, 0.06mmol), 2-chloro-1-methyl A solution of pyridin-1-onium (13 mg, 0.10 mmol) and triethylamine (20 mg, 0.20 mmol) in dichloromethane (1 mL) was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified through a C18 column (acetonitrile: containing 0.1% NH ₄ HCO ₃ =5-95%) to obtain (S)-5-((7-((tert-butoxycarbonyl)(3-(2-chloroacrylamide) yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino tert-butyl)-2,2-dimethylpiperidine-1-carboxylic acid tert Butyl ester (15 mg, yield: 65.5%), LC-MS m/z: 696[M+H] ⁺ ;

2), (S)-2-chloro-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1 ,Synthesis of 5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide:

At room temperature, (S)-5-((7-((tert-butoxycarbonyl)(3-(2-chloroacrylamido)benzyl)amino)-3-isopropylpyrazolo [1,5-a]pyrimidin-5-yl)amino tert-butyl)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (15 mg, 0.02 mmol) in dichloromethane (0.9 mL) To the solution, 2,2,20 trifluoroacetic acid (0.3 mL) was added dropwise, and the resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified through a C18 column (acetonitrile: containing 0.1% NH 4HCO 3 pure water = 5-95% elution) to obtain (S)-2-chloro-N-(3-(((5-((6,6- Dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (2.0 mg, yield : 18.7%), LC-MS m/z: 496[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.67–7.65(m,2H),7.55–7.51(m,1H),7.35(t,J＝7.6Hz,1H),7.24–7.20(m,1H ),6.43(d,J＝2.0Hz,1H),5.96(d,J＝2.0Hz,1H),5.18(s,1H),4.64–4.54(m,2H),3.49–3.46(m,3H) ,3.02–2.80(m,1H),1.94–1.87(m,1H),1.81–1.69(m,1H),1.68–1.57(m,2H),1.32–1.25(m,12H).

Example 42, N-(3-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1 Synthesis of ,5-a]pyrimidin-7-yl)amino)methyl)phenyl)cyclopent-1-en-1-carboxamide (compound 42):

1), (3R, 4R)-4-((((7-((tert-butoxycarbonyl)(3-(cyclopent-1-en-1-carboxamido)benzyl)amino)-3- Synthesis of isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

Dissolve (3R, 4R)-4-((((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-5-yl)amino)methyl tert-butyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (35.0 mg, 0.06 mmol) and cyclopent-1-ene-1-carboxylic acid (10 mg, 0.09mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (33mg, 0.09mmol) and N,N-diisopropyl A solution of ethylamine (22 mg, 0.17 mmol) in N,N-dimethylformamide (2 mL) was stirred at 25°C for 16 hours. The resulting mixed reaction solution was eluted by C18 column chromatography (acetonitrile: pure water = 5-95% ) was purified to obtain (3R, 4R)-4-((((7-((tert-butoxycarbonyl)(3-(cyclopent-1-en-1-carboxamido)benzyl)amino)-3- Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (25 mg, yield: 61.7%), LC- MS m/z: 704[M+H] ⁺ ;

2), N-(3-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1, Synthesis of 5-a]pyrimidin-7-yl)amino)methyl)phenyl)cyclopent-1-en-1-carboxamide:

There is (3R, 4R)-4-((((7-((tert-butoxycarbonyl)(3-(cyclopent-1-en-1-carboxamido)benzyl)amino)-3- Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (25 mg, 0.04 mmol) in dichloromethane (3 mL ) solution, add 2,2,2-trifluoroacetic acid (1 mL) for 2 hours. The resulting mixed reaction solution is concentrated under reduced pressure. The residue is purified by C18 column chromatography (acetonitrile: water = 5-95% elution) to obtain N -(3-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-7-yl)amino)methyl)phenyl)cyclopent-1-ene-1-carboxamide (10 mg, yield: 55.9%), LC-MS m/z: 504[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD) δ7.80 (s, 1H), 7.71 (s, 1H), 7.47 (d, J = 8.0Hz, 1H), 7.33 (t, J = 8.0Hz, 1H), 7.16 ( d,J＝7.6Hz,1H),6.69(s,1H),5.29(s,1H),4.74–4.72(m,1H),4.63(s,2H),3.57(s,2H),3.38(s ,2H),3.08–3.01 (m,1H),2.92(s,1H),2.79–2.72(m,1H),2.64(s,2H),2.55(s,2H),1.99(dd,J＝22.0,14.4Hz,3H), 1.73(s,1H),1.56(s,1H),1.29(dd,J=6.8,4.0Hz,6H).

Example 43, 2-chloro-N-(3-(((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)methyl)amino)-3-isopropyl Synthesis of pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acetamide (compound 43):

1), (3R, 4R)-4-((((7-((tert-butoxycarbonyl)(3-(2-chloroacetamido)benzyl)amino)-3-isopropylpyrazolo[ Synthesis of 1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester:

Under 0°C conditions, (3R, 4R)-4-((((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[ 1,5-a]pyrimidin-5-yl)amino)methyl tert-butyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.066 mmol) and triethylamine (20.0 mg, 0.20 mmol ) in dichloromethane (0.5 mL), a solution of 2-chloroacetyl chloride (9 mg, 0.08 mmol) in dichloromethane (0.5 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95% elution) to obtain (3R, 4R)-4-((((7-((tert-butoxy) Carbonyl)(3-(2-chloroacetamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine -1-tert-butylcarboxylate (25 mg, yield: 55.6%), LC-MS m/z: 686 [M+H] ⁺ ;

2), 2-chloro-N-(3-(((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyra Synthesis of azozo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acetamide:

There is (3R, 4R)-4-((((7-((tert-butoxycarbonyl)(3-(2-chloroacetamido)benzyl)amino)-3-isopropylpyrazolo[ 1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (25.0 mg, 0.045 mmol) was added dropwise to a solution of dichloromethane (1.2 mL) 2,2,2-trifluoroacetic acid (0.4 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction solution was concentrated under reduced pressure. The residue was passed through C18 column chromatography (acetonitrile: containing 0.1% NH ₃ ·H ₂ O Pure water = 5-95% elution) purification to obtain 2-chloro-N-(3-(((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl) )amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acetamide (5.6 mg, yield: 31.6%), LC-MS m /z：486[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.84 (s, 1H), 7.73 (s, 1H), 7.42 (d, J = 8.0Hz, 1H), 7.36 (t, J = 7.6Hz, 1H) ,7.20(d,J＝7.2Hz,1H),5.36(s,1H),4.68(s,2H),4.17(s,2H),3.67-3.56(m,2H),3.51-3.49(m,3H ),3.09-3.02(m,1H),2.97-2.91(m,1H),2.77(t,J＝11.2Hz,1H),2.05-1.95(m,1H),1.84-1.73(m,1H), 1.64-1.50(m,1H),1.31(d,J＝2.4Hz,3H),1.29(d,J＝2.4Hz,3H).

Example 44, (E)-N-(3-((((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)methyl)amino)-3-isopropyl Synthesis of pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-2-methylbut-2-enamide (compound 44):

1), (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-((E)-2-methylbut-2-enamido)benzyl)amino)- Synthesis of 3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

(3R, 4R)-4-((((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine- 5-yl)amino)methyltert-butyl)-3-hydroxypiperidine-1-carboxylate (30 mg, 0.049 mmol) and (2E)-2-methylbut-2-enoic acid (7.36 mg, 0.074 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (27.50mg, 0.098mmol) and 1-methyl-1H-imidazole (16mg, 0.20mmol) Dimethylformamide (1 mL) solution was stirred at room temperature overnight. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 65-85% elution) to obtain (3R, 4R)-4 -(((7-((tert-butoxycarbonyl)(3-((E)-2-methylbut-2-enamido)benzyl)amino)-3-isopropylpyrazolo[1 ,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (21 mg, yield: 61.7%), LC-MS m/z: 692[M +H] ⁺ ;

2), (E)-N-(3-((((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)methyl)amino)-3-isopropylpyra Synthesis of azolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-2-methylbut-2-enamide

Dissolve (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-((E)-2-methylbut-2-enamido)benzyl)amino)- 3-Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (21 mg, 0.030 mmol) in dichloromethane (0.9 mL) solution and 2,2,2-trifluoroacetic acid (0.3 mL), and stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 15-30% elution) (E)-N-(3-((((5-((((3R,4R))-3-hydroxypiperidine -4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-2-methylbut-2-ene Amide (9 mg, yield: 60.3%), LC-MS m/z: 492[M+H] ⁺ ;

1H NMR (400MHz, MeOD-d ₄ ): δ7.65 (d, J = 15.0Hz, 2H), 7.47 (d, J = 7.6Hz, 1H), 7.30 (t, J = 7.6Hz, 1H), 7.14 (d,J＝7.8Hz,1H),6.46(d,J＝7.0Hz,1H),5.11(d,J＝60.3Hz,1H),4.54(s,2H),3.95(d,J＝13.7Hz ,1H),3.48(s,1H),3.36(s,1H),3.18(d,J＝14.4Hz,1H),2.99(d,J＝33.8Hz,2H),2.78(s,1H),1.89 (s,4H),1.81(d,J＝6.7Hz,3H),1.66(s,2H),1.28(t,J＝7.2Hz,6H).

Example 45, N-(3-(((3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-7 Synthesis of -yl)amino)methyl)phenyl)acrylamide (compound 45):

1), 4-(7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3, Synthesis of tert-butyl 6-dihydropyridine-1(2H)-carboxylate

At room temperature, (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (5g, 11.21 mmol) and (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (3.05 g, 13.45 mmol) in 1,4-dioxane (50 mL) To the solution, add 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.82g, 1.12mmol), potassium carbonate (4.65g, 33.63mmol) and water (12.5mg, 0.694 mmol). The resulting mixed reaction liquid was heated to 90°C and stirred for 4 hours under the protection of nitrogen gas. After cooling, the obtained mixed reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain 4-(7-((tert-butoxycarbonyl)(3-nitrogen) (benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (4g, Yield: 60%), LC-MS m/z: 593[M+H] ⁺ ;

2), 4-(7-((3-Aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3, Synthesis of tert-butyl 6-dihydropyridine-1(2H)-carboxylate

In solution, there is 4-(7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3, To a solution of 6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (4g, 6.75mmol) and iron (1.13g, 20.25mmol) in ethanol (40mL) and water (10mL), ammonium chloride (0.72 g, 13.5mmol). The resulting mixture was stirred at 70°C for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: 0.1% formic acid in pure water = 25%-65% elution) to obtain 4-(7-((3-aminobenzyl)(tert-butoxy) Carbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3.2g, collected Rate: 84%), LC-MS m/z: 563[M+H] ⁺ ;

3), 4-(7-((3-Acrylamidobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)- Synthesis of tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate

At 0°C, 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 is dissolved -A solution of -3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (100mg, 0.178mmol) in dichloromethane (2mL) was added with triethylamine (54mg, 0.534mmol) at 0°C, 0 °C and stir for 30 minutes. Then, a solution of prop-2-enoyl chloride (19 mg, 0.214 mmol) in dichloromethane (0.5 mL) was added to the above reaction solution. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) Obtain 4-(7-((3-acrylamidobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3, 6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (60 mg, yield: 58%), LC-MS m/z: 617 [M+H] ⁺ ;

4), N-(3-(((3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-7- Synthesis of methyl)amino)methyl)phenyl)acrylamide

4-(7-((3-Acrylamidobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3, A mixed solution of tert-butyl 6-dihydropyridine-1(2H)-carboxylate (60 mg, 0.097 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 8 hours. . The obtained mixed reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain N-(3-(((3-isopropyl-5-( 1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (20 mg, yield: 49% ), LC-MS m/z:417[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.905 (s, 1H), 7.757 (s, 1H), 7.534 (d, J = 8.0Hz, 1H), 7.316 (t, J = 8.0Hz, 1H) ,7.170(d,J＝7.6Hz,1H),6.553(s,1H),6.430-6.340(m,2H),6.158(s,1H),5.748(dd,J＝2.4,2.8Hz,1H), 4.704(s,2H),3.866-3.846(m,2H),3.424(t,J＝6.0Hz,2H),3.270-3.184(m,1H),2.928-2.924(m,2H),1.364(d, J＝6.8Hz,6H).

Example 46, N-(3-(((3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-7 Synthesis of -base)amino)methyl)phenyl)ethylenesulfonamide (compound 46):

1), 4-(7-((tert-butoxycarbonyl)(3-(vinylsulfonamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Synthesis of tert-butyl)-3,6-dihydropyridine-1(2H)-carboxylate

At 0°C, 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 is dissolved -Triethylamine (54mg, 0.534mmol) was added to a solution of -3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (100mg, 0.178mmol) in dichloromethane (2mL), and the temperature was maintained at 0℃ Stir for 30 minutes. Then, a solution of vinyl sulfonyl chloride (27 mg, 0.214 mmol) in dichloromethane (0.5 mL) was added to the above mixed reaction solution. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain 4-(7-((tert-butoxycarbonyl)(3-( Vinylsulfonamide)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert. Butyl ester (60 mg, yield: 52%), LC-MS m/z: 653[M+H] ⁺ ;

2), N-(3-(((3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-7- Synthesis of methyl)amino)methyl)phenyl)ethylenesulfonamide

The dissolved 4-(7-((tert-butoxycarbonyl)(3-(vinylsulfonamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- A mixed solution of tert-butyl)-3,6-dihydropyridine-1(2H)-carboxylate (60mg, 0.097mmol) in dichloromethane (3mL) and 2,2,2-trifluoroacetic acid (1mL), Stir at room temperature for 8 hours. The obtained mixed reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain N-(3-(((3-isopropyl-5-( 1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)ethylenesulfonamide (20 mg, yield: 48 %), LC-MS m/z: 452[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.982 (s, 1H), 7.329-7.309 (m, 2H), 7.187 (d, J = 7.6Hz, 1H), 7.065 (d, J = 8.0Hz, 1H),6.638-6.572(m,2H),6.190(s,1H),2.991(d,J＝1.64Hz,1H),5.804(d,J＝10Hz,1H),4734(s,2H),3.909 -3.901(m,2H),3.464(t,J＝6Hz 2H),3.295-3.243(m,1H),2.948(m,1H),1.390(d,J＝6.8Hz,6H).

Example 47, N-(3-(((3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-7 Synthesis of -yl)amino)methyl)phenyl)butan-2-amide (compound 47):

1), 4-(7-((3-(but-2-ynylamido)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine- Synthesis of 5-yl)-3,6-tert-butyldihydropyridine-1(2H)-carboxylic acid tert-butyl ester

Will dissolve 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3, 6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (60mg, 0.107mmol), butan-2-ynoic acid (13.2mg, 0.157mmol), 2-(7-azobenzotriazole) - N,N-dimethyl of N,N,N',N'-tetramethylurea hexafluorophosphate (51 mg, 0.134mmol) and N,N-diisopropylethylamine (40.8mg, 0.316mmol) Formamide (1 mL) solution was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 25%-65% elution) to give 4-(7-((3-(but-2-ynamido)) Benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3,6-tert-butyldihydropyridine-1(2H)- Tert-butyl carboxylate (40 mg, yield: 59%), LC-MS m/z: 629[M+H] ⁺ ;

2), N-(3-(((3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-7- Synthesis of methyl)amino)methyl)phenyl)butan-2-amide

The dissolved 4-(7-((3-(but-2-ynylamido)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine- 5-yl)-3,6-tert-butyldihydropyridine-1(2H)-carboxylic acid tert-butyl ester (40 mg, 0.064 mmol) and 2,2,2-trifluoroacetic acid (0.5 mL) and dichloromethyl The solution of alkane (1.5 mL) was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 15%-55% elution) to obtain N-(3-(((3-isopropyl-5- (1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)butan-2-amide (21 mg, collected rate: 52%), LC-MS m/z: 429[M+H] ⁺

¹ H NMR (400MHz, MeOD-d4): δ7.87 (s, 1H), 7.64 (s, 1H), 7.46 (d, J = 8.4Hz, 1H), 7.30 (t, J = 8.0Hz, 1H) ,7.16(d,J＝7.6 1H),6.55(s,1H),6.08(s,1H),4.66(s,2H),3.52(d,J＝2.8Hz,2H),3.28–3.21(m, 1H), 3.06 (t, J = 5.8 Hz, 2H), 2.62 (s, 2H), 2.00 (s, 3H), 1.35 (d, J = 3.4 6H).

Example 48, (E)-4-(dimethylamino)-N-(3-(((3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyridin) Synthesis of azolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)but-2-enamide (compound 48):

1), (E)-4-(7-((tert-butoxycarbonyl)(3-(4-(dimethylamino)but-2-enamido)benzyl)amino)-3-isopropyl Synthesis of tert-butyl pyrazolo[1,5-a]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

Will dissolve 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3, 6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (100 mg, 0.18 mmol), (E)-4-(dimethylamino)but-2-enoic acid (35 mg, 0.27 mmol), 2-( 7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (136mg, 0.35mmol) and N,N-diisopropylethylamine (153mg, 1.19 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 16 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (E)-4-(7-((tert-butoxycarbonyl)(3-( 4-(dimethylamino)but-2-enamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3,6-dihydropyridine -1(2H)-tert-butylcarboxylate (45mg, yield: 37.5%), LC-MS m/z: 674[M+H] ⁺ ;

2), (E)-4-(dimethylamino)-N-(3-(((3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazole) Synthesis of [1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)but-2-enamide

(E)-4-(7-((tert-butoxycarbonyl)(3-(4-(dimethylamino)but-2-enamido)benzyl)amino)-3-isopropyl A solution of pyrazolo[1,5-a]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (45 mg, 0.08 mmol) in dichloromethane (0.9 mL) , add 2,2,2-trifluoroacetic acid (0.3mL) dropwise. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (E)-4-(dimethylamino)-N- (3-(((3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl Base) phenyl) but-2-enamide (20 mg, yield: 63.2%), LC-MS m/z: 474 [M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d ₄ ): δ7.90 (s, 1H), 7.74 (s, 1H), 7.51 (d, J = 8.0Hz, 1H), 7.33 (t, J = 8.0Hz, 1H ),7.18(d,J＝4.0Hz,1H),6.87-6.81(m,1H),6.56(s,1H),6.38(d,J＝12.0Hz,1H),6.16(s,1H),4.71 (s,2H),3.85(s,2H),3.58(s,2H),3.41(t,J＝4.0Hz,2H),3.31-3.30(m,1H),2.93(s,2H),2.61( s,6H),1.36(d,J＝4.0Hz,6H)

Example 49, N-(3-(((3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-7 Synthesis of -yl)amino)methyl)phenyl)-3-methylbut-2-enamide (compound 49):

1), 4-(7-((tert-butoxycarbonyl)(3-(3-methylbut-2-enamido)benzyl)amino)-3-isopropylpyrazolo[1,5- Synthesis of a]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

At 0°C, 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 is dissolved -To a solution of -3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (60 mg, 0.106 mmol) in dichloromethane (1.5 mL), add triethylamine (54 mg, 0.534 mmol). Stir at 0°C for 30 minutes. Then, a solution of 3-methylbut-2-enoyl chloride (15.1 mg, 0.128 mmol) in dichloromethane (0.5 mL) was added dropwise to the above reaction solution. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: water containing 0.1% formic acid = 25%-65% elution) to give 4-(7-((tert-butoxycarbonyl)(3-(3- Methylbut-2-enamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H) - tert-butyl carboxylate (35 mg, yield: 51%), LC-MS m/z: 645 [M+H] ⁺ ;

2), N-(3-(((3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-7- Synthesis of methyl)amino)methyl)phenyl)-3-methylbut-2-enamide

The dissolved 4-(7-((tert-butoxycarbonyl)(3-(3-methylbut-2-enamido)benzyl)amino)-3-isopropylpyrazolo[1,5- a]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (35 mg, 0.054 mmol) in 2,2,2-trifluoroacetic acid (0.5 mL) and dichloro A solution of methane (1.5 mL) was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water (20 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography using (water containing 0.1% acetonitrile: 0.1% formic acid = 15%-55% elution) to give N-(3-(((3-isopropyl-5-(1, 2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-3-methylbut-2-enamide ( 15mg, yield: 62%), LC-MS m/z: 445[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d ₄ ): δ7.92 (s, 1H), 7.67 (s, 1H), 7.50 (d, J = 8.0Hz, 1H), 7.24 (t, J = 8.0Hz, 1H ),7.06(d,J＝8.0Hz,1H),6.63(s,1H),6.12(s,1H),5.83(s,1H),4.60(s,2H),3.37(m,2H),3.17 –3.10(m,1H),2.85(t,J＝6.0Hz,2H),2.42(s,2H),2.13(s,3H),1.84(s,3H),1.32(d,J＝4.0Hz 6H ).

Example 50, N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)benzene Synthesis of acrylamide (compound 50):

1), 4-(7-((3-Acrylamidobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine -Synthesis of 1-carboxylic acid tert-butyl ester

At 0°C, 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 is dissolved To a solution of tert-butyl piperidine-1-carboxylate (100 mg, 0.18 mmol) in dichloromethane (1 mL), triethylamine (50 mg, 0.54 mmol) was added, and the mixture was stirred at 0° C. for 30 minutes. Then, acryloyl chloride (20 mg, 0.22 mmol) in dichloromethane (0.2 mL) was added dropwise to the above reaction solution. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which could be directly used in the next step without further purification, LC-MS m/z: 619[M+H] ⁺ ;

2), N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl )Synthesis of acrylamide

At room temperature, 4-(7-((3-acrylamidobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 is dissolved in To a solution of tert-butyl-piperidine-1-carboxylate (80 mg, 0.13 mmol) in dichloromethane (1.5 mL), 2,2,2-trifluoroacetic acid (0.5 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 35%-80% elution) to obtain N-(3-(((3-isopropyl-5-(piperidine) -4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (40 mg, yield: 74%), LC-MS m/z: 419[ M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.89 (s, 1H), 7.75 (s, 1H), 7.49 (d, J = 8.0Hz, 1H), 7.32 (t, J = 8.0Hz, 1H) ,7.17(d,J＝8.0Hz,1H),6.41-6.34(m,2H),5.90(s,1H),5.78-5.73(m,1H),4.68(s,2H),3.50-3.45(m ,3H),3.44(s,1H),3.08(s,1H),3.00-2.90(m,1H),2.15-2.00(m,4H),1.35(d,J＝8.0Hz,6H).

Example 51, N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)benzene Synthesis of methacrylamide (compound 51):

1), 4-(7-((tert-butoxycarbonyl)(3-methacrylamidobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl) Synthesis of piperidine-1-carboxylic acid tert-butyl ester

At 0°C, 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 is dissolved A solution of tert-butyl piperidine-1-carboxylate (30.0 mg, 0.05 mmol) and triethylamine (15 mg, 0.15 mmol) in dichloromethane (1.0 mL) was added dropwise to methacryloyl chloride (10 mg, 0.10mmol). The resulting mixed reaction solution was stirred at room temperature for 16 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 5-95% elution) to obtain 4-(7-((tert-butoxycarbonyl)(3-methylpropene) Amidobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (24 mg, yield: 71.4%), LC -MS m/z:633[M+H] ⁺ ;

2), N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl )Synthesis of methacrylamide

In solution, there is 4-(7-((tert-butoxycarbonyl)(3-methacrylamidobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl) To a solution of piperidine-1-carboxylic acid tert-butyl ester (24 mg, 0.04 mmol) in dichloromethane (3 mL), 2,2,2-trifluoroacetic acid (1 mL) was added, and the resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 5-95% elution) to obtain N-(3-(((3-isopropyl-5-(piperidin-4-yl))pyrazolo[1, 5-a]pyrimidin-7-yl)amino)methyl)phenyl)methacrylamide (10 mg, yield: 60.9%), LC-MS m/z: 433[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD) δ7.89 (s, 1H), 7.71 (s, 1H), 7.46 (d, J = 8.4Hz, 1H), 7.32 (t, J = 8.0Hz, 1H), 7.18 ( d,J＝8.0Hz,1H),5.91(s,1H),5.76(s,1H),5.49(s,1H),4.67(s,2H),3.46(s,2H),3.43(s,1H ),3.25–3.19(m,1H),3.07(t,J＝12.0Hz,2H),2.11–2.08(m,1H),2.06(s,2H),2.03(s,1H),2.00(s, 3H),1.35(s,3H),1.34(s,3H).

Example 52, 2-fluoro-N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino) Synthesis of methyl)phenyl)acrylamide (compound 52):

1), 4-(7-((3-Aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine- Synthesis of 1-carboxylic acid tert-butyl ester

Will dissolve 4-(7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3, A solution of tert-butyl 6-dihydropyridine-1(2H)-carboxylate (1.2g, 2.0mmol) and palladium on carbon (500mg) in methanol (20mL) was stirred at room temperature overnight under a hydrogen atmosphere. The obtained mixed reaction liquid was filtered, and methanol (3×50 mL) was used for the filter cake. The filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was directly used in the next step without further purification. LC-MS m/z: 565[M+H] ⁺ ;

2), 4-(7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 Synthesis of tert-butyl-piperidine-1-carboxylate

Will dissolve 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine- 1-tert-butylcarboxylate (100mg, 0.18mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (100mg, 0.36mmol), 1-methylimidazole (58mg, 0.71 mmol) and 2-fluoroacrylic acid (24 mg, 0.27 mmol) in N,N-dimethylformamide (2 mL), stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% FA = 40-85% elution) to obtain 4-(7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)) Benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (70 mg, yield: 62.5%), LC-MS m/z: 637[M+H] ⁺ ;

3), 2-fluoro-N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl Synthesis of phenyl)acrylamide

In solution, there is 4-(7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 To a solution of tert-butyl-piperidine-1-carboxylate (70 mg, 0.11 mmol) in dichloromethane (1.5 mL), 2,2,2-fluoroacetic acid (0.5 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 35%-80% elution) to obtain 2-fluoro-N-(3-(((3-isopropyl-5-( Piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (30 mg, yield: 62.5%), LC-MS m/z: 437[M+H]+;

¹ H NMR (400MHz, MeOD-d4): δ7.88(s,1H),7.73(s,1H),7.57(d,J＝8.0Hz,1H),7.35(t,J＝8.0Hz,1H) ,7.23(d,J＝8.0Hz,1H),5.91(s,1H),5.69(dd,J＝44.0,4.0Hz,1H),5.29(dd,J＝16.0,4.0Hz,1H),4.68( s,2H),3.27-3.15(m,3H),2.85-2.75(m,3H),1.95-1.85(m,2H),1.85-1.75(m,2H),1.34(s,3H),1.33( s,3H).

Example 53, N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)benzene Synthesis of cyclopent-1-ene-1-carboxamide (compound 53):

1), 4-(7-((tert-butoxycarbonyl)(3-(cyclopent-1-en-1-carboxamido)benzyl)amino)-3-isopropylpyrazolo[1,5 -Synthesis of tert-butyl a]pyrimidin-5-yl)piperidine-1-carboxylate

Will dissolve 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine- 1-tert-butylcarboxylate (59.0mg, 0.10mmol), cyclopent-1-ene-1-carboxylic acid (22mg, 0.20mmol), 2-(7-azobenzotriazole)-N,N ,N',N'-tetramethylurea hexafluorophosphate (56mg, 0.14mmol) and N,N-diisopropylethylamine (38mg, 0.30mmol) in N,N-dimethylformamide (2mL ) solution was stirred at room temperature for 16 hours. The obtained mixed reaction solution was purified by C18 column chromatography (acetonitrile: water = 5-95% elution) to obtain 4-(7-((tert-butoxycarbonyl)(3-(cyclopent-1-en-1-carboxamido) )benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (45 mg, yield: 65.4%), LC- MS m/z: 659[M+H] ⁺ ;

2), N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl )Synthesis of cyclopent-1-ene-1-carboxamide

In solution, there is 4-(7-((tert-butoxycarbonyl)(3-(cyclopent-1-en-1-carboxamido)benzyl)amino)-3-isopropylpyrazolo[1,5 -To a solution of tert-butyl a]pyrimidin-5-yl)piperidine-1-carboxylate (45 mg, 0.07 mmol) in dichloromethane (3 mL), 2,2,2-trifluoroacetic acid (1 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 5-95% elution) to obtain N-(3-(((3-isopropyl-5-(piperidin-4-yl))pyrazolo[1, 5-a]pyrimidin-7-yl)amino)methyl)phenyl)cyclopent-1-ene-1-carboxamide (10 mg, yield: 31.9%), LC-MS m/z: 459 [M+ H] ⁺ ;

¹ H NMR (400MHz, MeOD) δ7.89 (s, 1H), 7.73 (s, 1H), 7.47 (d, J = 7.6Hz, 1H), 7.31 (t, J = 8.0Hz, 1H), 7.17 ( d,J＝7.6Hz,1H),6.68(s,1H),5.91(s,1H),4.67(s,2H),4.57(s,1H),3.43(s,1H),3.39(s,1H ),3.26–3.19(m,1H),3.02(t,J＝12.4Hz,2H),2.90(d,J＝10.8Hz,1H),2.64(t,J＝7.6Hz,2H),2.54(dd ,J＝7.6,2.4Hz,2H),2.03(d,J＝4.8Hz,3H),1.99(d,J＝7.6Hz,2H),1.35(d,J＝2.4Hz,3H),1.33(s ,3H).

Example 54, 2-chloro-N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino) Synthesis of methyl)phenyl)acetamide (compound 54):

1), 4-(7-((tert-butoxycarbonyl)(3-(2-chloroacetamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Synthesis of piperidine-1-carboxylic acid tert-butyl ester

At 0°C, 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 is dissolved To a solution of tert-butyl piperidine-1-carboxylate (100 mg, 0.18 mmol) in dichloromethane (1 mL), triethylamine (50 mg, 0.50 mmol) was added, and the mixture was stirred at 0° C. for 30 minutes. Then, a solution of 2-chloroacetyl chloride (24 mg, 0.22 mmol) in dichloromethane (0.2 mL) was added dropwise to the above reaction solution. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which could be directly used in the next step without further purification, LC-MS m/z: 641[M+H] ⁺ ;

2), 2-chloro-N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl Synthesis of phenyl)acetamide

At room temperature, 4-(7-((tert-butoxycarbonyl)(3-(2-chloroacetamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a To a solution of pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (0.08g, 0.12mmol) in dichloromethane (1.5mL), 2,2,2-trifluoroacetic acid (0.5mL) was added dropwise . The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 35%-80% elution) to obtain 2-chloro-N-(3-(((3-isopropyl-5 -(piperidin-4-yl) Pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acetamide (40 mg, yield: 72%), LC-MS m/z: 441[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.89 (s, 1H), 7.73 (s, 1H), 7.40 (d, J = 8.0Hz, 1H), 7.33 (t, J = 8.0Hz, 1H) ,7.20(d,J＝8.0Hz,1H),5.92(s,1H),4.67(s,2H),4.18(s,2H),3.51-3.44(m,2H),3.27-3.18(m,1H ),3.14-3.15(m,2H),2.98-2.90(m,1H),2.12-1.98(m,4H),1.35(s,3H),1.34(s,3H).

Example 55, N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)benzene Synthesis of acrylamide (compound 50):

1) Synthesis of (5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (500 mg, 1.12 mmol) and ring Propylboronic acid (116 mg, 1.34 mmol), tetrakis(triphenylphosphine)palladium (126 mg, 0.11 mmol) and cesium carbonate (1.1 g, 3.36 mmol) in 1,4-dioxane (8 mL) and water (2 mL ) mixed solution was heated to 90°C and stirred overnight under argon protection. After cooling, the mixed reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 40-65% elution) to obtain (5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidine-7- (3-nitrobenzyl)carbamic acid tert-butyl ester (250 mg, yield: 49.3%), LC-MS m/z: 452[M+H] ⁺ ;

2) Synthesis of tert-butyl (3-aminobenzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate

Dissolve (5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (250 mg, 0.55 mmol) A solution of iron (149 mg, 2.75 mmol) in ethanol (4 mL) and ammonium chloride aqueous solution (1 mL) was heated to 70° C. and stirred for 2 hours. After cooling, the mixed reaction solution was filtered, and the filter cake was washed with ethyl acetate (10 mL×3). The filtrate was collected and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS m/z: 422[M+H] ⁺ .

3) Synthesis of tert-butyl (3-acrylamidobenzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate

At 0°C, dissolve (3-aminobenzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester ( To a solution of 50 mg, 0.118 mmol) and N,N-diisopropylethylamine (65 mg, 0.50 mmol) in dichloromethane (2 mL), acryloyl chloride (13 mg, 0.144 mmol) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95% elution) to obtain (3-acrylamidobenzyl) (5-cyclopropyl-3-isopropylpyra) Azolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (33 mg, yield: 58.5%), LC-MS m/z: 476 [M+H] ⁺ ;

4), Synthesis of N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide

Dissolve (3-acrylamidobenzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (33 mg) at room temperature. , 0.069 mmol) in dichloromethane (0.9 mL), 2,2,2-trifluoroacetic acid (0.3 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: containing 0.1% NH 4HCO 3 = 5-95% elution) to give N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1, 5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (10 mg, yield: 38.6%), LC-MS m/z: 376 [M+H] ⁺ ;

δ7.96(s,1H),7.73(s,1H),7.53(d,J＝8.0Hz,1H),7.34(t,J＝8.0Hz,1H),7.16(d,J＝8.0Hz,1H ),6.44–6.31(m,2H),5.77–5.74(m,2H),4.72(s,2H),3.26–3.18(m,1H),2.09–2.02(m,1H),1.34–1.30(m ,6H),1.13–1.09(m,2H),1.03–0.98(m,2H).

Example 56, N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)methacrylene Synthesis of amides (compound 56):

1) Synthesis of tert-butyl (5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-methacrylamidobenzyl)carbamate

Dissolve (3-aminobenzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (50 mg, 0.12 mmol), Methacrylic acid (12.3 mg, 0.14 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (68 mg, 0.18 mmol) and A solution of N,N-diisopropylethylamine (46 mg, 0.36 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at room temperature overnight. The residue was purified by C18 column chromatography (acetonitrile: 0.1% NH ₃ ·H ₂ O in pure water = 5-95% elution) to obtain (5-cyclopropyl-3-isopropylpyrazolo[1,5- a] Pyrimidin-7-yl)(3-methacrylamidobenzyl)carbamic acid tert-butyl ester (35 mg, yield: 60.1%), LC-MS m/z: 490 [M+H] ⁺ ;

2), N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)methacrylamide Synthesis

(5-Cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-methacrylamidobenzyl)carbamic acid tert-butyl ester (35.0 mg) was dissolved , 0.071 mmol) in dichloromethane (1.2 mL), 2,2,2-trifluoroacetic acid (0.4 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain N-(3-(((5-cyclopropyl-3-isopropyl) Pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)methacrylamide (13 mg, yield: 46.8%), LC-MS m/z: 390 [M+H ] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.82 (s, 1H), 7.63 (s, 1H), 7.55 (d, J = 9.2Hz, 1H), 7.33 (d, J = 9.2Hz, 1H) ,7.17(d,J＝7.6Hz,1H),5.76(s,1H),5.70(s,1H),5.48(s,1H),4.64(s,2H),3.25-3.18(m,1H), 2.00(s,3H),1.98-1.93(m,1H),1.33(s,3H),1.31(s,3H),0.97-0.91(m,4H).

Example 57, N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-2- Fluoroacrylamide (chemical Synthesis of compound 57):

1), (5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(2-fluoroacrylamido)benzyl)carbamic acid tert-butyl ester Synthesis

Dissolve (3-aminobenzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (50 mg, 0.12 mmol), 2-Fluoroprop-2-enoic acid (16 mg, 0.18 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (67 mg, 0.24 mmol) and 1-methyl-1H- A solution of imidazole (39 mg, 0.47 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 1 hour. The obtained reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95% elution) to obtain (5-cyclopropyl-3-isopropylpyrazolo[1,5-a ]pyrimidin-7-yl)(3-(2-fluoroacrylamido)benzyl)carbamic acid tert-butyl ester (28 mg, yield: 47.8%), LC-MS m/z: 494 [M+H] ⁺ ;

2), N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-2-fluoro Synthesis of acrylamide

(5-Cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(2-fluoroacrylamido)benzyl)carbamate tert-butyl ester (28 mg, 0.056 mmol) in dichloromethane (0.9 mL), 2,2,2-trifluoroacetic acid (0.3 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95% elution) to obtain N-(3-((((5-cyclopropyl-3-isopropylpyrazole) And[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-2-fluoroacrylamide (2.14 mg, yield: 9.6%), LC-MS m/z: 394 [M+ H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.87(s,1H),7.70(s,1H),7.59(d,J＝8.0Hz,1H),7.36(t,J＝8.0Hz,1H) ,7.21(d,J＝8.0Hz,1H),5.72(s,1H),5.69(dd,J＝46.4Hz,3.6Hz,1H),5.27(dd,J＝15.2Hz,3.6Hz,1H), 4.67(s,2H),3.25–3.12(m,1H),2.02–1.94(m,1H),1.32(d,J=7.2Hz,6H),1.03–0.93(m,4H).

Example 58, N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)ethanesulfonamide Synthesis of (compound 58):

1), (5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(vinylsulfonamido)benzyl)carbamic acid tert-butyl ester synthesis

At 0°C, dissolve (3-aminobenzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester ( To a solution of 40 mg, 0.095 mmol) and triethylamine (29 mg, 0.29 mmol) in dichloromethane (1.5 mL), a solution of vinyl sulfonyl chloride (15 mg, 0.11 mmol) in dichloromethane (0.5 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature overnight. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: 0.1% NH ₄ HCO ₃ in pure water = 5-95% elution) to obtain (5-cyclopropyl-3-isopropylpyrazolo[1,5-a] Pyrimidin-7-yl)(3-(vinylsulfonamido)benzyl)carbamic acid tert-butyl ester (20 mg, yield: 41.2%), LC-MS m/z: 512 [M+H] ⁺ ;

2), N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)ethanesulfonamide synthesis

At room temperature, (5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(vinylsulfonamido)benzyl)amino To a solution of tert-butyl formate (20 mg, 0.04 mmol) in dichloromethane (1.2 mL), 2,2,2-trifluoroacetic acid (0.4 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH3.H2O = 5-95% elution) to obtain N-(3-(((5-cyclopropyl-3-isopropylpyrazolo) [1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)ethanesulfonamide (5.9 mg, yield: 36.6%), LC-MS m/z: 412[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.84(s,1H),7.29(t,J＝8.0Hz,1H),7.20(s,1H),7.14(d,J＝7.6Hz,1H) ,7.08(d,J＝7.6Hz,1H),6.56(q,J＝16.8,10.0Hz,1H),5.95(d,J＝16.4Hz,1H),5.75(d,J＝10.0Hz,1H) ,5.63(s,1H),4.62(s,2H),3.25-3.18(m,1H),1.98-1.92(m,1H),1.33(s,3H),1.31(s,3H),0.98-0.89 (m,4H).

Example 59, N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)cyclopent- Synthesis of 1-ene-1-carboxamide (compound 59):

1), (3-(cyclopent-1-en-1-carboxamido)benzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl )Synthesis of tert-butyl carbamate

Dissolve (3-aminobenzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (50 mg, 0.12 mmol) in N,N-diisopropylethylamine (46mg, 0.36mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate ( 70.0 mg, 0.18 mmol) and cyclopent-1-ene-1-carboxylic acid (21 mg, 0.18 mmol) in N,N-dimethylformamide (2 mL), stirred at room temperature for 1 hour. The obtained mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95% elution) to obtain (3-(cyclopent-1-en-1-carboxamido) benzyl (5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (36 mg, yield: 58.7%), LC-MS m/ z: 516[M+H] ⁺ ;

2), N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)cyclopent-1 -Synthesis of ene-1-carboxamide

To the solution is (3-(cyclopent-1-en-1-carboxamido)benzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl ) to a solution of tert-butyl carbamate (36 mg, 0.69 mmol) in dichloromethane (0.9 mL), 2,2,2-trifluoroacetic acid (0.3 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 0.5 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95% elution) to obtain N-(3-((((5-cyclopropyl-3-isopropylpyrazole) And[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)ring Pent-1-ene-1-carboxamide (18 mg, yield: 62.0%), LC-MS m/z: 416 [M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.96 (s, 1H), 7.73 (s, 1H), 7.60 (d, J = 8.0Hz, 1H), 7.36 (t, J = 8.0Hz, 1H) ,7.28(d,J＝8.0Hz,1H),6.68(s,1H),5.70(s,1H),4.65(s,2H),3.26–3.18(m,1H),2.68–2.50(m,4H ),2.10-1.83(m,3H),1.38–1.30(m,6H),0.98–0.87(m,4H).

Example 60, N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)butan-2 -Synthesis of acetylenic amide (compound 60):

1), tert-butyl (3-(but-2-ynamido)benzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate Synthesis of esters

Dissolve (3-aminobenzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (50 mg, 0.12 mmol), But-2-ynoic acid (12 mg, 0.14 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (69 mg, 0.18 mmol ), and a solution of triethylamine (37 mg, 0.36 mmol) in dichloromethane (1.5 mL) was stirred at room temperature overnight. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (3-(but-2-ynamido)benzyl) (5-cyclo Propyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (20 mg, yield: 34.6%), LC-MS m/z: 488 [M+ H] ⁺ ;

2), N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)butan-2- Synthesis of acetylenic amides

At room temperature, 3-(but-2-ynamido)benzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) is dissolved To a solution of tert-butyl carbamate (20 mg, 0.041 mmol) in dichloromethane (1.2 mL), 2,2,2-trifluoroacetic acid (0.4 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain N-(3-(((5-cyclopropyl-3-isopropyl) Pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)but-2-ynamide (7.0 mg, yield: 44%), LC-MS m/z: 388[ M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.82 (s, 1H), 7.59 (s, 1H), 7.49 (d, J = 8.0Hz, 1H), 7.31 (t, J = 7.6Hz, 1H) ,7.15(d,J＝7.2Hz,1H),5.69(s,1H),4.62(s,2H),3.25-3.18(m,1H),2.01(s,3H),1.99-1.92(m,1H ),1.33(s,3H),1.31(s,3H),0.98-0.90(m,4H).

Example 61, 2-chloro-N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl )Synthesis of acetamide (compound 61):

1), (3-(2-chloroacetamido)benzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester synthesis

At 0°C, dissolve (3-aminobenzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester ( To a solution of 40 mg, 0.095 mmol) and N,N-diisopropylethylamine (37 mg, 0.29 mmol) in dichloromethane (1.5 mL), 2-chloroacetyl chloride (12 mg, 0.11 mmol) in dichloromethane was added dropwise. (0.5mL) solution. The resulting mixed reaction solution was stirred overnight. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95% elution) to obtain (3-(2-chloroacetamido)benzyl)(5-cyclopropyl-3 -Isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (23 mg, yield: 48.7%), LC-MS m/z: 498[M+H] ⁺ ;

2), 2-chloro-N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl) Synthesis of acetamide

at room temperature. (3-(2-Chloroacetamido)benzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester ( To a solution of 23 mg, 0.046 mmol) in dichloromethane (1.2 mL), 2,2,2-trifluoroacetic acid (0.4 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain 2-chloro-N-(3-(((5-cyclopropyl-3 -Isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acetamide (8.3 mg, yield: 45.2%), LC-MS m/z: 398[ M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.01 (s, 1H), 7.70 (s, 1H), 7.47 (d, J = 8.0Hz, 1H), 7.35 (t, J = 7.6Hz, 1H) ,7.18(d,J＝7.6Hz,1H),5.76(s,1H),4.75(s,2H),4.15(s,2H),3.28-3.20(m,1H),2.12-2.03(m,1H ),1.35(s,3H),1.33(s,3H),1.18-1.13(m,2H),1.05-1.01(m,2H).

Example 62, (E)-N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl Synthesis of )-4-(dimethylamino)but-2-enamide (compound 62):

1), (E)-(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(4-(dimethylamino)butan-2- Synthesis of enamido)benzyl)carbamic acid tert-butyl ester

(3-Aminobenzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (100 mg, 0.23 mmol), (2E )-4-(dimethylamino)but-2-enoic acid (59 mg, 0.46 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl A solution of urea hexafluorophosphate (135 mg, 0.35 mmol) and N, N-diisopropylethylamine (153 mg, 1.18 mmol) in N, N-dimethylformamide (1 mL) was stirred at room temperature for 16 hours. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-100%) to obtain (E)-(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidine- 7-yl)(3-(4-(dimethylamino)but-2-enamido)benzyl)carbamic acid tert-butyl ester (88 mg, yield: 69.6%), LC-MS m/z: 533[ M+H] ⁺ ;

2), (E)-N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl) -4-(Dimethylamino)butan -Synthesis of 2-enamide

Dissolve ((E)-(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(4-(dimethylamino)butan-2- A mixed solution of enamido)benzyl)carbamic acid tert-butyl ester (80 mg, 0.11 mmol) in 2,2,2-trifluoroacetic acid (0.2 mL) and dichloromethane (0.8 mL) was stirred at room temperature for 4 hours. The mixture was The reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (E)-N-(3-(((( 5-Cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-4-(dimethylamino)but-2-enamide (60mg, yield: 92.4%), LC-MS: m/z=433[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.83 (s, 1H), 7.63 (s, 1H), 7.59 (d, J = 8.0Hz, 1H), 7.34 (t, J = 8Hz, 1H), 7.17(d,J＝8Hz,1H),6.88–6.81(m,1H),6.36(d,J＝16Hz,1H),5.69(s,1H),4.65(s,2H),3.57-3.51(m ,2H),3.24-3.17(m,1H),2.58(d,J＝12.5Hz,6H),1.98–1.92(m,1H),1.32(d,J＝8Hz,6H),0.95–0.93(m ,4H).

Example 63, (Z)-N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl Synthesis of )-2-methylbut-2-enamide (compound 63):

1), (Z)-(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(2-methylbut-2-enamido) )Synthesis of benzyl)carbamic acid tert-butyl ester

Dissolve (3-aminobenzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (50 mg, 0.12 mmol), (Z)-2-methylbut-2-enoic acid (20 mg, 0.20 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (70 mg, 0.25 mmol) and 1- A solution of methyl-1H-imidazole (40 mg, 0.49 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95% elution) (Z)-(5-cyclopropyl-3-isopropylpyrazolo[1, tert-butyl 5-a]pyrimidin-7-yl)(3-(2-methylbut-2-enamido)benzyl)carbamate (37 mg, yield: 61.9%), LC-MS m/z :504[M+H] ⁺ ;

2), (Z)-N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl) -Synthesis of 2-methylbut-2-enamide

At room temperature, (Z)-(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(2-methylbutyl- To a solution of tert-butyl 2-enamido)benzyl)carbamate (37 mg, 0.07 mmol) in dichloromethane (0.9 mL), 2,2,2-trifluoroacetic acid (0.3 mL) was added dropwise. The resulting mixed solution was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95% elution) to obtain (Z)-N-(3-(((5-cyclopropyl-3-iso) Propylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-2-methylbut-2-enamide (13 mg, yield: 43.8%), LC-MS m/z:404[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.87 (s, 1H), 7.61 (s, 1H), 7.53 (d, J = 8.0Hz, 1H), 7.31 (t, J = 8.0Hz, 1H) ,7.13(d,J＝8.0Hz,1H),6.47–6.40(m,1H),5.69(s,1H),4.62(s,2H),3.24–3.16(m,1H),1.98–1.92(m ,1H),1.88 (t,J＝1.2Hz,3H),1.80(dd,J＝6.8,0.8Hz,3H),1.31(d,J＝6.8Hz,6H),0.96–0.90(m,4H).

Example 64, N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)cyclobutan- Synthesis of 1-ene-1-carboxamide (compound 64):

1), (3-(cyclobut-1-en-1-carboxamido)benzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl )Synthesis of tert-butyl carbamate

Dissolve (3-aminobenzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (100 mg, 0.24 mmol), Cyclbut-1-ene-1-carboxylic acid (35 mg, 0.35 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (135 mg, 0.35 mmol) and N, N-diisopropylethylamine (153 mg, 1.19 mmol) in N, N-dimethylformamide (1 mL) were stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=0-100%) to obtain (3-(cyclobut-1-en-1-carboxamido)benzyl)(5-cyclopropyl-3- Isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate tert-butyl ester (40 mg, yield: 33%), LC-MS m/z: 501[M+H] ⁺ ;

2), N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)cyclobutan-1 -Synthesis of ene-1-carboxamide

To the solution is (3-(cyclobut-1-en-1-carboxamido)benzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl ) tert-butyl carbamate (40 mg, 0.08 mmol) in dichloromethane (0.9 mL), 2,2,2-trifluoroacetic acid (0.3 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain N-(3-(((5-cyclopropyl-3-isopropyl) Pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)cyclobut-1-ene-1-carboxamide (20 mg, yield: 62.5%), LC-MS: m /z＝402[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.90 (s, 1H), 7.70 (s, 1H), 7.57 (d, J = 8.0Hz, 1H), 7.33 (t, J = 7.6Hz, 1H) ,7.16(d,J＝8.0Hz,1H),6.77(s,1H),5.73(s,1H),4.69(s,2H),3.25-3.19(m,1H),2.79(t,J＝2.8 Hz,2H),2.49(t,J＝2.4Hz,2H),2.04-1.98(m,1H),1.33(d,J＝7.2Hz,6H),1.04(d,J＝8.4Hz,2H), 0.99-0.95(m,2H)

Example 65, (R)-2-fluoro-N-(3-(4-(((8-isopropyl-2-(piperidin-3-yloxy))pyrazolo[1,5-a Synthesis of ][1,3,5]triazin-4-yl)amino)methyl)indoline-1-carbonyl)phenyl)-N-methacrylamide (compound 65):

1), N-((1H-indol-4-yl)methyl)-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5] Synthesis of triazin-4-amine

Dissolve 4-chloro-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1400mg, 5.76mmol), (1H-indola A solution of indol-4-yl)methylamine (982 mg, 6.92 mmol) and N,N-diisopropylethylamine (2229 mg, 17.28 mmol) in acetonitrile (5 mL) was stirred at 20°C for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to obtain N-((1H-indol-4-yl)methyl)-8-isopropyl-2-(methyl) Thio)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1000 mg, yield: 49.0%), LC-MS m/z: 353[M+H] ⁺ ;

2), N-(Indolin-4-ylmethyl)-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine- Synthesis of 4-amines

Dissolve N-((1H-indol-4-yl)methyl)-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5] A solution of triazin-4-amine (1000 mg, 2.83 mmol) and sodium cyanoborohydride (535 mg, 8.50 mmol) in acetic acid (5 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure, then diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which could be directly used in the next step without further purification. LC-MS m/z: 355[M+H] ⁺ ;

3), 4-(((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl) Synthesis of Indoline-1-carboxylic acid benzyl ester

Dissolve N-(Indolin-4-ylmethyl)-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine- A mixed solution of 4-amine (1000 mg, 2.82 mmol), sodium bicarbonate (473 mg, 5.63 mmol) and benzyl chloroformate (718 mg, 4.22 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50%) to obtain 4-(((8-isopropyl-2-(methylthio)pyrazolo[1,5-a]) [1,3,5]Triazin-4-yl)amino)methyl)indoline-1-carboxylic acid benzyl ester (1000 mg, yield: 72.4%), LC-MS m/z: 489[ M+H] ⁺ ;

4), 4-(((8-isopropyl-2-(methylsulfonyl)pyrazole[1,5-a][1,3,5]triazin-4-yl)amino)methyl) Synthesis of Indoline-1-carboxylic acid benzyl ester

Will dissolve 4-(((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl) A solution of indoline-1-carboxylic acid benzyl ester (1000 mg, 2.04 mmol) and m-chlorobenzoic acid (1058 mg, 6.13 mmol) in toluene (60 mL) was stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50%) to obtain 4-(((8-isopropyl-2-(methylsulfonyl)pyrazole) [1,5-a] [1,3,5]Triazin-4-yl)amino)methyl)indoline-1-carboxylic acid benzyl ester (600 mg, yield: 56.4%), LC-MS m/z: 521 [M+ H] ⁺ ;

5), (R)-4-((((2-((1-(tert-butoxycarbonyl)piperidin-3-yl)oxy)-8-isopropylpyrazolo[1,5- Synthesis of a][1,3,5]triazin-4-yl)amino)methyl)indoline-1-carboxylic acid benzyl ester

Will dissolve 4-(((8-isopropyl-2-(methylsulfonyl)pyrazole[1,5-a][1,3,5]triazin-4-yl)amino)methyl) Indoline-1-carboxylic acid benzyl ester (400 mg, 0.77 mmol), a solution of (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (196 mg, 0.92 mmol) and sodium hydride (46 mg, 1.15 mmol) in dichloromethane (16 mL) was stirred at room temperature. 1 hour. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-65% elution) to obtain (R)-4-((((2-((1-(tert-butoxycarbonyl))piperidine- 3-yl)oxy)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)indoline-1-carboxy Acid benzyl ester (400mg, yield: 81.0%), LC-MS m/z: 642[M+H] ⁺ ;

6), (R)-3-((4-((Indolin-4-ylmethyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5] Synthesis of triazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester

Dissolve (R)-4-((((2-((1-(tert-butoxycarbonyl)piperidin-3-yl)oxy)-8-isopropylpyrazolo[1,5- a][1,3,5]triazin-4-yl)amino)methyl)indoline-1-carboxylic acid benzyl ester (400 mg, 0.62 mmol) and palladium on carbon (188 mg) in methanol (3 mL) The solution was stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixed reaction solution was filtered, and the filter cake was washed with methanol. The filtrate was collected and concentrated under reduced pressure to obtain the crude product, which could be used directly in the next step without further purification, LC-MS m/z :508[M+H] ⁺ ;

7), (R)-3-((4-(((1-(3-(2-fluoro-N-methacrylamido)benzoyl)indolin-4-yl)methyl)amino Synthesis of )-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester

Dissolve (R)-3-((4-((Indolin-4-ylmethyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5] Triazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (120 mg, 0.23 mmol), 3-(2-fluoro-N-methacrylamide) benzoic acid (78 mg, 0.35 mmol) , 1-methylimidazole (77mg, 0.94mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (132mg, 0.47mmol) in N,N-dimethylformamide ( 2 mL) solution and stirred at room temperature for 1 hour. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: water = 0-60% elution) to obtain (R)-3-((4-(((1-(3-(2-fluoro-N-methylpropene) Amido)benzoyl)indolin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl) Oxy)piperidine-1-carboxylic acid tert-butyl ester (110 mg, yield: 65.3%), LC-MS m/z: 713 [M+H] ⁺ ;

8), (R)-2-fluoro-N-(3-(4-(((8-isopropyl-2-(piperidin-3-yloxy))pyrazolo[1,5-a] Synthesis of [1,3,5]triazin-4-yl)amino)methyl)indoline-1-carbonyl)phenyl)-N-methacrylamide

Dissolve (R)-3-((4-(((1-(3-(2-fluoro-N-methacrylamide)benzoyl)indolin-4-yl)methyl)amino )-8-Isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (100mg, 0.14mmol) A solution of dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 0-95% elution) to obtain (R)-2-fluoro-N-(3-(4-((8-isopropyl-2-(piperidine) -3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)indoline-1-carbonyl)phenyl)-N - Methacrylamide (30 mg, yield: 34.9%), LC-MS m/z: 613[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.86(s,1H),7.65–7.52(m,2H),7.51–7.40(m,2H),7.08(s,2H),5.41–5.17(m ,2H),5.09(d,J＝16.0Hz,1H),4.75(s,2H),4.09(s,2H),3.44(dd,J＝13.2,3.6Hz,1H),3.36(d,J＝ 6.4Hz,4H),3.22(dd,J＝20.0,11.6Hz,3H),3.07(dt,J＝13.6,8.8Hz,2H),2.13–2.01(m,2H),2.01–1.89(m,1H ),1.79(dd,J＝9.6,4.2Hz,1H),1.30(d,J＝6.8Hz,6H).

Example 66, (R)-N-(3-(4-((((2-((6,6-dimethylpiperidin-3-yl)oxy)oxy)-8-isopropylpyrazolo [1,5-a][1,3,5]triazin-4-yl)amino)methyl)indoline-1-carbonyl)phenyl)-2-fluoro-N-methacrylamide ( Synthesis of compound 66):

1), (R)-4-((((2-((1-(tert-butoxycarbonyl)-6,6-dimethylpiperidin-3-yl)oxy)-8-isopropyl Synthesis of pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)indoline-1-carboxylic acid benzyl ester

The dissolved 4-(((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl ) Indoline-1-carboxylic acid benzyl ester (200 mg, 0.38 mmol), (R)-5-hydroxy-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (105 mg, 0.46 mmol) ) and a solution of sodium hydride (46 mg, 1.15 mmol) in tetrahydrofuran (3 mL) was stirred at room temperature for 1 hour, and the mixed reaction solution was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-65%)) to obtain (R)-4-((((2-((1-(tert-butoxycarbonyl))-6,6 -Dimethylpiperidin-3-yl)oxy)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)di Hydroindole-1-carboxylic acid benzyl ester (200 mg, yield: 77.6%), LC-MS m/z: 670 [M+H] ⁺ ;

2), (R)-5-((4-((Indolin-4-ylmethyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5] Synthesis of triazin-2-yl)oxytert-butyl)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

Dissolved (R)-4-((((2-((1-(tert-butoxycarbonyl))-6,6-dimethylpiperidin-3-yl)oxy)-8-isopropyl Pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)indoline-1-carboxylic acid benzyl ester (200 mg, 0.30 mmol) and palladium on carbon (94 mg) in methanol (3 mL), stirred at room temperature for 1 hour under hydrogen atmosphere. Filter the mixed reaction solution, wash the filter cake with methanol, collect the filtrate and concentrate under reduced pressure to obtain the crude product, which can be used directly in the next step without further purification. .LC-MS m/z: 536[M+H] ⁺ ;

3), (R)-5-((4-(((1-(3-(2-fluoro-N-methacrylamido)benzoyl)indolin-4-yl)methyl)amino )-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert. Synthesis of butyl ester

Dissolve (R)-5-((4-((Indolin-4-ylmethyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5] Triazin-2-yl)oxytert-butyl)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (120 mg, 0.22 mmol), 3-(2-fluoro-N-methylpropene Amino)benzoic acid (75 mg, 0.34 mmol), 1-methylimidazole (73 mg, 0.90 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (125 mg, 0.44 mmol) A solution of N,N-dimethylformamide (2 mL) was stirred at room temperature for 1 hour. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: water = 0-60% elution) to obtain (R)-5-((4-(((1-(3-(2-fluoro-N-methyl) Acrylamide)benzoyl)indolin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl )oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (110 mg, yield: 66.1%), LC-MS m/z: 741 [M+H] ⁺ ;

4), (R)-N-(3-(4-((((2-((6,6-dimethylpiperidin-3-yl)oxy))-8-isopropylpyrazolo[ Synthesis of 1,5-a][1,3,5]triazin-4-yl)amino)methyl)indoline-1-carbonyl)phenyl)-2-fluoro-N-methacrylamide

Dissolve (R)-5-((4-(((1-(3-(2-fluoro-N-methacrylamide)benzoyl)indolin-4-yl)methyl)amino )-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert. A solution of butyl ester (100 mg, 0.13 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at 25°C for 1 hour. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 0-95% elution) to obtain (R)-N-(3-(4-((((2-((6,6-dimethylpiperidine- 3-yl)oxy)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)indoline-1-carbonyl )Phenyl)-2-fluoro-N-methacrylamide (30 mg, yield: 34.6%), LC-MS m/z: 641 [M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.87(s,1H),7.62–7.41(m,4H),7.09(s,2H),5.35–5.15(m,2H),5.09(d,J ＝16.8Hz,1H),4.76(s,2H),4.58(s,1H),4.11(s,2H),3.45(d,J＝13.6Hz,1H),3.37(s,4H),3.22(t ,J＝8.0Hz,2H),3.11–3.01(m,1H),2.08–2.01(m,2H),1.94(d,J＝6.8Hz,1H),1.64(d,J＝14.0Hz,1H) ,1.40(d,J＝4.0Hz,6H),1.31(d,J＝6.8Hz,6H).

Example 67, N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-3- Synthesis of methylbut-2-enamide (compound 67):

1), (5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) (3-(3-methylbut-2-enamido)benzyl) Synthesis of tert-butyl carbamate

At 0°C, dissolve (3-aminobenzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester ( To a solution of 100 mg, 0.24 mmol) in dichloromethane (4 mL), N,N-diisopropylethylamine (92 mg, 0.71 mmol) and 3-methylbut-2-enoyl chloride (31 mg, 0.28 mmol) were added. The resulting mixed reaction solution was stirred at room temperature overnight. The mixed reaction solution was added to MeOH solution and purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ H ₂ O = 5-95% elution) to obtain (5-cyclopropyl-3-isopropylpyrazole) Tert-butyl[1,5-a]pyrimidin-7-yl)(3-(3-methylbut-2-enamido)benzyl)carbamate (80 mg, yield: 66.8%), LC- MS m/z:504[M+H] ⁺ ;

2), N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-3-methyl Synthesis of butylbut-2-enamide

In solution, there is (5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(3-methylbut-2-enamido)benzyl) To a solution of tert-butyl carbamate (80 mg, 0.16 mmol) in dichloromethane (2.0 mL), 2,2,2-trifluoroacetic acid (0.5 mL) was added. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction solution was concentrated under reduced pressure, and the residue was purified by C18 column chromatography (acetonitrile: containing 0.1% NH 3·H 2O = 5-95% elution) to obtain N-(3-(((5-cyclopropyl- 3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-3-methylbut-2-enamide (20 mg, yield: 31.2%), LC-MS m/z: 404[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ7.82(s,1H),7.59(s,1H),7.51(s,1H),7.30(t,J＝8.0Hz,1H),7.12(d,J＝ 8.0Hz,1H),5.84(s,1H),5.70(s,1H),4.63(s,2H),3.24–3.18(m,1H),2.17(s,3H),1.96(s,1H), 1.90(s,3H),1.33(s,3H),1.31(s,3H),0.96(s,1H),0.94(s,3H).

Example 68, (R)-3-acrylamido-N-(3-((8-isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a] Synthesis of [1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide (compound 68):

1), (R)-3-((4-((3-(3-Acrylamidobenzoylamino)benzyl)amino)-8-isopropylpyrazolo[1,5-a][ Synthesis of tert-butyl 1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylate

Dissolve (R)-3-((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2 -(yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.31 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl N,N-dimethyl urea hexafluorophosphate (178 mg, 0.47 mmol), N,N-diisopropylethylamine (120 mg, 0.93 mmol) and 3-acrylamidobenzoic acid (89 mg, 0.47 mmol) Formamide (2 mL) solution was stirred at room temperature for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain (R)-3-((4-((3-(3-acrylamidobenzene) Carboxylamino)benzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylic acid tert. Butyl ester (100mg, yield: 50.0%), LC-MS m/z: 655[M+H] ⁺ ;

2), (R)-3-acrylamido-N-(3-((8-isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][ Synthesis of 1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide

At room temperature, (R)-3-((4-((3-(3-acrylamidobenzoylamino)benzyl)amino)-8-isopropylpyrazolo[1,5 -In a solution of [1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.15 mmol) in dichloromethane (1.5 mL), add 2 dropwise ,2,2-trifluoroacetic acid (0.5mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: 0.1% formic acid in pure water = 5%-95% elution) to obtain (R)-3-acrylamido-N-(3-((8-isopropyl Base-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide ( 70mg, yield: 82.6%), LC-MS m/z: 555[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.20 (s, 1H), 7.86 (s, 1H), 7.77 (s, 1H), 7.61 (d, J = 28.0Hz, 2H), 7.49-7.42 ( m,1H),7.38-7.30(m,2H),7.16(d,J＝8Hz,1H),5.23(s,1H),4.57(s,2H),4.45(d,J＝12.0Hz,1H) ,3.09-3.00(m,2H),2.88-2.80(m,1H),2.72(d,J＝8.0Hz,2H),2.56-2.44(m,2H),2.32(s,1H),1.98-1.91 (m,1H),1.78(d,J＝12.0Hz,1H),1.68-1.56(m,1H),1.31(s,3H),1.29(s,3H).

Example 69, N-(3-(((5-(((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1, Synthesis of 5-a]pyrimidin-7-yl)amino)methyl)phenyl)-3-propionamidobenzamide (compound 69):

1), (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-(3-propionamidobenzoylamino)benzyl)amino)-3-isopropylpyra Synthesis of Azolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Under room temperature and nitrogen protection, dissolve (3R, 4R)-4-((((7-(3-aminobenzyl)(tert-butoxycarbonyl)amino)-3- Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl tert-butyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol) and 3- To a solution of propionylaminobenzoic acid (40 mg, 0.21 mmol) in N,N-dimethylformamide (2.0 mL), 2-(7-azobenzotriazole)-N,N,N' was added, N'-tetramethylurea hexafluorophosphate (100 mg, 0.264 mmol) and N,N-diisopropylethylamine (69 mg, 0.53 mmol). The resulting mixed reaction solution was stirred at room temperature for 3 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (3R, 4R)-4-(((7-(tert-butoxy ylcarbonyl)(3-(3-propionamidobenzoylamino)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)- 3-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (40 mg, yield: 31%), LC-MS m/z: 785[M+H] ⁺ ;

2), N-(3-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5 -Synthesis of -a]pyrimidin-7-yl)amino)methyl)phenyl)-3-propionamidobenzamide

There is (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-(3-propionamidobenzoylamino)benzyl)amino)-3-isopropylpyridine) in solution. Azolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.051 mmol) in dichloromethane (2.0 mL), 2,2,2-Trifluoroacetic acid (0.5 mL) was added. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain N-(3-(((5-(((3R, 4R)- 3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-3-propionamide methyl benzamide (20 mg, yield: 67%), LC-MS m/z: 5859[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ8.46(s,1H),8.16(s,1H),7.76(s,1H),7.67(s,1H),7.66–7.57(m,3H),7.40( dt,J＝33.6,8.0Hz,2H),7.19(d,J＝7.6Hz,1H),5.20(s,1H),4.57(d,J＝2.8Hz,2H),3.97(d,J＝14.0 Hz,1H),3.50(d,J＝9.2Hz,1H),3.37(d,J＝4.0Hz,1H),3.22–3.10(m,1H),3.00(ddd,J＝33.6,18.8,9.6Hz ,2H),2.77(t,J＝11.6Hz,1H),2.42(q,J＝7.6Hz,2H),1.91(t,J＝9.2Hz,1H),1.63(dd,J＝22.0,9.6Hz ,2H),1.28(t,J＝7.2Hz,6H),1.21(t,J＝7.6Hz,3H).

Example 70, (S)-3-acrylamido-N-(3-(((2-((6,6-dimethylpiperidin-3-yl)amino))-8-isopropylpyrazole Synthesis of [1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide (compound 70):

1), (S)-N ² -(6,6-dimethylpiperidin-3-yl)-8-isopropyl-N ⁴ -(3-nitrobenzyl)pyrazolo[1,5 -Synthesis of [a][1,3,5]triazine-2,4-diamine

At room temperature, 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5] is dissolved in the solution. To a solution of triazin-4-amine (100 mg, 0.26 mmol) and (3S)-6,6-dimethylpiperidin-3-amine (167 mg, 1.3 mmol) in dimethyl sulfoxide (3 mL), fluorine was added Cesium compound (79 mg, 0.52 mmol). The resulting mixture was heated to 120°C and stirred for 16 hours. The mixed reaction solution was diluted with water (10 mL), and extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 30-50% elution) to obtain (S)-N ² -(6,6-dimethylpiperidin-3-yl)-8-iso Propyl-N ⁴ -(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (66 mg, yield: 58.9%), LC-MS m/z: 439[M+H] ⁺ ;

2), (S)-5-((tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-8-isopropylpyrazolo[1,5- Synthesis of a][1,3,5]triazin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

(S)-N ² -(6,6-dimethylpiperidin-3-yl)-8-isopropyl-N ⁴ -(3-nitrobenzyl)pyrazolo[1,5 -a][1,3,5]triazine-2,4-diamine (130 mg, 0.30 mmol), di-tert-butyl dicarbonate (262 mg, 1.2 mmol) and 4-dimethylaminopyridine (110 mg, 0.90 mmol) in tetrahydrofuran (3 mL), triethylamine (91 mg, 0.90 mmol) was added. The resulting mixed reaction solution was heated to 50° C. and stirred for 16 hours. The mixed reaction solution was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 50-70% elution) to obtain (S)-5-((tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)() 3-nitrobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)-2,2-dimethylpiper Tert-butylpyridine-1-carboxylate (115 mg, yield: 52.5%), LC-MS m/z: 739[M+H] ⁺ ;

3), (S)-5-((4-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-8-isopropylpyrazolo[1,5-a][1,3 ,5] Synthesis of triazin-2-yltert-butoxycarbonyl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

At room temperature, dissolve (S)-5-((tert-butoxycarbonyl)(4-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-8-isopropylpyrazolo [1,5-a][1,3,5]triazin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (120 mg, 0.16 mmol) in ethanol ( 4 mL) solution and ammonium chloride solution (1 mL), add iron (53 mg, 0.95 mmol), and the resulting mixed reaction solution was heated to 70°C and stirred for 2 hours. After cooling, the mixed reaction solution was filtered through a Celite pad and washed with ethyl acetate (3×20 mL). The filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-30% elution) to obtain (S)-5-((4-((3-aminobenzyl))(tert-butoxycarbonyl)amino )-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yltert-butoxycarbonyl)amino)-2,2-dimethylpiperidine-1 -tert-butyl carboxylate (105 mg, yield: 91.2%), LC-MS m/z: 709 [M+H] ⁺ ;

4), (S)-5-((4-((3-(3-acrylamidobenzoylamino)benzyl)(tert-butoxycarbonyl)amino)-8-isopropylpyrazolo[ Synthesis of tert-butyl 1,5-a][1,3,5]triazin-2-yl)(tert-butoxycarbonyl)amino)-2,2-dimethylpiperidine-1-carboxylate

(S)-5-((4-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-8-isopropylpyrazolo[1,5-a][1,3 ,5]Triazin-2-yltert-butoxycarbonyl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (170mg, 0.28mmol), 3-(prop-2-ene To a solution of amido)benzoic acid (64 mg, 0.34 mmol) in N,N-dimethylformamide (5 mL), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (157 mg , 0.56 mmol) and 1-methylimidazole (46 mg, 0.56 mmol). The mixed reaction solution was stirred at room temperature for 1 hour. The mixed reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by C18 column chromatography (containing acetonitrile and pure water containing 0.1% NH ₃ ·H ₂ O = 0-100% elution) to obtain (S)-5-((4-((3-(3-propene) Amidobenzoylamino)benzyl)(tert-butoxycarbonyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)( tert-butoxycarbonyl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (67 mg, yield: 31.6%), LC-MS m/z: 882[M+H] ⁺ ;

5), (S)-3-Acrylamide-N-(3-(((2-((6,6-dimethylpiperidin-3-yl)amino))-8-isopropylpyrazolo [1,5-a][1,3,5]triazine-4- Synthesis of methyl)amino)methyl)phenyl)benzamide

Dissolve (S)-5-((4-((3-(3-acrylamidobenzoylamino)benzyl)(tert-butoxycarbonyl)amino)-8-isopropylpyrazolo[ 1,5-a][1,3,5]triazin-2-yl)(tert-butoxycarbonyl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.08 mmol) of dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) were stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: 0-100% elution with acetonitrile containing 0.1% formic acid) to obtain (29 mg, 62.8%), LC-MS m/z: 582 [M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.55(s,1H),7.88(s,1H),7.77–7.61(m,3H),7.54–7.43(m,2H),7.34(t,J ＝7.8Hz,1H),7.19(d,J＝7.6Hz,1H),6.42(dd,J＝9.4,6.0Hz,2H),5.81(dd,J＝9.4,2.6Hz,1H),4.76(s ,2H),4.08(s,1H),3.07–2.91(m,2H),2.03-1.89(m,2H),1.80-1.76(s,2H),1.29(d,J＝3.7Hz,12H), 0.90(s,1H).

Example 71, (S)-N-(1-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino))-3-isopropylpyrazolo[1 Synthesis of ,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-1H-pyrazol-4-yl)acrylamide (compound 71):

1) Synthesis of (2-(4-nitro-1H-pyrazol-1-yl)benzyl)carbamic acid tert-butyl ester

At room temperature, (2-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (100 mg, 0.398 mmol) and 4-nitro-1H-pyrazole (75 mg, 0.66 mmol) were dissolved in To a solution of methanol (2 mL), sodium hydroxide (223 mg, 5.58 mmol) and cuprous chloride (279 mg, 2.79 mmol) were added. The obtained mixed reaction liquid was heated to 60°C and stirred for 16 hours. After cooling, the resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (2-(4-nitro-1H-pyrazol-1-yl) ) Benzyl) tert-butyl carbamate (50 mg, yield: 39.3%), LC-MS m/z: 319[M+H] ⁺ ;

2), Synthesis of (2-(4-nitro-1H-pyrazol-1-yl)phenyl)methanamine

To a solution of (2-(4-nitro-1H-pyrazol-1-yl)benzyl)carbamic acid tert-butyl ester (500mg, 1.57mmol) in dichloromethane (6mL) at room temperature , add 2,2,2-trifluoroacetic acid (2mL) dropwise. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which could be directly used in the next step without further purification. LC-MS m/z: 219[M+H] ⁺ ;

3), 5-chloro-3-isopropyl-N-(2-(4-nitro-1H-pyrazol-1-yl)benzyl)pyrazolo[1,5-a]pyrimidine-7- Synthesis of amines

At room temperature, (2-(4-nitro-1H-pyrazol-1-yl)phenyl)methanamine (340mg, 1.56mmol) and 5,7-dichloro-3-isopropylpyridine were dissolved in the solution. To a solution of azolo[1,5-a]pyrimidine (429 mg, 1.87 mmol) in isopropanol (5 mL), N,N-diisopropylethylamine (604 mg, 4.68 mmol) was added. The obtained mixed reaction liquid was heated to 60°C and stirred for 4 hours. After cooling, the obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with saturated brine (1×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain 5-chloro-3-isopropyl-N-(2-(4 -Nitro-1H-pyrazol-1-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (500 mg, yield: 78.2%), LC-MS m/z: 412[ M+H] ⁺ ;

4), (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) (2-(4-nitro-1H-pyrazol-1-yl)benzyl) Synthesis of tert-butyl carbamate

At room temperature, 5-chloro-3-isopropyl-N-(2-(4-nitro-1H-pyrazol-1-yl)benzyl)pyrazolo[1,5-a] is dissolved in the solution. To a solution of pyrimidin-7-amine (500 mg, 1.22 mmol) in tetrahydrofuran (5 mL), di-tert-butyl dicarbonate (530 mg, 2.43 mmol) and 4-dimethylaminopyridine (74 mg, 0.608 mmol) were added. The resulting mixed reaction solution was stirred at 50°C for 2 hours. After cooling, the resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine (1×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (5-chloro-3-isopropylpyrazolo[1,5 -a]pyrimidin-7-yl)(2-(4-nitro-1H-pyrazol-1-yl)benzyl)carbamic acid tert-butyl ester (500 mg, yield: 80.4%), LC-MS m/ z:512[M+H] ⁺ ;

5), (2-(4-amino-1H-pyrazol-1-yl)benzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino Synthesis of tert-butyl formate

At room temperature, (5-chloro-3-isopropylpyrazolo[1,5-A]pyrimidin-7-yl)(2-(4-nitro-1H-pyrazol-1-yl) was dissolved into ) To a solution of benzyl)tert-butyl carbamate (250 mg, 0.489 mmol) and iron (110 mg, 1.96 mmol) in ethanol (4 mL), aqueous ammonium chloride solution (1 mL) was added. The resulting mixed reaction solution was heated to 70°C and stirred for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with saturated brine (1×40 mL), dried over anhydrous N sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (2-(4-amino-1H-pyrazol-1-yl) )benzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (160 mg, yield: 68.0%), LC-MS m/ z: 482[M+H] ⁺ ;

6), (2-(4-Acrylamido-1H-pyrazol-1-yl)benzyl) (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl )Synthesis of tert-butyl carbamate

At room temperature, (2-(4-amino-1H-pyrazol-1-yl)benzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidine-7 was dissolved into -To a solution of tert-butyl carbamate (160 mg, 0.333 mmol) and acryloyl chloride (36 mg, 0.40 mmol) in tetrahydrofuran (2 mL), sodium bicarbonate (33.5 mg, 0.40 mmol) and water (2 mL) were added. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixture was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The remaining residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (2-(4-acrylamide-1H-pyrazole-1) -(yl)benzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (100 mg, yield: 56.2%), LC-MS m/z: 536[M+H] ⁺ ;

7), (S)-(3-(4-acrylamido-1H-pyrazol-1-yl)benzyl)(5-((6,6-dimethylpiperidin-3-yl)amino) Synthesis of tert-butyl 3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate

At room temperature, (2-(4-acrylamido-1H-pyrazol-1-yl)benzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidine was dissolved into -7-yl)carbamic acid tert-butyl ester (100 mg, 0.187 mmol) and (S)-6,6-dimethylpiperidin-3-amine (29 mg, 0.224 mmol) in 1,6-dioxane ( 2mL) solution, add (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-di Hydrogen-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (16 mg, 0.019 mmol) and cesium carbonate (183 mg, 0.561 mmol). The resulting mixed reaction solution was heated at 90°C under argon protection and stirred for 4 hours. After cooling, the resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The remaining residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (S)-(3-(4-acrylamide-1H-) Pyrazol-1-yl)benzyl)(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-7 -tert-butyl carbamate (30 mg, yield: 25.6%), LC-MS m/z: 628 [M+H] ⁺ ;

8), (S)-N-(1-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino))-3-isopropylpyrazolo[1, Synthesis of 5-a]pyrimidin-7-yl)amino)methyl)phenyl)-1H-pyrazol-4-yl)acrylamide

In solution, there is (S)-(3-(4-acrylamido-1H-pyrazol-1-yl)benzyl)(5-((6,6-dimethylpiperidin-3-yl)amino) -To a solution of tert-butyl 3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (30 mg, 0.048 mmol) in dichloromethane (0.6 mL), add 2,2, 2-Trifluoroacetic acid (0.2 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (10 mg, yield: 39.7%), LC-MS m/z :528[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.29(s,1H),7.86(s,1H),7.60-7.58(m,2H),7.46-7.43(m,3H),6.39-6.32(m ,2H),5.79-5.76(m,1H),5.06(s,1H),4.47(s,2H),3.92-3.87(m,1H),3.23-3.16(m,1H),3.05-3.02(m ,1H),2.80-2.72(m,1H),1.93-1.92(m,1H),1.71-1.66(m,2H),1.59-1.56(m,1H),1.28-1.26(m,6H),1.24 -1.22(m,6H).

Example 72, (R)-N-(3-((5-((6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5- Synthesis of a]pyrimidin-7-yl)amino)phenyl)acrylamide (compound 72):

1), (R)-5-((7-((3-Acrylamidophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine- Synthesis of 5-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

Tert-butyl (3-acrylamidophenyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (154 mg, 0.67 mmol) was dissolved in To the toluene solution (2mL), add (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyldi-tert-butylphosphine (74mg, 0.134mmol), carbonic acid Cesium (753 mg, 2.01 mmol) and tert-butyl (3-acrylamidophenyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (418 mg ,0.92mmol). The resulting mixed reaction solution was heated at 140°C in the microwave and stirred for 2 hours. The obtained mixed reaction solution was diluted with MeOH and purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95%) to obtain (R)-5-((7-((3- Acrylamidophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2,2-dimethylpiperidine -1-tert-butylcarboxylate (100mg, yield: 45.6%), LC-MS m/z: 649[M+H] ⁺ ;

2), (R)-N-(3-((5-((6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a Synthesis of ]pyrimidin-7-yl)amino)phenyl)acrylamide

There is (R)-5-((7-((3-acrylamidophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine- To a solution of 5-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.062 mmol) in dichloromethane (2.0 mL), 2,2,2-tris Fluoroacetic acid (0.5 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3·H 2O = 5-95% elution) to obtain (R)-N-(3-((5-((6,6-di Methylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)acrylamide (20 mg, yield: 72.4%) . LC-MS m/z:449[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ8.02(s,1H),7.86(s,1H),7.42(t,J＝8.0Hz,1H),7.33(d,J＝8.0Hz,1H),7.16 (d,J＝8.8Hz,1H),6.51–6.33(m,2H),5.97(s,1H),5.81(d,J＝11.6Hz,1H),5.50(s,1H),3.57(d, J＝14.0Hz,1H),3.48(s,1H),3.13(d,J＝6.4Hz,1H),2.11(s,2H),2.01(d,J＝13.6Hz,1H),1.69(d, J＝14.4Hz,1H),1.44(s,6H),1.36(d,J＝6.8Hz,6H).

Example 73, N-(3-(((3-isopropyl-5-((piperidin-4-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino )Synthesis of methyl)phenyl)acrylamide (compound 73):

1), 4-((((7-((3-acrylamidobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Synthesis of tert-butyl)amino)methyl)piperidine-1-carboxylate

At room temperature and under nitrogen protection, dissolve (3-acrylamidobenzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (50 mg, 0.11 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (27.4 mg, 0.13 mmol) and cesium carbonate (108 mg, 0.33 mmol) in 1,4-dioxane ( 1mL) solution, add (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3- Dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (9.24 mg, 0.011 mmol). The resulting mixed reaction liquid was heated to 90°C and stirred for 4 hours under the protection of nitrogen gas. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-60% elution) to obtain 4-((((7-((3-acrylamidobenzyl))(tert-butoxycarbonyl)amino )-3-Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (30 mg, yield: 43.5%), LC- MS m/z: 648[M+H] ⁺ ;

2), N-(3-(((3-isopropyl-5-((piperidin-4-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino) Synthesis of methyl)phenyl)acrylamide

The dissolved 4-(((7-((3-acrylamidobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl )Amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.046 mmol) mixed solution in dichloromethane (0.6 mL) and 2,2,2-trifluoroacetic acid (0.2 mL) was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 4HCO 3 = 20 to 70% elution) to obtain N-(3-(((3-isopropyl-5-((piperidine- 4-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (9 mg, yield: 43.5%), LC-MS m/z :448[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.65 (s, 2H), 7.56 (d, J = 8.0Hz, 1H), 7.32 (t, J = 8.0Hz, 1H), 7.16 (d, J = 7.6Hz,1H),6.44-6.31(m,2H),5.75(dd,J＝9.2,2.4Hz,1H),5.13(s,1H),4.55(d,J＝9.2Hz,2H),3.36( d,J＝13.2Hz,3H),3.28(s,1H),3.10-3.03(m,1H),2,94-2.86(m,2H),1.95-1.87(m,3H),1.46-1.35( m,2H),1.29(d,J＝6.8Hz,6H).

Example 74, (R)-3-(2-fluoroacrylamido)-N-(3-(((8-isopropyl-2-(piperidin-3-yloxy))pyrazolo[1 Synthesis of ,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide (compound 74):

1), (R)-3-((4-((3-(3-(2-fluoroacrylamido)benzamido)benzyl)amino)-8-isopropylpyrazolo[1, Synthesis of tert-butyl 5-a][1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylate

At room temperature, (R)-3-((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5] Triazin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (20 mg, 0.083 mmol) and 3-(2-fluoroacrylamido)benzoic acid (11 mg, 0.050 mmol) in acetonitrile (1.5 mL ) solution, add N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (24mg, 0.083mmol) and 1-methyl-1H-imidazole (14mg, 0.166mmol). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water (50 mL) and added with ethyl acetate. Extract with ester (3 × 50 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (R)-3-((4-((3-(3- (2-fluoroacrylamido)benzamido)benzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy ) Piperidine-1-carboxylic acid tert-butyl ester (20 mg, yield: 71.6%), LC-MS m/z: 673 [M+H] ⁺ ;

2), (R)-3-(2-fluoroacrylamido)-N-(3-((8-isopropyl-2-(piperidin-3-yloxy)pyrazolo[1, Synthesis of 5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)benzamide

At room temperature, (R)-3-((4-((3-(3-(2-fluoroacrylamido)benzamido)benzyl)amino)-8-isopropylpyrazole is dissolved into A solution of tert-butyl[1,5-a][1,3,5]triazin-2-yl)oxy)piperidine-1-carboxylate (20 mg, 0.030 mmol) in dichloromethane (0.6 mL) , add 2,2,2-trifluoroacetic acid (0.2mL) dropwise. The resulting mixed reaction solution was stirred at room temperature for 2 hours. . The obtained mixed reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (R)-3-(2-fluoroacrylamido)-N- (3-(((8-isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino) Methyl)phenyl)benzamide (10 mg, yield: 58.7%), LC-MS m/z: 573[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.20–8.19(m,1H),7.84(s,1H),7.83(s,1H),7.82–7.80(m,1H),7.69(d,J ＝8.0Hz,1H),7.57(d,J＝8.0Hz,1H),7.49(t,J＝8.0Hz,1H),7.35(t,J＝8.0Hz,1H),7.21–7.19(m,1H ),5.70(dd,J＝46.8,3.6Hz,1H),5.33(dd,J＝15.2,3.6Hz,1H),5.19–5.14(m,1H),4.79(s,2H),3.24–3.20( m,1H),3.07–3.02(m,2H),2.91–2.87(m,2H),2.04–1.98(m,1H),1.93–1.84(m,2H),1.67–1.61(m,1H), 1.29(d,J＝6.8Hz,6H).

Example 75, (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5- Synthesis of a]pyrimidin-7-yl)amino)methyl)phenyl)-3-(2-fluoroacrylamido)benzamide (compound 75):

1), (S)-5-((7-((tert-butoxycarbonyl)(3-(3-(2-fluoroacrylamido)benzoylamino)benzyl)amino)-3-isopropyl Synthesis of pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

Dissolve (S)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- tert-butyl)amino)-2,2-tert-butyldimethylpiperidine-1-carboxylate (80mg, 0.13mmol), 3-(2-fluoroprop-2-enamido)benzoic acid (33mg , 0.16mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (73mg, 0.26mmol) and 1-methyl-1H-imidazole (43mg, 0.52mmol) N,N - Dimethylformamide (2 mL) solution, stirred at room temperature overnight. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 10 to 95% elution) to obtain (S)-5-((7-((tert-butoxycarbonyl)(3) -(3-(2-fluoroacrylamido)benzoylamino)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2 - Dimethylpiperidine-1-carboxylic acid tert-butyl ester (25 mg, yield: 24%), LC-MS m/z: 799[M+H] ⁺ ;

2), (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a Synthesis of ]pyrimidin-7-yl)amino)methyl)phenyl)-3-(2-fluoroacrylamido)benzamide

Dissolve (S)-5-((7-((tert-butoxycarbonyl)(3-(3-(2-fluoroacrylamido)benzoylamino)benzyl)amino)-3-isopropyl pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (25 mg, 0.031 mmol) in dichloromethane (0.031 mmol ) and 2,2,2-trifluoroacetic acid (0.2 mL) were stirred at room temperature for 0.5 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3H 2O = 10~95% elution) to obtain (S)-N-(3-(((5-((6,6-di Methylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-3-(2-fluoroacrylamide base) benzamide (1.5 mg, yield: 8.0%), LC-MS m/z: 599[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4) δ8.21 (s, 1H), 7.79 (d, J = 15.2Hz, 2H), 7.71–7.66 (m, 2H), 7.58 (s, 1H), 7.49 (t ,J＝7.9Hz,2H),7.36(t,J＝7.8Hz,2H),7.19(s,1H),5.75(dd,J＝46.5,3.4Hz,1H),5.33(dd,J＝15.2, 3.4Hz,1H),5.21(s,1H),4.58(s,2H),4.17–4.11(m,1H),3.55–3.46(m,1H),3.09(dd,J＝18.6,11.4Hz,3H ),1.99(s,1H),1.76(s,4H),1.38(d,J＝6.4Hz,6H),1.30(dd,J＝6.9,3.1Hz,6H).

Example 76, (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5- Synthesis of a]pyrimidin-7-yl)amino)methyl)phenyl)-2-fluoroacrylamide (compound 76):

1), (S)-5-((7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1,5 -Synthesis of a]pyrimidin-5-yl)amino tert-butyl)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

Dissolve (S)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- tert-butyl (amino)-2,2-tert-butyldimethylpiperidine-1-carboxylate (60 mg, 0.10 mmol), 2-fluoroprop-2-enoic acid (10.7 mg, 0.12 mmol), N ,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (55.6mg, 0.4mmol) and 1-methyl-1H-imidazole (30mg, 0.37mmol) N,N-dimethylmethane A solution of amide (1 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: containing 0.1% NH ₄ HCO ₃ =10~95% elution) to obtain (S)-5-((7-((tert-butoxycarbonyl)(3-(2) -Fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)aminotert-butyl)-2,2-dimethylpiperidine-1 -tert-butyl carboxylate (40 mg, yield: 60%), LC-MS m/z: 680 [M+H] ⁺ ;

2), (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a Synthesis of ]pyrimidin-7-yl)amino)methyl)phenyl)-2-fluoroacrylamide

Dissolve (S)-5-((7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1,5 -a] Pyrimidin-5-yl)amino tert-butyl)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.06 mmol) in dichloromethane (0.6 mL) and 2,2,2- Trifluoroacetic acid (0.2 mL) was stirred at room temperature for 0.5 hours. The mixed reaction was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: containing 0.1% NH ₄ HCO ₃ =10~95% elution) to obtain (S)-N-(3-(((5-((6,6-dimethyl) piperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-2-fluoroacrylamide (2.9 mg, 10 %), LC-MS m/z: 480[M+H] ⁺ ; 1H NMR (400MHz, MeOD-d4): δ7.69 (s, 1H), 7.66 (s, 1H), 7.56 (d, J＝ 7.9Hz,1H),7.34(t,J＝7.9Hz,1H),7.20(d,J＝7.7Hz,1H),5.69(dd,J＝46.5,3.4Hz,1H),5.29(dd,J＝ 15.2,3.4Hz,1H),5.18(s,1H),4.55(s,2H),4.18–4.11(m,1H),3.51(dd,J＝12.7,3.9Hz,1H),3.10(ddd,J ＝20.8,13.1,8.3Hz,2H),2.01–1.72(m,4H),1.39(d,J＝7.0Hz,6H),1.30(dd,J＝6.9,2.8Hz,6H).

Example 77, (E)-N-(3-((5-chloro-4-(2-oxoindolin-3-yl)pyrimidin-2-yl)amino)phenyl)-3-(4 Synthesis of -(dimethylamino)but-2-enamido)benzamide (compound 77):

1), Synthesis of 3-(2,5-dichloropyrimidin-4-yl)indolin-2-one

At 0°C, to a solution of N,N-dimethylformamide (4 mL) in which indolin-2-one (400 mg, 3.00 mmol) was dissolved, sodium hydride (180 mg, 4.51 mmol, mass fraction 60 %), the resulting mixed reaction liquid was stirred at 25°C for 30 minutes, and then 2,4,5-trichloropyrimidine (707 mg, 3.91 mmol) was added to the above mixed reaction liquid, and the obtained mixed reaction liquid was stirred at room temperature for 3 hours. The obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-65% elution) to obtain 3-(2,5-dichloropyrimidin-4-yl)indolin-2-one (300 mg, yield :35.9%), LC-MS m/z: 280[M+H] ⁺ ;

2), Synthesis of 3-(2-((3-aminophenyl)amino)-5-chloropyrimidin-4-yl)indolin-2-one

Dissolve 3-(2,5-dichloropyrimidin-4-yl)indolin-2-one (300mg, 1.08mmol), tris(dibenzylideneacetone)palladium (196mg, 0.22mmol), 4, 1 of 5-bisdiphenylphosphine-9,9-dimethylxanthene (124 mg, 0.22 mmol), cesium carbonate (1047 mg, 3.21 mmol) and benzene-1,3-diamine (138 mg, 1.29 mmol) , 4-dioxane (6mL) solution, heated to 120°C under nitrogen protection and stirred for 4 hours. After cooling, the resulting mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain 3-(2-((3-aminophenyl)amino)-5 -Chloropyrimidin-4-yl)indolin-2-one (180 mg, yield: 47.7%), LC-MS m/z: 352 [M+H] ⁺ ;

3), (E)-N-(3-((5-chloro-4-(2-oxoindolin-3-yl)pyrimidin-2-yl)amino)phenyl)-3-(4- Synthesis of (dimethylamino)but-2-enamido)benzamide

Dissolve 3-(2-((3-aminophenyl)amino)-5-chloropyrimidin-4-yl)indolin-2-one (40 mg, 0.11 mmol), (E)-3-(4 -(Dimethylamino)but-2-enamido)benzoic acid (37 mg, 0.15 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (65 mg, 0.23 mmol) and A solution of 1-methylimidazole (37 mg, 0.45 mmol) in acetonitrile (3 mL) was kept at room temperature overnight. The residue was purified by C18 column chromatography (acetonitrile: pure water = 0-95% elution) to obtain (E)-N-(3-((5-chloro-4-(2-oxoindolin-3-yl) )pyrimidin-2-yl)amino)phenyl)-3-(4-(dimethylamino)but-2-enamido)benzamide (8 mg, yield: 12%), LC-MS m/ z:582[M+H] ⁺ ;

1H NMR (400MHz, MeOD): δ8.45(s,1H),8.19(s,1H),7.92(s,1H),7.79(d,J＝8.0Hz,1H),7.66(d,J＝8.0 Hz,1H),7.48(t,J＝8.0Hz,1H),7.33(t,J＝8.0Hz,2H),7.23–7.18(m,2H),7.18-7.12(m,1H),7.02–6.95 (m,2H),6.92(d,J＝7.8Hz,2H),6.30(d,J＝16.0Hz,1H),3.19(d,J＝8.0Hz,2H),2.30(s,6H).

Example 78, 2-fluoro-N-(3-(((8-isopropyl-2-((((3R,4R))-3-methoxypiperidin-4-yl)methyl)amino )Synthesis of pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acrylamide (compound 78):

1) Synthesis of (3R, 4R)-4-((dibenzylamino)methyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester

At 0°C, (3R, 4R)-4-((dibenzylamino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.8g, 1.95mmol) was dissolved in N , to N-dimethylformamide (8mL) solution, add sodium hydride (195mg, 4.88mmol) in batches. The resulting mixed reaction solution was stirred at room temperature for 0.5 hours. Methyl iodide (277 mg, 1.95 mmol) was added to the above reaction solution in batches. The resulting mixed reaction solution was stirred at room temperature for 5 hours. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (3R, 4R)-4-((dibenzylamino)methyl)- 3-Methoxypiperidine-1-carboxylic acid tert-butyl ester (500mg, yield: 60.5%), LC-MS m/z: 425[M+H] ⁺ ;

2) Synthesis of (3R, 4R)-4-(aminomethyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (3R, 4R)-4-((dibenzylamino)methyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (0.5g, 1.18mmol) and P palladium on carbon (150mg ) in methanol (5 mL), stirred at room temperature for 16 hours under the protection of hydrogen. The mixed reaction was filtered, and the filter cake was washed with methanol (3×50 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was used directly in the next step. LC-MS m/z: 245[M+H] ⁺ ;

3), (3R, 4R)-4-(((8-isopropyl-4-((3-nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5] Synthesis of triazin-2-yl)amino)methyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazine-4- 1,4-Dioxyamine (100 mg, 0.26 mmol) and (3R, 4R)-4-(aminomethyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (313 mg, 1.28 mmol) Six-ring solution (5 mL), heated to 100°C and stirred for 16 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (3R, 4R)-4-((8-isopropyl- 4-((3-nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)methyl)-3-methoxypiperidine -1-tert-butylcarboxylate (70mg, yield: 49.3%), LC-MS m/z: 555[M+H] ⁺ ;

4), (3R, 4R)-4-(((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]tri Synthesis of tert-butyl azin-2-yl)amino)methyl)-3-methoxypiperidine-1-carboxylate

Dissolve (3R, 4R)-4-(((8-isopropyl-4-((3-nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5] Triazin-2-yl)amino)methyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.13 mmol) and iron (35.4 mg, 0.65 mmol) in ethanol (2 mL) and chlorine Ammonium chloride aqueous solution (0.5 mL) was heated to 70°C and stirred for 2 hours. The mixed reaction solution was filtered, and the filter cake was washed with methanol (3×5 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was directly used in the next step. LC-MS m/z: 525[M+H]+;

5), (3R, 4R)-4-(((4-((3-(2-fluoroacrylamido)benzyl)amino)-8-isopropylpyrazolo[1,5-a][ Synthesis of 1,3,5]triazin-2-yl)amino)methyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (3R, 4R)-4-(((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]tri Azin-2-yl)amino)methyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.095 mmol), 2-fluoroacrylic acid (13 mg, 0.14 mmol), N, N, N A solution of ',N'-tetramethylchloroformamidine hexafluorophosphate (53 mg, 0.19 mmol) and 1-methylimidazole (31 mg, 0.38 mmol) in acetonitrile (2 mL) was stirred at room temperature for 2 hours. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain (3R, 4R)-4-(((4-((3-(2-fluoroacrylamide) )benzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)methyl)-3-methoxypiperidine- 1-tert-butylcarboxylate (50 mg, yield: 87.9%), LC-MS m/z: 597[M+H] ⁺ ;

6), 2-fluoro-N-(3-(((8-isopropyl-2-((((3R,4R)-3-methoxypiperidin-4-yl)methyl)amino) Synthesis of pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acrylamide

At room temperature, (3R, 4R)-4-(((4-((3-(2-fluoroacrylamido)benzyl)amino)-8-isopropylpyrazolo[1, 5-a][1,3,5]triazin-2-yl)amino)methyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.083 mmol) in dichloromethane ( 5 mL) solution, add 2,2,2-trifluoroacetic acid (1 mL) dropwise. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: containing 0.1% FA formic acid = 5-95% elution) to obtain 2-fluoro-N-(3-(((8-isopropyl-2-((((( (3R,4R)-3-methoxypiperidin-4-yl)methyl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl Base) phenyl) acrylamide (30 mg, yield: 72.1%), LC-MS m/z: 497 [M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.69 (d, J = 12.0Hz, 2H), 7.57 (d, J = 8.0Hz, 1H), 7.32 (t, J = 8.0Hz, 1H), 7.21 (d,J＝8.0Hz,1H),7.76-7.62(m,1H),5.31-5.25(m,1H),4.75(s,2H),3.63-3.57(m,1H),3.49-3.39(m ,2H),3.37(s,3H),3.05-2.98(m,2H),2.90(s,1H),2.48(s,1H),2.34(s,1H),1.84–1.60(m,2H), 1.27(d,J＝8.0Hz,6H).

Example 79, (R)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5 Synthesis of -a]pyrimidin-7-yl)amino)methyl)phenyl)-3-(2-fluoroacrylamido)benzamide (compound 79):

1), (R)-5-((7-((tert-butoxycarbonyl)(3-(3-(2-fluoroacrylamido)benzamido)benzyl)amino)-3-isopropyl Synthesis of pyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

Dissolve (R)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- tert-butyl)-2,2-dimethylpiperidine-1-carboxylate (120 mg, 0.20 mmol), 3-(2-fluoroacrylamido)benzoic acid (50 mg, 0.24 mmol), 2 -(7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (90mg, 0.24mmol), N,N-diisopropylethylamine (76.4 mg, 0.6 mmol) in N,N-dimethylformamide (3 mL), stirred at room temperature for 16 hours. The mixed reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (3×30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (acetonitrile H pure water containing 0.1% formic acid = 0 to 100% elution) to obtain (R)-5-((7-((tert-butoxycarbonyl)(3-(3) -(2-fluoroacrylamido)benzamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2,2-di Methylpiperidine-1-carboxylic acid tert-butyl ester (140 mg, yield: 88.7%), LC-MS m/z: 799 [M+H] ⁺ ;

2), (R)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5- Synthesis of a]pyrimidin-7-yl)amino)methyl)phenyl)-3-(2-fluoroacrylamido)benzamide

Dissolve (R)-5-((7-((tert-butoxycarbonyl)(3-(3-(2-fluoroacrylamido)benzamido)benzyl)amino)-3-isopropyl pyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.175 mmol) in dichloromethane (3 mL ) and 2,2,2-trifluoroacetic acid (1mL) solution, stir at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ H ₂ O = 0-100% elution) to obtain (R)-N-(3-(((5-((6,6 -Dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-3-(2- Fluoroacrylamido)benzamide (90 mg, yield: 85.7%), LC-MS m/z: 599[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.21(t,J＝1.8Hz,1H),7.81–7.77(m,3H),7.69(d,J＝8.0Hz,1H),7.60(d, J＝8.0Hz,1H),7.49(t,J＝7.9Hz,1H),7.37(t,J＝7.9Hz,1H),7.20(d,J＝7.7Hz,1H),5.75(dd,J＝ 46.5,3.5Hz,1H),5.46–5.41(m,1H),5.34(dd,J＝15.1,3.5Hz,1H),4.65(s,2H),3.61–3.38(m,3H),3.16–3.04 (m,1H),2.06(dd,J＝7.9,4.1Hz,2H),2.00–1.91(m,1H),1.67(dt,J＝8.8,4.2Hz,1H),1.41(d,J＝4.0 Hz, 6H), 1.32 (d, J = 6.9Hz, 6H).

Example 80, N-(3-(((2-((((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methyl)amino)-8-isopropyl Synthesis of pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acrylamide (compound 80):

1), N ² -(((3R,4R)-3-fluoropiperidin-4-yl)methyl)-8-isopropyl-N ⁴ -(3-nitrobenzyl)pyrazolo[1 ,Synthesis of 5-a][1,3,5]triazine-2,4-diamine

(3R, 4R)-3-fluoro-4-(((8-isopropyl-4-((3-nitrobenzyl)amino)amino)pyrazolo[1,5-a][1, 3,5]triazin-2-yl) To a solution of amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.369 mmol) in dichloromethane (1.5 mL), 2,2,2-trifluoroacetic acid (0.5 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which could be used directly in the next step without further purification. LC-MS m/z:443[M+H] ⁺ ;

2), N ² -(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methyl)-8-isopropyl-N ⁴ -(3-nitrobenzyl) Synthesis of pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

N ² -(((3R,4R)-3-fluoropiperidin-4-yl)methyl)-8-isopropyl-N ⁴ -(3-nitrobenzyl)pyrazolo[1 ,5-a][1,3,5]triazine-2,4-diamine (150mg, 0.339mmol) and paraformaldehyde (20.3mg, 0.667mmol) in tetrahydrofuran (2mL), add acetic acid (43mg , 0.667mmol), stir at 0°C for 30 minutes. Then, sodium triacetoxyborohydride (140 mg, 0.667 mmol) was added to the above reaction solution. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water (5 mL), and extracted with ethyl acetate (3×40 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to give N ² -(((3R,4R)-3-fluoro-1-methylpiperidine -4-yl)methyl)-8-isopropyl-N ⁴ -(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazine-2,4- Diamine (60 mg, yield: 38.9%), LC-MS m/z: 457[M+H] ⁺ ;

3), N ⁴ -(3-aminobenzyl)-N ² -((((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methyl)-8-isopropyl Synthesis of pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Dissolved N ² -(((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methyl)-8-isopropyl-N ⁴ -(3-nitrobenzyl) Solution of pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (55 mg, 0.121 mmol) and iron (27.0 mg, 0.482 mmol) in ethanol (2 mL) and chloride Aqueous ammonium solution (0.5 mL). The resulting mixed reaction liquid was heated to 70°C and stirred for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography ((acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain N ⁴ -(3-aminobenzyl)-N ² -( (((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methyl)-8-isopropylpyrazolo[1,5-a][1,3,5]tri Azine-2,4-diamine (37 mg, yield: 72.0%), LC-MS m/z: 427 [M+H] ⁺ ;

4), N-(3-(((2-((((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methyl)amino)-8-isopropylpyra Synthesis of azozo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acrylamide

At room temperature, N ⁴ -(3-aminobenzyl)-N ² -((((3R, 4R)-3-fluoro-1-methylpiperidin-4-yl)methyl)-8 is dissolved in -Isopropylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (30 mg, 0.070 mmol) and triethylamine (21.3 mg, 0.211 mmol) dichloride In methane (2 mL) solution, acryloyl chloride (7.61 mg, 0.085 mmol) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water (30 mL) and diluted with ethyl acetate (3 × 30 mL). ) extraction. The combined organic phases were washed with saturated brine (1×10mL). Dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The residue was purified by C18 column chromatography ((acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (10 mg, yield: 29.6%), LC-MS m/ z:481[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.63(s,2H),7.54-7.52(m,1H),7.32-7.28(m,1H),7.10-7.08(m,1H),6.45-6.41 (m,1H),6.30-6.23(m,1H),5.78-5.76(m,1H),4.71-4.70(m,1H),4.60-4.47(m,1H),3.73-3.69(m,1H) ,3.53-3.51(m,1H),3.22-3.21(m,1H),3.06-3.00(m,1H),2.85-2.82(m,1H),2.39(s,3H),2.13-2.02(m, 2H),1.90-1.80(m,2H),1.50-1.44(m,1H),1.28(d,J＝6.8Hz,6H).

Example 81, 2-fluoro-N-(3-(((2-((((3R,4R)-3-fluoro-1-methylpiperidin-4-yl)methyl)amino)-8 Synthesis of -isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acrylamide (compound 81):

At room temperature, N ⁴ -(3-aminobenzyl)-N ² -((((3R, 4R)-3-fluoro-1-methylpiperidin-4-yl)methyl)-8 is dissolved in -Isopropylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (37.0 mg, 0.087mmol) and 2-fluoroacrylic acid (9.38mg, 0.104mmol) To the dichloromethane (2mL) solution, 2-chloro-1-methylpyridine iodide (26.6mg, 0.104mmol) and triethylamine (26.3mg, 0.261mmol) were added. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine (1 × 10 mL) and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. The residue Purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution), 2-fluoro-N-(3-(((2-(((((( 3R, 4R)-3-fluoro-1-methylpiperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine -4-yl)amino)methyl)phenyl)acrylamide (1.2 mg, yield: 2.8%), LC-MS m/z: 499 [M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.68-7.67(m,1H),7.60-7.58(m,1H),7.32(t,J＝8.0Hz,1H),7.20-7.19(m,1H ),5.69(dd,J＝46.4,3.6Hz,1H),5.28(dd,J＝15.2,3.6Hz,1H),4.76-4.74(m,2H),4.43-4.31(m,1H),3.73- 3.68(m,1H),3.69-3.45(m,1H),3.04-2.99(m,2H),2.70-2.65(m,1H),2.27(s,3H),2.02-1.83(m,2H), 1.81-1.77(m,1H),1.27(d,J=7.2Hz,6H).

Example 82, N-(3-(((2-((6,6-dimethylpiperidin-3-yl)oxy)-8-isopropylpyrazolo[1,5-a][ Synthesis of 1,3,5]triazin-4-yl)amino)methyl)phenyl)-3-(2-fluoroacrylamido)benzamide (compound 82):

1), 5-((4-((3-(3-(2-fluoroacrylamido)benzamido)benzyl)amino)-8-isopropylpyrazolo[1,5-a] Synthesis of [1,3,5]triazin-2-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

Will dissolve 5-((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)oxygen tert-butyl)-2,2-dimethylpiperidine-1-carboxylate (100mg, 0.196mmol), 3-(2-fluoroacrylamido)benzoic acid (49mg, 0.236mmol), 2-(7 -Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (111 mg, 0.294mmol) and N,N-diisopropylethylamine (76mg, 0.588mmol) ) in N,N-dimethylformamide (1 mL) was stirred for 4 hours. The mixed reaction was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50%) to obtain 5-((4-((3-(3-(2-fluoroacrylamido)benzamido)benzylamide) )Amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)oxy)-2,2-dimethylpiperidine-1-carboxy Tert-butyl acid ester (75mg, yield: 54.6%), LC-MS m/z: 701[M+H] ⁺ ;

2), N-(3-(((2-((6,6-dimethylpiperidin-3-yl)oxy)-8-isopropylpyrazolo[1,5-a][1 Synthesis of ,3,5]triazin-4-yl)amino)methyl)phenyl)-3-(2-fluoroacrylamido)benzamide

At room temperature, 5-((4-((3-(3-(2-fluoroacrylamido)benzamido)benzyl)amino)-8-isopropylpyrazolo[1, 5-a][1,3,5]triazin-2-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.1 mmol) in dichloromethane ( 3 mL) solution, 2,2,2-trifluoroacetic acid (1 mL) was added dropwise at room temperature, and the resulting mixed reaction solution was stirred at room temperature for 4 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography to obtain N-(3-(((2-((6,6-dimethylpiperidin-3-yl)oxy)-8-isopropylpyrazolo[ 1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-3-(2-fluoroacrylamido)benzamide (6.25 mg, yield: 10 %), LC-MS m/z: 601[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ8.24(s,1H),7.91(s,1H),7.87(s,1H),7.77(d,J＝8.0Hz,1H),7.70(d,J＝ 8.0Hz,1H),7.50(t,J＝8.0Hz,2H),7.35(t,J＝8.0Hz,1H),7.20(d,J＝7.2Hz,1H),5.75(dd,J＝46.4, 3.2Hz,1H),5.34(dd,J＝15.2,3.2Hz,2H),4.79(s,3H),4.56(s,2H),3.45(d,J＝16.8Hz,1H),3.06(dt, J＝13.6,6.8Hz,1H),2.04(s,2H),1.63(d,J＝14.2Hz,1H),1.36(d,J＝6.8Hz,6H),1.30(dd,J＝6.8,1.2 Hz,6H).

Example 83, (S, E)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1, Synthesis of 5-a]pyrimidin-7-yl)amino)methyl)phenyl)-2-methylbut-2-enamide (compound 83):

1), (S, E)-5-((7-((tert-butoxycarbonyl)(3-(2-methylbut-2-enamido)benzyl)amino)-3-isopropyl Synthesis of tert-butyl pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylate

Dissolve (S)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- (E)Amino)-2,2-tert-butyldimethylpiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.05 mmol), (E)-2-methylbut-2-enoic acid (8 mg, 0.08 mmol) and N,N-dimethylmethane of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (17 mg, 0.06 mmol) The solution of amide (1 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain (S, E)-5-((7-((tert-butoxycarbonyl)) (3-(2-methylbut-2-enamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2- Dimethylpiperidine-1-carboxylic acid tert-butyl ester (25 mg, yield: 73.5%), LC-MS m/z: 690 [M+H] ⁺ ;

2), (S, E)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5 Synthesis of -a]pyrimidin-7-yl)amino)methyl)phenyl)-2-methylbut-2-enamide

(S, E)-5-((7-((tert-butoxycarbonyl)(3-(2-methylbut-2-enamido)benzyl)amino)-3-isopropyl) pyridine A solution of zolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (25 mg, 0.036 mmol) in dichloromethane (1.5 mL) , add 2,2,2-trifluoroacetic acid (0.3mL) dropwise. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5%-95% elution) (S, E)-N-(3-(((5-((6,6-di Methylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-2-methylbutan-2- Enamide (10 mg, yield: 56.4%), LC-MS m/z: 490[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.64(d,J＝8.0Hz,2H),7.47(d,J＝8.0Hz,1H),7.30(t,J＝8.0Hz,1H),7.14 (d,J＝8.0Hz,1H),6.45(d,J＝8.0Hz,1H),5.18(s,1H),4.56-4.54(m,4H),4.00(s,1H),3.10-3.00( m,1H),3.00-2.80(m,1H),1.92-1.92(m,1H),1.89(s,3H),1.81(d,J＝8.0Hz,3H),1.76-1.54(m,3H) ,1.31–1.23(m,12H).

Example 84, N-(3-(((3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl))pyrazolo[1,5-a]pyrimidine-7 Synthesis of -yl)amino)methyl)phenyl)methacrylamide (compound 84):

1), 4-(7-((tert-butoxycarbonyl)(3-methacrylamidobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl) -Synthesis of tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate

Will dissolve 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3, 6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (50mg, 0.089mmol), 2-methylprop-2-enoic acid (11.5mg, 0.13mmol), 1-methyl-1H-imidazole ( 14.6 mg, 0.18 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (100 mg, 0.36 mmol) in N,N-dimethylformamide (1 mL), stirred at room temperature 4 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing H 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain 4-(7-((tert-butoxycarbonyl)(3- Methacrylamidobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl Ester (35 mg, yield: 62.4%), LC-MS m/z: 631 [M+H]

2), N-(3-(((3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-7- Synthesis of methyl)amino)methyl)phenyl)methacrylamide

In solution, there is 4-(7-((tert-butoxycarbonyl)(3-methacrylamidobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl) -To a solution of tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate (30 mg, 0.048 mmol) in dichloromethane (0.6 mL), add 2,2,2-trifluoroacetic acid (0.2 mL) . The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain N-(3-(((3-isopropyl-5-(1, 2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)methacrylamide (5 mg, 24.4%), LC -MS m/z:431[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d ₄ ): δ7.90 (s, 1H), 7.74-7.71 (m, 1H), 7.49–7.45 (m, 1H), 7.31 (t, J = 8.0Hz, 1H) ,7.20-7.16(m,1H),6.58–6.54(m,1H),6.16(s,1H),5.77–5.75(m,1H),5.50–5.47(m,1H),4.70(s,2H) ,3.84–3.80(m,2H),3.38(t,J＝8.0Hz,2H),3.27-3.19(m,1H),2.92–2.86(m,2H),2.01–1.99(m,3H),1.37 (s,3H),1.35(s,3H).

Example 85, 2-fluoro-N-(3-(3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidine Synthesis of -7-yl)amino)methyl)phenyl)acrylamide (compound 85):

1), 4-(7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 Synthesis of -tert-butyl)-3,6-dihydropyridine-1(2H)-carboxylate

Will dissolve 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3, 6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (50mg, 0.089mmol), 2-fluoroprop-2-enoic acid (12.02mg, 0.13mmol), N,N,N',N'- A solution of tetramethylchloroformamidine hexafluorophosphate (50 mg, 0.18 mmol) and 1-methyl-1H-imidazole (29 mg, 0.36 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 4 hours. The residue was purified by C18 column chromatography (acetonitrile: acetonitrile containing 0.1% NH3.H2O = 5–95% elution) to give 4-(7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)) Benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (30 mg, collected Rate: 53.2%), LC-MS m/z: 635[M+H] ⁺ ;

2), 2-fluoro-N-(3-(3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidine- Synthesis of 7-yl)amino)methyl)phenyl)acrylamide

At room temperature, 4-(7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1,5- a] Pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (30 mg, 0.047 mmol) in dichloromethane (0.6 mL), add 2,2,2 dropwise -Trifluoroacetic acid (0.2 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH3.H2O = 5–95% elution) to obtain 2-fluoro-N-(3-(3-isopropyl-5-(1,2 ,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (5 mg, 24.4%), LC-MS m /z:435[M+H] ⁺ ; ¹ H NMR (400MHz, MeOD-d ₄ ): δ8.08 (d, J = 6.4Hz, 1H), 7.83 (s, 1H), 7.54–7.49 (m, 1H),7.36(t,J＝7.9Hz,1H),7.24(d,J＝7.7Hz,1H),6.62(d,J＝1.6Hz,1H),6.32(d,J＝6.0Hz,1H) ,5.69(dd,J＝46.5,3.5Hz,1H),5.29(dd,J＝15.2,3.5Hz,1H),4.82(s,2H),3.92(d,J＝3.1Hz,2H),3.46( t, J＝6.1Hz, 2H), 3.29 (d, J＝4.9Hz, 1H), 2.89 (dd, J＝7.9, 5.9Hz, 2H), 1.36 (d, J＝6.9Hz, 6H).

Example 86, (E)-4-(dimethylamino)-1-(6-(((5-(((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino) Synthesis of -3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)indolin-1-yl)but-2-en-1-one (compound 86) :

1), Synthesis of N-((1H-indol-6-yl)methyl)-5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine

To a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (200 mg, 0.87 mmol) in acetonitrile (4 mL), N, N-diisopropylethyl ethyl was added. Amine (337 mg, 2.61 mmol) and (1H-indol-6-yl)methanamine (152 mg, 1.04 mmol). The obtained mixed reaction liquid was heated to 60°C and stirred for 16 hours. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain N-((1H-indol-6-yl)methyl)-5- Chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (180 mg, yield: 60.9%), LC-MS m/z: 340[M+H] ⁺ ;

2), Synthesis of 5-chloro-N-(indol-6-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine

N-((1H-indol-6-yl)methyl)-5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (180 mg, 0.53 mmol) was dissolved in the solution. To a solution of acetic acid (4 mL), sodium cyanoborohydride (100 mg, 1.59 mmol) was added. The resulting mixed reaction solution was stirred at room temperature for 16 hours. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain 5-chloro-N-(indol-6-ylmethyl)-3- Isopropylpyrazolo[1,5-a]pyrimidin-7-amine (150mg, yield: 82.8%), LC-MS m/z: 342[M+H] ⁺ ;

3), Synthesis of 6-(((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)indoline-1-carboxylic acid benzyl ester

Dissolve 5-chloro-N-(indol-6-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (150 mg, 0.43 mmol) in tetrahydrofuran and water (3mL, v:v=1:1) solution, add sodium bicarbonate (72mg, 0.86mmol), and then add benzyl chloroformate (110mg, 0.65mmol) after 10 minutes. The resulting mixed reaction solution was stirred at room temperature for 16 hours. The mixed reaction solution was quenched with MeOH and purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH3.H2O = 5-95% elution) to obtain 6-(((5-chloro-3-isopropylpyra) Azolo[1,5-a]pyrimidin-7-yl)amino)methyl)indoline-1-carboxylic acid benzyl ester (130 mg, yield: 62.2%), LC-MS m/z: 476 [M +H] ⁺ ;

4), 6-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)indoline-1- Synthesis of benzyl carboxylate

6-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)indoline-1-carboxylic acid benzyl ester ( 130 mg, 0.27 mmol), a solution of di-tert-butyl dicarbonate (88 mg, 0.41 mmol) and 4-dimethylaminopyridine (3.3 mg, 0.03 mmol) in tetrahydrofuran (2.0 mL) was heated at 50°C and stirred for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain 6-((tert-butoxycarbonyl)(5-chloro-3-isopropyl) Pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)indoline-1-carboxylic acid benzyl ester (150 mg, yield: 95.4%), LC-MS m/z: 576[M+H] ⁺ ;

5), 6-(((tert-butoxycarbonyl)(5-(((((3R,4R)-1-(tert-butoxycarbonyl)-3-hydroxypiperidin-4-yl)methyl)amino) Synthesis of -3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)indoline-1-carboxylic acid benzyl ester

In solution, there is 6-((tert-butoxycarbonyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)indoline-1- A solution of benzyl carboxylate (150 mg, 0.26 mmol) in 1,4-dioxane (2 mL), (R)-(-)-1-[(S)-2-(dicyclohexylphosphine)di Ferrocene]ethyl di-tert-butylphosphine (21 mg, 0.03 mmol), cesium carbonate (254 mg, 0.78 mmol) and (3R, 4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylic acid Tert-butyl ester (72 mg, 0.31 mmol). The resulting mixed reaction solution was heated in microwave at 140°C and stirred for 2 hours. The mixed reactant MeOH was diluted and purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain 6-((tert-butoxycarbonyl)(5- (((((3R,4R)-1-(tert-butoxycarbonyl)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-7-yl)amino)methyl)indoline-1-carboxylic acid benzyl ester (120 mg, yield: 60%), LC-MS m/z: 770 [M+H] ⁺ ;

6), (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(indolin-6-ylmethyl)amino)-3-isopropylpyrazolo[1,5- Synthesis of a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Will dissolve 6-(((tert-butoxycarbonyl)(5-(((((3R,4R))-1-(tert-butoxycarbonyl)-3-hydroxypiperidin-4-yl)methyl)amino) -3-Isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)indoline-1-carboxylic acid benzyl ester (120 mg, 0.16 mmol) and palladium on carbon (24 mg ) in methanol (2mL) was stirred at room temperature overnight. The resulting mixed reaction solution was filtered and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% wash de) to obtain (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(indolin-6-ylmethyl)amino)-3-isopropylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (97.4 mg, yield: 98.3%), LC-MS m/z: 636 [M+H ] ⁺ ;

7), (3R, 4R)-4-(((7-((tert-butoxycarbonyl))((1-((E)-4-(dimethylamino)but-2-enoyl)indoline -6-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl Synthesis of esters

Will dissolve 3R, 4R)-4-(((7-((tert-butoxycarbonyl)(indolin-6-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a ]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol) and (E)-4-(dimethylamino)but-2-ene N, N-Dimethylformamide (2.0 mL) was stirred at room temperature for 3 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (3R, 4R)-4-(((7-((tert-butoxy) Carbonyl)((1-((E)-4-(dimethylamino)but-2-enoyl)indolin-6-yl)methyl)amino)-3-isopropylpyrazolo[1, 5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (100 mg, yield: 85.1%),

LC-MS m/z: 747[M+H] ⁺ ;

8), (E)-4-(dimethylamino)-1-(6-(((5-(((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)- Synthesis of 3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)indolin-1-yl)but-2-en-1-one

At room temperature, (3R, 4R)-4-(((7-((tert-butoxycarbonyl))((1-((E)-4-(dimethylamino)but-2-enoyl) )indolin-6-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1- To a solution of tert-butyl carboxylate (100 mg, 0.13 mmol) in dichloromethane (2.0 mL) was added 2,2,2-trifluoroacetic acid (0.5 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3·H 2O = 5-95% elution) to obtain (E)-4-(dimethylamino)-1-(6-(((( 5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino) Methyl)indolin-1-yl)but-2-en-1-one (40 mg, yield: 54.6%), LC-MS m/z: 547[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD) δ8.28 (s, 1H), 7.86 (d, J = 4.0Hz, 1H), 7.28 (d, J = 7.6Hz, 1H), 7.17 (d, J = 7.6Hz, 1H),6.93–6.78(m,2H),4.70(s,2H),4.29(t,J＝8.4Hz,2H),4.00(d,J＝6.4Hz,2H),3.66(td,J＝10.4 ,4.4Hz,1H),3.58(dd,J＝14.4,4.4Hz,1H),3.42(dd,J＝12.0,4.4Hz,2H),3.33(s,1H),3.24(t,J＝8.4Hz ,2H),3.09(dt,J＝13.6,6.8Hz,1H),2.99–2.94(m,1H),2.92(s,6H),2.81–2.74(m,1H),2.10–2.02(m,1H) ),1.85(s,1H),1.65–1.53(m,1H),1.30(s,3H),1.28(s,3H).

Example 87, N-(3-(((2-(((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino)-8-isopropylpyra Synthesis of azozo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acrylamide (compound 87):

1), 8-isopropyl-2-(methylthio)-N-(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazine-4-amine Synthesis

Dissolve 4-chloro-2-(methylsulfonyl)-8-(prop-2-yl)pyrazolo[1,5-a][1,3,5]triazine (500mg, 2.06mmol) A solution of (3-nitrophenyl)methylamine (378 mg, 2.47 mmol) and N,N-diisopropylethylamine (799 mg, 6.18 mmol) in isopropyl alcohol (2 mL) was heated to 60°C and stirred for 16 hours. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with ethyl acetate: petroleum ether = 20 to 65%) to obtain 8-isopropyl-2-(methylthio)-N-(3-nitrobenzyl)pyridine. Azolo[1,5-a][1,3,5]triazin-4-amine (546mg, yield: 73.6%), LC-MS m/z: 359[M+H] ⁺ ;

2), (3R, 4R)-4-(((8-isopropyl-4-((3-nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5] Synthesis of triazin-2-yl)amino)methyl)-1-methylpiperidin-3-ol

Dissolve 8-isopropyl-2-(methylthio)-N-(3-nitrobenzyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (100 mg, 0.28 mmol) and 3-chloroperoxybenzoic acid (242 mg, 1.40 mmol) in toluene (2 mL) were stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (2 mL), and (3R, 4R)-4-(aminomethyl)-1-methylpiperidin-3-ol (40 mg, 0.28 mmol) was added. The resulting mixed reaction solution was stirred at 90°C for 16 hours. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-65% elution) to obtain (3R, 4R)-4-(((8-isopropyl-4-((3-nitrobenzyl) yl)amino)pyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)methyl)-1-methylpiperidin-3-ol (117 mg, yield: 92.6%), LC-MS m/z: 455[M+H] ⁺ ;

3), (3R, 4R)-4-(((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]tri Synthesis of azin-2-yl)amino)methyl)-1-methylpiperidin-3-ol

Dissolve (3R, 4R)-4-(((8-isopropyl-4-((3-nitrobenzyl)amino)pyrazolo[1,5-a][1,3,5] A solution of triazin-2-yl)amino)methyl)-1-methylpiperidin-3-ol (200 mg, 0.44 mmol) and palladium on carbon (70 mg) in methanol (2 mL) was heated and stirred at room temperature for 1.5 hours under a hydrogen atmosphere. The mixed reaction solution was filtered, and the filter cake was washed with methanol (3×20 mL). The filtrate was collected and concentrated under reduced pressure to obtain the crude product (160 mg, yield: 85.6%), LC-MS m/z: 425 [M+H] ⁺ ;

4), N-(3-(((2-((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino)-8-isopropylpyrazole Synthesis of [1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acrylamide

At 0°C, dissolve (3R, 4R)-4-(((4-((3-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1 ,3,5]triazin-2-yl)amino)methyl)-1-methylpiperidin-3-ol (100 mg, 0.24 mmol) and triethylamine (73 mg, 0.72 mmol) in dichloromethane (1 mL ) solution, add acryloyl chloride (23 mg, 0.25 mmol) dropwise. The resulting mixed reaction solution was stirred from 0°C to room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-60% elution) to obtain N-(3-(((2-((((3R, 4R))-3-hydroxy-1 -Methylpiperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl) Phenyl)acrylamide (63 mg, yield: 55.9%), LC-MS m/z: 479 [M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ7.69 (s, 2H), 7.51-7.53 (m, 1H), 7.28-7.32 (m, 1H), 7.15 (d, J = 8.0Hz, 1H), 6.35- 6.37(m,2H),5.74-5.77(m,1H),4.74(s,2H),3.46-3.48(m,1H),3.30-3.31(m,2H),3.13(s,3H),2.97- 2.99(m,1H),2.62(s,3H),2.49-2.50(m,1H),1.85(s,1H),1.61(s,2H),1.26-1.28(m,6H).

Example 88, (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-ethylpyrazolo[1,5-a Synthesis of ]pyrimidin-7-yl)amino)methyl)-4-fluorophenyl)butan-2-amide (compound 88):

1), Synthesis of 5-chloro-3-ethyl-N-(2-fluoro-5-nitrobenzyl)pyrazolo[1,5-a]pyrimidin-7-amine

Dissolve 5,7-dichloro-3-ethylpyrazolo[1,5-a]pyrimidine (500mg, 2.31mmol) and (4-fluoro-3-nitrophenyl)methanamine (590mg, 3.46 mmol) and N,N-diisopropylethylamine (896 mg, 6.93 mmol) in isopropyl alcohol (5 mL) was stirred at room temperature for 16 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-95% elution) to obtain 5-chloro-3-ethyl-N-(2-fluoro-5-nitrobenzyl)pyrazole. And[1,5-a]pyrimidin-7-amine (727mg, yield: 89.7%), LC-MS m/z: 350[M+H] ⁺ ;

2) Synthesis of tert-butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)(2-fluoro-5-nitrobenzyl)carbamate

Dissolve 5-chloro-3-ethyl-N-(2-fluoro-5-nitrobenzyl)pyrazolo[1,5-a]pyrimidin-7-amine (720 mg, 2.06 mmol) and dicarbonate A solution of di-tert-butyl ester (1798 mg, 8.24 mmol) and 4-dimethylaminopyridine (126 mg, 1.03 mmol) in tetrahydrofuran (7 mL) was heated at 50°C and stirred for one hour. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-95% elution) to obtain (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl) ( 2-Fluoro-5-nitrobenzyl)carbamic acid tert-butyl ester (900mg, yield: 97.1%), LC-MS m/z: 450[M+H] ⁺ ;

3), (S)-(5-((6,6-dimethylpiperidin-3-yl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)( Synthesis of 2-fluoro-5-nitrobenzyl)carbamic acid tert-butyl ester

tert-butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)(2-fluoro-5-nitrobenzyl)carbamate (40mg, 0.089mmol ) and (3S)-6,6-dimethylpiperidin-3-amine (46 mg, 0.36 mmol) and cesium carbonate (58 mg, 0.18 mmol) and (SP-4-1)-[1,3-bis[ 2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (7.48 mg, 0.0089 mmol) of 1,4-dioxane (1 mL) solution was sealed in a microwave tube, heated under microwave at 110°C, and stirred for 2 hours. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution with ethyl acetate: petroleum ether = 3:1) to obtain (S)-(5-((6,6-dimethylpiperidin-3-yl)amino)-3 -Ethylpyrazolo[1,5-a]pyrimidin-7-yl)(2-fluoro-5-nitrobenzyl)carbamic acid tert-butyl ester (41 mg, yield: 85.1%), LC-MS m /z：542[M+H] ⁺

4), (S)-5-((7-((tert-butoxycarbonyl)(2-fluoro-5-nitrobenzyl)amino)-3-ethylpyrazolo[1,5-a] Synthesis of tert-butyl pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylate

Dissolve (S)-(5-((6,6-dimethylpiperidin-3-yl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)( 2-Fluoro-5-nitrobenzyl)carbamic acid tert-butyl ester (100 mg, 0.18 mmol) and 4-dimethylaminopyridine (11.00 mg, 0.09 mmol) and di-tert-butyl dicarbonate (157 mg, 0.72 mmol) A solution of tetrahydrofuran (1 mL) was heated to 50°C and stirred for 2 hours. The mixed reaction solution was decompressed. The residue was purified by silica gel column chromatography (elution with ethyl acetate:petroleum ether=3:1) to obtain (S)-5-((7-((tert-butoxycarbonyl)(2-fluoro-5-nitrogen) ((benzyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (97 mg , Yield: 81.9%) LC-MS m/z: 642[M+H] ⁺

5), (S)-5-((7-((5-amino-2-fluorobenzyl)(tert-butoxycarbonyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidine Synthesis of -5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

Dissolve (S)-5-((7-((tert-butoxycarbonyl)(2-fluoro-5-nitrobenzyl)amino)-3-ethylpyrazolo[1,5-a] A solution of pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (74 mg, 0.12 mmol) and palladium on carbon (46 mg) in methanol (1.5 mL) under hydrogen atmosphere , stir at room temperature for 2 hours. The mixed reaction solution was filtered, and the filter cake was washed with methanol (3×20 mL). Collect, filter and concentrate under reduced pressure to obtain (S)-5-((7-((tert-butoxycarbonyl)(2-fluoro-5-nitrobenzyl)amino)-3-ethylpyrazolo[1,5 -a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (65 mg, yield: 92.1%), LC-MS m/z: 612 [M +H] ⁺ .

6), (S)-5-((7-((5-(but-2-ynamido)-2-fluorobenzyl)(tert-butoxycarbonyl)amino)-3-ethylpyrazolo[ Synthesis of 1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

Dissolve (S)-5-((7-((tert-butoxycarbonyl)(2-fluoro-5-nitrobenzyl)amino)-3-ethylpyrazolo[1,5-a] Pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (77 mg, 0.13 mmol) and butan-2-ynoic acid (13 mg, 0.16 mmol) and 2-( 7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (74mg, 0.20mmol) and N,N-diisopropylethylamine (50.40mg, 0.39 mmol) of N,N dimethylformamide (1 mL) was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-60% elution) to obtain (S)-5-((7-(((5-(but-2-ynamido)) -2-Fluorobenzyl)(tert-butoxycarbonyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1 - tert-butyl carboxylate (76 mg, yield: 89.2%), LC-MS m/z: 678 [M+H] ⁺ .

7), (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-ethylpyrazolo[1,5-a] Synthesis of pyrimidin-7-yl)amino)methyl)-4-fluorophenyl)butan-2-amide

(S)-5-((7-((5-(but-2-ynamido)-2-fluorobenzyl)(tert-butoxycarbonyl)amino)-3-ethylpyrazolo[ To a solution of 1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (120 mg, 018 mmol) in dichloromethane (1.5 mL), add dropwise 2,2,2-trifluoroacetic acid (0.5 mL). The resulting mixed reaction solution was stirred at room temperature for 3 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain (S)-N-(3-(((5-((6,6-dimethylpiperdine) (Din-3-yl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)-4-fluorophenyl)butan-2-amide (40 mg, 47.3 %), LC-MS m/z: 478[M+H] ⁺ .

¹ H NMR (400MHz, MeOD-d ₄ ): δ7.89–7.81 (m, 2H), 7.78 (s, 1H), 7.37 (s, 1H), 7.12 (t, J = 9.2Hz, 1H), 5.34 (brs,1H),4.69(s,2H),4.11(s,1H),3.58–3.46(m,2H),3.16-3.13(m,1H),2.67–2.55(m,2H),2.04-2.02 (m,1H),2.01(s,3H),1.92-1.89(m,3H),1.46(d,J＝16.0Hz,6H),1.24(t,J＝7.6Hz,3H).

Example 89, (E)-N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl )Synthesis of but-2-enamide (compound 89):

1), (E)-(3-(but-2-enoylamino)benzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) Synthesis of tert-butyl carbamate

Dissolve (3-aminobenzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (50 mg, 0.12 mmol), (2E)-But-2-enoic acid (15.5 mg, 0.18 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (69 mg, 0.18 mmol) and ethyldiisopropylamine (46.5 mg, 0.36 mmol) in N,N-dimethylformamide (1 mL) were stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-60% elution) to obtain (E)-(3-(but-2-enoylamino)benzyl)(5 -Cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (47 mg, yield: 81.0%), LC-MS m/z: 490[ M+H] ⁺ ;

2), (E)-N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl) Synthesis of but-2-enamide

Dissolved (E)-(3-(but-2-enoylamino)benzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) A solution of tert-butyl carbamate (37 mg, 0.076 mmol) in hydrochloric acid\dioxane (1 mL, 4M) was stirred at room temperature for 8 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-60% elution) to obtain (E)-N-(3-(((5- Cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)but-2-enamide (12 mg, yield: 40.7%), LC-MS m/z: 390[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ7.82(s,1H),7.63–7.53(m,2H),7.31(t,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H) ,6.95-6.86(m,1H),6.09(d,J＝12.0Hz,1H),5.69(d,J＝4.0Hz,1H),4.63(s,2H),3.23-3.19(m,1H), 1.99–1.92(m,1H),1.92–1.85(m,3H),1.32(d,J=8.0Hz,6H),0.97–0.84(m,4H).

Example 90, N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)benzene Synthesis of butyl-2-amide (compound 90):

1), 4-(7-((3-(but-2-ynylamido)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine- Synthesis of tert-butyl 5-yl)piperidine-1-carboxylate

Will dissolve 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine- tert-butyl 1-carboxylate (50 mg, 0.089 mmol) and but-2-ynoic acid (12 mg, 0.14 mmol) and 2-chloro-1-methylpyridine iodide (114 mg, 0.44 mmol) and ethyl diisopropyl A solution of amine (35 mg, 0.27 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature overnight. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-60% elution) to obtain 4-(7-((3-(but-2-ynamido)benzyl) (tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (54 mg, yield: 96.7%), LC-MS m/z:631[M+H] ⁺ ;

2), N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl )Synthesis of butan-2-amide

The dissolved 4-(7-((3-(but-2-ynylamido)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine- 5-yl)piperidine-1-carboxylic acid tert-butyl ester (54 mg, 0.086 mmol) was stirred in dichloromethane (0.9 mL) and 2,2,2-trifluoroacetic acid (0.3 mL) at room temperature for 4 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-60% elution) to obtain N-(3-(((3-isopropyl-5-(piperidin-4-yl)) Pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)butan-2-amide (30 mg, yield: 81.3%), LC-MS m/z: 431 [M+ H]+;

¹ H NMR (400MHz, MeOD-d ₄ ): δ7.89 (s, 1H), 7.69 (s, 1H), 7.39 (d, J = 8.0Hz, 1H), 7.30 (t, J = 8.0Hz, 1H ),7.16(d,J＝8.0Hz,1H),5.90(s,1H),4.65(s,2H),3.49-3.46(m,2H),3.30-3.26(m,1H),3.24-3.21( m,2H),3.13–3.10(m,1H),2.11-2.06(m,4H),2.05(s,3H),1.35(d,J＝8.0Hz,6H).

Example 91, 2-chloro-N-(3-(3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidine Synthesis of -7-yl)amino)methyl)phenyl)acrylamide (compound 91):

1), 4-(7-((tert-butoxycarbonyl)(3-(2-chloroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine- Synthesis of tert-butyl 5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

At room temperature, 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl is dissolved in the solution. )-3,6-Dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (60 mg, 0.11 mmol) in N,N-dimethylformamide (2 mL), add 2-chloroacrylic acid (17 mg, 0.15mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (46mg, 0.12mmol) and N,N-diisopropyl Ethylamine (42 mg, 0.3 mmol). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The mixed reaction solution was diluted with water (15 mL), and extracted with ethyl acetate (3×5 mg). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile and pure water containing 0.1% formic acid = 50-80% elution) to give 4-(7-((tert-butoxycarbonyl)(3-(2-chloroacrylamide) )benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (20mg, Yield: 28.9%), LC-MS m/z: 651[M+H] ⁺ ;

2), 2-Chloro-N-(3-(3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidine- Synthesis of 7-yl)amino)methyl)phenyl)acrylamide

At room temperature, 4-(7-((tert-butoxycarbonyl)(3-(2-chloroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1,5 -To a solution of tert-butyl a]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (20 mg, 0.03 mmol) in dichloromethane (1.5 mL), add 2,2 dropwise , 2-trifluoroacetic acid (0.5 mL). The resulting mixture was stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure and purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 30-50% elution) to obtain 2-chloro-N-(3-(3-isopropyl-5) -(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (10 mg, yield: 72.2%), LC-MS m/z: 451[M+H] ⁺ ;

1H NMR (400MHz, MeOD): δ7.97(s,1H),7.78(s,1H),7.48(d,J＝8.0Hz,1H),7.36(t,J＝7.8Hz,1H),7.24( d,J＝7.7Hz,1H),6.59(s,1H),6.43(d,J＝2.0Hz,1H),6.23(s,1H),5.96(d,J＝2.0Hz,1H),4.75( s,2H),3.89(d,J＝3.1Hz,2H),3.44(t,J＝6.1Hz,2H),3.29-3.23(m,1H),2.99-2.92(m,2H),1.36(d ,J＝8.0Hz,6H).

Example 92, N-(3-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1 Synthesis of ,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (compound 92):

1) Synthesis of tert-butyl (3-aminobenzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (330 mg, 0.74 mmol) and iron (208 mg, 3.7 mmol) ammonium chloride aqueous solution (1 mL) and ethanol (4 mL) solution, heated to 85°C and stirred for 6 hours. After cooling, The mixed reaction solution was filtered, and the filter cake was washed with dichloromethane (3×10 mL). Collect and concentrate under reduced pressure to obtain the crude product, which can be used directly in the next step without further purification. LC-MS m/z: 416[M+H] ⁺ ;

2) Synthesis of tert-butyl (3-acrylamidobenzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate

At 0°C, dissolve (3-aminobenzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (210 mg, To a solution of dichloromethane (5 mL) and triethylamine (153 mg, 1.52 mmol), acryloyl chloride (55 mg, 0.61 mmol) was slowly added. The resulting mixed reaction solution was stirred at room temperature overnight. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (3-acrylamidobenzyl) (5-chloro-3-isopropyl) Pyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (200mg, yield: 84.2%), LC-MS: m/z: 470[M+H] ⁺ ;

3), (3R, 4R)-4-(((7-((3-acrylamidobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Synthesis of pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (3-acrylamidobenzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (200mg, 0.43mmol), (3R, 4R)-4-(Aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (118 mg, 0.51 mmol) and (SP-4-1)-[1,3-bis[2 ,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium ( A solution of 353 mg, 0.42 mmol) and cesium carbonate (347 mg, 1.07 mmol) in 1,4-dioxane (4 mL) was heated to 100°C and stirred overnight. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (3R, 4R)-4-(((7-((3-acrylamide (benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid Tert-butyl ester (100 mg, yield: 35.3%), LC-MS m/z: 664[M+H] ⁺ ;

4), N-(3-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1, Synthesis of 5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide

At room temperature, (3R, 4R)-4-(((7-((3-acrylamidobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1, To a solution of 5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.12 mmol) in dichloromethane (1.2 mL), add dropwise 2,2,2-trifluoroacetic acid (0.4 mL). The resulting mixed reaction solution was stirred at room temperature for 4 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) N-(3-(((5-((((3R, 4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (8.25mg, yield: 14.7%), LC-MS m/z: 464[M+H]+;

¹ H NMR (400MHz, MeOD): δ7.88(s,1H),7.79(s,1H),7.43–7.50(m,1H),7.32–7.39(m,1H),7.15-i7.19(m ,1H),6.31-6.46(m,2H),5.74-5.79(m,1H),5.39(s,1H),4.70(s,2H),3.56-3.65(m,1H),3.44-3.56(m ,2H),3.35-3.42(m,1H),3.07(dt,J＝12.0,8.0Hz,1H),2.85-2.95(m,1H),2.70-2.79(m,1H),1.95-2.04(m ,1H),1.74-1.85(m,1H),1.45-1.59(m,1H),1.30(d,J=8.0Hz,6H).

Example 93, (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-ethylpyrazolo[1,5-a Synthesis of ]pyrimidin-7-yl)amino)methyl)phenyl)butan-2-amide (compound 93):

1), (S)-5-((7-((3-(but-2-ynynylamido)benzyl)(tert-butoxycarbonyl)amino)-3-ethylpyrazolo[1,5- Synthesis of a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

At room temperature, (S)-5-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidine was dissolved into N, N of -5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (60.0 mg, 0.101 mmol) and butan-2-ynic acid (10.2 mg, 0.12 mmol) -Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (46mg, 0.121mmol) to a solution of dimethylformamide (1mL) and triethylamine (31 mg, 0.31 mmol). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid, pure water containing 0.1% formic acid = 25%-65% elution) to obtain (S)-5-((7-((3-(but- 2-ynylamino)benzyl)(tert-butoxycarbonyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine -1-tert-butylcarboxylate (30.0mg, 45.0%), LC-MS m/z: 660[M+H] ⁺ ;

2), (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-ethylpyrazolo[1,5-a] Synthesis of pyrimidin-7-yl)amino)methyl)phenyl)butan-2-amide

(S)-5-((7-((3-(but-2-amidino)benzyl)(tert-butoxycarbonyl)amino)-3-ethylpyrazolo[1,5- a] Pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (30.0mg, 0.046mmol) in dichloromethane (0.6mL), add dropwise 2, 2,2,-Trifluoroacetic acid (0.2 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% FA: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (S)-N-(3-(((5-(( 6,6-dimethylpiperidin-3-yl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)butan-2-amide (10mg, yield: 47.9%), LC-MS m/z: 460[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.69-7.66(m,2H),7.45-7.43(m,1H),7.34-7.30(m,1H),7.17-7.15(m,1H),5.19 -5.18(m,1H),4.55(s,2H),4.21-4.17(m,1H),3.54-3.51(m,1H),3.16-3.10(m,1H),2.65-2.60(m,2H) ,2.04-2.00(m,4H),1.92-1.88(m,1H),1.82-1.77(m,2H),1.44-1.42(m,6H),1.28-1.24(m,3H).

Example 94, N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)benzene methyl)-3-methylbutan-2- Synthesis of enamide (compound 94):

1), 4-(7-((tert-butoxycarbonyl)(3-(3-methylbut-2-enamido)benzyl)amino)-3-isopropylpyrazolo[1,5 -Synthesis of tert-butyl a]pyrimidin-5-yl)piperidine-1-carboxylate

At 0°C, 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 is dissolved To a solution of tert-butyl piperidine-1-carboxylate (50 mg, 0.09 mmol) in dichloromethane (0.5 mL), triethylamine (27 mg, 0.27 mmol) was added and stirred at 0°C for 30 minutes. At 0°C, a solution of 3-methylbut-2-enoyl chloride (12 mg, 0.099 mmol) dissolved in dichloromethane (0.2 mL) was added dropwise to the above mixed solution. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z: 647[M+H] ⁺ ;

2), N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl )-Synthesis of 3-methylbut-2-enamide

At room temperature, 4-(7-((tert-butoxycarbonyl)(3-(3-methylbut-2-enamido)benzyl)amino)-3-isopropylpyrazole is dissolved in To a solution of [1,5-a]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.08 mmol) in dichloromethane (0.5 mL), 2,2,2-trifluoroacetic acid was added dropwise (50mg, 0.08mmol). The resulting mixture was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid in pure water = 35%-80% elution) N-(3-(((3-isopropyl-5-(piperidin-4-yl)) Pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-3-methylbut-2-enamide (2.22 mg, yield: 6.5%), LC-MS m /z：447[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ7.89(s,1H),7.69(s,1H),7.39(s,1H),7.32(d,J＝8.0Hz,1H),7.16(d,J＝ 7.6Hz,1H),5.91(s,1H),4.92(s,1H),4.66(s,2H),3.47(d,J＝12.5Hz,2H),3.32(s,1H),3.22(s, 1H),3.09(d,J＝8.0Hz,4H),2.96-2.93(m,1H),2.10-2.03(m,4H),1.81(s,3H),1.35(d,J＝4.0Hz,6H ).

Example 95, (S)-N-(3-((((5-((6,6-dimethylpiperidin-3-yl)amino))-3-isopropylpyrazolo[1,5 Synthesis of -a]pyrimidin-7-yl)amino)methyl)phenyl)-3-methylbut-2-enamide (compound 95):

1), (S)-5-((7-((tert-butoxycarbonyl)(3-(3-methylbut-2-enamido)benzyl)amino)-3-isopropylpyrazole Synthesis of tert-butyl[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylate

Dissolve (S)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- (hydroxy)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (25mg, 0.041mmol), 3-methylbut-2-enoic acid (6.2mg, 0.062mmol), 2-chloro - A solution of 1-methylpyridine iodide (32 mg, 0.12 mmol) and triethylamine (25 mg, 0.25 mmol) in dichloromethane (2 mL) was stirred at room temperature overnight. The obtained mixed reaction solution was concentrated under reduced pressure and the crude product could be used directly in the next step without further purification. LC-MS m/z: 690[M+H] ⁺ ; 2), (S)-N-(3-((((5-((6,6-dimethylpiperidin-3-yl)amino Synthesis of )-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-3-methylbut-2-enamide

Dissolve (S)-5-((7-((tert-butoxycarbonyl)(3-(3-methylbut-2-enamido)benzyl)amino)-3-isopropylpyrazole And[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (20 mg, 0.029 mmol) in dichloromethane (1.5 mL) and 2 , 2,2-trifluoroacetic acid (0.3 mL) solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3·H 2O = 5-95% elution) to obtain (S)-N-(3-((((5-((6,6 -Dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-3-methylbutan- 2-enamide (8 mg, yield: 56.3%), LC-MS m/z: 490 [M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ7.64 (d, J = 12.0Hz, 2H), 7.45 (d, J = 8.4Hz, 1H), 7.28 (t, J = 8.0Hz, 1H), 7.11 (d ,J＝7.8Hz,1H),5.84(s,1H),5.17(s,1H),4.53(s,2H),4.05(s,1H),3.39(s,2H),3.11–2.99(m, 2H),2.18(s,3H),1.96(s,1H),1.90(s,3H),1.69(s,2H),1.35–1.28(m,12H).

Example 96, (3-(((3-isopropyl-5-((3-methylpiperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl) Synthesis of amino)methyl)phenyl)dimethylphosphine oxide (compound 96):

1), Synthesis of (3-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)dimethylphosphine oxide

Dissolve (3-(aminomethyl)phenyl)dimethylphosphine oxide (300mg, 1.64mmol), 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine ( A solution of 450 mg, 1.97 mmol) and N,N-diisopropylethylamine (633 mg, 4.92 mmol) in isopropyl alcohol (3.0 mL) was heated to 80°C and stirred overnight. After cooling, the obtained mixed reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-20% elution) to obtain (3-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidine- 7-yl)amino)methyl)phenyl)dimethylphosphine oxide (319 mg, yield: 51.8%), LC-MS m/z: 377[M+H] ⁺ ;

2), 3-((7-((3-(dimethylphosphoryl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy) Synthesis of -tert-butyl 3-methylpiperidine-1-carboxylate

Dissolve (3-(((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)dimethylphosphine oxide (100 mg, 0.27mmol), tert-butyl 3-hydroxy-3-methylpiperidine-1-carboxylate (150mg, 0.69mmol), tris(dibenzylideneacetone)palladium (25mg, 0.027mmol), (R)-1 - A solution of [(SP)-2-(dicyclohexylphosphine)ferrocenyl]ethyldi-tert-butylphosphine (27 mg, 0.05 mmol) and cesium carbonate (260 mg, 0.80 mmol) in toluene (1.5 mL) in argon Under air protection, microwave at 140°C and stir for 1 hour. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain 3-((7-((3-(dimethylphosphoryl)benzyl)amino)-3 -Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)-3-methylpiperidine-1-carboxylic acid tert-butyl ester (26 mg, yield: 11.7%), LC- MS m/z: 556[M+H] ⁺ ;

3), (3-(((3-isopropyl-5-((3-methylpiperidin-3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino )Synthesis of methyl)phenyl)dimethylphosphine oxide

There will be dissolved 3-((7-((3-(dimethylphosphoryl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy) A solution of -3-methylpiperidine-1-carboxylic acid tert-butyl ester (26 mg, 0.047 mmol) in dichloromethane (4 mL) and 2,2,2-trifluoroacetic acid (0.1 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5% to 95% elution) to obtain (3-(((3-isopropyl-5-((3-methylpiperidine) -3-yl)oxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)dimethylphosphine oxide (8 mg, yield: 37.5%), LC-MS m/z: 456[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ7.85 (d, J = 12.0Hz, 1H), 7.75 (s, 1H), 7.69-7.62 (m, 2H), 7.60-7.54 (m, 1H), 5.43 ( s,1H),4.67(s,2H),3.55-3.51(m,1H),3.10–3.02(m,1H),2.97-2.92(m,1H),2.75–2.57(m,3H),1.77( d,J＝16.0Hz,6H),1.67-1.62(m,2H),1.59(s,3H),1.54-1.49(m,1H),1.33(d,J＝8.0Hz,6H).

Example 97, (E)-4-(dimethylamino)-N-(3-((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)methyl)amino Synthesis of )-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)but-2-enamide (compound 97):

1), (3R, 4R)-4-((((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a Synthesis of ]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamic acid tert-butyl ester (200mg, 0.464mmol), ( 3R, 4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (160 mg, 0.696 mmol), (SP-4-1)-[1,3-bis[2, 6-Bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (39 mg ,0.046mmol) and cesium carbonate (453 mg, 1.39 mmol) in 1,4-dioxane (4 mL), heated to 90°C and stirred overnight under argon protection. After cooling, the obtained mixed reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10%-40% elution) to obtain (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3- Nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (125 mg , Yield: 43.10%), LC-MS m/z: 626[M+H] ⁺ ;

2), (3R, 4R)-4-((((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Synthesis of pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (3R, 4R)-4-((((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a ]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (125 mg, 0.2 mmol) and palladium carbon (20 mg) in methanol (2 mL) under a hydrogen atmosphere, stirred at room temperature 2 hours. The mixed reaction solution was filtered, and the filter cake was washed with methanol (3×10 mL). The filtrate was collected, concentrated under reduced pressure, and filtered to obtain (3R, 4R)-4-((((7-((3-aminophenyl))( tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester ( 102mg, yield: 85.7%), LC-MS m/z: 596[M+H] ⁺ ;

3), Synthesis of (E)-4-bromobut-2-enoyl chloride

Combine (E)-4-bromobutyl-2-enoic acid (100 mg, 0.61 mmol) and oxalyl chloride (193 mg, 1.52 mmol) in N,N-dimethylformamide) and dichloromethane (2 mL, v: v=1:60) mixed solution was stirred at room temperature for 1 hour. The obtained mixed reaction solution was concentrated under reduced pressure to obtain a crude product without further purification, which was used directly in the next step.

4), (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-((E)-4-(dimethylamino)but-2-enamido)phenyl) Synthesis of tert-butyl amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate

Dissolve (3R, 4R)-4-((((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.168 mmol), dimethylamine (90 mg, 2 mmol) and N,N-diisopropylethyl ethyl A solution of amine (110 mg, 0.85 mmol) in tetrahydrofuran (2 mL) was stirred at room temperature overnight. The resulting mixed solution was diluted with water and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (10 mL) and anhydrous. Dry over sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified by silica gel column chromatography (methanol: dichloromethane = 5%-15% elution) to obtain (3R, 4R)-4-(((7-(tert Butoxycarbonyl)(3-((E)-4-(dimethylamino)but-2-enamido)phenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine -5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (60 mg, yield: 50.5%), LC-MS m/z: 707 [M+H] ⁺ ;

5), (E)-4-(dimethylamino)-N-(3-((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino) Synthesis of -3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)but-2-enamide

Will dissolve (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-((E)-4-(dimethylamino)but-2-enamido)phenyl) Amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (60 mg, 0.085 mmol) A solution of dichloromethane (1.5 mL) and 2,2,2-trifluoroacetic acid (0.5 mL) was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (E)-4-(dimethylamino)-N-(3-(( 5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) Amino)phenyl)but-2-enamide (25mg, yield: 58.1%), LC-MS m/z: 507[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ8.44(brs,1H),7.93(s,1H),7.73(s,1H),7.40(t,J＝8.0Hz,1H),7.33(d,J＝ 8.0Hz,1H),7.13(d,J＝8.0Hz,1H),6.95–6.84(m,1H),6.47(d,J＝8.0Hz,1H),3.99(d,J＝8.0Hz,1H) ,3.69(d,J＝8.0Hz,2H),3.63-3.59(m,2H),3.43-3.39(m,1H),3.12-3.05(m,1H),3.01-2.93(m,1H),2.76 -2.71(m,1H),2.69(s,6H),1.96(d,J＝8.0Hz,1H),1.74-1.66(m,2H),1.31(t,J＝6.7Hz,6H),1.16( m,1H).

Example 98, 2-fluoro-N-(3-((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyra Synthesis of azolo[1,5-a]pyrimidin-7-yl)amino)phenyl)acrylamide (compound 98):

1) Synthesis of (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(2-fluoroacrylamido)phenyl)carbamic acid tert-butyl ester

Dissolve (3-aminophenyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (400 mg, 1.0 mmol), 2- Fluoroacrylic acid (135 mg, 1.5 mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (562 mg, 2 mmol) and 1-methylimidazole (328 mg, 4 mmol) N,N- A solution of dimethylformamide (4 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-90% elution) to obtain (170 mg, yield: 36.0%), LC-MS m/z: 474[M+H] ⁺ ;

2), (3R, 4R)-4-((((7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)phenyl)amino)-3-isopropylpyrazolo Synthesis of [1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(2-fluoroacrylamido)phenyl)carbamic acid tert-butyl ester (70 mg , 0.15mmol), (3R, 4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (41mg, 0.18mmol), (SP-4-1)-[1, 3-Bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methyl A solution of palladium (12.6 mg, 0.015 mmol) and cesium carbonate (147 mg, 0.45 mmol) in 1,4-dioxane (1.5 mL) was heated to 100°C under nitrogen protection and stirred overnight. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was passed through C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) Purification gave (3R, 4R)-4-((((7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)phenyl)amino)-3-isopropylpyrazolo[ 1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (35 mg, said yield: 35.2%), LC-MS m/z: 668 [M+H] ⁺ ;

3), 2-fluoro-N-(3-((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazole Synthesis of [1,5-a]pyrimidin-7-yl)amino)phenyl)acrylamide

There is (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)phenyl)amino)-3-isopropylpyrazolo[ 1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (35 mg, 0.05 mmol) in dichloromethane (0.6 mL), dropwise 2,2,2-Trifluoroacetic acid (0.2 mL) was added. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain 2-fluoro-N-(3-(((5-(((((( 3R, 4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)acrylamide ( 2.74mg, yield: 11.2%), LC-MS m/z: 468[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.80 (s, 1H), 7.64 (s, 1H), 7.32 (q, J = 8.3Hz, 2H), 7.08 (d, J = 7.0Hz, 1H) ,5.71–5.68(m,1H),5.58(d,J＝3.5Hz,1H),5.23(s,1H),3.89(d,J＝10.6Hz,1H),3.49–3.44(m,1H), 3.32–3.27(m,2H),3.13–3.08(m,2H),2.97(dd,J＝13.9,7.1Hz,1H),2.89(t,J＝12.4Hz,1H),2.75–2.68(m, 1H), 1.88 (dd, J＝25.0, 13.6Hz, 1H), 1.62–1.57 (m, 1H), 1.24–1.22 (m, 3H), 1.20 (s, 3H).

Example 99, N-(3-((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1, Synthesis of 5-a]pyrimidin-7-yl)amino)phenyl)acrylamide (compound 99):

1), (3R, 4R)-4-((((7-((3-acrylamidophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5- Synthesis of a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (3-acrylamidophenyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (50 mg, 0.11 mmol), (3R, 4R)-4-(Aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (31 mg, 0.13 mmol), (SP-4-1)-[1,3-bis[2 ,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium ( 9.24 mg, 0.011 mmol) and cesium carbonate (108 mg, 0.33 mmol) in 1,4-dioxane (1 mL), under nitrogen protection, heated to 100°C and stirred overnight. After cooling, the resulting mixed reaction was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain (3R, 4R)-4-((((7-((3-acrylamidophenyl)) (tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (45mg, yield: 63.1%), LC-MS m/z: 650[M+H] ⁺ ;

2), N-(3-((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5 -Synthesis of a]pyrimidin-7-yl)amino)phenyl)acrylamide

There is (3R, 4R)-4-((((7-((3-acrylamidophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5- a] To a solution of pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (45 mg, 0.069 mmol) in dichloromethane (0.6 mL), add 2,2 dropwise , 2-trifluoroacetic acid (0.2mL). The resulting mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) N-(3-((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-7-yl)amino)phenyl)acrylamide (13 mg, yield: 41.7%), LC-MS m/z: 450[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ8.11(s,1H),7.93(s,1H),7.47(t,J＝8.1Hz,1H),7.33(d,J＝7.9Hz,1H),7.18 (d,J＝8.1Hz,1H),6.49–6.35(m,2H),5.84–5.74(m,2H),3.64–3.58(m,1H),3.54(s,1H),3.39(d,J ＝12.0Hz,2H),3.27(s,1H),3.16–3.08(m,1H),2.98(t,J＝11.1Hz,1H),2.80(t,J＝11.1Hz,1H),2.08(d ,J＝15.3Hz,1H),1.88(s,1H),1.60(s,1H),1.33(d,J＝6.9Hz,6H).

Example 100, (S)-N-(3-((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a Synthesis of ]pyrimidin-7-yl)amino)phenyl)acrylamide (compound 100):

1), (S)-5-((7-((3-Acrylamidophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine- Synthesis of tert-butyl 5-yl)amino)-2,2-dimethylpiperidine-1-carboxylate

At 0°C, dissolve (S)-5-((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5- a] Pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (15 mg, 0.025 mmol) in dichloromethane (0.5 mL), add triethylamine (7.58 mg, 0.075mmol), stir at 0°C for 30 minutes. At 0°C, acryloyl chloride (2.53 mg, 0.028 mmol) dissolved in dichloromethane (0.2 mL) was added dropwise to the above reaction solution. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction solution was concentrated under reduced pressure to obtain a crude product without further purification, which could be used directly in the next step. LC-MS m/z: 648[M+H] ⁺ ;

2), (S)-N-(3-((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a] Synthesis of pyrimidin-7-yl)amino)phenyl)acrylamide

At room temperature, (S)-5-((7-((3-acrylamidophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5 -To a solution of tert-butyl a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylate (25 mg, 0.04 mmol) in dichloromethane (0.6 mL), add 2 dropwise, 2,2-Trifluoroacetic acid (0.2 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (S)-N-(3-((5-((6,6- Dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)acrylamide (1.36 mg, yield: 7.9 %), LC-MS m/z: 448[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.95 (s, 1H), 7.69 (s, 1H), 7.38 (t, J = 8.0Hz, 1H), 7.31 (d, J = 7.3Hz, 1H) ,7.11(d,J＝6.8Hz,1H),6.50–6.35(m,2H),5.81(d,J＝10.8Hz,2H),4.00(s,1H),3.14–3.08(m,1H), 2.80(s,1H),1.96(s,1H),1.71(d,J＝10.8Hz,2H),1.58(s,1H),1.32(dd,J＝6.8,1.6Hz,6H),1.23(d ,J＝4.4Hz,6H).

Example 101, (S)-1-acryloyl-N-(3-(((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)methyl)amino)- Synthesis of 3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)azetidine-2-carboxamide (compound 101):

1), Synthesis of (S)-1-acryloylazetidine-2-carboxylic acid

To a solution of (S)-azetidine-2-carboxylic acid (100 mg, 1 mmol) dissolved in dichloromethane (1 mL) at 0°C, add triethylamine (303 mg, 3 mmol), 0°C Stir for 30 minutes. At 0°C, a solution of acryloyl chloride (99 mg, 1.1 mmol) in dichloromethane (0.5 mL) was added dropwise to the above mixed reaction liquid system. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixed reaction solution was concentrated under reduced pressure and the crude product was used directly in the next step without further purification. LC-MS m/z: 156[M+H] ⁺ ;

2), (3R, 4R)-4-(((7-((3-((S)-1-acryloylazetidine-2-carboxamido))benzyl)(tert-butoxycarbonyl Synthesis of )amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (3R, 4R)-4-((((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (75 mg, 0.12 mmol), (S)-1-acryloylazetidine-2-carboxylic acid Acid (22mg, 0.144mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (67mg, 0.24mmol) and N-methylimidazole (79mg, 0.96mmol) N,N -Dimethylformamide (1mL) solution was heated to 30°C and stirred for 2 hours under nitrogen protection. After cooling, the resulting mixed reaction solution was passed through C18 column chromatography (acetonitrile: 0.1% NH ₃ ·H ₂ O in pure water = 5- 95% elution) purification gave (3R, 4R)-4-(((7-((3-(S)-1-acryloylazetidine-2-carboxamido)benzyl)(tert. Butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (25 mg , Yield: 27%), LC-MS m/z: 747[M+H] ⁺ ;

3), (S)-1-acryloyl-N-(3-(((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)methyl)amino)-3 -Synthesis of isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)azetidine-2-carboxamide

At room temperature, (3R, 4R)-4-(((7-((3-((S)-1-acryloylazetidine-2-carboxamido))benzyl)(tert. Butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (25 mg , 0.03 mmol) in dichloromethane (0.6 mL), 2,2,2 trifluoroacetic acid (0.2 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3·H 2O = 5-95% elution) to obtain (S)-1-acryloyl-N-(3-(((5-( (((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl Base) phenyl) azetidine-2-carboxamide (2.82 mg, yield: 15.5%), LC-MS m/z: 547 [M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ7.67(s,1H),7.60(s,1H),7.52(t,J＝12.2Hz,1H),7.32(t,J＝7.8Hz,1H),7.15 (d,J＝7.8Hz,1H),6.38(dd,J＝17.0,10.2Hz,1H),6.27(dd,J＝17.0,2.0Hz,1H),5.79(dd,J＝10.2,2.0Hz, 1H),5.13(s,1H),4.55(d,J＝9.6Hz,2H),4.30(dt,J＝23.0,7.3Hz,1H),3.96(d,J＝13.1Hz,1H),3.47( s,2H),3.20–3.11(m,1H),2.99(dt,J＝31.0,9.3Hz,2H),2.80(d,J＝5.7Hz,4H),2.67–2.54(m,1H),2.42 (dd,J＝9.6,5.8 Hz,1H),1.88(d,J＝11.1Hz,1H),1.64(s,2H),1.27(d,J＝7.2Hz,6H).

Example 102, N-(1-(2-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)methyl)amino)-3-isopropylpyrazole Synthesis of [1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-1H-pyrazol-4-yl)acrylamide (compound 102):

1), (3R, 4R)-4-((((7-((tert-butoxycarbonyl)(2-(4-nitro-1H-pyrazol-1-yl)phenyl)amino)-3 Synthesis of -isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Dissolved (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(2-(4-nitro-1H-pyrazol-1-yl)benzyl) Tert-butyl carbamate (100 mg, 0.20 mmol) and (3R, 4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (54 mg, 0.24 mmol) in ethanol (2 mL) The solution was heated to 80°C and stirred for 2 hours. The obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (1×10 mL), dried with anhydrous sulfuric acid, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (3R, 4R)-4-((((7-(( tert-Butoxycarbonyl)(2-(4-nitro-1H-pyrazol-1-yl)phenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl )Amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (60 mg, yield: 43.5%), LC-MS m/z: 706 [M+H] ⁺ ;

2), (3R, 4R)-4-(((7-((2-(4-amino-1H-pyrazol-1-yl)benzyl)(tert-butoxycarbonyl)amino)-3- Synthesis of isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (3R, 4R)-4-((((7-(tert-butoxycarbonyl)(2-(4-nitro-1H-pyrazol-1-yl)phenyl)amino)-3 -Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (60.0 mg, 0.085 mmol) and iron (19.0 mg, 0.34 mmol) in ethanol (1.6 mL) and ammonium chloride in water (0.4 mL) at room temperature. The resulting mixture was stirred at 70 °C for 2 h. After cooling, the resulting mixture was diluted with water and washed with ethyl acetate (3× 50 mL) extraction. The combined organic phases were washed with saturated brine (1 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was passed through C18 column chromatography (acetonitrile containing 0.1% formic acid: (3R, 4R)-4-((((7-((2-(4-amino-1H-pyrazol-1-yl)benzyl))( tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester ( 40mg, yield: 69.6%), LC-MS m/z: 676[M+H] ⁺ ;

3), (3R, 4R)-4-((((7-((2-(4-acrylamido-1H-pyrazol-1-yl)benzyl)(tert-butoxycarbonyl)amino)- Synthesis of 3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

At room temperature, (3R, 4R)-4-((((7-((2-(4-amino-1H-pyrazol-1-yl)benzyl))(tert-butoxycarbonyl)amino )-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (40.0 mg, 0.059 mmol) and To a solution of acryloyl chloride (6.33 mg, 0.07 mmol) in tetrahydrofuran (2 mL), a solution of sodium bicarbonate (5.97 mg, 0.07 mmol) in water (2 mL) was added. The resulting mixed reaction solution was stirred at room temperature for 2 hours. Add water to the obtained mixed reaction solution Dilute and extract with ethyl acetate (3×40mL). The combined organic phases were washed with saturated brine (1×20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was passed through C18 Column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) purified to obtain (3R, 4R)-4-(((7-((2-(4- Acrylamide-1H-pyrazol-1-yl)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl (3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30 mg, yield: 69.5%), LC-MS m/z: 730 [M+H] ⁺ ;

4), N-(1-(2-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo Synthesis of [1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-1H-pyrazol-4-yl)acrylamide

At room temperature, dissolve (3R, 4R)-4-((((7-((2-(4-acrylamido-1H-pyrazol-1-yl))benzyl)(tert-butoxycarbonyl) )amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.041mmol) In dichloromethane (0.6 mL), 2,2,2-trifluorotrifluoroacetic acid (0.2 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was diluted with water and diluted with ethyl acetate ( 3 × 30 mL) extraction. The combined organic phases were washed with saturated brine (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was passed through C18 column chromatography (acetonitrile containing 0.1% formic acid: containing 0.1% Pure water of formic acid = 25%-65% elution) purification to obtain N-(1-(2-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl))methyl )Amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-1H-pyrazol-4-yl)acrylamide (10 mg, yield : 45.9%), LC-MS m/z: 530[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.28(s,1H),7.86(s,1H),7.58(s,1H),7.59-7.57(m,1H),7.47-7.45(m,3H ),6.40-6.37(m,2H),5.81-5.78(m,1H),5.05(s,1H),4.48(s,2H),3.98-3.95(m,1H),3.50-3.46(m,2H ),3.19-3.13(m,2H),3.03-2.92(m,2H),2.80-2.74(m,1H),1.94-1.90(m,1H),1.68-1.62(m,2H),1.26(t ,J＝7.2Hz,6H).

Example 103, 3-acrylamido-N-(3-((5-(((((3R,4S)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropyl Synthesis of pyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)benzamide (compound 103):

1), (3R, 4S)-4-(((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a] Synthesis of pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamic acid tert-butyl ester (150 mg, 0.35 mmol), ( 3R, 4S)-4-(Aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (96.6 mg, 0.42 mmol), (SP-4-1)-[1,3-bis[2 ,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium ( 29.4 mg, 0.035 mmol) and cesium carbonate (342 mg, 1.05 mmol) in 1,4-dioxane (1.5 mL). Under nitrogen protection, heat to 100°C and stir overnight. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (3R, 4S)-4-(((7-((tert-butoxy) Carbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid Tert-butyl ester (100mg, yield: 46%), LC-MS m/z: 626[M+H] ⁺ ;

2), (3R, 4S)-4-((((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Synthesis of pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (3R, 4S)-4-(((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol) and iron (46 mg, 0.8 mmol) in ethanol (0.8 mL) and ammonium chloride ( 0.2mL) solution, protected by nitrogen, heated to 70°C and stirred for 1 hour. After cooling, the obtained mixed reaction liquid was filtered, and the filter cake was washed with methanol (3×15 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product without further purification, which could be used directly in the next step. LC-MS m/z: 596[M+H] ⁺ ;

3), (3R, 4S)-4-(((7-((3-(3-acrylamidobenzoyl)phenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo Synthesis of [1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (3R, 4S)-4-((((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (45mg, 0.076mmol), 3-acrylamidobenzoic acid (22mg, 0.114mmol), N,N, N',N'-tetramethylchloroformamidine hexafluorophosphate (43 mg, 0.15 mmol) and 1-methylimidazole (25 mg, 0.304 mmol) in N,N-dimethylformamide (0.5 mL) were stirred at room temperature. 1 hour. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-90% elution) to obtain (3R, 4S)-4-(((7-( (3-(3-Acrylamidobenzoyl)phenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl )-3-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (40 mg, yield: 69.0%), LC-MS m/z: 769 [M+H] ⁺ ;

4), 3-acrylamido-N-(3-((5-(((((3R,4S)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropyl Synthesis of pyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)benzamide

(3R, 4S)-4-(((7-((3-(3-acrylamidobenzoyl)phenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo) [1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (40 mg, 0.052 mmol) in dichloromethane (0.6 mL), dropwise Add 2,2,2-trifluoroacetic acid (0.2 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) 3-acrylamide-N-(3-((5-((((( (3R,4S)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)benzyl Amide (2.64mg, yield: 9%), LC-MS m/z: 569[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ8.45 (s, 1H), 8.15 (s, 1H), 7.89 (s, 1H), 7.70 (d, J = 7.4Hz, 1H), 7.62 (s, 1H) ,7.53–7.46(m,2H),7.39(d,J＝8.3Hz,1H),7.19(d,J＝6.8Hz,1H),6.50–6.37(m,2H),5.87–5.80(m,2H ),4.06(s,1H),3.68–3.59(m,1H),3.34(s,3H),3.17–3.14(m,1H),3.13–3.08(m,1H),3.04(t,J＝12.8 Hz,1H),2.10–1.99(m,1H),1.92(d,J＝13.1Hz,1H),1.74(d,J＝12.9Hz,1H),1.33(dd,J＝6.9,3.3Hz,6H ).

Example 104, 3-acrylamido-N-(3-((2-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-8-isopropyl base Synthesis of pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)phenyl)benzamide (compound 104):

1), 8-isopropyl-2-(methylthio)-N-(3-nitrophenyl)pyrazolo[1,5-a][1,3,5]triazine-4-amine Synthesis

At 0°C, 4-chloro-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (1g, 4.13mmol ) and 3-nitroaniline (742 mg, 5.37 mmol) in acetonitrile (20 mL), add N,N-diisopropylethylamine (1.6 g, 12.40 mmol). The resulting mixed reaction solution was stirred at room temperature for 4 hours. The obtained mixed reaction liquid was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain 8-isopropyl-2-(methylthio)-N-(3- Nitrophenyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1.2g, yield: 84.5%), LC-MS m/z: 345[M+ H] ⁺

2), 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrophenyl)pyrazolo[1,5-a][1,3,5]triazine-4- Synthesis of amines

8-Isopropyl-2-(methylthio)-N-(3-nitrophenyl)pyrazolo[1,5-A][1,3,5]triazin-4-amine will be dissolved (1g, 2.91mmol) and m-chloroperoxybenzoic acid (750mg, 4.36mmol) in dichloromethane (15mL), stirred at room temperature for 3 hours. The obtained mixed reaction liquid was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain 8-isopropyl-2-(methylsulfonyl)-N-( 3-Nitrophenyl)pyrazolo[1,5-a][1,3,5]triazin-4-amine (1 g, yield: 65.0%).

LC-MS m/z:377[M+H] ⁺ ;

3), (3R, 4R)-3-hydroxy-4-(((8-isopropyl-4-((3-nitrophenyl)amino)pyrazolo[1,5-a][1, Synthesis of tert-butyl 3,5]triazin-2-yl)amino)methyl)piperidine-1-carboxylate

The dissolved 8-isopropyl-2-(methylsulfonyl)-N-(3-nitrophenyl)pyrazolo[1,5-a][1,3,5]triazine-4- 1,4-dioxane of amine (800 mg, 2.12 mmol) and (3R, 4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (587 mg, 2.55 mmol) (5 mL) solution was heated to 100°C and stirred for 16 hours. After cooling, the obtained mixed reaction solution was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated brine (1 × 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (3R, 4R)-3-hydroxy-4-((8-iso Propyl-4-((3-nitrophenyl)amino)pyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)methyl)piperidine-1- Tert-butyl carboxylate (600 mg, yield: 53.7%), LC-MS m/z: 527 [M+H] ⁺

4), (3R, 4R)-4-(((4-((3-aminophenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]tri Synthesis of tert-butyl azin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate

Dissolve (3R, 4R)-3-hydroxy-4-(((8-isopropyl-4-((3-nitrophenyl)amino)amino)pyrazolo[1,5-a][1, A solution of tert-butyl 3,5]triazin-2-yl)amino)methyl)piperidine-1-carboxylate (500 mg, 0.95 mmol) and iron (267 mg, 4.75 mmol) in ethanol (8 mL) and saturated chloride Ammonium aqueous solution (2 mL), heated to 70°C and stirred for 2 hours. The mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (3R, 4R)-4-(((4-((3-amino Phenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxy Tert-butyl acid ester (300mg, yield: 63.6%), LC-MS m/z: 497[M+H] ⁺

5), (3R, 4R)-4-(((4-((3-(3-acrylamidobenzoylamino)phenyl)amino)-8-isopropylpyrazolo[1,5- Synthesis of a][1,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

There is (3R, 4R)-4-(((4-((3-aminophenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]tri N,N- of tert-butylazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (200 mg, 0.403 mmol) and 3-acrylamidobenzoic acid (116 mg, 0.604 mmol) To the dimethylformamide (3mL) solution, add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (100mg, 0.264mmol) and N,N-diisopropylethylamine (69 mg, 0.53 mmol). The resulting mixed reaction solution was stirred at room temperature for 3 hours. The obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (3R, 4R)-4-(((4-((3-( 3-Acrylamidobenzoylamino)phenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)methyl) -3-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (130 mg, yield: 48.2%), LC-MS m/z: 670 [M+H] ⁺ ;

6), 3-Acrylamide-N-(3-((2-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-8-isopropyl Synthesis of pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)phenyl)benzamide

Dissolve (3R, 4R)-4-(((4-((3-(3-acrylamidobenzoylamino)phenyl)amino)-8-isopropylpyrazolo[1,5- a][1,3,5]Triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (60 mg, 0.089 mmol) in dichloromethane (3 mL) and 2 , 2,2-trifluoroacetic acid (1mL) solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 3 H 2O = 5-95% elution) to obtain 3-acrylamido-N-(3-((2-((((( (3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl )Amino)phenyl)benzamide (40mg, yield: 78.3%), LC-MS m/z: 570[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ8.45-8.38 (m, 3H), 8.23 (s, 1H), 7.70 (s, 1H), 7.60 (d, J = 8.0Hz, 1H), 7.42 (t, J＝8.0Hz,1H),7.35-7.28(m,2H),6.37–6.29(m,2H),5.73(d,J＝8.0Hz,1H),3.80-3.75(m,2H),3.60-3.49 (m,2H),3.40-3.36(m,1H),2.95-2.90(m,1H),2.85-2.79(m,1H),2.73-2.68(m,1H),1.95-1.92(m,1H) ,1.76-1.72(m,1H),1.61-1.52(m,1H),1.20(d,J=8.0Hz,6H).

Example 105, (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5- a]pyrimidin-7-yl)amino] Synthesis of methyl)phenyl)methacrylamide (compound 105):

1), (S)-5-((7-((tert-butoxycarbonyl)(3-methacrylamidobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine Synthesis of -5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

(S)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- (methyl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (30.0 mg, 0.05 mmol) and triethylamine (15 mg, 0.15 mmol)) in dichloromethane (1.0 mL) , add methacryloyl chloride (10 mg, 0.10 mmol) dropwise. The resulting mixed reaction solution was stirred at room temperature overnight. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water = 5-95%) to obtain (S)-5-((7-((tert-butoxycarbonyl)(3-methacrylamidobenzyl)amino)- 3-Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (22 mg, yield: 66.0%) , LC-MS m/z: 676[M+H] ⁺ ;

2), (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a Synthesis of ]pyrimidin-7-yl)amino]methyl)phenyl)methacrylamide

At room temperature, (S)-5-((7-((tert-butoxycarbonyl)(3-methacrylamidobenzyl)amino)-3-isopropylpyrazolo[1, To a solution of 5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (22 mg, 0.03 mmol) in dichloromethane (3 mL), 2, 2,2-Trifluoroacetic acid (1 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water = 5-95% elution) to obtain (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl) )amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino]methyl)phenyl)methacrylamide (10 mg, yield: 64.5%), LC-MS m/z:476[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD) δ7.66 (s, 2H), 7.49 (d, J = 8.4Hz, 1H), 7.31 (t, J = 8.0Hz, 1H), 7.16 (d, J = 7.6Hz, 1H),5.77(s,1H),5.49(s,1H),5.19(s,1H),4.55(s,2H),4.16(s,1H),3.53(dd,J＝12.8,3.6Hz,1H ),3.11(d,J＝5.2Hz,1H),3.09–3.03(m,1H),2.00(s,3H),1.89(dd,J＝12.0,7.2Hz,1H),1.79(dd,J＝ 22.4,12.0Hz,3H),1.40(d,J＝6.8Hz,6H),1.30(dd,J＝6.8,3.2Hz,6H).

Example 106, 2-chloro-N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl )Synthesis of acrylamide (compound 106):

1), (3-(2-Chloroacrylamide)benzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester Synthesis

At room temperature, tert-butyl (3-aminobenzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (40 mg, 0.095 mmol) in dichloromethane (1.5 mL), triethylamine (58 mg, 0.57 mmol) and 2-chloro-1-methylpyridinium iodide (73 mg, 0.29 mmol) were added. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5-95% elution) to obtain (3-(2-chloroacrylamido)benzyl)(5-cyclopropyl- 3-Isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (20 mg, yield: 41.4%), LC-MS m/z: 510[M+H] ⁺ ;

2), 2-chloro-N-(3-(((5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl) Synthesis of acrylamide

At room temperature, (3-(2-chloroacrylamide)benzyl)(5-cyclopropyl-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) To a solution of tert-butyl carbamate (20.0 mg, 0.039 mmol) in dichloromethane (1.2 mL), 2,2,2-trifluoroacetic acid (0.4 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH3.H2O = 5-95% elution) to obtain (5.6 mg, yield: 34.8%), LC-MS m/z: 410 [M+ H] ⁺ ; ¹ H NMR (400MHz, MeOD-d4): δ7.94 (s, 1H), 7.70 (s, 1H), 7.54 (d, J = 8.0Hz, 1H), 7.37 (t, J = 8.0 Hz,1H),7.22(d,J＝7.6Hz,1H),6.43(d,J＝2.0Hz,1H),5.95(d,J＝2.0Hz,1H),5.75(s,1H),4.72( s,2H),3.26-3.19(m,1H),2.08-2.01(m,1H),1.34(s,3H),1.32(s,3H),1.14-1.06(m,2H),1.03-0.97( m,2H).

Example 107, N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)benzene Synthesis of cyclobut-1-ene-1-carboxamide (compound 107):

1), 4-(7-((tert-butoxycarbonyl)(3-(cyclobut-1-en-1-carboxamido)benzyl)amino)-3-isopropylpyrazolo[1, Synthesis of tert-butyl 5-a]pyrimidin-5-yl)piperidine-1-carboxylate

Will dissolve 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine- 1-tert-butylcarboxylate (100mg, 0.18mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (103mg, 0.27mmol) ), a solution of N,N-diisopropylethylamine (115 mg, 0.89 mmol) and cyclobut-1-ene-1-carboxylic acid (26 mg, 0.27 mmol) in N,N-dimethylformamide (2 mL) , stir at room temperature for 2 hours. The obtained mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain 4-(7-((tert-butoxycarbonyl)(3-(cyclobut- 1-En-1-carboxamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (80 mg, collected Rate: 70.0%), LC-MS m/z: 645[M+H] ⁺ ;

2), N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl )Synthesis of cyclobut-1-ene-1-carboxamide

At room temperature, 4-(7-((tert-butoxycarbonyl)(3-(cyclobut-1-en-1-carboxamido)benzyl)amino)-3-isopropylpyrazole is dissolved in the solution To a solution of [1,5-a]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.12 mmol) in dichloromethane (1.5 mL), 2,2,2-trifluorocarbon was added dropwise Acetic acid (0.5 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5%-95% elution) to obtain N-(3-(((3-isopropyl-5-(piperidine-4- yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)cyclobut-1-ene-1-carboxamide (50 mg, yield: 90.6%), LC-MS m/z: 445[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.89 (s, 1H), 7.75 (s, 1H), 7.49 (d, J = 8.0Hz, 1H), 7.31 (t, J = 8.0Hz, 1H) ,7.17(d,J＝4.0Hz,1H),6.78(s,1H),5.90(s,1H),4.66(s,2H),3.49-3.41(m,3H),3.25-3.18(m,1H ),3.11-3.02(m,2H),2.96-2.88(m,1H),2.78((t,J＝4.0Hz,2H),2.51-2.47(m,2H),2.10-1.99(m,4H) ,1.35(s,3H),1.33(s,3H).

Example 108, (E)-N-(3-((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl Synthesis of (ethyl)phenyl)-2-methylbut-2-enamide (compound 108):

1), (E)-4-(7-((tert-butoxycarbonyl)(3-(2-methylbut-2-enamido)benzyl)amino)-3-isopropylpyrazolo Synthesis of [1,5-a]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester

At 0°C, 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 is dissolved -A solution of piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.18 mmol) in dichloromethane (1 mL), add triethylamine (55 mg, 0.54 mmol), stir at 0°C for 30 minutes, and then stir at 0°C , a solution of (E)-2-methylbut-2-enoyl chloride (26 mg, 0.22 mmol) in dichloromethane (0.2 mL) was added dropwise to the above mixed reaction solution. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was directly used in the next step without further purification. LC-MS m/z: 647[M+H] ⁺ ;

2), (E)-N-(3-((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl Synthesis of )phenyl)-2-methylbut-2-enamide

At room temperature, dissolve (E)-4-(7-((tert-butoxycarbonyl)(3-(2-methylbut-2-enamido)benzyl)amino)-3-iso To a solution of propylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.12 mmol) in dichloromethane (1.5 mL), add 2,2, 2-Trifluoroacetic acid (0.5 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5%-95% elution) to obtain (E)-N-(3-((3-isopropyl-5-(piperidine) -4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-2-methylbut-2-enamide (40 mg, yield: 72.4%), LC-MS m/z: 447[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.88(s,1H),7.67(s,1H),7.47(d,J＝8.0Hz,1H),7.31(t,J＝8.0Hz,1H) ,7.16(d,J＝8.0Hz,1H),6.48-6.40(m,1H),5.91(s,1H),4.66(s,2H),3.27-3.20(m,3H),2.91-2.82(m ,3H),1.98-1.92(m,2H),1.89(s,3H),1.88-1.83(m,2H),1.81(d,J＝4.0Hz,3H),1.35(s,3H),1.33( s,3H).

Example 109, (E)-4-(dimethylamino)-N-(3-((3-isopropyl-5-(piperidin-4-yl))pyrazolo[1,5-a] Synthesis of pyrimidin-7-yl)amino)methyl)phenyl)but-2-enamide (compound 109):

1), (E)-4-(7-(tert-butoxycarbonyl)(3-(4-(dimethylamino)but-2-enamido)benzyl)amino)-3-isopropyl Synthesis of tert-butyl pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate

Will dissolve 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine- 1-tert-butylcarboxylate (100mg, 0.18mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (101.mg, N , N-dimethylformamide (2mL) solution was stirred at room temperature for 2 hours. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain (E)-4-(7-(tert-butoxycarbonyl)(3-(4-( Dimethylamino)but-2-enamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester ( 80mg, yield: 66.9%), LC-MS m/z: 676[M+H] ⁺ ;

2), (E)-4-(dimethylamino)-N-(3-((3-isopropyl-5-(piperidin-4-yl))pyrazolo[1,5-a]pyrimidine Synthesis of -7-yl)amino)methyl)phenyl)but-2-enamide

At room temperature, (E)-4-(7-(tert-butoxycarbonyl)(3-(4-(dimethylamino)but-2-enamido)benzyl)amino)- To a solution of tert-butyl 3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (80 mg, 0.12 mmol) in dichloromethane (1.5 mL), add 2 drops ,2,2-trifluoroacetic acid (0.5mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5%-95% elution) to obtain (E)-4-(dimethylamino)-N-(3-((3- Isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)but-2-enamide (50 mg, yield: 88.7%), LC-MS m/z: 476[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.89 (s, 1H), 7.72 (s, 1H), 7.53 (d, J = 8.0Hz, 1H), 7.33 (t, J = 8.0Hz, 1H) ,7.18(d,J＝8.0Hz,1H),6.89-6.79(m,1H),6.43(d,J＝16Hz,1H),5.91(s,1H),4.68(s,2H),3.72(d ,J＝4.0Hz,2H),3.48(d,J＝16Hz,2H),3.27-3.19(m,1H),3.14-3.06(m,2H),2.98-2.90(m,1H),2.71(s ,6H),2.13-2.02(m,4H),1.36(s,3H),1.34(s,3H).

Example 110, N-(3-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1 Synthesis of ,5-a]pyrimidin-7-yl)amino)methyl)phenyl)methacrylamide (compound 110):

1), (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-methacrylamidobenzyl)amino)-3-isopropylpyrazolo[1,5- Synthesis of a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (3R, 4R)-4-((((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.049 mmol), methacryloyl chloride (7.68 mg, 0.074 mmol) and triethylamine (14.93 mg, 0.148 mmol) in dichloromethane (1.0 mL) was stirred at room temperature overnight. The resulting mixed reaction solution was concentrated under reduced pressure to a crude product, which could be used directly in the next step without further purification. (18 mg, yield: 54. .0%, LC-MS m/z: 678[M+H] ⁺ ;

2), N-(3-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1, Synthesis of 5-a]pyrimidin-7-yl)amino)methyl)phenyl)methacrylamide

The dissolved (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-methacrylamidobenzyl)amino)-3-isopropylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (18 mg, 0.027 mmol) in dichloromethane (1 mL) and 2,2,2-trifluoroacetic acid (0.1 mL) solution and stirred at room temperature for 2 hours. The mixed reaction was filtered overnight and concentrated under reduced pressure. The residue was purified by C18 column chromatography (eluting with acetonitrile and water) to give N-(3-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino) -3-Isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)methacrylamide (6 mg, yield: 47.2%), LC-MS m/z :478[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ7.64 (d, J = 8.0Hz, 2H), 7.52 (d, J = 8.6Hz, 1H), 7.32 (t, J = 7.8Hz, 1H), 7.16 (d ,J＝8.2Hz,1H),5.77(s,1H),5.48(s,1H),5.18(s,1H),4.54(s,2H),3.92(s,1H),3.37(s,2H) ,3.10(s,1H),3.04(d,J＝7.5Hz,2H),2.59(s,1H),2.45(t,J＝11.3Hz,1H),2.00(s,3H),1.69(d, J＝11.9Hz,1H),1.48(s,2H),1.28(dd,J＝9.3,7.0Hz,6H).

Example 111, (R, E)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1, Synthesis of 5-a]pyrimidin-7-yl)amino)methyl)phenyl)but-2-enamide (compound 111):

1), (R, E)-5-((7-((3-(but-2-enamido)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1 ,Synthesis of 5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

Dissolve (R)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- (170mg, 0.280mmol) and 2-(7-azobenzotriazole)-N,N,N', N'-tetramethylurea hexafluorophosphate (160 mg, 0.420 mmol) and N,N-diisopropylethylamine (109 mg, 0.840 mmol) and (E)-but-2-enoic acid (31 mg, 0.364 mmol) in N,N-dimethylformamide (2.5 mL), stirred at room temperature for 16 hours. The crude product obtained by concentrating the mixed reaction solution under reduced pressure does not require further purification and can be directly used in the next step. LC-MS m/z: 676[M+H] ⁺ ;

2), (R, E)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5 -Synthesis of a]pyrimidin-7-yl)amino)methyl)phenyl)but-2-enamide

Dissolve (R,E)-5-((7-((3-(but-2-enamido)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1 ,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.148 mmol) in dichloromethane (4 mL) and 2,2,2 - A solution of trifluoroacetic acid (1 mL) was stirred at room temperature for 3 hours. The mixed reaction solution was filtered and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water) to obtain (R, E)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino))-3 -Isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)but-2-enamide (8 mg, yield: 37.9%), LC-MS m/z :476[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.66 (d, J = 4.4Hz, 2H), 7.50 (d, J = 7.7Hz, 1H), 7.30 (t, J = 7.9Hz, 1H), 7.13 (d,J＝7.7Hz,1H),6.91(dq,J＝13.8,6.9Hz,1H),6.09(dd,J＝15.2,1.7Hz,1H),5.18(s,1H),4.61–4.45( m,3H),4.16(dd,J＝8.6,4.1Hz,1H),3.52(dd,J＝12.6,3.9Hz,1H),3.18–3.00(m,2H),1.90(dd,J＝6.8, 1.4Hz, 4H), 1.81–1.71 (m, 2H), 1.40 (d, J = 7.7Hz, 6H), 1.30 (dd, J = 6.9, 3.0Hz, 6H).

Example 112, (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5- Synthesis of a]pyrimidin-7-yl)amino]methyl)phenyl)cyclopent-1-ene-1-carboxamide (compound 112):

1), (S)-5-((7-((tert-butoxycarbonyl)(3-(cyclopent-1-en-1-carboxamido)benzyl)amino)-3-isopropylpyra Synthesis of tert-butyl azolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylate

Dissolve (S)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- (base)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.05 mmol), cyclopent-1-ene-1-carboxylic acid (11 mg, 0.10 mmol), 2-( 7-Azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (28mg, 0.07mmol) and N,N-diisopropylethylamine (19mg, 0.15 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at room temperature for 2 hours. The residue was purified by C18 column chromatography (acetonitrile: pure water = 5-95% elution) to obtain (S)-5-((7-((tert-butoxycarbonyl)(3-(cyclopent-1-ene-) 1-Carboxamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid Tert-butyl ester (23 mg, yield: 66.4%), LC-MS m/z: 702[M+H] ⁺ ;

2), (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a Synthesis of ]pyrimidin-7-yl)amino]methyl)phenyl)cyclopent-1-en-1-carboxamide

At room temperature, (S)-5-((7-((tert-butoxycarbonyl)(3-(cyclopent-1-en-1-carboxamido)benzyl)amino)-3 -Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (23 mg, 0.03 mmol) dichloromethane ( 3 mL) solution, add 2,2,2-trifluoroacetic acid (1 mL) dropwise for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 5-95% elution) to obtain (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)) Amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino]methyl)phenyl)cyclopent-1-ene-1-carboxamide (10 mg, yield: 60.8 %), LC-MS m/z: 502[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD) δ7.67 (d, J = 3.6 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.15 (d, J＝7.6Hz,1H),6.68(s,1H),5.17(d,J＝13.2Hz,1H),4.55(d,J＝7.6Hz,2H),4.13(s,1H),3.48(s, 1H),3.12(s,1H),3.09–3.04(m,1H),2.64(s,2H),2.55(s,2H),2.01(dd,J＝15.2,7.6Hz,3H),1.86(d ,J＝8.0Hz,1H),1.76(s,2H),1.39(d,J＝6.4Hz,6H),1.30(dd,J＝6.8,3.2Hz,6H).

Example 113, (S)-N-(4-chloro-3-((((2-((6,6-dimethylpiperidin-3-yl)amino))-8-isopropylpyrazolo Synthesis of [1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-2-fluoroacrylamide (compound 113):

1), (S)-N ⁴ -(2-chloro-5-nitrobenzyl)-N ² -(6,6-dimethylpiperidin-3-yl)-8-isopropylpyrazolo Synthesis of [1,5-a][1,3,5]triazine-2,4-diamine

Dissolve N-(2-chloro-5-nitrobenzyl)-8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine -A solution of 4-amine (50 mg, 0.13 mmol) and m-chloroperoxybenzoic acid (67 mg, 0.39 mmol) in toluene (40 mL) was stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure. Add 1,4-dioxane () to the residue to dissolve, then add (3S)-6,6-dimethylpiperidin-3-amine (83mg, 0.65mmol) and triethylamine (39mg, 0.39mmol) join in. The resulting mixed reaction solution was heated to 100°C and stirred overnight. After cooling, the mixed reaction solution was filtered and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water = 0-35% elution) to obtain (S)-N ⁴ -(2-chloro-5-nitrobenzyl)-N ² -(6,6-di Methylpiperidin-3-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazine-2,4-diamine (40 mg, yield: 66.5%) , LCMS m/z: 473[M+H] ⁺ ;

2), (S)-5-((4-((2-chloro-5-nitrobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5 Synthesis of triazin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

Dissolve (S)-N ⁴ -(2-chloro-5-nitrobenzyl)-N ² -(6,6-dimethylpiperidin-3-yl)-8-isopropylpyrazolo [1,5-a][1,3,5]triazine-2,4-diamine (35 mg, 0.05 mmol), di-tert-butyl dicarbonate (17 mg, 0.08 mmol) and N,N-diisopropyl Ethylamine (20mg, 0.16mmol) dichloromethane (2mL) solution, heated to 60°C and stirred for 1 hour. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-25% elution) to obtain (S)-5-((4-((2-chloro-5-nitrobenzyl)amino)- 8-Isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester ( 25mg, yield: 58.9%), LC-MS m/z: 573[M+H] ⁺ ;

3), (S)-5-((4-((5-amino-2-chlorobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5] Synthesis of triazin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

Dissolve (S)-5-((4-((2-chloro-5-nitrobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5 ]triazin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (25 mg, 0.04 mmol) and iron (10 mg, 0.18 mmol) in ethanol (0.8 mL) and chlorine The aqueous ammonium solution (0.2 mL) was heated to 70°C and stirred for 2 hours. The mixed reaction solution was filtered, the filter cake was washed with methanol, and the filtrate was collected and concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z:543[M+H] ⁺

4), (S)-5-((4-((2-chloro-5-(2-fluoroacrylamido)benzyl)amino)-8-isopropylpyrazolo[1,5-a] Synthesis of [1,3,5]triazin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

Dissolve (S)-5-((4-((5-amino-2-chlorobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5] Triazin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.05 mmol), 2-fluoroprop-2-enoic acid (6 mg, 0.07 mmol), 1-methylimidazole (18 mg, 0.22 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (31 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL ) solution was stirred at room temperature for 16 hours. The mixed reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-65% elution) to obtain (S)-5-((4-((2-chloro-5-(2-fluoroacrylamido)) Benzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)-2,2-dimethylpiperidine-1- Tert-butyl carboxylate (12 mg, yield: 37.3%), LC-MS m/z: 615[M+H] ⁺ ;

5), (S)-N-(4-chloro-3-((((2-((6,6-dimethylpiperidin-3-yl)amino))-8-isopropylpyrazolo[ Synthesis of 1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-2-fluoroacrylamide

Dissolve (S)-5-((4-((2-chloro-5-(2-fluoroacrylamido)benzyl)amino)-8-isopropylpyrazolo[1,5-a] A solution of [1,3,5]triazin-2-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (12 mg, 0.02 mmol) in dichloromethane (0.6 mL) and 2,2,2-Trifluoroacetic acid (0.2 mL) was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (acetonitrile: pure water = 0-35% elution) to obtain (S)-N-(4-chloro-3-(((2-((6,6-dimethyl) piperidin-3-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-2- Fluoroacrylamide (0.87mg, yield: 8.6%), LC-MS m/z: 515[M+H] ⁺ ; ¹ H NMR (400MHz, MeOD-d4): δ7.76 (s, 1H), 7.68 (t, J = 7.2Hz, 2H), 7.38 (d, J = 6.4Hz, 1H), 5.67 (d, J = 46.4Hz,1H),5.26(d,J＝15.2Hz,1H),4.80–4.76(m,2H),3.88(s,1H),3.02(dd,J＝19.2,13.2Hz,2H),2.72( s,1H),1.88(s,1H),1.62(d,J＝12.8Hz,2H),1.49(s,1H),1.30(s,1H),1.30–1.23(m,6H),1.17(s ,6H).

Example 114, N-(3-((2-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5 Synthesis of -a][1,3,5]triazin-4-yl)amino)phenyl)acrylamide (compound 114):

1), (3R, 4R)-4-(((4-((3-acrylamidophenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5 Synthesis of triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

At 0°C, sodium hydride (36 mg, 1.50 mmol) was added in batches to the dissolved (3R, 4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (138 mg , 0.60 mmol) in a solution of dimethyl sulfoxide (2 mL), and the resulting mixed reaction solution was stirred at room temperature for 30 minutes. Then the dissolved N-(3-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino )Phenyl)acrylamide (200 mg, 0.50 mmol) solution in dimethyl sulfoxide (2 mL) was added dropwise to the above mixed reaction solution. The resulting mixed reaction solution was heated to 90°C and stirred for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (3R, 4R)-4-(((4-((3- Acrylamidophenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)methyl)-3-hydroxypiperidine- 1-tert-butylcarboxylate (100mg, yield: 36.4a%), LC-MS m/z: 551[M+H] ⁺ ;

2), N-(3-((2-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5- Synthesis of a][1,3,5]triazin-4-yl)amino)phenyl)acrylamide

Dissolve (3R, 4R)-4-(((4-((3-acrylamidophenyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5 ]Triazin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.18 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) solution at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain N-(3-((2-((((3R, 4R) -3-Hydroxypiperidin-4-yl)methyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)phenyl ) Acrylamide (50 mg, yield: 50%), LC-MS m/z: 451 [M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.515 (s, 1H), 8.431 (s, 2H), 7.995 (s, 1H), 7.372 (t, J = 8.0Hz, 1H), 7.299 (d, J＝7.2Hz,1H),7.135(d,J＝7.6Hz,1H),5.821(s,1H),3.418-3.385(m,1H),3.258-3.237(m,2H),3.153-3.084(m ,1H),2.922(s,2H),2.556(s,2H),2.375(s,2H),1.798(d,J＝14.4Hz,1H),1.348-1.320(m,6H).

Example 115, (R)-N-(3-((5-((2,2-dimethylpiperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a Synthesis of ]pyrimidin-7-yl)amino]phenyl)acrylamide (compound 115):

1), (R)-(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) Synthesis of (3-nitrophenyl)carbamic acid tert-butyl ester

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamic acid tert-butyl ester (500mg, 1.16mmol), ( R)-6,6-dimethylpiperidin-3-amine (371.2mg, 2.9mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropanol) base)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (97.5 mg, 0.12 mmol) and cesium carbonate ( 1.89g, 5.8mmol) of 1,4-dioxane (10mL), under argon protection, heated to 100°C and stirred overnight. After cooling. The obtained mixed reaction liquid was filtered. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (R)-(5-((6,6-dimethylpiperidine- 3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamic acid tert-butyl ester (350 mg, yield: 57.7%) , LC-MS m/z: 524[M+H] ⁺ ;

2), (R)-5-((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Synthesis of tert-butyl (methyl)amino)-2,2-dimethylpiperidine-1-carboxylate

Dissolved (R)-(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) A solution of (3-nitrophenyl)carbamate tert-butyl ester (350 mg, 0.67 mmol) and di-tert-butyl dicarbonate (439 mg, 2.01 mmol) in dichloromethane (5 mL) was heated to 50°C and stirred overnight. After cooling. The mixed reaction solution was filtered and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (R)-5-((7-((tert-butoxycarbonyl)(3 -Nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (100mg, yield: 24.0%), LC-MS m/z: 624[M+H] ⁺ ;

3), (R)-5-((7-((3-Aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- (Al)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

Dissolve (R)-5-((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.16 mmol) and iron (45.0 mg, 0.80 mmol) in an aqueous solution of ammonium chloride 1 (0.5 mL) and ethanol ( 2.0 mL) solution was heated to 70°C and stirred for 2 hours. After cooling. The mixed reaction solution was filtered, and the filter cake was washed with dichloromethane (3×5 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which could be used directly in the next step without further purification. LC-MS m/z: 594[M+H] ⁺ ;

4), (R)-5-((7-((3-acrylamidophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine- Synthesis of tert-butyl 5-yl)amino)-2,2-dimethylpiperidine-1-carboxylate

At 0°C, dissolve (R)-5-((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5- a] To a solution of pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (80 mg, 0.14 mmol) in dichloromethane (1 mL), add triethylamine (68.4 mg, 0.68 mmol), stirred at 0°C for 30 minutes. A solution of acryloyl chloride (14.7 mg, 0.22 mmol) in dichloromethane (0.2 mL) was then added dropwise at 0°C. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without further purification. LC-MS m/z:648[M+H] ⁺ ;

5), (R)-N-(3-((5-((2,2-dimethylpiperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a] Synthesis of pyrimidin-7-yl)amino]phenyl)acrylamide

At room temperature, (R)-5-((7-((3-acrylamidophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5 -To a solution of tert-butyl a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylate (80 mg, 0.12 mmol) in dichloromethane (1.5 mL), add 2 dropwise, 2,2-Trifluoroacetic acid (0.5 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH4HCO3 = 3%-95% elution) to obtain (S)-N-(3-((5-((2,2-dimethyl Piperidin-4-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino]phenyl)acrylamide (50 mg, yield: 90.4%), LC- MS m/z:448[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.71 (s, 1H), 7.39 (t, J = 8.0Hz, 1H), 7.27 (d, J = 12.0Hz, 1H), 7.13-7.09 (m, 1H),6.50-6.35(m,2H),5.84-5.79(m,2H),4.20-4.11(m,1H),3.51(dd,J＝12.0,8.0Hz,1H),3.15-3.06(m, 2H),2.06-1.99(m,1H),1.90-1.83(m,2H),1.83-1.69(m,2H),1.37(s,6H),1.33(dd,J＝8.0,8.0Hz,6H

Example 116, (R)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5- Synthesis of a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (compound 116):

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (450 mg, 1 mmol) and iron ( 280 mg, 5 mmol) in ethanol (4 mL) and ammonium chloride aqueous solution (1 mL), heated to 70°C and stirred for 1 hour. After cooling, the mixed reaction solution was filtered, and the filter cake was washed with methanol (3×10 ml). The filtrate was collected and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (3-aminobenzyl)(5-chloro-3-isopropylpyra) Azolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (400mg, yield: 95.3%), LC-MS m/z: 416[M+H] ⁺ ;

(3-Aminobenzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (400 mg, 0.96 mmol) and acryloyl chloride were dissolved To a solution of (104 mg, 1.15 mmol) in dichloromethane (5 mL), N,N-diisopropylethylamine (372 mg, 2.88 mmol) was added. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (3-acrylamidobenzyl) (5-chloro-3-isopropyl) tert-butyl pyrazolo[1,5-a]pyrimidin-7-yl)carbamate (300 mg, yield: 66.4%), LC-MS m/z: 470[M+H] ⁺ ;

3), (R)-(3-Acrylamidobenzyl)(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5 -Synthesis of tert-butyl a]pyrimidin-7-yl)carbamate

Dissolve (3-acrylamidobenzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (300 mg, 0.64 mmol), ( R)-6,6-dimethylpiperidin-3-amine (99mg, 0.77mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl) )phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (9.4 mg, 0.01 mmol) and cesium carbonate (110 mg , 0.34 mmol) in 1,4-dioxane (5.0 mL), heated to 90°C and stirred overnight under argon protection. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: water = 5-95% elution) to obtain (R)-(3-acrylamidobenzyl)(5-((6,6-dimethylpiperidine-3- tert-butyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (120 mg, yield: 33.5%), LC-MS m/z: 562[ M+H] ⁺ ;

4), (R)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a Synthesis of ]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide

In solution, (R)-(3-acrylamidobenzyl)(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5 -To a solution of tert-butyl a]pyrimidin-7-yl)carbamate (40 mg, 0.07 mmol) in dichloromethane (2.0 mL), 2,2,2-trifluoroacetic acid (0.5 mL) was added. The resulting mixed reaction solution was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH3·H2O=5-95% elution) to obtain (R)-N-(3-(((5-((6,6- Dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (20 mg, yield: 60.8%), LC-MS m/z: 462[M+H] ⁺ ; ¹ H NMR (400MHz, MeOD): δ7.65 (d, J=7.6Hz, 2H), 7.56 (d, J=8.0Hz ,1H),7.32(t,J＝7.6Hz,1H),7.15(d,J＝6.8Hz,1H),6.46–6.28(m,2H),5.75(d,J＝9.6Hz,1H),5.17 (s,1H),4.55(s,2H),3.85(s,1H),3.18–3.01 (m,2H),2.75–2.66(m,1H),1.89(s,1H),1.62(s,2H),1.53(d,J＝11.6Hz,1H),1.28(d,J＝6.0Hz, 6H),1.18(s,6H).

Example 117, (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5- Synthesis of a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (compound 117):

1), (S)-(3-Acrylamidobenzyl)(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5 -Synthesis of tert-butyl a]pyrimidin-7-yl)carbamate

Dissolve (3-acrylamidobenzyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (100 mg, 0.21 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole- A solution of 2-ylidene]dichloro(2-methylpyridine)palladium (17.6 mg, 0.02 mmol) and cesium carbonate (342 mg, 1.05 mmol) in 1,4-dioxane (2 mL) was heated to 110°C and stirred overnight. . After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain (S)-(3-acrylamidobenzyl)(5-((6,6-dimethyl tert-butylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (80 mg, yield: 67%), LC-MS m/z: 562[M+H] ⁺ ;

2), (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a Synthesis of ]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide

At room temperature, dissolve (S)-(3-acrylamidobenzyl)(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo To a solution of [1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (80 mg, 0.14 mmol) in dichloromethane (1.5 mL), 2,2,2,-trifluoroacetic acid (0.5 mL) was added dropwise ). The resulting mixed reaction liquid was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5%-95% elution) to obtain (S)-N-(3-(((5-((6,6-di Methylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (50 mg, yield: 76 %), LC-MS m/z: 462[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.68(s,1H),7.67(s,1H),7.52(d,J＝8.0Hz,1H),7.32(t,J＝8.0Hz,1H) ,7.15(d,J＝8.0Hz,1H),6.42-6.30(m,2H),5.78-5.73(m,1H),5.17(s,1H),4.56(s,2H),4.19-4.10(m ,1H),3.56-3.50(m,1H),3.16-3.12(m,1H),3.10-3.03(m,1H),2.05-1.95(m,1H),1.92-1.85(m,1H),1.83 -1.73(m,2H),1.41(s,3H),1.39(s,3H),1.32(d,J＝4.0Hz,3H),1.30(d,J＝4.0Hz,3H).

Example 118, N-(3-(((5-(1-fluoroethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl )Synthesis of butan-2-amide (compound 118):

Dissolve N-(3-aminobenzyl)-5-(1-fluoroethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (40 mg, 0.12 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (56 mg, 0.15 mmol) and N,N-diisopropyl A solution of ethylamine (47mg, 0.37mmol) and but-2-ynoic acid (13mg, 0.15mmol) in N,N-dimethylformamide (1mL) was stirred at room temperature for 16 Hour. The obtained mixed reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine (1×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to obtain (2.28 mg, yield: 4.8%), LC-MS m/z: 394 [M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.03 (s, 1H), 7.61 (s, 1H), 7.48 (d, J = 8.0Hz, 1H), 7.28 (t, J = 8.0Hz, 1H ),7.09(d,J＝8.0Hz,1H),6.06(s,1H),5.61–5.44(m,1H),4.62(s,2H),3.19–3.12(m,1H),2.01(s, 3H), 1.55 (dd, J＝24.0, 4.0Hz, 3H), 1.30 (d, J＝8.0, 6H).

Example 119, 2-fluoro-N-(3-(((5-(1-fluoroethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl Synthesis of phenyl)acrylamide (compound 119):

1), Synthesis of 1-(3-isopropyl-7-((3-nitrobenzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)ethanol-1-ol

Dissolve 1-(3-isopropyl-7-((3-nitrobenzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one (300 mg, 0.850 mmol), a solution of sodium borohydride (48 mg, 1.28 mmol) and aqueous sodium hydroxide solution (0.2 mL, 0.085 mmol, 0.4 M) in ethanol (5 mL) was stirred at room temperature for 16 hours. The obtained mixed reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to obtain 1-(3-isopropyl-7-((3-nitrobenzyl)amino)pyrazolo[ 1,5-a]pyrimidin-5-yl)ethanol-1-ol (200mg, yield: 66.3%), LC-MS m/z: 356[M+H] ⁺ ;

2), Synthesis of 5-(1-fluoroethyl)-3-isopropyl-N-(3-nitrobenzyl)pyrazolo[1,5-a]pyrimidin-7-amine

At -78°C, 1-(3-isopropyl-7-((3-nitrobenzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)ethyl- To a solution of 1-alcohol (200 mg, 0.56 mmol) in dichloromethane (3 mL), diethylamine sulfur trifluoride (182 mg, 1.13 mmol) was added in portions, and stirred at -78°C for 0.5 hours. Then the temperature was raised to 0°C and stirred for 0.5 hours. The obtained mixed reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to obtain 5-(1-fluoroethyl)-3-isopropyl-N-(3-nitrobenzyl) Pyrazolo[1,5-a]pyrimidin-7-amine (150mg, yield: 74.6%), LC-MS m/z: 358[M+H] ⁺ ;

3), Synthesis of N-(3-aminobenzyl)-5-(1-fluoroethyl)-3-isopropylpyrazolo[1,5-a]pyrimidine-7-amine

Dissolve 5-(1-fluoroethyl)-3-isopropyl-N-(3-nitrobenzyl)pyrazolo[1,5-a]pyrimidin-7-amine (150 mg, 0.42 mmol) A solution of iron (118 mg, 2.10 mmol) in ethanol (4 mL) and ammonium chloride aqueous solution (1 mL) was heated to 70°C and stirred for 2 hours. After cooling, The obtained mixed reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to obtain N-(3-aminobenzyl)-5-(1-fluoroethyl)-3-isopropylpyra Azolo[1,5-a]pyrimidin-7-amine (120mg, yield: 87.3%), LC-MS m/z: 328[M+H] ⁺ ;

4), 2-fluoro-N-(3-(((5-(1-fluoroethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl )Synthesis of phenyl)acrylamide

Dissolve N-(3-aminobenzyl)-5-(1-fluoroethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (40 mg, 0.12 mmol), 2-fluoroacrylic acid (16.5mg, 0.18mmol), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (69mg, 0.25mmol) and 1-methylimidazole (40mg, 0.49mmol) A solution of N,N-dimethylformamide (1 mL) was stirred at room temperature for 3 hours. The obtained mixed reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine (1×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to obtain 2-fluoro-N-(3-(((5-(1-fluoroethyl))-3-isopropyl Pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (2.39 mg, yield: 5%), LC-MS m/z: 400 [M+H ] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.06 (s, 1H), 7.74 (s, 1H), 7.62 (d, J = 8.0Hz, 1H), 7.33 (t, J = 8.0Hz, 1H ),7.17(d,J＝8.0Hz,1H),6.10(s,1H),5.74–5.47(m,2H),5.40(dd,J＝16.0,4.0Hz,1H),4.67(s,2H) ,3.20–3.13(m,1H),1.57(dd,J＝24.0,4.0Hz,3H),1.30(d,J＝8.0,6H).

Example 120, 2-fluoro-N-(3-(((5-(1-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)ethyl)- Synthesis of 3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (compound 120):

1), (5-(1-ethoxyvinyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester Synthesis

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (3.0g, 6.74mmol), A solution of (1-ethoxyvinyl)tributylstannane (3.66 g, 10.1 mmol) and tetrakis(triphenylphosphine)palladium (779 mg, 0.67 mmol) in 1-methyl-2-pyrrolidone (50 mL), argon Under protection, heat to 110°C and stir for 16 hours. After cooling, the obtained mixed reaction solution was diluted with water (300 mL) and extracted with ethyl acetate (3×300 mL). The combined organic phases were washed with saturated brine (1×300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to obtain (5-(1-ethoxyvinyl)-3-isopropylpyrazolo[1,5- a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (2.0g, yield: 61.7%), LC-MS m/z: 482[M+H] ⁺ ;

2), Synthesis of 1-(3-isopropyl-7-((3-nitrobenzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one

The dissolved 5-(1-ethoxyvinyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester ( 2.0 g, 4.16 mmol) in dichloromethane (20 mL) and 2,2,2-trifluoroacetic acid (7 mL), stirred at room temperature for 2 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH 4HCO 3 = 10 to 95% elution) to obtain 1-(3-isopropyl-7-((3-nitrobenzyl)amino) )Pyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one (1.0g, said yield: 68%), LC-MS m/z: 354[M+H] ⁺ ;

3), (3R, 4R)-3-hydroxy-4-(((1-(3-isopropyl-7-((3-nitrobenzyl)amino)amino)pyrazolo[1,5-a] Synthesis of pyrimidin-5-yl)ethyl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester

Dissolve 1-(3-isopropyl-7-((3-nitrobenzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one (300 mg, 0.85 mmol), (3R, 4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxy tert-butyl ester (235 mg, 1.02 mmol) and sodium cyanoborohydride (267 mg, 4.25 mmol) in methanol ( 5mL) solution was heated to 70°C and stirred for 16 hours. After cooling, the obtained mixed reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to obtain (3R, 4R)-3-hydroxy-4-(((1-(3-isopropyl-7- ((3-nitrobenzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)ethyl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (300 mg, yield : 62%), LC-MS m/z: 568[M+H] ⁺ ;;

4), (3R, 4R)-4-(((1-(7-((3-aminobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl Synthesis of )ethyl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (3R, 4R)-3-hydroxy-4-(((1-(3-isopropyl-7-((3-nitrobenzyl)amino)amino)pyrazolo[1,5-a] Pyrimidin-5-yl)ethyl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.53 mmol) and iron (148 mg, 2.64 mmol) in ethanol (4 mL) and aqueous ammonium chloride (1 mL ) solution was heated to 70°C and stirred for 3 hours. After cooling, the obtained mixed reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to obtain (3R, 4R)-4-(((1-(7-((3-aminobenzyl)amino)) -3-Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (200 mg, yield: 70.4%), LC-MS m/z: 538[M+H] ⁺ ;

5), (3R, 4R)-4-(((1-(7-((3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1,5- Synthesis of a]pyrimidin-5-yl)ethyl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (3R, 4R)-4-(((1-(7-((3-aminobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl )ethyl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (100mg, 0.19mmol), 2-fluoroacrylic acid (25mg, 0.28mmol), N,N,N',N' - A solution of tetramethylchloroformamidine hexafluorophosphate (105 mg, 0.37 mmol) and 1-methylimidazole (61 mg, 0.75 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 3 hours. The obtained mixed reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with saturated brine (1×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to obtain (3R, 4R)-4-(((1-(7-((3-(2-fluoroacrylamide) tert-butyl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)ethyl)amino)methyl)-3-hydroxypiperidine-1-carboxylate Ester (60 mg, yield: 52.9%), LC-MS m/z: 610[M+H] ⁺ ;

6), 2-fluoro-N-(3-(((5-(1-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)ethyl)-3 -Synthesis of isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide

(3R, 4R)-4-(((1-(7-((3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1,5- a] To a solution of pyrimidin-5-yl)ethyl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (60 mg, 0.098 mmol) in dichloromethane (1.5 mL), add 2, 2,2-trifluoroacetic acid (0.5 mL) and stirred at room temperature for 2 hours. The mixed reaction was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 10 to 95%) to obtain 2-fluoro-N-(3-(((5-(1-((((( 3R, 4R)-3-hydroxypiperidin-4-yl)methyl)amino)ethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl) Phenyl)acrylamide (5.0 mg, yield: 10%), LC-MS m/z: 510[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d ₄ ): δ7.97 (s, 1H), 7.78 (s, 1H), 7.51 (d, J = 8.0Hz, 1H), 7.35 (t, J = 8.0Hz, 1H ),7.22(d,J＝8.0Hz,1H),6.04(s,1H),5.69(dd,J＝48.0,4.0Hz,1H),5.29(dd,J＝12.0,4.0Hz,1H),4.71 (s,2H),4.47–4.38(m,1H),3.75–3.68(m,1H),3.43–3.35(m,3H),3.20–3.15(m,1H),3.03–2.95(m,2H) ,2.86–2.78(m,1H),2.14–2.01(m,2H),1.62(d,J＝4.0Hz,3H),1.51(d,J＝12.0Hz,1H),1.37(dd,J＝8.0 ,4.0Hz,6H).

Example 121, (S)-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a] Synthesis of pyrimidin-7-yl)amino)methyl)phenyl)dimethylphosphine oxide (compound 121):

Dissolve 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (150mg, 0.66mmol), (3-(aminomethyl)phenyl)dimethylphosphine oxide ( A solution of 100 mg, 0.55 mmol) and N,N-diisopropylethylamine (211 mg, 1.64 mmol) in isopropyl alcohol (3 mL) was heated to 80°C and stirred for 2 hours. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to obtain (3-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidine-7 -Amino)methyl)phenyl)dimethylphosphine oxide (170 mg, yield: 69%), LC-MS m/z: 377 [M+H] ⁺ ;

2) Synthesis of (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(dimethylphosphoryl)benzyl)carbamic acid tert-butyl ester

Dissolve (3-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)dimethylphosphine oxide (100 mg, 0.27 mmol), di-tert-butyl dicarbonate (180 mg, 0.83 mmol) and N,N-diisopropylethylamine (103 mg, 0.80 mmol), 4-dimethylaminopyridine (7 mg, 0.053 mmol) in tetrahydrofuran (3 mL ) solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-25% elution) to obtain (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl) (3-(Dimethylphosphoryl)benzyl)carbamic acid tert-butyl ester (110 mg, yield: 87%), LC-MS m/z: 477 [M+H] ⁺ ;

3), (S)-(3-(dimethylphosphoryl)benzyl)(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo Synthesis of [1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(dimethylphosphoryl)benzyl)carbamic acid tert-butyl ester (70 mg, 0.15mmol), (S)-6,6-dimethylpiperidin-3-amine (30mg, 0.23mmol), (SP-4-1)-[1,3-bis[2,6-bis(1 -Ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (25 mg, 0.03 mmol) and A solution of cesium carbonate (160 mg, 0.48 mmol) in 1,4-dioxane (2 mL) was heated to 90°C and stirred for 16 hours under nitrogen. After cooling, the mixed reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane=0-10% elution) to obtain (S)-(3-(dimethylphosphoryl)benzyl)(5-((6,6-di Methylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (30 mg, yield: 36%), LC- MS m/z: 569[M+H] ⁺ ;

4), (S)-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine Synthesis of -7-yl)amino)methyl)phenyl)dimethylphosphine oxide

Dissolve (S)-(3-(dimethylphosphoryl)benzyl)(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo A solution of [1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (30 mg, 0.053 mmol) in dichloromethane (2 mL) and 2,2,2-trifluoroacetic acid (0.6 mL) was stirred at room temperature for 2 hours. . The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water = 0-95% elution) to obtain (S)-(3-(((5-((6,6-dimethylpiperidin-3-yl)yl)amino )-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)dimethylphosphine oxide (3 mg, yield: 12%), LC-MS m /z：469[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ7.84(d,J＝12.0Hz,1H),7.73–7.62(m,3H),7.59-7.52(m,1H),5.16(s,1H),4.62( s,2H),3.89-3.82(m,1H),3.09-3.03(m,1H),2.69–2.59(m,1H),1.93–1.84(m,1H),1.76(d,J＝13.4Hz, 6H),1.63–1.59(m,1H),1.53–1.47(m,1H),1.35(t,J＝8.0Hz,2H),1.28(dd,J＝8.0,4.0Hz,6H),1.15(d ,J＝4.0Hz,6H).

Example 122, (S)-(3-(((2-((6,6-dimethylpiperidin-3-yl)amino)-8-isopropylpyrazolo[1,5-a] Synthesis of [1,3,5]triazin-4-yl)amino)methyl)phenyl)dimethylphosphine oxide (compound 122):

1), (3-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl Synthesis of )phenyl)dimethylphosphine oxide

Dissolved (3-(((8-isopropyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl A solution of )phenyl)dimethylphosphine oxide (100 mg, 0.26 mmol) and m-3-chloroperoxybenzoic acid (89 mg, 0.51 mmol) in dichloromethane (3 mL) was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (3-((8-isopropyl-2-(methyl) Sulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)dimethylphosphine oxide (80 mg, yield: 74%), LC-MS m/z: 422[M+H] ⁺ ;

2), (S)-(3-(((2-((6,6-dimethylpiperidin-3-yl)amino)-8-isopropylpyrazolo[1,5-a][ Synthesis of 1,3,5]triazin-4-yl)amino)methyl)phenyl)dimethylphosphine oxide

The dissolved (3-((8-isopropyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl )phenyl)dimethylphosphine oxide (80mg, 0.19mmol), (S)-6,6-dimethylpiperidin-3-amine (36mg, 0.29mmol) and N,N-diisopropylethylamine (74 mg, 0.57 mmol) in isopropyl alcohol (2 mL) was added and heated to 90°C and stirred for 72 hours. The resulting mixed reaction solution was diluted with water and diluted with acetic acid Extract with ethyl ester (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (S)-(3-(((2-((6, 6-dimethylpiperidin-3-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)benzene base) dimethylphosphine oxide (20 mg, yield: 22%), LC-MS m/z: 470 [M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ8.51 (s, 1H), 7.93 (d, J = 12Hz, 1H), 7.70 (s, 1H), 77.66-7.63 (m, 2H), 7.55-7.51 (m ,1H),4.79(d,J=2.4Hz,2H),4.19-4.15(m,1H),3.47-3.44(m,1H),3.16-3.11(m,1H),3.03-2.97(m,1H ),2.04–2.01(m,1H),1.92-1.86(m,1H),1.82–1.76(m,8H),1.42(d,J＝5.6Hz,6H),1.27(d,J＝6.8Hz, 6H).

Example 123, N-(3-(((5-(4-aminopiperidin-1-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl Synthesis of phenyl)-2-fluoroacrylamide (compound 123):

1), (5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3- Synthesis of tert-butyl nitrobenzyl carbamate

At room temperature, diisopropylethylamine (175 mg, 1.35 mmol) was added dropwise to the dissolved (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)( tert-butyl 3-nitrobenzyl)carbamate (200 mg, 0.45 mmol) and tert-butyl piperidin-4-ylcarbamate (108 mg, 0.54 mmol) in dimethyl sulfoxide (5 mL). The obtained mixed reaction liquid was heated to 120°C and stirred for 6 hours. After cooling, the mixed reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (3×30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to obtain (5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropyl Tert-butyl pyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamate (240 mg, yield: 88%), LC-MS m/z: 610 [M +H] ⁺ ;

2), (3-aminobenzyl)(5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropylpyrazolo[1,5-a]pyrimidine Synthesis of -7-yl)carbamic acid tert-butyl ester

Palladium on carbon (140 mg) was added to the dissolved (5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropylpyrazolo[1,5-a]pyrimidine- 7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (140 mg, 0.23 mmol) in methanol (6 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour under a hydrogen atmosphere. The mixed reaction solution was filtered through diatomaceous earth, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to obtain (3-aminobenzyl)(5-(4-((tert-butoxycarbonyl)amino)piperidine-1) -tert-butyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (73 mg, yield: 54.84%), LC-MS m/z: 580 [M +H] ⁺ ;

3), (5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3- Synthesis of (2-fluoroacrylamido)benzyl)carbamic acid tert-butyl ester

At room temperature, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (73mg, 0.26mmol) was added to the dissolved (3-aminobenzyl) (5-(4-( (tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (73 mg, 0.13 mmol), 2-Fluoroacrylic acid (15 mg, 0.16 mmol) and 1-methyl-1H-imidazole (43 mg, 0.52 mmol) in N,N-dimethylformamide (2 mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The mixed reaction solution was diluted with water (30 mL), and extracted with ethyl acetate (3×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-50% elution) to obtain (5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropyl tert-butyl pyrazolo[1,5-a]pyrimidin-7-yl)(3-(2-fluoroacrylamido)benzyl)carbamate (49 mg, yield: 59.7%), LC-MS m /z:652[M+H] ⁺ ;

4), N-(3-(((5-(4-aminopiperidin-1-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl Synthesis of )phenyl)-2-fluoroacrylamide

Will dissolve 5-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-( A solution of tert-butyl 2-fluoroacrylamido)benzyl)carbamate (44 mg, 0.068 mmol) in dichloromethane (2 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 1 hour, and the mixed reaction was The liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% 2,2,2-trifluoroacetic acid = 10-45% elution) to obtain N-(3-(((5-(4-aminopiperidine) (Din-1-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-2-fluoroacrylamide (15 mg, yield: 49% ), LC-MS m/z: 452[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO): δ10.29(s,1H),7.84(t,J＝6.4Hz,1H),7.76(s,1H),7.66(s,1H),7.59(d,J＝ 8.0Hz,1H),7.30(t,J＝8.0Hz,1H),7.17(d,J＝8.0Hz,1H),5.74(d,J＝3.6Hz,0.5H),5.62(d,J＝4.0 Hz,0.5H),5.47(s,1H),5.42(d,J＝4.0Hz,0.5H),5.38(d,J＝4.0Hz,0.5H),4.54(d,J＝8.0Hz,2H) ,4.15(d,J＝8.0Hz,2H),3.00-2.93(m,1H),2.88-2.81(m,3H),1.69(d,J＝8.0Hz,2H),1.25(d,J＝8.0 Hz,6H),1.16-1.20(m,2H).

Example 124, 2-fluoro-N-(2-(3-isopropyl-5-((3R,4R)-3-methoxypiperidin-4-yl)methyl)amino)pyrazolo Synthesis of [1,5-a]pyrimidin-7-yl)isoindolin-5-yl)acrylamide (compound 124):

1), Synthesis of 5-chloro-3-isopropyl-7-(5-nitroisoindolin-2-yl)pyrazolo[1,5-a]pyrimidine

To a solution of 5-nitroisoindoline (2.79g, 17mmol) in N,N-dimethylformamide (20mL) at 0°C, sodium hydride (943mg, 39.3mmol) was added. The resulting mixed reaction solution was stirred at room temperature for 1 hour. At room temperature, 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (3g, 13.1mmol) was added to the above mixed reaction solution, and the resulting mixed reaction solution was stirred at room temperature for 12 hours. . At 0℃ condition Then, the mixed reaction solution was added with water to quench the reaction, and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine (1×100 mL), dried over anhydrous sodium sulfate, filtered, and the mixed reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 15%-30% elution) to obtain 5-chloro-3-isopropyl-7-(5-nitroisoindolin-2-yl) ) Pyrazolo[1,5-a]pyrimidine (2.1g, yield: 45%), LC-MS m/z: 358[M+H] ⁺ ;

2), Synthesis of 2-(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)isoindolin-5-amine

Dissolve 5-chloro-3-isopropyl-7-(5-nitroisoindolin-2-yl)pyrazolo[1,5-a]pyrimidine (1g, 2.80mmol) and iron (784mg , 14 mmol) ethanol (6 mL) and ammonium chloride aqueous solution (1.5 mL), heated to 70°C and stirred overnight under argon protection. The mixed reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 15%-30% elution) to obtain 2-(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidine-7- base)isoindoline-5-amine (500mg, yield: 54.5%), LC-MS m/z: 328[M+H] ⁺ ;

3), N-(2-(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)isoindolin-5-yl)-2-fluoroacrylamide synthesis

Dissolve 2-(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)isoindolin-5-amine (400mg, 1.22mmol), N-(3 -Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (465mg, 2.44mmol), N-hydroxybenzotriazole (331mg, 2.44mmol) and triethylamine (370mg, 3.66mmol) ) in N,N-dimethylformamide (4 mL), stirred at room temperature for 1 hour under nitrogen protection. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain N-(2-(5-chloro-3-isopropylpyrazole) And[1,5-a]pyrimidin-7-yl)isoindolin-5-yl)-2-fluoroacrylamide (120 mg, yield: 24.6%), LC-MS m/z: 400 [M+ H] ⁺ ;

4), (3R, 4R)-4-(((7-(5-(2-fluoroacrylamido)isoindolin-2-yl)-3-isopropylpyrazolo[1,5- Synthesis of a]pyrimidin-5-yl)amino)methyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve N-(2-(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)isoindolin-5-yl)-2-fluoroacrylamide ( 60mg, 0.15mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-di Hydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (25 mg, 0.03 mmol), cesium carbonate (147 mg, 0.45 mmol) and (3R, 4R)-4-(aminomethyl) A solution of -3-methoxypiperidine-1-carboxylic acid tert-butyl ester (47 mg, 0.20 mmol) in 1,4-dioxane (3 mL) was heated to 90°C and stirred for 12 hours under nitrogen protection. Filter the mixed reaction solution, The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 20-65% elution) to obtain (3R, 4R)-4-(((7-(5-(2-fluoroacrylamido)isoindole) Dolin-2-yl)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (30mg, yield: 33%), LC-MS m/z: 608[M+H] ⁺ ;

5), 2-fluoro-N-(2-(3-isopropyl-5-((3R,4R)-3-methoxypiperidin-4-yl)methyl)amino)pyrazolo[ Synthesis of 1,5-a]pyrimidin-7-yl)isoindolin-5-yl)acrylamide

Dissolve (3R, 4R)-4-(((7-(5-(2-fluoroacrylamido)isoindolin-2-yl)-3-isopropylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.049 mmol) in dichloromethane (3 mL) and 2,2,2-tris A solution of fluoroacetic acid (1 mL) was stirred at room temperature for 3 hours. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (12 mg, yield: 48%), LC-MS m/z: 508 [ M+H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ7.75 (s, 1H), 7.64 (s, 1H), 7.56 (dd, J = 8.0, 2.0Hz, 1H), 7.35 (d, J = 8.0Hz, 1H) ,5.72(dd,J＝48.0,4.0Hz,1H),5.34–5.27(m,2H),5.18(d,J＝4.0Hz,4H),3.70-3.63(m,1H),3.44(s,3H ),3.41–3.34(m,2H),3.18–3.12(m,1H),3.12–3.07(m,1H),3.02(dd,J＝8.6,4.2Hz,1H),2.64-2.55(m,1H ),2.50–2.43(m,1H),1.98-1.83(m,1H),1.84(s,1H),1.46–1.35(m,1H),1.29(d,J＝8.0Hz,6H).

Example 125, 2-fluoro-N-(3-(((3-isopropyl-5-((((3R,4R))-3-methoxypiperidin-4-yl)methyl)amino )Synthesis of pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (compound 125):

1), (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a] Synthesis of pyrimidin-5-yl)amino)methyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (300mg, 0.67mmol), ( 3R, 4R)-4-(Aminomethyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (197 mg, 0.81 mmol), (SP-4-1)-[1,3-bis[ 2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (57 mg, 0.067 mmol) and cesium carbonate (659 mg, 2.02 mmol) in 1,4-dioxane (5 mL), under argon protection, heated to 90°C and stirred for 12 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (3R, 4R)-4-(((7-((tert-butoxy) Carbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-methoxypiperidine-1- Tert-butyl carboxylate (246 mg, yield: 60%), LC-MS m/z: 654[M+H] ⁺ ;

2), (3R, 4R)-4-((((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Synthesis of pyrimidin-5-yl)amino)methyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-5-yl)amino)methyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (220 mg, 0.34 mmol) and iron (77 mg, 1.37 mmol) in aqueous ammonium chloride solution (0.5 mL) The solution was heated to 70°C and ethanol (2.0 mL) and stirred for 4 hours. After cooling, the mixed reaction solution was filtered, and the filter cake was washed with methanol (3 × 10 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which could be used directly in the next step without further purification. LC-MS m/z: 624[M+H] ⁺ ;

3), (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[ Synthesis of 1,5-a]pyrimidin-5-yl)amino)methyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (3R, 4R)-4-((((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-5-yl)amino)methyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (174 mg, 0.28 mmol), 2-fluoroacrylic acid (30 mg, 0.33 mmol), 1-methyl- A solution of 1H-imidazole (92 mg, 1.11 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (157 mg, 0.56 mmol) in N,N-diformamide (2 mL) was heated for 60 ° C for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (3R, 4R)-4-(((7 -((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl tert-butyl)-3-methoxypiperidine-1-carboxylate (117 mg, yield: 60%), LC-MS m/z: 696 [M+H] ⁺ ;

4), 2-fluoro-N-(3-(((3-isopropyl-5-((((3R,4R)-3-methoxypiperidin-4-yl)methyl)amino) Synthesis of pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide

There is (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[ In a solution of 1,5-a]pyrimidin-5-yl)amino)methyl)-3-methoxypiperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.07 mmol) in dichloromethane (1.2 mL), 2,2,2-trifluoroacetic acid (0.4 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain 2-fluoro-N-(3-(((3-isopropyl-5 -((((3R,4R)-3-methoxypiperidin-4-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)benzene acrylamide (26 mg, yield: 73%), LC-MS m/z: 496 [M+H] ⁺ ;

1H NMR (400MHz, MeOD-d4) δ7.68(s,1H),7.64(s,1H),7.59(d,J＝7.7Hz,1H),7.34(t,J＝7.8Hz,1H),7.21 (d,J＝7.5Hz,1H),5.69(dd,J＝46.5,3.3Hz,1H),5.28(dd,J＝15.2,3.4Hz,1H),5.21(s,1H),4.57(s, 2H),3.55 (dd,J＝13.5,4.6Hz,1H),3.36(s,3H),3.26(d,J＝6.2Hz,3H),3.11–3.05(m,1H),3.04–2.97(m,1H), 2.91(d,J＝12.8Hz,1H),2.46(t,J＝12.9Hz,1H),2.35–2.26(m,1H),1.81(d,J＝11.9Hz,1H),1.67(s,1H ),1.29(d,J＝6.9Hz,6H).

Example 126, 2-fluoro-N-(3-(((5-(1-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)ethyl)- Synthesis of 3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (compound 126A and compound 126B):

1), 5-((7-((3-Acrylamidobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl) Synthesis of tert-butyloxy)-2,2-dimethylpiperidine-1-carboxylate

At 0°C, 5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine- To a solution of 5-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (60 mg, 0.10 mmol) in dichloromethane (1 mL), triethylamine (30 mg, 0.30 mmol), stir at 0°C for 30 minutes. Then, a solution of acryloyl chloride (11 mg, 0.12 mmol) in dichloromethane (0.5 mL) was added dropwise to the above mixed reaction solution at 0°C. The resulting reaction mixture was stirred at room temperature for 2 hours. The mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain 5-((7-((3-acrylamidobenzyl))( tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2,2-dimethylpiperidine-1-carboxylate Ester (50 mg, yield: 76.5%), LC-MS m/z: 663[M+H] ⁺ ;

2), N-(3-(((5-((6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidine- Synthesis of 7-yl)amino)methyl)phenyl)acrylamide

Will dissolve 5-((7-((3-acrylamidobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl) A solution of tert-butyloxy)-2,2-dimethylpiperidine-1-carboxylate (50 mg, 0.08 mmol) in dichloromethane (2 mL) and 2,2,2-trifluoroacetic acid (0.5 mL) Stir at room temperature for 2 hours. The resulting mixed reaction solution was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, and filtered. Concentrate under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain N-(3-(((5-((6,6-di Methylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (28 mg, yield: 80%), LC-MS m/z: 463[M+H] ⁺ ;

3), (S)-N-(3-(((5-((6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5- a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide or enantiomer and (R)-N-(3-(((5-((6,6-dimethylpiperidine) Synthesis of -3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide or enantiomers

The racemate (40 mg, 0.09 mmol) was passed through supercritical fluid chromatography (chromatographic conditions: system: Waters SFC 150; column: 250*40mm 10μm; Mobile phase A: Supercritical CO ₂ ; Mobile phase B: EtOH (+0.1% 7.0mol/l Ammonia in MeOH), A: B = 65:35; Check wavelength: 214nm; Flow rate: 120mL/min; Column temperature: RT; column pressure: 100bar) were separated and purified to obtain two isomers: BIOT-002-4045 and BIOT-002-4046:

BIOT-002-4045 (compound 126A): Peak 1: 2.148min; (10mg, yield: 25%), LC-MS m/z: 463[M+H] ⁺ ; 1H NMR (400MHz, MeOD): δ7 .76(s,1H),7.65–7.56(m,2H),7.32(t,J＝7.6Hz,1H),7.15(d,J＝7.6Hz,1H),6.43-6.30(m,2H), 5.74(dd,J＝12.0,4.0Hz,1H),5.38(s,1H),5.14–5.07(m,1H),4.59(s,2H),3.19–3.05(m,2H),3.01–2.93( m,1H),2.05–1.96(m,1H),1.93–1.80(m,1H),1.73-1.66(m,1H),1.55–1.42(m,1H),1.32(d,J＝7.2Hz, 6H),1.18(s,6H).

BIOT-002-4046 (compound 126B): Peak 2: 2.783 min (10 mg, yield: 25%), LC-MS m/z: 463 [M+H] ⁺ ; ¹ H NMR (400MHz, MeOD) δ7. 79(s,1H),7.69(s,1H),7.54(d,J＝8.0Hz,1H),7.32(t,J＝8.0Hz,1H),7.15(d,J＝7.6Hz,1H), 6.44-6.30(m,2H),5.75(dd,J＝12.0,4.0Hz,1H),5.46–5.40(m,2H),4.61(s,2H),3.54-3.50(m,1H),3.46- 3.41(m,1H),3.13-3.06(m,1H),2.09–2.02(m,2H),2.00–1.89(m,1H),1.69-1.64(m,1H),1.42(d,J＝2.4 Hz, 6H), 1.32 (d, J = 6.8Hz, 6H).

Example 127, (R)-3-acrylamido-N-(3-((3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidine Synthesis of -7-yl)amino)phenyl)benzamide (compound 127):

1), (R)-3-((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 Synthesis of -(yl)oxy)piperidine-1-carboxylic acid tert-butyl ester

To a solution of (R)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (154 mg, 0.77 mmol) dissolved in N,N-dimethylformamide (2 mL) at 0°C, sodium hydride was added (19mg, 0.77mmol). The resulting mixed reaction solution was stirred at room temperature for 30 minutes, and then

(5-Chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamic acid tert-butyl ester (332mg, 0.77mmol) was added to the above mixed reaction solution middle. The resulting mixed reaction solution was stirred at room temperature for 2 hours. The mixed reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 10-50% elution) to obtain (R)-3-((7-((tert-butoxycarbonyl)(3-nitrophenyl)) Amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (300 mg, 65.4%), LC-MS m/z :597[M+H] ⁺ ;

2), (R)-3-((7-((3-Aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- Synthesis of tert-butyl)piperidine-1-carboxylate

Dissolve (R)-3-((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 A solution of -yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (120 mg, 0.20 mmol) and iron (57 mg, 1.0 mmol) in ethanol (4 mL) and aqueous ammonium chloride solution (1.0 mL) was heated to 70°C and stirred 2 Hour. After cooling, the mixed reaction solution was filtered, and the filter cake was washed with methanol (3×20 mL). The filtrate was collected and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (R)-3-((7-((3-aminophenyl)( Tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (100 mg, yield: 87.7 %), LC-MS m/z: 567[M+H] ⁺ ;

3), (R)-3-((7-((3-(3-acrylamidobenzamido)phenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine Synthesis of -5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester

At room temperature, (R)-3-((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.18 mmol) and 3-acrylamidobenzoic acid (40 mg, 0.21 mmol) in N,N-dimethylformamide ( 2.0mL) solution was added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (100mg, 0.26mmol) and N,N-diiso Propylethylamine (69 mg, 0.53 mmol). The resulting mixed reaction solution was stirred at room temperature for 3 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (R)-3-((7-((3-(3- Acrylamidobenzoylamino)phenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester (40 mg , Yield: 35.4%), LC-MS m/z: 640[M+H] ⁺ ;

4), (R)-3-acrylamido-N-(3-((3-isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidine- Synthesis of 7-yl)amino)phenyl)benzamide

At room temperature, (R)-3-((7-((3-(3-acrylamidobenzoylamino)phenyl)amino)-3-isopropylpyrazolo[1,5 -To a solution of tert-butyl a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (40 mg, 0.067 mmol) in dichloromethane (2.0 mL), add 2,2,2-trifluoroacetic acid ( 0.5mL). The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (R)-3-acrylamido-N-(3-((3- Isopropyl-5-(piperidin-3-yloxy)pyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)benzamide (20 mg, yield: 59.3%), LC-MS m/z: 540[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO): δ10.44(d,J＝12.0Hz,2H),8.20(s,1H),7.94(d,J＝12.0Hz,2H),7.87(s,1H),7.73 –7.65(m,2H),7.50(t,J＝8.0Hz,1H),7.42(t,J＝8.0Hz,1H),7.16(d,J＝8.0Hz,1H),6.49-6.43(m, 1H),6.33-6.28(m,1H),5.79(d,J＝12.0Hz,1H),5.66(s,1H),5.07(s,1H),3.22-3.16(m,1H),3.11–3.06 (m,1H),2.79(s,1H),2.73(s,1H),2.67-2.63(m,1H),2.01(s,2H),1.76–1.47(m,4H),1.32(d,J =8.0Hz,6H).

Example 128, 3-acrylamido-N-(3-((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropyl Synthesis of pyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)benzamide (compound 128):

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrophenyl)carbamic acid tert-butyl ester (120 mg, 0.28 mmol), ( SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2 -Ylidene](2-methylpyridine)palladium dichloride (24 mg, 0.028 mmol), cesium carbonate (272 mg, 0.83 mmol) and (3R, 4R)-4-(aminomethyl)-3-hydroxypiperidine- A solution of 1-carboxylic acid tert-butyl ester (77 mg, 0.33 mmol) in 1,4-dioxane (3 mL) was heated to 90°C and stirred overnight under nitrogen protection. After cooling, the mixed reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-15% elution) to obtain (3R, 4R)-4-(((7-(tert-butyl Oxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1- Tert-butyl carboxylate (90 mg, yield: 52%), LC-MS m/z: 626 [M+H] ⁺ ;

Dissolve (3R, 4R)-4-((((7-((tert-butoxycarbonyl)(3-nitrophenyl)amino)-3-isopropylpyrazolo[1,5-a ]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (92 mg, 0.15 mmol) and iron (42 mg, 0.74 mmol) in ethanol (4 mL) and aqueous ammonium chloride (1mL) solution, under argon protection, heated to 70°C and stirred overnight. After cooling, the mixed reaction solution was filtered, and the filter cake was washed with methanol (3 × 20mL). The filtrate was collected and concentrated under reduced pressure. The residue was passed through C18 column chromatography (acetonitrile) :Pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) purification to obtain (3R, 4R)-4-((((7-((3-aminophenyl))(tert-butoxy) Carbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (80 mg, yield :91%), LC-MS m/z: 596[M+H] ⁺ ;

3), (3R, 4R)-4-(((7-((3-(3-acrylamidobenzoyl)phenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo Synthesis of [1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

Dissolve (3R, 4R)-4-((((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (68 mg, 0.11 mmol), 2-(7-azobenzotriazole)-N, N, N', N'-tetramethylurea hexafluorophosphate (76 mg, 0.2 mmol), N, N-diisopropylethylamine (44 mg, 0.34 mmol) and 3-acrylamidobenzoic acid (28 mg, 0.15 mmol) ) in N,N-dimethylformamide (2.5 mL) was stirred at room temperature for 16 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was eluted by silica gel column chromatography (ethyl acetate: petroleum ether = 20-65% ) was purified to obtain (3R, 4R)-4-(((7-((3-(3-acrylamidobenzoyl)phenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo [1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30 mg, yield: 34%), LC-MS m/z: 769 [M+H] ⁺ ;

4), 3-acrylamido-N-(3-((5-(((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropyl Synthesis of pyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)benzamide

Dissolve (3R, 4R)-4-(((7-((3-(3-acrylamidobenzoyl)phenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo [1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.039 mmol) in dichloromethane (3 mL) and A solution of 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 3 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 15-45% elution) to obtain (7 mg, yield: 31.5%), LC-MS m/z: 569 [M+ H] ⁺ ;

¹ H NMR (400MHz, MeOD): δ8.33(s,1H),8.03(s,1H),7.75–7.66(m,3H),7.50(t,J＝8.0Hz,1H),7.46–7.36( m,2H),7.15(d,J＝8.0Hz,1H),6.50-6.43(m,1H),6.42-6.39(m,1H),5.86–5.77(m,2H),4.02(d,J＝ 14.6Hz,1H),3.58–3.51(m,1H),3.40–3.36(m,1H),3.38-3.32(m,1H),3.29-3.22(m,1H),3.11-3.05(m,1H) ,2.98-2.91(m,1H),2.83-2.74(m,1H),1.99-1.02(m,1H),1.77-1.63(m,2H),1.31(t,J＝8.0Hz,6H).

Example 129, N-(3-(((5-(((8-azabicyclo[3.2.1]oct-3-yl)methyl)amino)-3-isopropylpyrazolo[1, Synthesis of 5-a]pyrimidin-7-yl)amino)methyl)phenyl)butan-2-amide (compound 129):

1), 3-(((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino Synthesis of )methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (200mg, 0.45mmol), 3 -(Aminomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (129 mg, 0.45 mmol), (SP-4-1)-[1,3-bis[2 ,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium ( 38 mg, 0.045 mmol), and a solution of cesium carbonate (439 mg, 1.35 mmol) in 1,4-dioxane (5 mL), under argon protection, heated to 90°C and stirred overnight. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain 3-(((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino) -3-Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester ( 280mg, yield: 96.0%), LC-MS m/z: 650[M+H] ⁺ ;

2), 3-(((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino Synthesis of )methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

Will dissolve 3-(((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino ) Methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (280 mg, 0.43 mmol) and iron (121 mg, 2.16 mmol) in aqueous ammonium chloride (1 mL) and ethanol (4 mL) solution was heated to 70°C and stirred for 2 hours. After cooling, the mixed reaction solution was filtered, and the filter cake was washed with methanol (3×10 mL). The filtrate was collected and concentrated under reduced pressure to obtain 3-(((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- (base)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (260 mg, yield: 97%), LC-MS m/z: 620 [M+ H] ⁺ ;

3), 3-(((7-((3-(but-2-ynylamido)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] Synthesis of pyrimidin-5-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

The dissolved 3-(((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino )Methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (86mg, 0.14mmol), butan-2-ynoic acid (18mg, 0.21mmol), O-(7 -Azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (79 mg, 0.21 mmol) and N,N-diisopropylethylamine (54 mg , 0.42 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 16 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain 3-(((7-((3-(but-2-ynamido)benzyl) )(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-8-azabicyclo[3.2.1]octane- 8-tert-butylcarboxylate (60mg, yield: 63%), LC-MS m/z: 686[M+H] ⁺ ;

4), N-(3-(((5-(((8-azabicyclo[3.2.1]oct-3-yl)methyl)amino)-3-isopropylpyrazolo[1,5 -Synthesis of a]pyrimidin-7-yl)amino)methyl)phenyl)butan-2-amide

In solution, there is 3-(((7-((3-(but-2-ynylamido)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a] A solution of pyrimidin-5-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (60 mg, 0.09 mmol) in dichloromethane (3 mL) was added dropwise 2,2,2-trifluoroacetic acid (1 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain N-(3-(((5-(((8-azabicyclo[3.2.1]octane) -3-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)butan-2-amide (30 mg, yield :71%), LC-MS m/z: 486[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD) δ7.74(s,1H),7.66(s,1H),7.42(d,J＝8.0Hz,1H),7.35-7.30(m,1H),7.15(d,J ＝7.6Hz,1H),5.17(s,1H),4.61(s,2H),3.99(s,2H),3.25(d,J＝6.0Hz,2H),3.11-3.06(m,1H),2.18 (s,1H),2.10-2.04(m,2H),2.02(s,3H),1.88(d,J＝8.4Hz,2H),1.80(d,J＝15.2Hz,2H),1.60-1.50( m,2H),1.30(d,J＝6.8Hz,6H).

Example 130, N-(3-(((5-(((8-azabicyclo[3.2.1]oct-3-yl)methyl)amino)-3-isopropylpyrazolo[1, Synthesis of 5-a]pyrimidin-7-yl)amino)methyl)phenyl)-2-fluoroacrylamide (compound 130):

1), 3-(((7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine Synthesis of -5-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

The dissolved 3-(((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino ) Methyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (86 mg, 0.14 mmol), 2-fluoroacrylic acid (19 mg, 0.21 mmol), 2-(7-azobenzene) Triazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (79mg, 0.21mmol) and N,N-diisopropylethylamine (54mg, 0.42mmol) N, A solution of N-dimethylformamide (3 mL) was stirred at room temperature for 16 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain 3-(((7-((tert-butoxycarbonyl))(3-(2-fluoropropene) Amino)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8 -tert-butyl carboxylate (60 mg, yield: 62.5%),

LC-MS m/z: 692[M+H] ⁺ ;

2), N-(3-(((5-(((8-azabicyclo[3.2.1]oct-3-yl)methyl)amino)-3-isopropylpyrazolo[1,5 -Synthesis of -a]pyrimidin-7-yl)amino)methyl)phenyl)-2-fluoroacrylamide

At room temperature, 3-(((7-((tert-butoxycarbonyl)(3-(2-fluoroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1, A solution of tert-butyl 5-a]pyrimidin-5-yl)amino)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.09 mmol) in dichloromethane (3 mL) , add 2,2,2-trifluoroacetic acid (1mL) dropwise. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain N-(3-(((5-(((8-azabicyclo[3.2.1]octane) -3-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-2-fluoroacrylamide (30 mg, collected Rate: 70%), LC-MS m/z: 492[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD) δ7.70 (s, 2H), 7.56 (d, J = 8.0Hz, 1H), 7.36-7.31 (m, 1H), 7.21 (d, J = 7.6Hz, 1H), 5.69(dd,J＝46.4,3.6Hz,1H),5.29(dd,J＝15.2,3.2Hz,1H),5.16(s,1H),4.60(s,2H),3.98(s,2H),3.25 (d,J＝6.4Hz,2H),3.11-3.05(m,1H),2.26-2.17(m,1H),2.09-2.00(m,2H),1.88(d,J＝8.0Hz,2H), 1.81(d,J＝13.6Hz,2H),1.60-1.50(m,2H),1.30(d,J＝6.8Hz,6H).

Example 131, (1s,4R)-4-acrylamido-N-(3-(5-chloro-2-(((S)-6,6-dimethylpiperidin-3-yl)amino) Synthesis of pyrimidin-4-yl)-1H-indol-6-yl)cyclohexane-1-carboxamide (compound 131):

1), Synthesis of 3-(2,5-dichloropyrimidin-4-yl)-6-nitro-1H-indole

A solution of 2,4,5-trichloropyrimidine (2.0g, 10.99mmol) and anhydrous aluminum chloride (731mg, 5.50mmol) dissolved in 1,2-dichloroethane (20mL) was heated under nitrogen protection. Stir at 80°C for 30 minutes. Then, a solution of 6-nitro-1H-indole (594 mg, 3.64 mmol) in 1,2-dichloroethane (5 mL) was added dropwise to the above mixed reaction solution. The resulting mixed reaction liquid was heated to 80°C and stirred for 2.5 hours. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: 0.1% NH ₃ ·H ₂ O in pure water = 5-95% elution) to obtain 3-(2,5-dichloropyrimidin-4-yl)-6-nitro -1H-indole (787mg, yield: 70%), LC-MS m/z: 309[M+H] ⁺ ;

2), Synthesis of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole-6-amine

Dissolve 3-(2,5-dichloropyrimidin-4-yl)-6-nitro-1H-indole (1.0g, 3.25mmol) and iron (912mg, 16.23mmol) in an aqueous ammonium chloride solution (2mL ) and ethanol (8 mL) solution was heated to 70°C and stirred for 2 hours. After cooling, the mixed reaction solution was filtered, and the filter cake was washed with dichloromethane (3×10 mL). The filtrate was collected and concentrated under reduced pressure to obtain a crude product, which could be used directly in the next step without further purification. LC-MS m/z: 279[M+H] ⁺ ;

3), (1s, 4s)-4-acrylamido-N-(3-(2,5-dichloropyrimidin-4-yl)-1H-indol-6-yl)cyclohexane-1-methyl Synthesis of amides

Dissolve 3-(2,5-dichloropyrimidin-4-yl)-1H-indole-6-amine (300mg, 1.08mmol), 2-(7-azobenzotriazole)-N, N,N',N'-tetramethylurea hexafluorophosphate (615mg, 1.62mmol), N,N-diisopropylethylamine (698mg, 5.40mmol) and (1s,4s)-4-acrylamide A solution of cyclohexane-1-carboxylic acid (319 mg, 1.62 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: 0.1% formic acid in pure water = 5-95% elution) to obtain (1s, 4s)-4-acrylamide-N-(3-(2,5-di Chloropyrimidin-4-yl)-1H-indol-6-yl)cyclohexane-1-carboxamide (120 mg, yield: 24.3%), LC-MS m/z: 458 [M+H] ⁺ ;

4), (1s, 4R)-4-acrylamido-N-(3-(5-chloro-2-(((S)-6,6-dimethylpiperidin-3-yl)amino)pyrimidine Synthesis of -4-yl)-1H-indol-6-yl)cyclohexane-1-carboxamide

Dissolve (1s, 4s)-4-acrylamido-N-(3-(2,5-dichloropyrimidin-4-yl)-1H-indol-6-yl)cyclohexane-1-methyl Amide (120 mg, 0.26 mmol), (S)-6,6-dimethylpiperidin-3-amine (84.0 mg, 0.66 mmol), N,N-diisopropylethylamine (168 mg, 1.3 mmol) and A solution of potassium fluoride (23 mg, 0.39 mmol) in dimethyl sulfoxide (2.0 mL) was heated to 110°C and stirred overnight. After cooling, the residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (1s, 4s)-4-acrylamide-N-(3 -(2,5-Dichloropyrimidin-4-yl)-1H-indol-6-yl)cyclohexane-1-carboxamide (30 mg, still yield: 21.0%), LC-MS m/z: 550[M+H] ⁺ ; ¹ H NMR (400MHz, MeOD-d ₄ ): δ8.50 (d, J = 12.0Hz, 1H), 8.41 (s, 1H), 8.24 (s, 1H), 7.91 ( d,J＝12.0Hz,1H),7.24(dd,J＝12.0,4.0Hz,1H),6.41-6.32(m,1H),6.27-6.20(m,1H),5.65(dd,J＝8.0, 4.0Hz,1H),4.28-4.20(m,1H),4.08-4.02(m,1H),3.47-3.41(m,1H),3.27-3.19(m,1H),2.58-2.50(m,1H) ,2.20-2.10(m,1H),1.97-1.87(m,6H),1.81-1.68(m,5H),1.44(s,6H).

Example 132, 3-acrylamido-N-(3-((2-(((((3R,4S)-3-hydroxypiperidin-4-yl)methyl)amino)-5-(tri Synthesis of fluoromethyl)pyrimidin-4-yl)amino)phenyl)benzamide (compound 132):

1), Synthesis of N ¹ -(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)benzene-1,3-diamine

4-Chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (150 mg, 0.658 mmol) and benzene-1,3-diamine (85 mg, 0.79 mmol) were dissolved in isopropanol ( 3 mL) solution, add N, N-diisopropylethylamine (255 mg, 1.97 mmol). The resulting mixed reaction solution was heated to 70°C and stirred for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain N ¹ -(2-(methylthio)-5-(trifluoro) Methyl)pyrimidin-4-yl)benzene-1,3-diamine (150 mg, yield: 76.0%), LC-MS m/z: 301[M+H] ⁺ ;

2), Synthesis of 3-acrylamido-N-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)benzamide

At room temperature, N ¹ -(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)benzene-1,3-diamine (150 mg, 0.50 mmol) and 3- To a solution of acrylamidobenzoic acid (114 mg, 0.60 mmol) in acetonitrile (2 mL), 1-methyl-1H-imidazole (164 mg, 2.00 mmol) and N,N,N',N'-tetramethylchloromethane were added. Amidine hexafluorophosphate (281 mg, 1.00 mmol). The resulting mixed reaction solution was stirred at room temperature for 4 hours. After cooling, the obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain 3-acrylamido-N-(3-((2-(methyl Thio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)benzamide (150 mg, yield: 63.4%), LC-MS m/z: 474 [M+H] ⁺ ;

3), Synthesis of 3-acrylamido-N-(3-((2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)benzamide

Dissolve 3-acrylamido-N-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)benzamide (70 mg, 0.148 mmol) and 3-chloroperoxybenzoic acid (51 mg 0.30 mmol) in dichloromethane (3 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3x 50 mL). The combined organic phases were washed with saturated brine (1x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain 3-acrylamido-N-(3-((2-(methyl Sulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)benzamide (50 mg, yield: 67%), LC-MS m/z: 506 [M+H] ⁺ ;

4), (3R, 4S)-4-(((4-((3-(3-acrylamidobenzoylamino)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl Synthesis of )amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

At room temperature, 3-acrylamido-N-(3-((2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)benzene is dissolved in 1,4-dioxane of carboxamide (50 mg, 0.099 mmol) and (3R,4S)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxytert-butyl ester (27 mg, 0.12 mmol) (2 mL) solution, add cesium fluoride (30 mg, 0.20 mmol). The resulting mixed reaction liquid was heated to 100°C and stirred for 2 hours. After cooling, the obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (3R, 4S)-4-(((4-((3- (3-Acrylamidobenzoylamino)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (50mg, yield: 77%), LC-MS m/z: 656[M+H] ⁺ ;

5), 3-acrylamido-N-(3-((2-(((((3R,4S)-3-hydroxypiperidin-4-yl)methyl)amino)-5-(trifluoro Synthesis of methyl)pyrimidin-4-yl)amino)phenyl)benzamide

At room temperature, dissolve (3R, 4S)-4-(((4-((3-(3-acrylamidobenzoylamino)phenyl)amino))-5-(trifluoromethyl)pyrimidine To a solution of -2-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.076 mmol) in dichloromethane (1.5 mL), 2,2,2-tris was added dropwise Fluoroacetic acid (0.5 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain 3-acrylamide-N-(3-((2-(( ((((3R,4S)-3-hydroxypiperidin-4-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)benzamide (30 mg, Yield: 70.8%), LC-MS m/z: 556[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.43(d,J＝8.0Hz,1H),8.20–8.18(m,1H),8.11(s,1H),8.03(s,1H),7.87( s,1H),7.64(d,J＝7.6Hz,1H),7.45(t,J＝8.0Hz,1H),7.35(t,J＝8.0Hz,1H),6.94-6.92(m,1H), 4.03(s,1H),3.85-3.80(m,1H),3.27-3.22(m,1H),3.19-3.16(m,1H),2.77-2.75(m,2H),2.60-2.57(m,1H ),2.54-2.51(m,1H),2.31(d,J＝7.2Hz,1H),2.20-2.14(m,1H),2.03-1.93(m,1H),1.77(s,1H),1.69- 1.66(m,1H).

Example 133, (S)-N-(3-((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a Synthesis of ]pyrimidin-7-yl)amino)phenyl)-3-(2-fluoroacrylamido)benzamide (compound 133):

1), (S)-5-((7-((tert-butoxycarbonyl)(4-(3-(2-fluoroacrylamido)benzamido)phenyl)amino)-3-isopropyl Synthesis of pyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

Dissolve (S)-5-((7-((3-aminophenyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5- (hydroxy)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (0.05g, 0.084m mol), N,N,N',N'-tetramethylchloroformamidine hexafluoro A solution of phosphate (0.13 g, 0.47 mmol) and 1-methyl-1H-imidazole (0.028 g, 0.34 mmol) in acetonitrile (0.5 mL) was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by preparative TLC (methanol: dichloromethane = 0-10% elution) to give (S)-5-((7-((tert-butoxycarbonyl)(4-(3-(2- Fluoroacrylamido)benzamido)phenyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine- 1-tert-butylcarboxylate (0.037g, yield: 56%), LC-MS m/z: 785[M+H] ⁺ ;

2), (S)-N-(3-((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a] Synthesis of pyrimidin-7-yl)amino)phenyl)-3-(2-fluoroacrylamido)benzamide

Dissolve (S)-5-((7-((tert-butoxycarbonyl)(4-(3-(2-fluoroacrylamido)benzamido)phenyl)amino)-3- Isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (37 mg, 0.047 mmol) and 2,2, A solution of 2-trifluoroacetic acid (54 mg, 0.47 mmol) in dichloromethane (0.37 mL) was stirred at room temperature for 1 hour. The mixed reaction solution was concentrated under reduced pressure. . The residue was purified by preparative TLC (methanol: dichloromethane = 0-10% elution) to obtain (S)-N-(3-((5-((6,6-dimethylpiperidine-3- (yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)phenyl)-3-(2-fluoroacrylamido)benzamide (10 mg, yield :36%), LC-MS m/z: 585[M+H] ⁺ ;

¹ H NMR (400MHz, MeOH-d4): δ8.22(s,1H),7.97(s,1H),7.84(d,J＝7.6Hz,1H),7.74(d,J＝7.2Hz,1H) ,7.69(s,1H),7.52(t,J＝7.6Hz,1H),7.43(d,J＝6.0Hz,1H),7.18–7.10(m,1H),5.75(dd,J＝46.4,3.2 Hz,1H),5.32(dd,J＝15.2,3.2Hz,1H),3.90(s,1H),3.35(s,1H),3.17–3.06(m,2H),2.65(dd,J＝12.8, 9.4Hz,1H),1.98–1.86(m,2H),1.74–1.48(m,3H),1.33(d,J＝1.2Hz,3H),1.31(d,J＝1.2Hz,3H),1.15( s,3H),1.11(s,3H).

Example 134, 2-fluoro-N-(3-(((5-(((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino)- Synthesis of 3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (compound 134):

1), (3-(2-fluoroacrylamido)benzyl)(5-(((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino Synthesis of )-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester

Dissolve (3-aminobenzyl)(5-((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino)-3-isopropylpyra Azolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (200mg, 0.38mmol), 2-(7-azobenzotriazole)-N,N,N',N' - N,N-dimethylurea hexafluorophosphate (214 mg, 0.57 mmol), N,N-diisopropylethylamine (147 mg, 1.14 mmol) and 2-fluoroacrylic acid (51.3 mg, 0.57 mmol) The methylformamide (2 mL) solution was stirred at room temperature for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain (3-(2-fluoropropene) Amino)benzyl)(5-(((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[ 1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (150 mg, yield: 66%), LC-MS m/z: 596 [M+H] ⁺ ;

2), 2-fluoro-N-(3-(((5-(((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino)-3 -Synthesis of isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide

Dissolve (3-(2-fluoroacrylamido)benzyl)(5-(((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)amino )-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (150 mg, 0.25 mmol) in dichloromethane (1.50 mL) and 2,2,2-tris The fluoroacetic acid (0.5 mL) solution was stirred at room temperature for 2 hours. The resulting mixed reaction solution was concentrated under reduced pressure. The residue was passed through C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) Purification gave 2-fluoro-N-(3-(((5-(((((3R,4R)-3-hydroxy-1-methylpiperidin-4-yl)methyl)methyl)amino)-3- Isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (100 mg, yield: 80%). LC-MS m/z: 496 [M+ H] ⁺ ;

¹ H NMR (400MHz, MeOD-d ₄ ): δ7.68-7.64 (m, 2H), 7.60 (d, J = 8.0Hz, 1H), 7.34 (t, J = 8.0Hz, 1H), 7.20 (d ,J＝8.0Hz,1H),5.76-5.62(m,1H),5.31-5.25(m,1H),5.17(s,1H),4.55(s,2H),3.96-3.87(m,1H), 3.37-3.34(m,1H),3.14-2.99(m,2H),2.95(dd,J＝12.0,4.0Hz,1H),2.82(d,J＝12.0Hz,1H),2.25(s,3H) ,2.02–1.93(m,1H),1.87(t,J＝12.0Hz,1H),1.67-1.59(m,1H),1.56-1.43(m,1H),1.37-1.31(m,1H),1.29 (d,J＝8.0Hz,3H),1.27(d,J＝8.0Hz,3H).

Example 135, (R)-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a] Pyrimidin-7-yl)amino) Synthesis of methyl)phenyl)dimethylphosphine oxide (compound 135):

1), (R)-(3-(dimethylphosphoryl)benzyl)(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo Synthesis of [1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester

Dissolve (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(dimethylphosphoryl)benzyl)carbamic acid tert-butyl ester (120 mg, 0.27mmol), (R)-6,6-dimethylpiperidin-3-amine (103mg, 0.81mmol), (SP-4-1)-[1,3-bis[2,6-bis(1 -Ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2-ylidene]dichloro(2-methylpyridine)palladium (23 mg, 0.027 mmol) and A solution of cesium carbonate (440 mg, 1.35 mmol) in 1,4-dioxane (2.0 mL) was heated to 100°C and stirred for 2 hours under argon protection. After cooling, the mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (R)-(3-(dimethylphosphoryl)benzyl)(5 -((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (100 mg, collected Rate: 70%), LC-MS m/z: 569[M+H] ⁺ ;

2), (R)-(3-(((5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine Synthesis of -7-yl)amino)methyl)phenyl)dimethylphosphine oxide

There is (R)-(3-(dimethylphosphoryl)benzyl)(5-((6,6-dimethylpiperidin-3-yl)amino)-3-isopropylpyrazolo in solution To a solution of [1,5-a]pyrimidin-7-yl)carbamic acid tert-butyl ester (100 mg, 0.18 mmol) in dichloromethane (1.5 mL), 2,2,2-trifluoroacetic acid (0.5 mL) was added dropwise . The resulting mixed reaction solution was stirred at room temperature for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 5%-95% elution) to obtain (R)-(3-(((5-((6,6-di Methylpiperidin-3-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)dimethylphosphine oxide (80 mg, collected Rate: 97%), LC-MS m/z: 469[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ8.50 (s, 1H), 7.85 (d, J = 12.0Hz, 1H), 7.71-7.61 (m, 3H), 7.57-7.51 (m, 1H), 5.18(s,1H),4.62(s,2H),4.20-4.12(m,1H),3.54(dd,J＝12.0,4.0Hz,1H),3.17-3.02(m,2H),2.04-1.95( m,1H),1.94-1.86(m,1H),1.86-1.80(m,1H),1.79(s,4H),1.75(s,3H),1.40(d,J＝8.0Hz,6H),1.31 (d,J＝4.0Hz,3H),1.29(d,J＝4.0Hz,3H).

Example 136, (R)-(3-(((5-((6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a Synthesis of ]pyrimidin-7-yl)amino)methyl)phenyl)dimethylphosphine oxide (compound 136):

1), (R)-5-((7-((3-(dimethylphosphoryl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl Synthesis of )oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

(3-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)dimethylphosphine oxide (150 mg, 0.40 mmol), (R)-5-hydroxy-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (137 mg, 0.60 mmol) and cesium carbonate (390 mg, 1.20 mmol) in toluene (2 mL) , add tris(dibenzylideneacetone)dipalladium (19mg, 0.02mmol) and (R)-1-[(S)-2-(dicyclohexylphosphine)ferrocene]ethyldi-tert-butylphosphine ( 22mg, 0.04mmol). The resulting mixed reaction solution was heated in the microwave at 140°C for 2 hours. The mixed reaction solution was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (R)-5-((7-((3-(dimethyl) Phosphoryl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert. Butyl ester (184mg, yield: 81%), LC-MS m/z: 570[M+H]+;

2), (R)-(3-(((5-((6,6-dimethylpiperidin-3-yl)oxy)-3-isopropylpyrazolo[1,5-a] Synthesis of pyrimidin-7-yl)amino)methyl)phenyl)dimethylphosphine oxide

In solution, there is (R)-5-((7-((3-(dimethylphosphoryl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl )oxy)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (180 mg, 0.32 mmol) in dichloromethane (1.5 mL), add 2,2,2-trifluoroacetic acid dropwise (0.5mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: containing 0.1% NH ₃ ·H ₂ O = 5-95% elution) to obtain (R)-(3-(((5-((6,6-dimethylpiperdine) (Din-3-yl)oxy)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)dimethylphosphine oxide (127 mg, yield: 86%), LC-MS m/z: 470[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ -d) δ7.85 (d, J＝12.0Hz, 1H), 7.72 (s, 1H), 7.59 (dd, J＝11.6, 7.6Hz, 1H), 7.54 (s, 1H),7.49(td,J＝7.6,3.0Hz,1H),5.47(s,1H),5.39(s,1H),4.59(s,2H),3.24(s,2H),3.12–3.06(m ,1H),2.00(d,J＝5.5Hz,2H),1.89(s,1H),1.75(dd,J＝13.0,3.7Hz,6H),1.59(d,J＝14.2Hz,1H),1.37 (d,J＝15.0Hz,6H),1.30(d,J＝6.9Hz,6H).

Example 137, (S)-7-(dimethylphosphoryl)-3-(2-((6,6-dimethylpiperidin-3-yl)amino)-5,5-dioxo- Synthesis of 6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-1H-indole-6-nitrile (compound 137):

1), Synthesis of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine 5,5-dioxide

Dissolve 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (1g, 4.83mmol) and 3-chloroperoxybenzoic acid (2.5g, 14.5mmol) in dichloride The methane (10 mL) solution was stirred at room temperature for 2 hours. The mixed reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0 to 39% elution) to obtain 2,4-dichloro-6,7-dihydrothio[3,2-d]pyrimidine 5,5 - Dioxide (994 mg, yield: 86%), LC-MS m/z: 238 [M+H] ⁺ ;

2), 7-bromo-3-(2-chloro-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-1H-indole-6 -Synthesis of nitriles

At 25°C, 1,2-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine 5,5-dioxide (28 mg, 0.12 mmol) was dissolved in To a solution of dichloroethane (0.5 mL), 7-bromo-1H-indole-6-nitrile (50 mg, 0.23 mmol) and aluminum trichloride (46 mg, 0.35 mmol) were added. The obtained mixed reaction liquid was heated to 80°C and stirred for 16 hours. The mixed reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 0 to 54% elution) to obtain 7-bromo-3-(2-chloro-5,5-dioxo-6) ,7-Dihydrothieno[3,2-d]pyrimidin-4-yl)-1H-indole-6-nitrile (18 mg, yield: 36%), LC-MS m/z: 423[M+ H] ⁺ ; 3), (S)-7-bromo-3-(2-((6,6-dimethylpiperidin-3-yl)amino)-5,5-dioxo-6,7 -Synthesis of dihydrothieno[3,2-d]pyrimidin-4-yl)-1H-indole-6-nitrile

Dissolve 7-bromo-3-(2-chloro-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-1H-indole-6 -Nitrile (50 mg, 0.12 mmol), (3S)-6,6-dimethylpiperidin-3-amine (23 mg, 0.177 mmol) and N,N-diisopropylethylamine (31 mg, 0.24 mmol) A solution of 1-methyl-2-pyrrolidone (0.5 mL) was heated to 130°C and stirred for 16 hours. The mixed reaction solution was filtered and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 0 to 37% elution) to obtain (S)-7-bromo-3-(2-((6,6-dimethylpiperdate) ((23mg, (23 mg) Yield: 38%), LC-MS m/z: 515[M+H] ⁺ ;

4), (S)-7-(dimethylphosphoryl)-3-(2-((6,6-dimethylpiperidin-3-yl)amino)-5,5-dioxo-6 ,Synthesis of 7-dihydrothieno[3,2-d]pyrimidin-4-yl)-1H-indole-6-nitrile

Dissolve (S)-7-bromo-3-(2-((6,6-dimethylpiperidin-3-yl)amino)-5,5-dioxo-6,7-dihydrothiophene And[3,2-d]pyrimidin-4-yl)-1H-indole-6-carbonitrile (50 mg, 0.097 mmol) and dimethylphosphine oxide (19 mg 0.24 mmol), 4,5-bisdiphenyl Phosphine-9,9-dimethylxanthene (39 mg, 0.068 mmol), palladium acetate (1.09 mg, 0.0049 mmol), potassium phosphate (230 mg, 0.1067 mmol) in N,N-dimethylformamide (1 mL) The solution was heated under argon gas at 150°C in the microwave and stirred for 1 hour. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% NH ₄ HCO ₃ = 30-70% elution) to obtain (S)-7-(dimethylphosphoryl)-3-(2-(( 6,6-dimethylpiperidin-3-yl)amino)-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)-1H-indola Indole-6-nitrile (5 mg, yield: 10%), LC-MS m/z: 513[M+H] ⁺ ;

1H NMR (400MHz, MeOD): δ8.76–9.15(m,2H),7.67(s,1H),4.32(s,1H),3.62(t,J＝8.0Hz,2H),3.46(m,1H ),3.33(m,2H),3.13(s,1H),2.12(m,7H),1.92(s,2H),1.79(m,1H),1.42(s,6H).

Example 138, N-(3-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1 Synthesis of ,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-3-methylbut-2-enamide (compound 138):

1), (3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-(3-methylbut-2-enamido)benzyl)amino)-3-isopropyl Synthesis of pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester

At room temperature, (3R, 4R)-4-((((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1, 5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.12 mmol), 3-methylbutan-2-methylbutan-2- To a solution of enoic acid (14 mg, 0.14 mmol) and N, N-diisopropylethylamine (45 mg, 0.35 mmol) in N, N-dimethylformamide (2 mL), 2-(7-azobenzene was added Triazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (87 mg, 0.23 mmol). The resulting mixed reaction solution was stirred at room temperature overnight. The obtained mixed reaction solution was diluted with water (10 mL) and used Extract with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (1 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was passed through C18 column chromatography (acetonitrile: containing 0.1% NH ₄ HCO ₃ pure water = 15-45% elution) purification to obtain (3R, 4R)-4-(((7-((tert-butoxycarbonyl))(3-(3-methylbut-2-ene) Amino)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester ( 43.15mg, yield: 54.3%), LC-MS m/z; 692[M+H] ⁺ ;

2), N-(3-(((5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-3-isopropylpyrazolo[1, Synthesis of 5-a]pyrimidin-7-yl)amino)methyl)phenyl)-3-methylbut-2-enamide

Will dissolve 3R, 4R)-4-(((7-((tert-butoxycarbonyl)(3-(3-methylbut-2-enamido)benzyl)amino)-3-isopropyl A solution of pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (18 mg, 0.027 mmol) in dichloromethane (1 mL) and A solution of 2,2,2-trifluoroacetic acid (0.3 mL) was stirred at room temperature for 2 hours. The mixed reaction solution was filtered, and the filter cake was washed with methanol (3×20 mL). Collect, filter and concentrate under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 15-45% elution) to obtain N-(3-(((5-((((3R, 4R))-3-hydroxypiper (Din-4-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)-3-methylbutan-2- Enamide (6 mg, yield: 47%),

LC-MS m/z: 492[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d ₄ ): δ7.74 (s, 1H), 7.66 (s, 1H), 7.43 (d, J = 8.0Hz, 1H), 7.29 (t, J = 8.0Hz, 1H ),7.11(d,J＝8.0Hz,1H),5.84(s,1H),5.23(s,1H),4.58(s,2H),3.91–3.71(m,1H),3.51(s,1H) ,3.40-3.37(m,2H),3.06-3.01(m,1H),2.94-2.90(m,1H),2.77(t,J＝12.0Hz,1H),2.18(s,3H),1.96-1.94 (m,1H),1.93(s,3H),1.74-1.69(m,1H),1.63-1.57(m,1H),1.30(s,3H),1.27(s,3H).

Example 139, N-(3-(((3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-7 Synthesis of -yl)amino)methyl)phenyl)cyclopent-1-ene-1-carboxamide (compound 139):

1), 4-(7-((tert-butoxycarbonyl)(3-(cyclopent-1-en-1-carboxamido)benzyl)amino)-3-isopropylpyrazolo[1,5 -Synthesis of tert-butyl a]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

At room temperature, 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl is dissolved in the solution. )-tert-butyl 3,6-dihydropyridine-1(2H)-carboxylate (50 mg, 0.088 mmol) and cyclopent-1-ene-1-carboxylic acid (12 mg, 0.11 mmol) Methylformamide (1.5 mL) was added with N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (50 mg, 0.18 mmol) and 1-methyl-1H-imidazole (29 mg, 0.36 mmol). . The resulting mixed reaction solution was stirred at room temperature for 4 hours. The obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated brine (1×20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain 4-(7-((tert-butoxycarbonyl)(3-(cyclo) Pent-1-en-1-carboxamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3,6-dihydropyridine-1( 2H)-tert-butyl carboxylate (42 mg, yield: 72.0%), LC-MS m/z: 657 [M+H] ⁺ ;

2), N-(3-(((3-isopropyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-7- Synthesis of methyl)amino)methyl)phenyl)cyclopent-1-ene-1-carboxamide

At room temperature, 4-(7-((tert-butoxycarbonyl)(3-(cyclopent-1-en-1-carboxamido)benzyl)amino)-3-isopropylpyrazolo [1,5-a]pyrimidin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (30 mg, 0.050 mmol) in dichloromethane (0.6 mL), dropwise Add 2,2,2-trifluoroacetic acid (0.2 mL). The resulting mixed reaction solution was stirred at room temperature for 2 hours. The obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated brine (1×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain N-(3-(((3-isopropyl-5-( 1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)cyclopent-1-en-1-methyl Amide (15 mg, yield: 72%), LC-MS m/z: 457[M+H] ⁺ ;

¹ H NMR (400MHz, MeOD-d4): δ7.90 (s, 1H), 7.74 (s, 1H), 7.47 (d, J = 8.0Hz, 1H), 7.31 (t, J = 8.0Hz, 1H) ,7.17(d,J＝8.0Hz,1H),6.67(t,J＝8.0Hz,1H),6.56(s,1H),6.16(s,1H),4.69(s,2H),3.82(d, J＝4Hz,2H),3.39(t,J＝4.0Hz,2H),3.27–3.20(m,1H),2.90(s,2H),2.66–2.52(m,4H),2.04-1.96(m, 2H),1.36(d,J＝8Hz,6H).

Example 140, (E)-N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino) Synthesis of methyl)phenyl)but-2-enamide (compound 140):

1), (E)-4-(7-((3-(but-2-enoylamino)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5- Synthesis of a]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester

At room temperature, 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl is dissolved in the solution. ) To a solution of piperidine-1-carboxylic acid tert-butyl ester (60 mg, 0.11 mmol) and (2E)-but-2-enoic acid (12 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (43 mg, 0.33 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate ( 50mg, 0.13mmol). The resulting mixed reaction solution was stirred at room temperature for 4 hours. The obtained mixed reaction liquid was diluted with water and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (E)-4-(7-((3-(but- 2-Enoylamino)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester ( 40mg, yield: 60%). LC-MS m/z: 633[M+H] ⁺ ;

2), (E)-N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl Synthesis of base)phenyl)but-2-enamide

Dissolve (E)-4-(7-((3-(but-2-enoylamino)benzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5- A solution of a]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (60 mg, 0.097 mmol) in dichloromethane (3 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 2 hours . The obtained mixed reaction solution was diluted with water, and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine (1×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile containing 0.1% formic acid: pure water containing 0.1% formic acid = 25%-65% elution) to obtain (E)-N-(3-(((3-isopropyl) Base-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)but-2-enamide (20 mg, yield: 49% ), LC-MS m/z: 433[M+H] ⁺ ; ¹ H NMR (400MHz, MeOD-d4): δ8.090 (s, 1H), 7.680 (s, 1H), 7.537 (d, J＝ 8.0Hz,1H),7.288(t,J＝8.0Hz 1H),7.079(d,J＝8.0Hz,1H),6.821-6.731(m,1H),6.114-6.072(m,1H),6.029(s ,1H),4.677(s,2H),3.370(d,J＝12.4Hz,2H),3.211-3.142(m,1H),3.012-2.923(m,3H),2.027-1.999(m,2H), 1.932-1.838(m,5H),1.306(d,J=8.0Hz,6H).

Example 141, 2-chloro-N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino) Synthesis of methyl)phenyl)acrylamide (compound 142):

1), 4-(7-((tert-butoxycarbonyl)(3-(2-chloroacrylamido)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidine-5 Synthesis of tert-butyl-piperidine-1-carboxylate

Will dissolve 4-(7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine- 1-tert-butylcarboxylate (50mg, 0.088mmol), 2-chloro-1-methylpyridinium iodide (68mg, 0.27mmol), triethylamine (54mg, 0.53mmol) and 2-chloroacrylic acid (11mg, 0.11 mmol) in dichloromethane (2 mL) was heated to 40°C and stirred for 8 hours. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5-95% elution) to obtain 4-(7-((tert-butoxycarbonyl)(3-(2-chloroacrylamide)) Benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (34 mg, yield: 59%), LC-MS m/z:653[M+H] ⁺ ;

2), 2-chloro-N-(3-(((3-isopropyl-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl Synthesis of phenyl)acrylamide

At room temperature, 4-(7-((tert-butoxycarbonyl)(3-(2-chloroacrylamide)benzyl)amino)-3-isopropylpyrazolo[1,5-a To a solution of pyrimidin-5-yl)piperidine-1-carboxylic acid tert-butyl ester (30 mg, 0.046 mmol) in dichloromethane (2 mL), 2,2,2-trifluoroacetic acid (0.4 mL) was added dropwise. The resulting mixed reaction solution was stirred at room temperature for 4 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5%-95% elution) to obtain 2-chloro-N-(3-(((3-isopropyl-5-( Piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acrylamide (2.2 mg, yield: 10.6%), LC-MS m/z : 453[M+H] ⁺ ; ¹ H NMR (400MHz, MeOD): δ7.89 (s, 1H), 7.73 (s, 1H), 7.45–7.52 (m, 1H), 7.35 (t, J = 8.0 Hz,1H),7.21-7.26(m,1H),6.41-6.45(m,1H),5.95-5.98(m,1H),5.91(s,1H),4.68(s,2H),3.47-3.51( m,1H),3.44-3.47(m,1H),3.26-3.21(m,1H),3.12-3.07(m,2H),2.91–2.99(m,1H),2.02–2.12(m,4H), 1.36(s,3H),1.34(s,3H).

Example 142, (S)-N-(3-(((3-cyclopropyl-5-((6,6-dimethylpiperidin-3-yl)amino))pyrazolo[1,5- Synthesis of a]pyrimidin-7-yl)amino]methyl)phenyl)but-2-ynamide (compound 142):

1), Synthesis of 3-cyclopropylpyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione

Dissolve 4-cyclopropyl-1H-pyrazole-5-amine (2g, 16mmol), sodium methoxide (7.1g, 129mmol) and 1,3-dimethylmalonate (2.58g, 19.5mmol). The methanol (20 mL) solution was added to 70°C and stirred for 16 hours. The obtained mixed reaction liquid was filtered, and the precipitated solid was collected, washed and dried to obtain 3-cyclopropylpyrazolo[1,5-a]pyrimidine-5,7(4H, 6H)-dione (2.58g, yield: 83.2%), LC-MS m/z: 192[M+H] ⁺ ;

2), Synthesis of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine

Dissolve 3-cyclopropylpyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (2.58g, 13.51mmol) and N,N-diisopropylethylamine ( 4.46 mL, 27.01 mmol) of phosphorus oxychloride (18.83 mL, 202.62 mmol), heated to 100°C and stirred for 16 hours. After cooling, the obtained mixed reaction solution was concentrated under reduced pressure, and then ice water was added thereto. The precipitated solid was collected by filtration and dried to obtain 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine. (1.37g, yield: 45%), LC-MS m/z: 228[M+H] ⁺ .

3), Synthesis of 5-chloro-3-cyclopropyl-N-(3-nitrobenzyl)pyrazolo[1,5-a]pyrimidin-7-amine

Dissolve 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (1.37g, 6.04mmol) and (3-nitrophenyl)methanamine hydrochloride (1.48g , 7.85mmol) and N,N-diisopropylethylamine (2.99mL, 18.12mmol) in isopropyl alcohol (10mL) solution was heated at 70°C and stirred for 3 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane:0-5% elution) to give 5-chloro-3-cyclopropyl-N-(3-nitrobenzyl)pyrazolo[1,5 -a]pyrimidin-7-amine (878mg, yield: 42%), LC-MS m/z: 344[M+H] ⁺ ;

4) Synthesis of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamate

Dissolve 5-chloro-3-cyclopropyl-N-(3-nitrobenzyl)pyrazolo[1,5-a]pyrimidin-7-amine (480 mg, 1.40 mmol), di-tert-butyl dicarbonate A solution of ester (367 mg, 1.68 mmol), 4-dimethylaminopyridine (256 mg, 2.1 mmol) and N,N-diisopropylethylamine (1.15 mL, 7.0 mmol) in dichloromethane (5 mL) was stirred at room temperature for 2 hours. . The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-2% elution) to obtain (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl) (3 -Nitrobenzyl)carbamic acid tert-butyl ester (575 mg, yield: 93%), LC-MS m/z: 444[M+H] ⁺ .

5), (S)-(3-cyclopropyl-5-((6,6-dimethylpiperidin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl) Synthesis report of (3-nitrobenzyl)carbamic acid tert-butyl ester

Dissolve (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamic acid tert-butyl ester (570mg, 1.29mmol), ( SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazole-2 -Ylidene]dichloro(2-methylpyridine)palladium (106 mg, 0.13 mmol), cesium carbonate (0.95 g, 2.91 mmol) and (3S)-6,6-dimethylpiperidin-3-amine (195 mg , 1.52 mmol) of 1,4-dioxane (5 mL) solution was heated to 100°C and stirred for 3 hours under argon protection. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane=0-1.2% elution) to obtain (S)-(3-cyclopropyl-5-((6,6-dimethylpiperidine-3- tert-butyl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)(3-nitrobenzyl)carbamate (110 mg, yield: 16%), LC-MS m/z: 536[M+H] ⁺ .

6), (S)-5-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidine-5- Synthesis of tert-butyl (methyl)amino)-2,2-dimethylpiperidine-1-carboxylate

Dissolved (S)-(3-cyclopropyl-5-((6,6-dimethylpiperidin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl) (3-nitrobenzyl)carbamic acid tert-butyl ester (110 mg, 0.21 mmol), N,N-diisopropylethylamine (80 mg, 0.62 mmol) and di-tert-butyl dicarbonate (90 mg, 0.41 mmol) dichloromethane (3mL) solution, heated to 60°C and stirred for 3 hours. After cooling, the obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: dichloromethane = 0-2% elution) to obtain (S)-5-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino) -3-Cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (97 mg, yield: 74 %), LC-MS m/z: 636[M+H] ⁺ .

7), (S)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidine-5- Synthesis of tert-butyl (methyl)amino)-2,2-dimethylpiperidine-1-carboxylate

Dissolve (S)-5-((7-((tert-butoxycarbonyl)(3-nitrobenzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidine-5- A solution of amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (97 mg, 0.15 mmol) and iron (43 mg, 0.76 mmol) in ethanol (4 mL) and ammonium chloride (2 mL) The aqueous solution was heated to 70°C and stirred for 3 hours. After cooling, the mixed reaction liquid was filtered, and the filter cake was washed with dichloromethane. The filtrate was collected and concentrated under reduced pressure to obtain (S)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-cyclopropylpyrazolo[1,5-a] Pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (70 mg, yield: 76%), LC-MS m/z: 606 [M+H] ⁺ .

8), (S)-5-((7-((3-(but-2-ynynylamido)benzyl)(tert-butoxycarbonyl)amino)-3-cyclopropylpyrazolo[1, Synthesis of 5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester

Dissolve (S)-5-((7-((3-aminobenzyl)(tert-butoxycarbonyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidine-5- (methyl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.12 mmol), 2-(7-azobenzotriazole)-N,N,N' , N'-tetramethylurea hexafluorophosphate (0.068g, 0.18mmol), N,N-diisopropylethylamine (0.047g, 0.36mmol) and but-2-ynoic acid (0.013g, 0.16 A solution of N,N-dimethylformyl (1 mL) in mmol) was stirred at room temperature for 2 hours. The obtained mixed reaction liquid was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane=0-1.2% elution) to obtain (S)-5-((7-((3-(but-2-ynamido)benzyl)( tert-butoxycarbonyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylate tert-butyl ester (50mg, yield: 64%), LC-MS m/z: 672[M+H] ⁺ .

9), (S)-N-(3-(((3-cyclopropyl-5-((6,6-dimethylpiperidin-3-yl)amino))pyrazolo[1,5-a Synthesis report of ]pyrimidin-7-yl)amino]methyl)phenyl)but-2-ynamide

The dissolved (S)-5-((7-((3-(but-2-ynynylamido)benzyl)(tert-butoxycarbonyl)amino)-3-cyclopropylpyrazolo[1, 5-a]pyrimidin-5-yl)amino)-2,2-dimethylpiperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.074 mmol) in 2,2,2-trifluoroacetic acid (1 mL) and A solution of dichloromethane (3 mL) was stirred at room temperature for 4 hours. The mixed reaction solution was concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile: pure water containing 0.1% formic acid = 5~95% elution) to obtain (S)-N-(3-(((3-cyclopropyl-5-((6, 6-Dimethylpiperidin-3-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino]methyl)phenyl)but-2-ynamide (4.53 mg, yield : 12%), LC-MS m/z: 472[M+H] ⁺ . ¹ H NMR (400MHz, MeOD-d ₄ ): δ7.63 (s, 1H), 7.54 (s, 1H), 7.42 ( d,J＝8.0Hz,1H),7.29(t,J＝8.0Hz,1H),7.13(d,J＝8.0Hz,1H),5.16(s,1H),4.52(s,2H),4.15( s,1H),3.51(dd,J＝12.0,4.0Hz,1H),3.16–3.10(m,1H),2.01(s,3H),1.99-1.85(m,1H),1.89–1.73(m, 4H),1.41(d,J＝8.0Hz,6H),0.84–0.79(m,2H),0.75-0.69(m,2H).

Example 142. Synthesis of other compounds:

The following compounds can be obtained by similar synthetic steps to compound 1 to compound 141 in Examples 1-141:

Test example 1 CDK7 activity test

1) Reagents and consumables:

2) Preparation before experiment and preparation of stock solution:

Preparation of 1x assay buffer solution: dilute 5X Enzymatic buffer 5 times with H ₂ O, dilute DTT (1M) to 1mM, and dilute MgCl ₂ (1M) to 50mM;

Substrate and ATP mixed solution: Substrate (1mM) and ATP (10mM) are diluted with 1x assay buffer to dilute the concentration to 2.5μM and 12.5μM respectively;

CDK7 recombinant enzyme: Dilute with 1x assay buffer solution to a concentration of 25ng/ul;

Compound: Provided by customer, dilute to 10mM with DMSO for later use.

3) Experimental methods and processes

4) Data processing and results:

The Luminescence of the compound well is recorded as Lum _compound , the Luminescence of the control well is recorded as Lum _vehicle , and the Luminescence of the blank control well is recorded as Lum _blank .

The inhibition rate is calculated using the following formula:

Inhibition rate=(Lum _vehicle -Lum _compound )/(Lum _vehicle -Lum _blank )×100%

Test example 2, tumor cell proliferation inhibitory activity test:

application The Luminescent Cell Viability Assay (CTG) detection kit detects the inhibitory effect of compounds on the proliferation of 4 cell lines.

Reagents and consumables

equipment

Test conditions

1. Test operation:

1) Prepare complete medium and mix thoroughly.

2) Resuscitate the cells and pass them for about two generations to select cell lines with good growth status.

3) Collect logarithmic growth phase cell counts and detect cell viability.

4) Resuspend the cells in complete culture medium to a suitable density.

5) Inoculate the cell suspension into a 96-well plate and add 100 μL of cell suspension to each well. Label the cell name, plate density, date and other details, and place the culture plate in a high-humidity, 37°C, 5% _CO2 incubator overnight.

6) Use DMSO to dilute the test reagent according to the required dilution factor to the corresponding concentration (9 concentration gradients, including 0 concentration). Then further dilute the test reagent with culture medium to a 5x working solution.

Compound dilution method (starting at 10mM, 4-fold gradient dilution, 9 concentration points):

7) According to the concentration of the compound, add the diluted compound into the corresponding cell well at a rate of 25 μL/well.

8) Place the cell plate in a high-humidity, 37°C, 5% CO ₂ incubator and incubate it for 72 hours.

9) Add 50 μL of CTG detection solution and incubate at room temperature in the dark for about 15 to 30 minutes.

10) After shaking gently, perform Luminescence mode measurement in Envision and calculate the inhibition rate.

11) Calculate the inhibitory rate of the drug on the growth of each cell according to the following formula:

Cell growth inhibition rate % = (1-As/Ac) × 100%

As: OA of sample (cells+CTG+test compound)

Ac: OA of normal growth cell control (cells+CTG+DMSO)

Use the software Graphpad Prism 6 and use the calculation formula XY-analysis/Nonlinear regression (curve fit)/Dose response-Inhibition/log (inhibitor) vs. response-Variable slope (four parameters) to fit the IC ₅₀ curve and calculate the IC ₅₀ value.

Table 1. Data analysis and results of some representative compounds on CDK7 enzyme activity and tumor cell proliferation inhibitory activity

From the above results, it can be seen that most of the representative compounds of the present invention have good CDK7 enzyme and tumor cell proliferation inhibitory activities. Compared with the clinical phase 2 reference molecule CT7001, the tumor cell proliferation activity of most compounds is several to dozens of times higher. Increase.

The above is an exemplary description of the implementation of the technical solution of the present invention. It should be understood that the protection scope of the present invention is not limited to the above-mentioned embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included in the protection scope of the claims of this application.

Claims

The compound represented by formula (I) or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof;

in,

Ring A, Ring C and Ring D are each independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, Alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

Ring B is arbitrarily independently non-existent or a monocyclic or polycyclic structure with 3 to 18 carbon atoms. The monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, and a heterocyclic ring. , paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

X 1 , X 2 , X 3 , and X 4 are each independently selected from -C(R d1 )– or -N-;

L 1 , L 2 and L 3 are each independently selected from the group consisting of absence, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 ) (R d2 )O-, -C(＝O)N(R d3 )-, -N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(＝O) 2 N(R d3 )-, -N(R d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)- , -C(=O)-, -C(=S)-, -S(=O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C (＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝ NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(=O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C( R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )– or -C(R d1 )(R d2 )S(=O) 2 -;

Each R 1 may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 substituted by C 3-10 cycloalkyl Heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN ;

Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, Heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3 -10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN;

Each R 3 may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 Alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocycle base, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 Heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure, the monocyclic ring Or the polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure The structure may contain 0 to more unsaturated ethylenic bonds; wherein the C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group base, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 3-10 cycloalkyl or C 3-10 hetero C 1-10 alkyl substituted by cycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute optional Optimally substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

Said hetero represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4.
The compound according to claim 1 or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof, which has the structure of formula (1-I),

in,

Ring A and ring C are each independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, Heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

Ring B is arbitrarily independently non-existent or a monocyclic or polycyclic structure with 3 to 18 carbon atoms. The monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, and a heterocyclic ring. , paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

X 1 , X 2 , X 3 , and X 4 are each independently selected from -C(R d1 )– or -N-;

L 1 , L 2 and L 3 are each independently selected from the group consisting of absence, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 ) (R d2 )O-, -C(＝O)N(R d3 )-, -N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(＝O) 2 N(R d3 )-, -N(R d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)- ,-C(＝O) -, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C (R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C (R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N( R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C( ＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 ) C(=S)-, -S(=O)C(R d1 )(R d2 )– or -C(R d1 )(R d2 )S(=O) 2 -;

Each R 1 may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 substituted by C 3-10 cycloalkyl Heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN ;

Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, Heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3 -10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN;

Each R 3 may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R 1 and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heterocyclic Aromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The above-mentioned C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkane base, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl , C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen , OCH 3 , carboxyl, OH, CN substituent substitution;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

Said hetero represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (1-IA),

in,

Ring A and ring C are each independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, Heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

Ring B is arbitrarily independently a monocyclic or polycyclic structure with 3 to 18 carbon atoms. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, paracyclic ring, Spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

L 1 and L 2 are each independently selected from a single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O- , -C(＝O)N(R d3 )-, -N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S (＝O) 2 N(R d3 )-, -N(R d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O )-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 ) C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N( R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(=NR d3 )-,- C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N (R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C (＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )– or -C(R d1 )(R d2 )S(=O) 2 -;

L 3 is independently selected from -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O) N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(＝O) 2 N(R d3 )-, -C( ＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C( R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O -, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 ) (R d2 )S(=O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )( R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )–or -C(R d1 ) (R d2 )S(=O) 2 -;

Each R 1 may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10- cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 substituted by C 3-10 cycloalkyl Heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN ;

Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitutes are optionally preferred. Substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;

Each R 3 may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R 1 and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heterocyclic Aromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The above-mentioned C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkane base, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen , OCH 3 , carboxyl, OH, CN substituent substitution;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

Said hetero represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (1-IB),

in,

Ring A and ring C are each independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, Heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

Ring B is arbitrarily independently non-existent or a monocyclic or polycyclic structure with 3 to 18 carbon atoms. The monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, and a heterocyclic ring. , paracyclic ring, spirocyclic ring or bridged ring structure; and the aliphatic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring The structure may contain 0 to more unsaturated ethylenic bonds;

L 1 , L 2 and L 3 are each independently selected from the group consisting of absence, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 ) (R d2 )O-, -C(＝O)N(R d3 )-, -N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(＝O) 2 N(R d3 )-, -N(R d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)- , -C(=O)-, -C(=S)-, -S(=O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C (＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝ NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(=O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C( R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )– or -C(R d1 )(R d2 )S(=O) 2 -;

Each R 1 may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10- cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 substituted by C 3-10 cycloalkyl Heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN ;

Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, Heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3 -10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN;

Each R 3 may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R 1 and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heterocyclic Aromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The above-mentioned C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkane base, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen , OCH 3 , carboxyl, OH, CN substituent substitution;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

Said hetero represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (1-IC),

in,

X 1 and X 0 are each independently selected from -CH– or -N-;

Ring C is arbitrarily independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms. The monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, and a polycyclic ring. Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

L 1 and L 3 are each independently selected from the group consisting of absence, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(＝O)N(R d3 )-, -N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )- , -S(＝O) 2 N(R d3 )-, -N(R d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C (＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )( R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 ) (R d2 )O-, -C(R d1 )(R d2 )C(＝O )N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 ) -, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )- , -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )– or -C(R d1 )(R d2 )S(=O) 2 -;

Each R 1 may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10- cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 substituted by C 3-10 cycloalkyl Heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN ;

Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms or heteroatom-containing groups such as C=O, S=O, S(=O) 2 , etc.; wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl Substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitutes are optionally preferably Substituted with 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

Said hetero represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (1-ID),

in,

Ring A and ring C are each independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, Heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

Ring B is arbitrarily independently a monocyclic or polycyclic structure with 3 to 18 carbon atoms. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, paracyclic ring, Spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

L 1 , L 2 and L 3 are each independently selected from the group consisting of absence, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 ) (R d2 )O-, -C(＝O)N(R d3 )-, -N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(＝O) 2 N(R d3 )-, -N(R d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)- , -C(=O)-, -C(=S)-, -S(=O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C (＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝ NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(=O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C( R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )– or -C(R d1 )(R d2 )S(=O) 2 -;

Each R 1 may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10- cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring The structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 3-10 cycloalkyl Or C 1-10 alkyl substituted by C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl Or the carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN;

Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10- cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2- 10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, Heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3 -10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN;

Each R 3 may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R 1 and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heterocyclic Aromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The above-mentioned C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkane base, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen , OCH 3 , carboxyl, OH, CN substituent substitution;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

Said hetero represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (1-IE),

in,

X 0 is independently selected from -CH– or -N-;

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

Ring C is arbitrarily independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms. The monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, and a polycyclic ring. Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

L 1 and L 3 are each independently selected from the group consisting of absence, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(＝O)N(R d3 )-, -N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )- , -S(＝O) 2 N(R d3 )-, -N(R d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C (＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )( R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O )N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 ) -, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )- , -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )– or -C(R d1 )(R d2 )S(=O) 2 -;

Each R 1 may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 substituted by C 3-10 cycloalkyl Heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN ;

Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10- cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms or heteroatom-containing groups such as C=O, S=O, S(=O) 2 , etc.; wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl Substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitutes are optionally preferably Substituted with 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl group, C 1-6 alkoxy group, -NH 2 , -NHC 1-6 alkyl group, -N(C 1-6 alkyl) 2 , oxy group, and Saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further selected from 1 to more hydrogen, deuterium, halogen, oxo, CN, Group substitutions of CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl; or any two R d1 , R d2 or R d3 may together with their attached carbons form 3 -18-membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; and The alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkyl, aryl, heteroaryl The group is optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

Said hetero represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (1-IF),

in,

X 0 and X are independently selected from -CH- or -N-;

Ring C is arbitrarily independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms. The monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, and a polycyclic ring. Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

L 1 and L 3 are each independently selected from the group consisting of absence, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(＝O)N(R d3 )-, -N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )- , -S(＝O) 2 N(R d3 )-, -N(R d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C (＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )( R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O )N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 ) -, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(=O) 2 N(R d3 )- , -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )– or -C(R d1 )(R d2 )S(=O) 2 -; and when L 1 When it does not exist or is a single bond, L 3 is not NH;

Each R 1 may be the same or different, independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH or selected from C 1-10 alkyl, C 2-10 alkene base, C 2-10 alkynyl or C 1-10 alkoxy group, dialkylphosphoroxy group, alkylsulfonyl group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated cycloalkyl group, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10- cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 substituted by C 3-10 cycloalkyl Heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN ;

Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH or selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, Aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3- 10- cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl-substituted carboxyl or carboxyl substitute; or any two R 1 carbon atoms connected to it on the ring Together they form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be selected arbitrarily. From aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated Ethylene bonds and 0 to more heteroatoms or groups containing heteroatoms such as C=O, S=O, S(=O) 2 , etc.; wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, Aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

Said hetero represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1 and 2.
The compound according to claim 1 or 2 or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof, which has the structure of formula (2-I),

in,

X is arbitrarily independently selected from N or CR;

Ring A and ring C are each independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, Heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

Ring B is arbitrarily independently selected from monocyclic or polycyclic structures that do not exist or have 3 to 18 carbon atoms. The monocyclic or polycyclic structures can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

L 1 and L 2 are each independently selected from the group consisting of absence, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(＝O)N(R d3 )-, -N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )- , -S(＝O) 2 N(R d3 )-, -N(R d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C (＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )( R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O )N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 ) -, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )- , -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )– or -C(R d1 )(R d2 )S(=O) 2 -;

L 3 is independently selected from -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O) N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(＝O) 2 N(R d3 )-, -C( ＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C( R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O -, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 ) (R d2 )S(=O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )( R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )–or -C(R d1 ) (R d2 )S(=O) 2 -;

R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1 -10 alkoxy;

Each R 1 may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 together with the carbon atoms connected to the ring form 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the The alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl group and C 2-10 alkenyl group , C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl , aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl The base, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN;

Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide base, N,N-dimethylbutenamide group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group , C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; Or any two R 1 and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, and aliphatic rings. , heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3- 10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring The alkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen, OCH 3 , carboxyl , OH, CN substituent substitution;

Each R 3 may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R 1 and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heterocyclic Aromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The above-mentioned C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkane base, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl , C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen , OCH 3 , carboxyl, OH, CN substituent substitution;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

Said hetero represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (2-IC),

in,

X 1 and X 0 are each independently selected from -CR– or -N-;

Ring C is arbitrarily independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms. The monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, and a polycyclic ring. Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

Ring B is arbitrarily independently selected from monocyclic or polycyclic structures that do not exist or have 3 to 18 carbon atoms. The monocyclic or polycyclic structures can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

L 1 and L 2 are each independently selected from the group consisting of absence, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(＝O)N(R d3 )-, -N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )- , -S(＝O) 2 N(R d3 )-, -N(R d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C (＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )( R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O )N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 ) -, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(=O) 2 N(R d3 )- , -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )– or -C(R d1 )(R d2 )S(=O) 2 -;

L 3 is independently selected from -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O) N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(＝O) 2 N(R d3 )-, -C( ＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C( R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O -, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 ) (R d2 )S(=O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )( R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )–or -C(R d1 ) (R d2 )S(=O) 2 -;

Each R may be the same or different and independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;

Each R 1 may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 together with the carbon atoms connected to the ring form 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the The alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl group and C 2-10 alkenyl group , C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl , aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl The base, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN;

Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide base, N,N-dimethylbutenamide group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group , C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; Or any two R 1 and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, and aliphatic rings. , heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3- 10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring The alkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen, OCH 3 , carboxyl , OH, CN substituent substitution;

Each R 3 may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R 1 and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heterocyclic Aromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The above-mentioned C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkane base, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl , C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen , OCH 3 , carboxyl, OH, CN substituent substitution;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

Said hetero represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (2-ID),

in,

X, X 1 and X 0 are each independently selected from -CR– or -N-;

Ring C is arbitrarily independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms. The monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, and a polycyclic ring. Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

L 1 is independently selected from the group consisting of absence, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(＝O)N(R d3 )-, -N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S( ＝O) 2 N(R d3 )-, -N(R d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C(＝O) -, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C (R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C (R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N( R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C( ＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 )(R d2 ) C(=S)-, -S(=O)C(R d1 )(R d2 )– or -C(R d1 )(R d2 )S(=O) 2 -;

L 3 is independently selected from -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O) N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(＝O) 2 N(R d3 )-, -C( ＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C( R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O -, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 ) (R d2 )S(=O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )( R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )–or -C(R d1 ) (R d2 )S(=O) 2 -;

Each R 0 may be the same or different and is independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy; and The hydrogen of R 0 is preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN, -N(R d1 )(R d2 );

Each R may be the same or different and independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;

Each R 1 may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 together with the carbon atoms connected to the ring form 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the The alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl group and C 2-10 alkenyl group , C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl , aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl The base, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN;

Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide base, N,N-dimethylbutenamide group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group , C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; Or any two R 1 and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, and aliphatic rings. , heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the lipid The alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocycle The base, C 1-10 alkylcarboxyl group or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

Said hetero represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (2-IE),

in,

X 0 is independently selected from -CR– or -N-;

Ring C is arbitrarily independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms. The monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, and a polycyclic ring. Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

L 1 and L 3 are each independently selected from the group consisting of absence, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(＝O)N(R d3 )-, -N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )- , -S(＝O) 2 N(R d3 )-, -N(R d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C (＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )( R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O )N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 ) -, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(=O) 2 N(R d3 )- , -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )– or -C(R d1 )(R d2 )S(=O) 2 -;

Each R 0 may be the same or different and is independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy; and The hydrogen of R 0 is preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN, -N(R d1 )(R d2 );

R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1 -10 alkoxy;

Each R 1 may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 together with the carbon atoms connected to the ring form 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the The alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl group and C 2-10 alkenyl group , C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl , aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl The base, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN;

Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide base, N,N-dimethylbutenamide group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group , C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; Or any two R 1 and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, and aliphatic rings. , heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3- 10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring The alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen, OCH 3 , carboxyl , OH, CN substituent substitution;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

Said hetero represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1, and 2;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (2-IF),

X 0 is independently selected from -CR– or -N-;

Ring C is arbitrarily independently selected from a monocyclic or polycyclic structure with 3 to 18 carbon atoms. The monocyclic or polycyclic structure may be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an alicyclic ring, a heterocyclic ring, and a polycyclic ring. Ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

L 1 and L 3 are each independently selected from the group consisting of absence, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(＝O)N(R d3 )-, -N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )- , -S(＝O) 2 N(R d3 )-, -N(R d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C (＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )( R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 ) (R d2 )O-, -C(R d1 )(R d2 )C(＝O )N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 ) -, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )- , -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )– or -C(R d1 )(R d2 )S(=O) 2 -;

Each R 0 may be the same or different and is independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, or C 1-10 alkoxy; and The hydrogen of R 0 is preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN, -N(R d1 )(R d2 );

R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1 -10 alkoxy;

Each R 1 may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 together with the carbon atoms connected to the ring form 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the The alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl group and C 2-10 alkenyl group , C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl , aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl The base, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN;

Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide base, N,N-dimethylbutenamide group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group , C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; Or any two R 1 and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, and aliphatic rings. , heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3- 10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring The alkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen, OCH 3 , carboxyl , OH, CN substituent substitution;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl Oxygen group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkyl group Oxygen, C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl ; And the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl groups are optionally substituted by 1 to more selected from hydrogen, deuterium, halogen, -CN, -OH , CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially Saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , Group substitution of OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl; or any two R d1 , R d2 or R d3 can together with their attached carbons form a 3-18 member Monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the aliphatic ring , heterocyclic, paracyclic, spirocyclic or bridged ring structures may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups are optional Ground is substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

Said hetero represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1 and 2.
The compound according to any one of claims 1 to 3 or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof, which has the structure of formula (II),

in,

Ring A' is arbitrarily independently selected from

Ring B' is arbitrarily independently selected from

Q, L and Z are arbitrarily independently selected from S, O, NR d3 or C(R 2 ) 2 ;

Each X, X 0 , X 1 or X 2 may be the same or different and independently selected from N or CR 2 ;

Y is independently selected from -O-, -S-, -NR d3 -, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )( R d2 )O-, -C(=O)N(R d3 )-, -C(=NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(=O ) 2 N(R d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 ) (R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )( R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 ) (R d2 )–or-C(R d1 )(R d2 )S(=O) 2 -;

Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 ' is optionally preferably 1 Substituted with at least a plurality of substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;

R 2 ' and R 3 ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-dimethylbutylamido, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3- 10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl or R 2 ' _ _ and R 3 ' and the carbon atoms connected to the ring together form a 4-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optional Optimally substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;

R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; more Further, the hydrogen on R 4 is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;

Each Ra, Rb , Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2- 10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N, N-bis (C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl , C 1-10 alkyloxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3 -10 cycloalkoxy, C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl , heteroaryl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by 1 to more selected from hydrogen, deuterium, halogen, - CN, -OH, CF 3 , C 1-6 alkyl group, C 1-6 alkoxy group, -NH 2 , -NHC 1-6 alkyl group, -N(C 1-6 alkyl) 2 , oxygen group, And saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further selected from 1 to more hydrogen, deuterium, halogen, oxo, CN , CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R a , R b , R d1 , R d2 or R d3 can be Together with its attached carbon, it forms a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or Bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkane Base, aryl, heteroaryl are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterogeneous representative represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily chosen from an integer among 0, 1, 2, 3 and 4.
The compound according to any one of claims 1 to 4 or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof, which has the structure of formula (3-I)

in,

Can be a double bond or a single bond;

when When it is a double bond, X is independently selected from N or CR; when When it is a single bond, X is independently selected from NR d3 or C(R) 2 ;

Y is independently selected from -O-, -S-, -NR d3 -, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )( R d2 )O-, -C(=O)N(R d3 )-, -C(=NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(=O ) 2 N(R d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 ) (R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )( R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 ) (R d2 )–or-C(R d1 )(R d2 )S(=O) 2 -;

R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;

Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 substituted by C 3-10 cycloalkyl Heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN ;

R 2 ' and R 3 ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-Dimethylcrotonyl, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3- 10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl or R 2 ' _ _ and R 3 ' and the carbon atoms connected to the ring together form a 4-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optional Optimally substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;

R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated ring Alkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, The C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute substituted by C 3-10 cycloalkyl is optionally preferably 1 to more selected from H, deuterium, Substituted by halogen, alkyl, OCH 3 , carboxyl, OH, CN substituents;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl Oxygen group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkyl group Oxygen, C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl ; And the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl groups are optionally substituted by 1 to more selected from hydrogen, deuterium, halogen, -CN, -OH , CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially Saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , Group substitution of OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl; or any two R d1 , R d2 or R d3 can together with their attached carbons form a 3-18 member Monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the aliphatic ring , heterocyclic, paracyclic, spirocyclic or bridged ring structures may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkyl, aryl, heteroaryl groups are optional Ground is substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterodyne represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (3-IA),

in,

X is arbitrarily independently selected from NR d3 or C(R) 2 ;

Y is independently selected from -O-, -S-, -NR d3 -, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )( R d2 )O-, -C(=O)N(R d3 )-, -C(=NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(=O ) 2 N(R d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 ) (R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )( R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 ) (R d2 )–or-C(R d1 )(R d2 )S(=O) 2 -;

R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1 -10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy;

Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 substituted by C 3-10 cycloalkyl Heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN ;

R 2 ' and R 3 ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-dimethylbutylamido, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3- 10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl or R 2 ' _ _ and R 3 ' and the carbon atoms connected to the ring together form a 4-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optionally preferably substituted with 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;

R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated ring Alkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, The C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute substituted by C 3-10 cycloalkyl is optionally preferably 1 to more selected from H, deuterium, Substituted by halogen, alkyl, OCH 3 , carboxyl, OH, CN substituents;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterodyne represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (3-IB),

in,

X is arbitrarily independently selected from N or CR;

Y is independently selected from -O-, -S-, -NR d3 -, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )( R d2 )O-, -C(=O)N(R d3 )-, -C(=NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(=O ) 2 N(R d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 ) (R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )( R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 ) (R d2 )–or-C(R d1 )(R d2 )S(=O) 2 -;

R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;

Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from aromatic Ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds And 0 to more heteroatoms; wherein the C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3 -10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl C 1-10 alkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute is optionally preferably 1 Substituted with multiple substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;

R 2 ' and R 3 ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-Dimethylcrotonyl, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3- 10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl or R 2 ' _ _ and R 3 ' and the carbon atoms connected to the ring together form a 4-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optional Optimally substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;

R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated ring Alkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, The C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute substituted by C 3-10 cycloalkyl is optionally preferably 1 to more selected from H, deuterium, Substituted by halogen, alkyl, OCH 3 , carboxyl, OH, CN substituents;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterodyne represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (3-IC),

in,

X is arbitrarily independently selected from N or CR;

R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterium Alkyl group, C 2-10 alkenyl group, C 1-10 alkoxy group, C 1-10 haloalkoxy group, C 1-10 deuterated alkoxy group, C 2-10 alkenyl group, C 2-10 alkynyl group ;

Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 substituted by C 3-10 cycloalkyl Heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN ;

R 2 ' and R 3 ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-Dimethylcrotonyl, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3- 10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl or R 2 ' _ _ and R 3 ' and the carbon atoms connected to the ring together form a 4-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optional Optimally substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;

R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated ring Alkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, The C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute substituted by C 3-10 cycloalkyl is optionally preferably 1 to more selected from H, deuterium, Substituted by halogen, alkyl, OCH 3 , carboxyl, OH, CN substituents;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterodyne represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily chosen from an integer among 0, 1, 2, 3 and 4.

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (3-ID),

in,

X is arbitrarily independently selected from N or CR;

Y and Z are independently selected from -O-, -S-, -NR d3 -, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(＝O)N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S( ＝O) 2 N(R d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O) –, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 ) (R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C( R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(=NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(=O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC (R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )–or-C(R d1 )(R d2 )S(=O) 2 -;

R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;

Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 substituted by C 3-10 cycloalkyl Heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN ;

Each R a and R b may be the same or different, and are independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 Cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1- 10 alkyl-substituted carboxyl or carboxyl substitute; or R a and R b together with the carbon atoms connected to the ring form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be optional Selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the aliphatic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more different Saturated olefinic bonds; and the cyclic structure is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;

R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated ring Alkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, The C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute substituted by C 3-10 cycloalkyl is optionally preferably 1 to more selected from H, deuterium, Substituted by halogen, alkyl, OCH 3 , carboxyl, OH, CN substituents;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, Group substitution of oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl; or any two R d1 , R d2 or R d3 may be attached thereto The carbons together form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, paracyclic rings, spirocyclic rings or bridged rings. structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkyl, Aryl and heteroaryl are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterodyne represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (3-IE),

in,

Y is independently selected from -O-, -S-, -NR d3 -, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )( R d2 )O-, -C(=O)N(R d3 )-, -C(=NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(=O ) 2 N(R d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 ) (R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )( R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 ) (R d2 )–or-C(R d1 )(R d2 )S(=O) 2 -;

R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;

Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 substituted by C 3-10 cycloalkyl Heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN ;

R a and R b may be the same or different, and are independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2- 10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy Base, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl base or C 1-10 alkyl substituted by C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute; or R a and R b together with the carbon atoms connected to the ring form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be arbitrarily selected from Aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefins bond; and the cyclic structure is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN; or R a and R b are connected to it on the ring The carbon atoms come together to form a carbonyl group or C=NR d3 structure;

R 2 ' and R 3 ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-dimethylbutylamido, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3 -10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl or R 2 _ _ _ ' and R 3 ' together with the carbon atoms connected to the ring form a 4-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, Heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure may contain any The best one is substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;

R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated ring Alkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, The C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute substituted by C 3-10 cycloalkyl is optionally preferably 1 to more selected from H, deuterium, Substituted by halogen, alkyl, OCH 3 , carboxyl, OH, CN substituents;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterogeneous representative represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (3-IF),

X is independently selected from -CR– or -N-;

L is independently selected from the group consisting of absence, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, - C(＝O)N(R d3 )-, -N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(＝ O) 2 N(R d3 )-, -N(R d3 )-, -O-, -S-, -C(=O)O-, -OC(=O)-, -C(=O)- , -C(=S)-, -S(=O)–, -S(=O) 2 –, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC( R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 ) C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C( ＝NR d3 )-,-C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-,-C(R d1 )(R d2 )S(＝O) 2 N( R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)-, -C (R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )– or -C(R d1 )(R d2 )S(=O) 2 -;

Y and Z are independently selected from -O-, -S-, -NR d3 -, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(＝O)N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S( ＝O) 2 N(R d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O) –, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 ) (R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )( R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 ) (R d2 )–or-C(R d1 )(R d2 )S(=O) 2 -;

R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;

Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 substituted by C 3-10 cycloalkyl Heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN ;

Each R a and R b may be the same or different, and are independently selected from hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 Alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 Cycloalkyl or C 3-10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1- 10 alkyl-substituted carboxyl or carboxyl substitute; or R a and R b together with the carbon atoms connected to the ring form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be optional Selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the aliphatic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more different Saturated olefinic bonds; and the cyclic structure is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;

R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated ring Alkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, The C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute substituted by C 3-10 cycloalkyl is optionally preferably 1 to more selected from H, deuterium, Substituted by halogen, alkyl, OCH 3 , carboxyl, OH, CN substituents;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterodyne represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (3-IG),

X is independently selected from -CR– or -N-;

Y is independently selected from -O-, -S-, -NR d3 -, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )( R d2 )O-, -C(=O)N(R d3 )-, -C(=NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(=O ) 2 N(R d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 ) (R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )( R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 ) (R d2 )–or-C(R d1 )(R d2 )S(=O) 2 -;

R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;

Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 substituted by C 3-10 cycloalkyl Heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN ;

R a and R b are independently selected from C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1- 10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl , aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3 -10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or the carbon to which R a and R b are attached to the ring The atoms together form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure. ; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optionally preferably 1 to more selected from H, deuterium , halogen, OCH 3 , carboxyl, OH, CN substituent substitution;

R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 6-20 spirocyclyl, C 7-20 bridged cyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic The ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 3-10 cycloalkyl or C C 1-10 alkyl substituted by 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl The substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , carboxyl, OH, and CN;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring Ring, parallel ring, spiro ring or bridge ring structure Can contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, Group substitution of oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterogeneous representative represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (3-IH),

in,

Y is independently selected from -O-, -S-, -NR d3 -, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )( R d2 )O-, -C(=O)N(R d3 )-, -C(=NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(=O ) 2 N(R d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 ) (R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )( R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 ) (R d2 )–or-C(R d1 )(R d2 )S(=O) 2 -;

Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl, C 2-10 Alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycle Alkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 substituted by C 3-10 cycloalkyl Heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN ;

R 2 ' and R 3 ' are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide, N ,N-dimethylbutylamido, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl, C 2-10 alkenyl, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3- 10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl or R 2 ' _ _ and R 3 ' and the carbon atoms connected to the ring together form a 4-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; and the cyclic structure is optional Optimally substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, and CN;

R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group, C 3-10 saturated or partially saturated ring Alkyl, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, The C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute substituted by C 3-10 cycloalkyl is optionally preferably 1 to more selected from H, deuterium, Substituted by halogen, alkyl, OCH 3 , carboxyl, OH, CN substituents;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N, N-bis (C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyloxy, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkylamino, C3-10 heterocycle Alkylamino, C 3-10 cycloalkoxy, C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkyl Sulfinyl, aryl, heteroaryl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally replaced by 1 to more hydrogen , deuterium, halogen, -CN, -OH, CF 3 , C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl ) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, Halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl group substitution; or any two R d1 , R d2 or R d3 can be Together with its attached carbon, it forms a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or Bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkane Base, aryl, heteroaryl are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterogeneous representative represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily chosen from an integer among 0, 1, 2, 3 and 4.
The compound according to any one of claims 1 to 5 or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof, which has the structure of formula (IE)

in,

Any independently selected from single or double bonds;

X and X 1 are arbitrarily independently selected from N or CR;

X 2 , X 3 and X 4 are arbitrarily independently selected from N, N(R d3 ), C(R d1 )(R d2 ) or CR;

Ring A and ring C are each independently selected from a monocyclic or polycyclic structure of 3 to 18 carbon atoms, and the monocyclic or polycyclic structure can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, Heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

Ring B is arbitrarily independently selected from monocyclic or polycyclic structures that do not exist or have 3 to 18 carbon atoms. The monocyclic or polycyclic structures can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds;

L 1 and L 2 are each independently selected from the group consisting of absence, single bond, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(＝O)N(R d3 )-, -N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )- , -S(＝O) 2 N(R d3 )-, -N(R d3 )-, -O-, -S-, -C(＝O)O-, -OC(＝O)-, -C (＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )( R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O )N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 ) -, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )- , -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 ) (R d2 )C(=S)-, -S(=O)C(R d1 )(R d2 )– or -C(R d1 )(R d2 )S(=O) 2 -;

L 3 is independently selected from -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )(R d2 )O-, -C(=O) N(R d3 )-, -C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(＝O) 2 N(R d3 )-, -C( ＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C( R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O -, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 ) (R d2 )S(=O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O-, -OC(＝O)C(R d1 )(R d2 )-, -C(R d1 )( R d2 )C(＝O)-, -C(R d1 )(R d2 )C(＝S)-, -S(＝O)C(R d1 )(R d2 )–or -C(R d1 ) (R d2 )S(=O) 2 -;

R is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy;

Each R 1 may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 together with the carbon atoms connected to the ring form 3-18 membered monocyclic or polycyclic structure, the monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure; and the The alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the C 1-10 alkyl group and C 2-10 alkenyl group , C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3-10 saturated or partially saturated heterocycloalkyl , aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl The base, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, OCH 3 , carboxyl, OH, CN;

Each R 2 may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, acrylamide base, N,N-dimethylbutenamide group, C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2-10 heteroalkyl group , C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycloalkyl C 1-10 alkyl substituted by C 3-10 cycloalkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl , C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; Or any two R 1 and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, and aliphatic rings. , heterocyclic, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein the C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, C 3- 10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring The alkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl carboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen, OCH 3 , carboxyl , OH, CN substituent substitution;

Each R 3 may be the same or different and is independently selected from the group consisting of absence, hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryl, alkylsulfonyl, acrylamide group, N,N-dimethylbutenamide group, -COOH or selected from C 1-10 alkyl group, C 2-10 alkenyl group, C 2-10 alkynyl group or C 1-10 alkoxy group, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or a carboxyl substitute; or any two R 1 and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure, and the monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heterocyclic Aromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or bridged ring structure may contain 0 to more unsaturated olefinic bonds; wherein The above-mentioned C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkane base, C 3-10 saturated or partially saturated heterocycloalkyl, aryl, heteroaryl , C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 cycloalkyl substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkylcarboxyl or carboxyl substitute is optionally preferably 1 to more selected from H, deuterium, halogen , OCH 3 , carboxyl, OH, CN substituent substitution;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterogeneous representative represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

n is arbitrarily selected from an integer among 0, 1, 2, 3, 4 and 5;

t is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

p is arbitrarily chosen from an integer among 0, 1 and 2.
The compound according to any one of claims 1-6 or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof, which has the structure of formula (4-I)

in,

Ring A' is arbitrarily independently selected from

Ring B' is arbitrarily independently selected from

Q and Z are arbitrarily independently selected from S, O, NR d3 or C(R 2 ) 2 ;

Each X, X 0 , X 1 or X 2 may be the same or different and independently selected from N or CR 2 ;

Y is independently selected from -O-, -S-, -NR d3 -, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )( R d2 )O-, -C(=O)N(R d3 )-, -C(=NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(=O ) 2 N(R d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 ) (R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )( R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 ) (R d2 )–or-C(R d1 )(R d2 )S(=O) 2 -;

Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 ' is optionally preferably 1 Substituted with at least a plurality of substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;

Each R 2 ' may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, Acrylamide group, N,N-dimethylbutyrylamide group, C 1-10 alkyl group, C 1-10 haloalkyl group, C 1-10 deuterated alkyl group, C 2-10 alkenyl group, C 1-10 Alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl base, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycle Alkyl-substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted Carboxyl or carboxyl substitute; further, the hydrogen on R 2 ' is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, CN;

R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; more Further, the hydrogen on R 4 is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;

Each Ra, Rb , Rd1 , Rd2 and Rd3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2- 10 alkenyl, C 2-10 alkynyl, C 1-10 alkylamino, N, N-bis (C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl , C 1-10 alkyloxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3 -10 cycloalkoxy, C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl , heteroaryl; and the alkyl, alkenyl, alkynyl, aryl, saturated or partially saturated cycloalkyl, heterocycloalkyl is optionally substituted by 1 to more selected from hydrogen, deuterium, halogen, - CN, -OH, CF 3 , C 1-6 alkyl group, C 1-6 alkoxy group, -NH 2 , -NHC 1-6 alkyl group, -N(C 1-6 alkyl) 2 , oxy group, And saturated or partially saturated C 3-6 cycloalkyl substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further selected from 1 to more hydrogen, deuterium, halogen, oxo, CN , CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R a , R b , R d1 , R d2 or R d3 can be Together with its attached carbon, it forms a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, aliphatic ring, heterocyclic ring, paracyclic ring, spirocyclic ring or Bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein, the cycloalkyl, heterocycloalkane Aryl, aryl, heteroaryl are optionally substituted by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterogeneous representative represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (4-IA),

in,

Q is arbitrarily independently selected from S, O, NR d3 or C(R 2 ') 2 ;

X, X 0 and X 1 are independently selected from N or CR 2 ';

Y is independently selected from -O-, -S-, -NR d3 -, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )( R d2 )O-, -C(=O)N(R d3 )-, -C(=NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(=O ) 2 N(R d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 ) (R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )( R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 ) (R d2 )–or-C(R d1 )(R d2 )S(=O) 2 -;

Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 ' is optionally preferably 1 Up to a plurality selected from H, deuterium, halogen Substituted with substituents of element, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;

Each R 2 ' may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, Acrylamide group, N,N-dimethylbutyrylamide group, C 1-10 alkyl group, C 1-10 haloalkyl group, C 1-10 deuterated alkyl group, C 2-10 alkenyl group, C 1-10 Alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl base, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycle Alkyl-substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute ;Furthermore, the hydrogen on R 2 ' is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;

R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; more Further, the hydrogen on R 4 is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterodyne represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (4-IB),

in,

Y is independently selected from -O-, -S-, -NR d3 -, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )( R d2 )O-, -C(=O)N(R d3 )-, -C(=NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(=O ) 2 N(R d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 ) (R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )( R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 ) (R d2 )–or-C(R d1 )(R d2 )S(=O) 2 -;

Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two Each R 1 ' and the carbon atoms connected to the ring together form a 3-18 membered monocyclic or polycyclic structure. The monocyclic or polycyclic structure can be arbitrarily selected from aromatic rings, heteroaromatic rings, aliphatic rings, heterocyclic rings, etc. Ring, paracyclic, spirocyclic or bridged ring structure; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; further The hydrogen on R 1 ' is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;

Each R 2 ' may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, Acrylamide group, N,N-dimethylbutyrylamide group, C 1-10 alkyl group, C 1-10 haloalkyl group, C 1-10 deuterated alkyl group, C 2-10 alkenyl group, C 1-10 Alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl base, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycle Alkyl-substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute ;Furthermore, the hydrogen on R 2 ' is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;

R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; more Further, the hydrogen on R 4 is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterogeneous representative represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (4-IC),

in,

Q is arbitrarily independently selected from S, O, NR d3 or C(R 2 ') 2 ;

X, X 0 , X 1 and X 2 are independently selected from N or CR 2 ';

Y is independently selected from -O-, -S-, -NR d3 -, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )( R d2 )O-, -C(=O)N(R d3 )-, -C(=NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(=O ) 2 N(R d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 ) (R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )( R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 ) (R d2 )–or-C(R d1 )(R d2 )S(=O) 2 -;

Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 ' is optionally preferably 1 Substituted with at least a plurality of substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;

Each R 2 ' may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl, -COOH, Acrylamide group, N,N-dimethylbutyrylamide group, C 1-10 alkyl group, C 1-10 haloalkyl group, C 1-10 deuterated alkyl group, C 2-10 alkenyl group, C 1-10 Alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2-10 heteroalkyl base, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3-10 heterocycle Alkyl-substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted by C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute ;Furthermore, the hydrogen on R 2 ' is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, CN;

R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; more Further, the hydrogen on R 4 is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterogeneous representative represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof, has the structure of formula (4-ID),

in,

X 0 and X 1 are independently selected from N or CR 2 ';

Y is independently selected from -O-, -S-, -NR d3 -, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )( R d2 )O-, -C(=O)N(R d3 )-, -C(=NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(=O ) 2 N(R d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(=O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 ) (R d2 )N(R d3 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C (R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(＝O)O -, -OC(=O)C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S )-, -S(＝O)C(R d1 )(R d2 )– or -C(R d1 )(R d2 )S(＝O) 2 -;

Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 ' is optionally preferably 1 Substituted with at least a plurality of substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;

Each R 2 ' or R 3 ' may be the same or different, and are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl , -COOH, acrylamide group, N,N-dimethylbutyrylamide group, C 1-10 alkyl group, C 1-10 haloalkyl group, C 1-10 deuterated alkyl group, C 2-10 alkenyl group, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or a carboxyl substitute; further, the hydrogen on R 2 ' is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, CN;

R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; more Further, the hydrogen on R 4 is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the alicyclic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterodyne represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

Preferably, the compound or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof has the structure of formula (4-IE),

in,

Each X 0 and X 1 may be the same or different and independently selected from N or CR 2 ';

Y is independently selected from -O-, -S-, -NR d3 -, -C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -C(R d1 )( R d2 )O-, -C(=O)N(R d3 )-, -C(=NR d3 )-, -C(R d1 )(R d2 )N(R d3 )-, -S(=O ) 2 N(R d3 )-, -C(＝O)O-, -OC(＝O)-, -C(＝O)-, -C(＝S)-, -S(＝O)–, -C(R d1 )(R d2 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )C(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )O-, -C(R d1 )(R d2 )C(＝O)N(R d3 )-, -C(R d1 )(R d2 )C(R d1 )(R d2 )N(R d3 )-, -C(R d1 )(R d2 )C(＝NR d3 )-, -C(R d1 )(R d2 )N(R d3 )C(R d1 ) (R d2 )-, -C(R d1 )(R d2 )S(＝O) 2 N(R d3 )-, -N(R d3 )C(R d1 )(R d2 )-, -OC(R d1 )(R d2 )-, -SC(R d1 )(R d2 )-, -C(R d1 )(R d2 )C(=O)O-, -OC(=O)C(R d1 )( R d2 )-, -C(R d1 )(R d2 )C(=O)-, -C(R d1 )(R d2 )C(=S)-, -S(=O)C(R d1 ) (R d2 )–or-C(R d1 )(R d2 )S(=O) 2 -;

Each R 1 ' may be the same or different, and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , -COOH, C 1-10 alkyl, C 2-10 alkenyl , C 2-10 alkynyl or C 1-10 alkoxy, dialkylphosphoroxy, alkylsulfonyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aromatic base, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 Cycloalkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl or carboxyl substitute; or any two R 1 ' carbon atoms connected to it on the ring Together, they form a 3-18 membered monocyclic or polycyclic structure, which can be arbitrarily selected from an aromatic ring, a heteroaromatic ring, an aliphatic ring, a heterocyclic ring, a paracyclic ring, a spirocyclic ring or a bridged ring structure; And the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; furthermore, the hydrogen on R 1 ' is optionally preferably 1 Substituted with at least a plurality of substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;

Each R 2 ' or R 3 ' may be the same or different and is independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH and -NH 2 , dialkylphosphoryloxy, alkylsulfonyl , -COOH, acrylamide group, N,N-dimethylbutyrylamide group, C 1-10 alkyl group, C 1-10 haloalkyl group, C 1-10 deuterated alkyl group, C 2-10 alkenyl group, C 1-10 alkoxy, C 1-10 haloalkoxy, C 1-10 deuterated alkoxy, C 2-10 alkenyl, C 2-10 alkynyl or C 1-10 alkoxy, C 2 -10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl, heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 3-10 cycloalkyl or C 3 -10 heterocycloalkyl substituted C 1-10 alkyl, C 2-10 heteroalkyl substituted with C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 1-10 alkyl substituted carboxyl Or a carboxyl substitute; further, the hydrogen on R 2 ' is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, CN;

R 4 is independently selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 2-10 heteroalkyl, C 3-10 saturated or partially saturated cycloalkyl, aryl , heteroaryl, C 3-10 saturated or partially saturated heterocyclyl, C 1-10 alkyl substituted by C 3-10 cycloalkyl or C 3-10 heterocycloalkyl, C 3-10 ring Alkyl-substituted C 2-10 heteroalkyl, C 3-10 heterocyclyl; and the alicyclic, heterocyclic, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds; more Further, the hydrogen on R 4 is optionally preferably substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN;

Each R d1 , R d2 and R d3 may be the same or different and are independently selected from hydrogen, deuterium, halogen, cyano, amino, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2 -10 alkynyl, C 1-10 alkylamino, N, N-di(C 1-10 alkyl) amino, C 1-10 alkyloxy, C 1-10 alkyl acyl, C 1-10 alkyl baseoxy group, C 1-10 alkylsulfonyl group, C 1-10 alkylsulfinyl group, C 3-10 cycloalkylamino group, C3-10 heterocycloalkylamino group, C 3-10 cycloalkoxy group , C 3-10 cycloalkyloyl, C 3-10 cycloalkoxyacetyl, C 3-10 cycloalkylsulfonyl and C 3-10 cycloalkylsulfinyl, aryl, heteroaryl; and The alkyl group, alkenyl group, alkynyl group, aryl group, saturated or partially saturated cycloalkyl group, and heterocycloalkyl group are optionally substituted by one to more hydrogen, deuterium, halogen, -CN, -OH, CF 3. C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N(C 1-6 alkyl) 2 , oxygen, and saturated or partially saturated C 3-6 cycloalkyl is substituted, and C 1-6 alkyl and C 1-6 alkoxy are optionally further substituted by 1 to more selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 and saturated or partially saturated C 3-6 cycloalkyl groups are substituted; or any two R d1 , R d2 or R d3 can form a 3-18 membered monocyclic ring together with the carbon to which they are attached. Or a polycyclic structure, the single ring or polycyclic structure can be arbitrarily selected from aromatic ring, heteroaromatic ring, alicyclic ring, heterocyclic ring, paracyclic ring, spiro ring or bridged ring structure; and the aliphatic ring, heterocyclic ring The ring, paracyclic, spirocyclic or bridged ring structure may contain 0 to more unsaturated olefinic bonds and 0 to more heteroatoms; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally replaced by 1 to more groups selected from hydrogen, deuterium, halogen, oxo, CN, CF 3 , OH, OCH 3 , OCH 2 CH 3 ;

The heterodyne represents any atom or group independently selected from O, N, S, S=O, S(=O) 2 , P, P=O and its isotopes;

The halogen is independently selected from F, Cl, Br, I and its isotopes;

m is arbitrarily selected from an integer among 0, 1, 2, 3, and 4;

Preferably, R 2 or R 2 ' is preferably selected from hydrogen, deuterium, halogen, -CN, dialkylphosphoroxy, alkylsulfonyl, -COOH, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 deuterated alkyl group, C 1-10 alkoxy group, C 1-10 haloalkoxy group, C 1-10 deuterated alkoxy group; further, the hydrogen on R 2 or R 2 ' is optional. Preferably, it is substituted by 1 to more substituents selected from H, deuterium, halogen, alkyl, OCH 3 , haloalkyl, carboxyl, OH, and CN.
The compound according to claims 1-7 or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof is selected from compounds with structures as listed in the embodiments of the present invention.
The compound of any one of claims 1 to 8 or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof, used for the preparation of prevention and/or treatment of CDKs targets discussed herein Use in drugs for point-related diseases including tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, psoriasis) and other diseases;
A pharmaceutical composition whose main active ingredient is the compound described in any one of claims 1 to 8 or its pharmaceutically acceptable salt, solvate, hydrate, isotope substitution or isomer thereof, and others Some auxiliary ingredients make it suitable for use in various forms of pharmaceutical dosage forms such as liquid preparations (including oral liquids, injections, eye drops, etc.) and solid preparations (including tablets, capsules, pills, granules, etc.). The pharmaceutical composition can be used to prepare drugs for preventing and/or treating CDKs target-related diseases discussed herein, including tumors, inflammation, autoimmune diseases (such as lupus erythematosus, psoriasis, psoriasis) and other diseases.