WO2025067540A1 - Pyrazolotriazine and pyrazolopyrimidine derivatives, preparation method therefor, pharmaceutical composition, and use thereof - Google Patents

Abstract

Provided are pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives represented by general formula (I) and/or pharmaceutically acceptable salts thereof, a pharmaceutical composition thereof, and the use of said derivatives as a pharmaceutically active agent for the prevention and/or treatment of diseases related to CDKs abnormal activity; the compound has a good effect of inhibiting cell proliferation in both solid tumours and blood tumours.

Description

Pyrazolotriazine and pyrazolopyrimidine derivatives, preparation methods, pharmaceutical compositions and uses thereof Technical Field

The present invention relates to the field of medicinal chemistry, and in particular, to a class of compounds as shown in general formula (I), preparation methods thereof, pharmaceutical compositions and their use in the preparation of degradation agents targeting cell cycle-dependent kinases (CDKs) for preventing and/or treating diseases or symptoms associated with abnormal activity of cell cycle-dependent kinases, and drugs for treating diseases or conditions associated with selective transcription of CDKs. The present invention also provides a pharmaceutically acceptable composition comprising the compound of the present invention and a method for using the composition to treat diseases or conditions associated with selective transcription of CDKs.

Background Art

Cyclin-dependent kinase (CDK) is an important target for tumor treatment. Cyclin-dependent kinase (CDK) is a type of serine/threonine kinase, which is mostly a heterodimeric complex composed of cell cycle catalytic kinase subunits and regulatory subunits. It is activated by binding to cell cycle proteins, thereby regulating the cell cycle and transcription process. Disturbance of CDK activity can directly or indirectly cause uncontrolled cell proliferation, increased DNA mutations, chromosome deletions and chromosome changes, etc., leading to the occurrence and development of tumors. CDK family proteins are involved in cell mitosis and transcription processes and play an important role in cell proliferation. Due to the abnormally active proliferation of tumor cells, abnormal activation of CDK is often observed in tumor cells, thereby promoting the growth of tumor cells. The CDK family has always been considered an important target in tumor treatment, but due to the highly conserved amino acid sequence of the ATP binding pocket between different CDK proteins, it is difficult to find small molecule inhibitors with high selectivity between CDK families. Currently on the market, drugs targeting the CDK family include Pfizer's Palbociclib, Novartis' Ribociclib, Eli Lilly's Abemaciclib, Hengrui's Dalpiciclib and G1 Therapeutics' Trilaciclib. Except for Trilaciclib, which is used to reduce the frequency of bone marrow suppression in patients with small cell lung cancer after chemotherapy, the indications of the other drugs are all for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) recurrent or metastatic breast cancer. Drugs targeting other targets of the CDK family are mostly in the clinical or preclinical research stage.

In the CDK family, CDK7 and CDK9 have recently attracted widespread attention from academia and major pharmaceutical companies. CDK7 has the dual functions of affecting the cell cycle and regulating the transcription process. CDK7 is the catalytic subunit of the CDK activating enzyme complex (CAK), which is composed of CDK7, cyclin H and MAT1. CAK can activate CDK proteins related to the cell cycle, including CDK1, CDK2, CDK4, and CDK6, through threonine phosphorylation, thereby affecting the progression of the cell cycle. In terms of transcriptional regulation, CDK7, as a component of the basal transcription factor TFIIH complex, can activate RNA polymerase II by serine phosphorylation of the C-terminal domain of RNA polymerase II, thereby regulating RNA polymerase II-mediated transcription initiation and elongation.

CDK9/Cyclin T1 (or T2) is part of the subunit of the positive transcription elongation factor b (P-TEFb) complex. It activates RNA polymerase II to initiate gene transcription elongation by phosphorylating the carboxyl terminal domain (CTD) of RNA polymerase. CDK9 is upstream of key molecules such as anti-apoptotic proteins Bcl-2, Mcl-1, XIAP, cell cycle regulatory proteins, and mitosis regulatory kinases that are closely related to tumors. CDK9 can be directly or indirectly regulated. For example, in chronic lymphocytic leukemia (CLL), downregulation of Bcl-2 can be achieved by inhibiting the activity of CDK9. 2 family to achieve therapeutic effects. CDK9 does not affect the regulation of the cell cycle. This specific regulation of CDK9 on the transcription process makes it one of the most promising anti-tumor targets in the CDK family. In addition, there are literature reports that CDK7/cyclin H and CDK9/cyclin T complexes can also inhibit the replication of HIV and HSV virus RNA, so there will be certain application prospects in the antiviral field.

CDK7 and CDK9 are important targets for the treatment of tumors. Currently, several CDK7 and CDK9 inhibitors have entered clinical research. However, due to the highly conservative structure of CDKs, most of them are non-selective inhibitors. Representative small molecule inhibitors include Flavopiridol, Roscovitine, SNS-032, R547, TG-02, AT-7519, etc., but there are relatively few studies on small molecule inhibitors that highly selectively target CDK7 or CDK9, or target CDK7 and CDK9 dual targets. Blocking the cell cycle by small molecule inhibitors on CDK7 and CDK9 to induce apoptosis and regulate transcription has become an important anti-tumor method. Since most of the known CDK9 inhibitors have disadvantages such as non-selectivity or unexpected toxicity, they may cause unforeseen side effects.

Cyclin-dependent kinase (CDK) 12 and CDK13 are important targets for disease treatment. CDK12 is a member of a subset of the CDK serine/threonine kinase family that phosphorylates the C-terminal domain (CTD) of RNA polymerase II. CDK12 in the CDK12/CyclinK complex regulates transcriptional, co-transcriptional, and post-transcriptional processes by phosphorylating Ser of the CTD of the RNA polymerase II complex. CDK13 is a kinase closely related to CDK12 that forms a complex with CyclinK and regulates the transcription of a different set of genes. CDK12 amplification and high expression levels suggest that the tumor-promoting effects of CDK12 are at least in part based on alternatively spliced mRNAs, increased DNA repair capacity, and increased stress tolerance. This information suggests that CDK12 is a potential target for the development of drugs to treat cancer and other diseases.

CDK-related kinases are closely related to the occurrence and development of tumors. Inhibitors or degraders targeting CDK9, CDK7 or CDK12-related kinase targets can regulate transcription CDKs, thereby regulating RNA polymerase II-mediated transcription initiation and extension, and effectively inhibiting the proliferation of tumor cells. The purpose of the present invention is to provide a class of compounds that can be used to treat and/or prevent or improve such diseases and/or conditions by designing and synthesizing new inhibitors or degraders targeting CDK. Therefore, the development of inhibitors and degraders targeting CDK has important scientific significance and research value.

Summary of the invention

One object of the present invention is to provide a compound as represented by the general formula (I) and its tautomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, pharmaceutical compositions containing the same, and uses thereof.

Another object of the present invention is to provide a method for preparing the compound represented by the general formula (I), an important intermediate for preparing the compound and a method for preparing the compound.

In a first aspect, the present invention provides a compound represented by general formula (I) and its tautomers, stereoisomers, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof.

Wherein, X is CH or N;

Y is selected from -NH-, -O- or absent;

R ¹ is selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the following group: hydroxyl, C ₁ -C ₃ alkyl, propynyl, -C ₁ -C ₃ alkylhydroxyl, C ₁ -C ₃ alkylcarbonyl, halogen, 3-8 membered heterocyclyl, amino, (C ₁ -C ₃ alkyl) _1-2amino , methylsulfonyl;

Selected from hydrogen, halogen, cyano, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the following group: deuterium, halogen, cyano, nitro, hydroxyl, amino, C ₁ -C ₃ alkyl, halogen-substituted C ₁ -C ₃ alkyl;

R ² is selected from hydrogen, deuterium, halogen and unsubstituted or halogenated C ₁ -C ₃ alkyl;

R ³ is selected from deuterium, halogen, cyano, hydroxyl, nitro, unsubstituted or halogenated C ₁ -C ₃ alkyl;

n is 1 or 2;

m is 0, 1, 2, 3 or 4;

Z is selected from NH, N, O or absent;

When Z is selected from NH or N, each independently selected from hydrogen, -C(O)R ⁴ , C ₁ -C ₃ alkyl substituted with R ⁵ , wherein R ⁴ is selected from C ₁ -C ₆ alkyl substituted with R ⁶ , 3-6 membered heterocycloalkyl substituted with R ⁶ , and C ₃ -C ₆ cycloalkyl substituted with R ⁶ , wherein each R ⁶ is independently selected from hydrogen, hydroxy, C ₁ -C ₃ alkyl-C(O)-, halogen, and carboxyl; R ⁵ is selected from hydrogen, hydroxy, halogen, and carboxyl;

When Z is selected from O or Z is absent, each Independently selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocyclyl, wherein the substitution means that one or more H on the group is substituted by a substituent independently selected from the group consisting of deuterium, oxo (=O), halogen, cyano, nitro, hydroxyl, amino, carboxyl, formylamino, C ₁ -C ₃ alkyl, halogen-substituted C ₁ -C ₃ alkyl;

The premise is that when Z does not exist, and Not simultaneously selected from the following substituents: is phenyl, pyridyl, thienyl, furyl, thiazolyl, pyrrolyl and pyrimidinyl, It is an unsubstituted C ₁ -C ₆ alkyl group or an unsubstituted C ₃ -C ₆ cycloalkyl group.

In another preferred embodiment, when Z is selected from O or Z is absent, each Independently selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, wherein the substitution means that one or more H on the group is substituted by a substituent independently selected from the following group: deuterium, oxo (=O), halogen, cyano, nitro, hydroxyl, amino, carboxyl, formylamino, C ₁ -C ₃ alkyl, halogen-substituted C ₁ -C ₃ alkyl.

In another preferred embodiment, the compound of general formula (I) has a structure shown in formula (I-1)-(I-4):

Among them, (I-2) Can be the same or different,

X is CH or N;

Y is selected from -NH-, -O- or absent;

R ¹ is selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the following group: hydroxyl, C ₁ -C ₃ alkyl, propynyl, -C ₁ -C ₃ alkylhydroxyl, C ₁ -C ₃ alkylcarbonyl, halogen, 3-8 membered heterocyclyl, amino, (C ₁ -C ₃ alkyl) _1-2amino , methylsulfonyl;

R ² , R ³ , m, and As defined in the present invention.

In another preferred embodiment, the compound of general formula (I) has a structure shown in formula (I-5)-(I-8):

Among them, (I-6) and (I-8) Can be the same or different,

Y is selected from -NH-, -O- or absent;

R ¹ is selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the following group: hydroxyl, C ₁ -C ₃ alkyl, propynyl, -C ₁ -C ₃ alkylhydroxyl, C ₁ -C ₃ alkylcarbonyl, halogen, 3-8 membered heterocyclyl, amino, (C ₁ -C ₃ alkyl) _1-2amino , methylsulfonyl;

Selected from hydrogen, halogen, cyano, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, amino, C ₁ -C ₃ alkyl, halogen-substituted C ₁ -C ₃ alkyl;

each independently selected from hydrogen, -C(O)R ⁴ , C ₁ -C ₃ alkyl substituted with R ⁵ , wherein R ⁴ is selected from C ₁ -C ₆ alkyl substituted with R ⁶ , 3-6 membered heterocycloalkyl substituted with R ⁶ , and C ₃ -C ₆ cycloalkyl substituted with R ⁶ , wherein each R ⁶ is independently selected from hydrogen, hydroxy, C ₁ -C ₃ alkylcarbonyl, halogen and carboxyl, and R ⁵ is selected from hydrogen, hydroxy, halogen and carboxyl;

R ² , R ³ and m are as defined in the present invention.

In another preferred embodiment, the compound of general formula (I) has a structure shown in formula (I-9)-(I-10):

wherein Y is selected from -NH-, -O- or absent;

R ¹ is selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, wherein the aforementioned substitution refers to substitution by one or more of the following substituents: hydroxyl, C ₁ -C ₃ alkyl, propynyl, hydroxyC ₁ -C ₃ alkyl, C ₁ -C ₃ alkylcarbonyl, halogen, heterocyclyl, amino, alkylamino, methylsulfonyl;

Selected from hydrogen, halogen, cyano, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the group consisting of deuterium, halogen, hydroxyl, C ₁ -C ₃ alkyl, halogen-substituted C ₁ -C ₃ alkyl;

Selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, wherein the substitution means that one or more H on the group is independently selected from the following group: deuterium, oxo (=O), halogen, cyano, nitro, hydroxyl, amino, carboxyl, formylamino, C ₁ -C ₃ alkyl, halogen-substituted C ₁ -C ₃ alkyl;

R ² , R ³ and m are as defined in the present invention.

In another preferred embodiment, the compound of general formula (I) has a structure shown by formula (I-11)-(I-12):

wherein Y is selected from -NH-, -O- or absent;

Selected from hydrogen, halogen, cyano, substituted C ₁ -C ₆ alkyl, substituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, amino, C ₁ -C ₃ alkyl, halogen-substituted C ₁ -C ₃ alkyl;

is selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, wherein the substitution means that one or more H on the group is independently selected from the following group: deuterium, oxo (=O), halogen, cyano, nitro, hydroxyl, amino, carboxyl, formylamino, C ₁ -C ₃ alkyl, halogen-substituted C ₁ -C ₃ alkyl,

R ¹ , R ² , R ³ and m are as defined in the present invention.

In another preferred embodiment, the compound of general formula (I) has a structure shown in formula (I-13)-(I-41):

Wherein, X is CH or N; _R1 and Y are as defined in the present invention.

In another preferred embodiment, the compound of the general formula (I) is characterized in that R ₁ -Y is selected from:

In another preferred embodiment, the compound is selected from the following group:

In another preferred embodiment, n, m, X, Y, Z, R ¹ , R ² , R ³ , and Optionally, it is independently any corresponding group of C1-C149.

The second aspect of the present invention provides a pharmaceutical composition, which comprises the compound as described in the first aspect of the present invention and one or more of its tautomers, stereoisomers, isotope compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, and pharmaceutically acceptable excipients.

The third aspect of the present invention provides the use of the compound as described in the first aspect of the present invention and its tautomers, stereoisomers, isotope compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof or the pharmaceutical composition as described in the second aspect of the present invention in the preparation of a drug for preventing and/or treating diseases or symptoms associated with abnormal activity of CDK or Cyclin K.

In another preferred embodiment, the CDK is selected from: CDK2, CDK9, CDK12, or Cyclin K, or a combination thereof.

In another preferred embodiment, the disease associated with abnormal activity of CDK or Cyclin K is cancer, pain, Central nervous system or immune system disorders.

In another preferred embodiment, the disease associated with abnormal activity of CDK or Cyclin K is a solid tumor or a blood tumor. Preferably, the disease is selected from the group consisting of myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, myelofibrosis, Burkitt's lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, ciliary body and chronic melanoma, iris melanoma, recurrent interocular melanoma, T-cell lymphoma, erythroid lymphoma, monocytic and monocytic leukemia, myeloid leukemia, blood disease, central nervous system lymphoma, meningioma, spinal cord tumor, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, astrocytoma, amyloidosis, complex regional pain syndrome type I, malignant melanoma, radiculopathy, glioblastoma, gliosarcoma, malignant glioma, refractory plasmacytoma, melanoma with extraocular extension, papillary and follicular thyroid cancer, breast cancer, prostate cancer, colorectal cancer, ovarian cancer, endometrial cancer, cervical cancer, hepatocellular carcinoma, stomach cancer, esophageal cancer, bladder cancer, small cell lung cancer, non-small cell lung cancer, Ewing sarcoma, glioblastoma, or primary macroglobulinemia.

In addition, the present invention also provides the use of the compound as described in the first aspect of the present invention and its tautomers, stereoisomers, isotope compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof in the preparation of CDK or Cyclin K inhibitors.

In another preferred embodiment, the CDK is selected from: CDK2, CDK9, CDK12, or a combination thereof.

The present invention also provides a method for preventing and/or treating diseases or symptoms associated with abnormal activity of CDK or Cyclin K, comprising the steps of administering to a subject in need thereof a compound as described in the first aspect of the present invention and its tautomers, stereoisomers, isotope compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, or a pharmaceutical composition as described in the second aspect of the present invention.

In another preferred embodiment, the subject is a human or non-human mammal, such as a rat or a mouse.

The present invention also encompasses any novel intermediates disclosed herein.

In another aspect of the present invention, there is provided a method for preparing the compound according to the first aspect of the present invention, wherein the method is selected from one of the following methods:

Synthesis method 1:

Step 1-1: Compound 1A reacts with Boc anhydride to obtain compound 1B;

Step 1-2: Compound 1B is subjected to hydrogenation reaction with Raney nickel to obtain compound 1C;

Step 1-3: Compound 1C and compound 1D are subjected to phosphorus oxychloride and N,N-dimethylbenzylamine to obtain a halogenated product, which is then subjected to nucleophilic substitution under alkaline conditions to obtain compound 1E;

Step 1-4: Compound 1E and compound 1F react under the conditions of sodium hydrogen and anhydrous N,N-dimethylformamide to obtain compound 1H;

Step 1-5: Compound 1E and compound 1G react under 1-methyl-2-pyrrolidone to obtain compound 1J;

Step 1-6: Compound 1H is reacted in the presence of dioxane hydrochloride to obtain compound 1I.

Step 1-7: Compound 1J is reacted in the presence of dioxane hydrochloride to obtain compound 1K.

R ₁ is the same as defined in the first aspect of the present invention;

Synthesis method 2:

Step 2-1: Compound 2A reacts with compound 2B in the presence of HATU and DIPEA to obtain compound 2C;

Step 2-2: Compound 2C is reacted in the presence of dioxane hydrochloride to obtain compound 2D;

Step 2-3: Compound 2D and compound 1D are reacted in the presence of phosphorus oxychloride and N,N-dimethylbenzylamine to obtain a halogenated product, which is then subjected to nucleophilic substitution under alkaline conditions to obtain compound 2E;

Step 2-4: Compound 2E and compound 2F react under the conditions of sodium hydrogen and anhydrous N,N-dimethylformamide to obtain compound 2I;

Step 2-5: Compound 2E and compound 2G react under 1-methyl-2-pyrrolidone to obtain compound 2J;

Step 2-6: Compound 2E and compound 2H react in 1-methyl-2-pyrrolidone to obtain compound 2K.

R ₃ is selected from -CH ₃ , -CH ₂ CH ₃ ,

R ₁ is the same as defined in the first aspect of the present invention;

Synthesis method three:

Step 3-1: Compound 3A and compound 1D are reacted in the presence of phosphorus oxychloride and N,N-dimethylbenzylamine to obtain a halogenated product, which is then subjected to nucleophilic substitution under alkaline conditions to obtain compound 3C;

Step 3-2: Compound 3B and compound 1D are reacted in the presence of phosphorus oxychloride and N,N-dimethylbenzylamine to obtain a halogenated product, which is then subjected to nucleophilic substitution under alkaline conditions to obtain compound 3D;

Step 3-3: Compound 3C and compound 3E react under 1-methyl-2-pyrrolidone to obtain compound 3F;

Step 3-4: Compound 3D and compound 3E react under 1-methyl-2-pyrrolidone to obtain compound 3G;

Step 3-5: Compound 3F is reacted in the presence of dioxane hydrochloride to obtain compound 3H;

Step 3-6: Compound 3G is reacted in the presence of dioxane hydrochloride to obtain compound 3I;

R ₁ is the same as defined in the first aspect of the present invention;

Synthesis method 4:

Step 4-1: Compound 4A and compound 1C react under the conditions of N,N-diisopropylethylamine and ethanol to obtain compound 4B;

Step 4-2: Compound 4A and compound 2D react under the conditions of N,N-diisopropylethylamine and ethanol to obtain compound 4C;

Step 4-3: Compound 4B reacts with Boc anhydride to obtain compound 4D;

Step 4-4: Compound 4C reacts with Boc anhydride to obtain compound 4E;

Step 4-5: Compound 4D and compound 4F react under 1-methyl-2-pyrrolidone to obtain compound 4G;

Step 4-6: Compound 4E and compound 4F react under 1-methyl-2-pyrrolidone to obtain compound 4H;

Step 4-7: Compound 4G is reacted in the presence of dioxane hydrochloride to obtain compound 4I;

Step 4-8: Compound 4H is reacted in the presence of dioxane hydrochloride to obtain compound 4J;

R ₁ is the same as defined in the first aspect of the present invention.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. The above description does not mean to limit the aspects of the present invention in any form.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the results of a protein blotting experiment showing the activity of some compounds of the present invention in degrading Cyclin K.

DETAILED DESCRIPTION

The present inventors have provided a class of CDK inhibitor compounds with novel structures and excellent anti-tumor activity through extensive and in-depth research, a large number of screenings and tests.

the term

When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, _-CH2O- is equivalent to _-OCH2- .

As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

The compounds shown in general formula (I) may contain one or more asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. The compounds of the present invention include all stereoisomeric forms, including but not limited to diastereomers, enantiomers and atropisomers and mixtures thereof (such as racemates), which are all included within the scope of the present invention.

The term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is a substituent described above or a substituent appearing in the examples. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. A cyclic substituent, such as a heterocycloalkyl, may be attached to another ring, such as a cycloalkyl, to form a spirobicyclic system, for example, two rings sharing one carbon atom. If not otherwise specified, substitution may refer to a group being substituted by one or more groups selected from the following: hydrogen, halogen, cyano, nitro, hydroxy, carboxyl, 4-10 membered heterocyclyl, C1-C6 alkyl, _C1 - _C6 alkoxy, halogen-substituted _C1 - _C6 alkyl, halogen-substituted _C1 - _C6 alkoxy, _C2 - _C6 alkenyl, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy-substituted _C1 - _C6 alkoxy, and _C1 - _C6 alkoxy substituted by _C1 - _C6 alkoxy.

It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. Substituent-substituted means including being substituted with a certain substituent or being unsubstituted.

The term "when the number of substituents is greater than 1, the R substituents may be the same or different substituents" mentioned in the present invention means that when there are multiple substituents in a certain structure, the substituent combination of R may be selected from a variety of different types of substituents.

The term "substituted" applies only to sites that can be substituted by substituents and does not include substitutions that are not achievable based on existing chemical knowledge.

The compounds represented by the general formula (I) may also exist in different tautomeric forms, all of which are included within the scope of the present invention.

The term "tautomer" refers to constitutional isomers of different energies that are interconvertible via a low energy barrier, the reaction typically resulting in the formal migration of a hydrogen atom or proton accompanied by conversion of a single bond and an adjacent double bond.

The term "stereoisomer" includes enantiomers, diastereomers, or mixtures thereof, such as racemates. The term "enantiomer" refers to stereoisomers that are mirror images of each other and are not superimposable.

"Diastereomers" refer to stereoisomers that have two or more chiral neutrals and are not mirror images.

"Racemate" refers to two stereoisomers that are mirror images of each other, with opposite optical rotations that cancel each other out.

"Pharmaceutically acceptable salts" refer to salts formed by drug molecules and corresponding organic acids, inorganic acids or organic bases, inorganic bases, such as hydrochloric acid, formic acid, trifluoroacetic acid, succinic acid, methanesulfonate, etc.

"Prodrug" refers to a class of compounds that are inactive or have low activity in vitro, but release active drugs through enzymatic or non-enzymatic conversion in vivo to exert their pharmacological effects.

"Hydrate" refers to a compound containing water.

The present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number from the original atoms. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as ^2H , ^3H , ^13C , ^11C , ^14C , ^15N , ^18O , ^17O , ^31P , ^32P , ^35S , ^18F and ^36Cl , respectively. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as radioactive isotopes of ^3H and ^14C , are also included, which are useful in tissue distribution experiments of drugs and substrates. Tritium, i.e. ^3H and carbon-14, i.e. ^14C , are relatively easy to prepare and detect. It is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. ² H, have advantages in certain therapies due to their good metabolic stability, such as increasing half-life in vivo or reducing dosage, and therefore, can be given priority in certain cases. Isotope-labeled compounds can be prepared by general methods by replacing readily available isotope-labeled reagents with non-isotope reagents and using the scheme disclosed in the examples. Preferably, the isotope compound is a deuterated compound, and more preferably, one or more H on carbon in the isotope compound is replaced by deuterium.

The term "plurality" refers to two or more, such as 2, 3, 4, 5 or 6.

The term "halogen" includes fluorine, chlorine, bromine or iodine.

The term "hydrocarbyl" refers to a substituent containing only carbon and hydrogen atoms, including, but not limited to, methyl, ethyl, isopropyl, propyl, cyclohexyl, phenyl, and the like.

The term "C ₁ -C ₆ alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms in the chain, such as an alkyl group containing 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group used herein or as part of another group has 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-3 alkyl), including but not limited to Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.

The term "C ₁ -C ₆ alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

The term "C ₁ -C ₆ alkoxycarbonyl" includes, but is not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. For example, "C ₃ -C ₈ cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentenyl, and cyclohexyl. Polycyclic cycloalkyl groups include spirocyclic, condensed, and bridged cycloalkyl groups.

The term "heterocyclic group" refers to a cyclic substituent containing one or more saturated and/or partially saturated monocyclic or polycyclic substituents, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur, oxo (=O) or S(O)m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon; the heterocyclic group may include a 3-8-membered heterocyclic group, preferably a 5-6-membered heterocyclic group, for example, propylene oxide, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; the heterocyclic group may be fused to an aryl, heteroaryl, or cycloalkyl ring, and the ring connected to the parent structure is a heterocyclic group. Heterocyclic groups include spirocyclic, fused ring, and bridged heterocyclic groups.

The term "aryl" refers to a 6-14-membered all-carbon monocyclic or fused polycyclic group with a conjugated p-electron system, preferably a 6- to 10-membered ring, preferably a 6- to 10-membered ring, more preferably a phenyl and a naphthyl, and most preferably a phenyl. The aryl ring may be fused to a heteroaryl, a heterocyclic or a cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring.

The term "heteroaryl" refers to a 5-14-membered aromatic group having 1 to 4 (e.g., 2 or 3) heteroatoms as ring atoms, with the remaining ring atoms being carbon, wherein the heteroatoms include oxygen, sulfur, and nitrogen. Preferably, it is 5-10 members. Heteroaryl is preferably 5-membered or 6-membered, such as thienyl, pyridyl, pyrrolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring,

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O)m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. The spiroheterocycle can be fused to a 6-10-membered aryl or 5-10-membered heteroaryl ring, wherein the ring connected to the parent structure is a spiroheterocycle.

The term "halogen-substituted alkyl" refers to a linear, branched or cyclic alkyl group substituted by a single or multiple halogens, including but not limited to 2-bromoethyl, 2-bromopropyl and the like.

The term "alkenyl" refers to an alkenyl group which may be of 2 to 10 carbons, such as ethenyl, propenyl, butenyl, styryl, phenylpropenyl.

The term "alkynyl" refers to an alkynyl group which may be 2-10 carbons, such as ethynyl, propynyl, butynyl, phenylethynyl, phenylpropenyl.

The term "hydroxy-substituted alkyl" refers to a linear, branched or cyclic alkyl group substituted by a single or multiple hydroxy groups, including but not limited to (S)-1-hydroxyisobutyl-2-yl, (R)-1-hydroxyisobutyl-2-yl, and the like.

In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

The present invention also encompasses any novel intermediates disclosed herein.

The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

The term "treatment" refers to therapeutic therapy. When referring to a specific condition, treatment means: (1) to alleviate the disease or condition; The invention relates to a method for treating a disorder or a condition in a manner that is directed to the treatment of the disorder or a problem in a patient's body. The method comprises: (a) interfering with one or more points in the biological cascade that leads to or causes the disorder or (b) one or more biological manifestations of the disorder, (c) ameliorating one or more symptoms, effects, or side effects associated with the disorder or one or more symptoms, effects, or side effects associated with the disorder or its treatment, or (d) slowing the progression of the disorder or one or more biological manifestations of the disorder.

The present invention provides a compound or a crystalline hydrate and a solvate with a structure as formula (I), and use thereof in preparing a drug for preventing and/or treating a disease or symptom associated with abnormal activity of CDK.

When the compound of the present invention contains a basic group, it can be prepared into a pharmaceutically acceptable salt, including inorganic acid salts and organic acid salts. Acids suitable for forming salts include (but are not limited to): inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid.

One aspect of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the general formula (I), and one or more of its stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates and crystalline forms, and at least one excipient, diluent or carrier.

A typical formulation is prepared by mixing the compound represented by the general formula (I) of the present invention and a carrier, diluent or excipient. Suitable carriers, diluents or excipients are well known to those skilled in the art, and include substances such as carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, and the like.

The specific carrier, diluent or excipient used will be determined according to the mode of use and purpose of the compound of the present invention. Solvents are generally selected based on solvents that are considered safe and effective for administration to mammals by those skilled in the art. Generally speaking, safe solvents are non-toxic aqueous solvents such as pharmaceutical water, and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300), etc. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents or other known additives to make the compound represented by formula (I) in an acceptable form for manufacture or use.

In this application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human), the medium including a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

When the compound of formula (I) of the present invention is used in combination with at least one other drug, the two drugs or multiple drugs can be used separately or in combination, preferably in the form of a pharmaceutical composition. The compound of formula (I) or pharmaceutical composition of the present invention can be administered to a subject separately or together in any known oral, intravenous, rectal, vaginal, transdermal, or other topical or systemic administration forms.

These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents or other known additives so that the pharmaceutical compositions can be manufactured or used in an acceptable form.

The drug of the present invention is preferably administered orally. Solid dosage forms for oral administration may include capsules, tablets, powders, Powder or granular preparation. In a solid dosage form, the compound or pharmaceutical composition of the present invention is mixed with at least one inert excipient, diluent or carrier. Suitable excipients, diluents or carriers include substances such as sodium citrate or dicalcium phosphate, or starch, lactose, sucrose, mannitol, silicic acid, etc.; binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, gum arabic, etc.; wetting agents such as glycerol, etc.; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates, sodium carbonate, etc.; solution retardants such as paraffin, etc.; absorption promoters such as quaternary ammonium compounds, etc.; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc. In the case of capsules and tablets, the dosage form may also include a buffer. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or other excipients such as high molecular weight polyethylene glycols.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compound of the present invention or its composition, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide; oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.); glycerol; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and dehydrated sorbitan; or a mixture of several of these substances, etc.

In addition to these inert diluents, the composition may also include excipients such as one or more of wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and perfuming agents.

In the case of suspensions, in addition to the compound or combination of the present invention, it may further contain a carrier such as a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or a mixture of several of these substances.

Compositions for rectal or vaginal administration are preferably suppositories and can be prepared by mixing the compound or combination of the present invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature but liquid at body temperature and melt in the rectum or vagina to release the active compound.

The compounds or pharmaceutical compositions of the present invention may be administered in other topical dosage forms, including creams, powders, sprays and inhalants. The drug may be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent or carrier and any desired preservative, buffer or propellant. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be included within the scope of the present invention.

Another aspect of the present invention provides the use of the compound represented by general formula (I) and its tautomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or the above-mentioned pharmaceutical compositions in the preparation of drugs for preventing and/or treating diseases or symptoms associated with abnormal activity of CDK.

The diseases associated with abnormal CDK activity include solid tumors such as breast cancer, colon cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer, and blood tumors such as acute lymphocytic leukemia, acute lymphocytic leukemia, cellular lymphoma, cellular lymphoma, myeloma, acute and chronic myeloid leukemia, and promyelocytic leukemia.

Another aspect of the present invention also provides the use of the compound represented by general formula (I) and its tautomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating diseases such as tumors, central nervous system diseases and immune diseases.

In a preferred embodiment, the disease includes, but is not limited to: cancer, diseases or functional disorders related to angiogenesis, pain (including but not limited to complex regional pain syndrome), macular degeneration and related functional disorders, skin diseases, lung functional disorders, immunodeficiency diseases, damage and functional disorders of the central nervous system, and TNFα-related diseases or functional disorders.

In another preferred embodiment, the cancer includes (but is not limited to): the disease is a solid tumor, a blood tumor, preferably, the disease is selected from: myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, myelofibrosis, Burkitt's lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, ciliary body and chronic melanoma, iris melanoma, recurrent interocular melanoma, T-cell lymphoma, erythroid lymphoma, monocytic and monocytic leukemia, myeloid leukemia, Central nervous system lymphoma, meningioma, spinal cord tumor, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, astrocytoma, amyloidosis, complex regional pain syndrome type I, malignant melanoma, radiculopathy, glioblastoma, gliosarcoma, malignant glioma, refractory plasmacytoma, melanoma with extraocular extension, papillary and follicular thyroid cancer, breast cancer, prostate cancer, colorectal cancer, ovarian cancer, endometrial cancer, cervical cancer, hepatocellular carcinoma, stomach cancer, esophageal cancer, bladder cancer, small cell lung cancer, non-small cell lung cancer, Ewing sarcoma, glioblastoma, pancreatic cancer, or primary macroglobulinemia.

The compounds provided by the present invention are also effective against blood tumors and myelomas, such as being useful for treating multiple myeloma and acute and chronic leukemia. The compounds provided by the present invention can be used to prevent or treat primary tumors and metastatic tumors.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions.

The main advantages of the present invention are:

1. The compounds of the present invention have excellent cancer cell inhibitory activity, especially the inhibitory activity on triple-negative breast cancer cells, which is superior to the drugs under clinical research and can be used to treat a variety of malignant tumors.

2. The compounds of the present invention are used as CDK kinase inhibitors, preferably having good selectivity and kinase activity for inhibiting CDK9.

3. In addition to the inhibitory activity of CDK kinase, it is unexpectedly found that some of the compounds of the present invention can be used as degraders of Cyclin K, and have a good degradation effect in tumor cells.

4. The compounds of the present invention have excellent pharmacokinetic properties.

Specific implementation methods

The present invention will be further described below in conjunction with specific examples, but these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

In all embodiments, ¹ H NMR spectrum testing instruments are 400MHz Bruker and 500MHz Bruker nuclear magnetic resonance instruments, and chemical shifts are expressed in δ (ppm); mass spectra are measured by MS mass spectrometry UPLC-MS (ESI); wherein the UPLC model is Waters HPLC H-CLASS, and the MS (ESI) model is Waters SQ Detector 2; anhydrous tetrahydrofuran is prepared by benzophenone/metal sodium reflux drying and deoxygenation, and anhydrous toluene and anhydrous dichloromethane are prepared by calcium chloride reflux drying; petroleum ether, ethyl acetate, dichloromethane and other solvents used for column chromatography mobile phases are purchased from Sinopharm Chemical Reagent Co., Ltd.; The thin layer chromatography silica gel plate (HSGF254) used in the test was from Sinopharm Chemical Reagent Co., Ltd.; the 200-300 mesh silica gel from Sinopharm Chemical Reagent Co., Ltd. was used for compound separation. The raw materials in the present invention can be obtained from commercial sources, such as the main reagents purchased from Sinopharm Chemical Reagent Co., Ltd., or prepared by methods inhibited in the art, or prepared according to the method described in the present invention.

EtOH: ethanol; DCM: dichloromethane; ACN: acetonitrile; TFA: trifluoroacetic acid; TEA: triethylamine; 1,4-dioxane: 1,4-dioxane; NaH: sodium hydride; H ₂ O: water; HATU: 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DMF: N,N-dimethylformamide; THF: tetrahydrofuran; DIPEA: N,N-diisopropylethylamine; AcOH: acetic acid; Raney Ni: Raney nickel; TBSCl: tert-butyldimethylchlorosilane; imidazole: imidazole; NMP: N-methylpyrrolidone; EA: ethyl acetate; DMAP: 4-dimethylaminopyridine; (Boc) ₂ O: di-tert-butyl dicarbonate; NaCl: sodium chloride; Na ₂ SO ₄ : sodium sulfate; POCl ₃ : phosphorus oxychloride; PhNMe ₂ : N,N-dimethylaniline; DMSO: dimethyl sulfoxide; N ₂ : nitrogen; toluene: toluene; Pd ₂ (dba) ₃ : tris(dibenzylideneacetone)dipalladium; rac-BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; Cs ₂ CO ₃ : cesium carbonate; NaOH: sodium hydroxide.

1. Preparation Example

[Control compound] N-Benzyl-8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazine-4-amine

Referring to the synthetic route of compound 1.6, compound 1.2 was replaced with benzylamine to prepare the control compound.

Example 1

[C1] N-(4-aminobenzyl)-8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazine-4-amine

Dissolve p-cyanoaniline (10 g, 84.65 mmol, 1.0 equiv) and 4-dimethylaminopyridine (2.07 g, 16.93 mmol, 0.2 equiv) in dichloromethane, cool to 0°C, add di-tert-butyl dicarbonate (19.45 mL, 84.65 mmol, 1.0 equiv), and warm to room temperature for 4 hours. After the reaction is complete, dichloromethane is added to dilute the reaction solution, and saturated sodium chloride is used. The aqueous solution was washed three times, the organic layers were combined, dried over anhydrous sodium sulfate, filtered and spin-dried, and column chromatography was performed to obtain a white solid 1.1 (14.31 g), with a yield of 77%. ¹ H NMR (500 MHz, DMSO-d6) δ9.90 (s, 1H), 7.71 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 1.48 (s, 9H).

Compound 1.1 (14.31 g, 65.56 mmol, 1.0 equiv) was dissolved in ammonia methanol, two tubes of Raney nickel were added, nitrogen was replaced 3 times, hydrogen was replaced 3 times, and the reaction was completed at room temperature for 4 hours. Methanol was added to dilute the reaction solution, filtered through diatomaceous earth, and dried to obtain product 1.2 (14.28 g) with a yield of 98%. ¹ H NMR (400 MHz, DMSO-d6) δ9.21 (s, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 3.61 (t, 2H), 1.46 (s, 9H).

Compound 1.3 (200 mg, 0.78 mmol, 1.0 equiv) was dissolved in 4 mL of phosphorus oxychloride, and N, N-dimethylbenzylamine (297 μL, 2.34 mmol, 3.0 equiv) was added and reacted at 100 ° C for 2 hours. After the reaction was completed, it was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in 4 mL of acetonitrile. Compound 1.2 (209 mg, 0.94 mmol, 1.2 equiv) was dissolved in 6 mL of acetonitrile, and the acetonitrile solution of the previous step and N, N-dimethylbenzylamine (258 μL, 1.56 mmol, 2.0 equiv) were added, and the temperature was raised to 50 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature, extracted with 150 mL of ethyl acetate 3 times, washed with saturated NaCl aqueous solution 3 times, and dried over anhydrous sodium sulfate. Filter, remove ethyl acetate, and obtain compound 1.4 (280 mg) by column chromatography with a yield of 78%. ¹ H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.30(s,1H),8.28–8.24(m,1H),7.39(d,J＝8.4Hz,2H),7.31( d,J＝8.6Hz,2H),4.66(d,2H),3.27(s,3H),3.18–3.15(m,1H),1.45(s,9H),1.30(d,J＝7.0Hz,6H).

1-Methyl-4-piperidinol (248 mg, 2.15 mmol, 5.0 equiv) was dissolved in 2 mL of anhydrous N, N-dimethylformamide, and 60% (w/w) sodium hydrogen (86 mg, 2.15 mmol, 5.0 equiv) was added at 0°C, and a 2 mL anhydrous N, N-dimethylformamide solution of compound 1.4 (200 mg, 0.43 mmol, 1.0 equiv) was added, and the mixture was heated to 50°C and reacted for 3 h. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, diluted with ethyl acetate, washed with a saturated sodium chloride aqueous solution, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, dried by spin drying, and column chromatography was performed to obtain compound 1.6 (132 mg) with a yield of 62%. ¹ H NMR (500MHz, DMSO-d6) δ9.30 (s, 1H), 9.21 (t, J = 6.3Hz, 1H), 7.91 (s, 1H), 7.38 (d,J＝8.2Hz,2H),7.22(d,J＝8.3Hz,2H),4.86(dd,J＝9.3,5.1Hz,1H),4.55(d,J ＝6.3Hz,2H),2.98–2.93(m,1H),2.68–2.63(m,2H),2.20(s,3H),2.18–2.10(m, 2H), 1.98–1.93 (m, 2H), 1.70–1.63 (m, 2H), 1.45 (s, 9H), 1.25 (d, J = 6.9Hz, 6H).

Compound 1.6 (132 mg, 0.27 mmol, 1.0 equiv) was dissolved in 4 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, stirred at room temperature for 1 h, dried by rotation, and purified by HPLC to obtain compound C1 (107 mg), with a yield of 99%. ¹ H NMR (500 MHz, DMSO-d6) δ9.39 (t, J = 3.8 Hz, 1H), 7.97 (s, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 4.0 Hz, 2H), 5.07–4.96 (m, 1H), 4.65 (d, J = 6.3 Hz, 2H), 3.01–2.95 (m, 1H), 2 .85–2.80(m,2H),2.74–2.72(m,1H),2.70–2.68(m,1H),2.24–2.15(m,2H),2.02(dd,J＝12.8,4.1Hz,1H),1.80–1.74(m,1H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI) theoretical value is C ₂₁ H ₂₉ N ₇ O[M+H] ⁺ :396.24, found value is 396.33.

Example 2

[C38] (S)-2-((4-((4-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)butan-1-ol

Compound 1.4 (30 mg, 0.065 mmol, 1.0 equiv) was dissolved in 2 mL of 1-methyl-2-pyrrolidone, (S)-(+)-2-amino-1-butanol (25 μL, 0.26 mmol, 4.0 equiv) was added, and the temperature was raised to 120°C for 5 h. After the reaction, the mixture was cooled to room temperature, and 60 mL of ethyl acetate was added for extraction, and the mixture was washed with saturated sodium chloride aqueous solution, and the organic phases were combined and dried with anhydrous sodium sulfate. The mixture was filtered, dried by spin drying, and column chromatography was performed to obtain compound 2.2 (22 mg) with a yield of 71%. ¹ H NMR (500MHz, DMSO-d6) δ9.29(s,1H),7.67(s,1H),7.37(d,J＝8.2Hz,2H),7.26(d,J＝8.0Hz,2H),6.58–6.46(m,1H),4.52(d,J＝6.5Hz,2H),3.87–3. 78(m,1H),3.46(d,2H),2.89(dt,J＝13.2,6.6Hz,1H),1.93–1.86(m,1H), 1.65–1.59(m,1H),1.45(s,9H),1.22(d,J＝7.3Hz,6H),0.87–0.82(m,3H).

Compound 2.2 (22 mg, 0.047 mmol, 1.0 equiv) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 1 h, and then dried by spin drying. Compound C38 (19 mg) was obtained by HPLC purification with a yield of 99%. ¹ H NMR (400 MHz, Methanol-d4) δ7.89 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 4.85–4.78 (m, 2H), 4.16–4.07 (m, 1H), 3.63 (d, J = 5.2 Hz, 2H), 3.06–2.97 (m, 1H), 1.72 (ddd, J = 13.5, 7.5, 5.8 Hz, 1H), 1.59 (dt, J = 14.4, 7.4 Hz, 1H), 1.29 (d, J = 7.0 Hz, 6H), 0.94 (t, J = 7.4 Hz, 3H). UPLC-MS (ESI) theoretical value is C ₁₉ H ₂₇ N ₇ O [M + H] ⁺ :370.23, the actual measured value is 370.32.

Example 3

[C2]N-(4-(((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

4-(N-Boc-aminomethyl)aniline (3 g, 13.50 mmol, 1.0 equiv) was dissolved in anhydrous DMF, acetic acid (927 μL, 16.20 mmol, 1.2 equiv) and DIPEA (23.5 mL, 135.0 mmol, 10.0 equiv) were added, reacted at room temperature for 1 h, diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, combined organic phases, dried over anhydrous sodium sulfate, filtered, dried by spin drying, and column chromatography to obtain a white solid 3.1 (3.25 g) with a yield of 91%. ¹ H NMR (400MHz, DMSO-d6) δ9.90 (s, 1H), 7.49 (d, J = 8.1Hz, 2H), 7.32 (t, J = 6.3Hz ,1H),7.13(d,J＝8.2Hz,2H),4.04(d,J＝6.2Hz,2H),2.02(s,3H),1.38(s,9H).

Compound 3.1 (3.25 g, 12.29 mmol, 1.0 equiv) was dissolved in 20 mL of dichloromethane, 10 mL of trifluoroacetic acid was added, stirred at room temperature for 1 h, dried by rotation, and purified by HPLC to obtain compound 3.2 (1.92 g), with a yield of 95%. ¹ H NMR (400 MHz, DMSO-d6) δ10.05 (s, 1H), 8.13 (s, 3H), 7.60 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 3.96 (q, J = 5.8 Hz, 2H), 2.04 (s, 3H).

Using compound 3.2 as raw material and referring to the synthesis of compound 1.6, compound C2 was prepared with a yield of 62%. ¹ H NMR (500 MHz, Methanol-d4) δ7.84 (s, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 5.21–5.14 (m, 1H), 4.72 (s, 2H), 3.18–3.12 (m, 2H), 3.08–3.03 (m, 1H), 3.01–2.88 (m, 2H), 2.67 (s, 3H), 2.15–2.11 (m, 1H), 2.11 (s, 3H), 2.10–2.07 (m, 1H), 2.02 (dd, J = 9.3, 3.8 Hz, 2H), 1.29 (d, J = 6.9 Hz, 6H). UPLC-MS (ESI) theoretical value is C ₂₃ H ₃₁ N ₇ O ₂ [M+H] ⁺ :438.25, found 438.34.

[C41]N-(4-(((8-isopropyl-2-(piperidin-4-ylamino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Using compound 3.3 as the raw material and referring to the synthetic route of compound C38, C41 was prepared with a yield of 37% by replacing (S)-(+)-2-amino-1-butanol with 1-tert-butyloxycarbonyl-4-aminopiperidine. ¹ H NMR (500 MHz, Methanol-d4) δ7.87 (s, 1H), 7.52 (d, J＝8.5 Hz, 2H), 7.36 (d, J＝8.6 Hz, 2H), 4.76 (s, 2H), 4.18 (t, J＝4.4 Hz, 1H), 3.43 (dt, J＝13.3, 3.7 Hz, 2H), 3.19–3.10 (m, 2H), 3.09–3.01 (m, 1H), 2.11 (s, 5H), 1.82–1.71 (m, 2H), 1.28 (d, J＝6.9 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₂ H ₃₀ N ₈ O[M+H] ⁺ : 423.25, found value 423.40.

[C42]N-(4-(((8-isopropyl-2-(piperidin-3-ylamino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Using compound 3.3 as the raw material and referring to the synthetic route of compound C38, (S)-(+)-2-amino-1-butanol was replaced with 1-tert-butyloxycarbonyl-3-aminopiperidine to prepare C42 with a yield of 35%. ¹ H NMR (500 MHz, Methanol-d4) δ7.89 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 4.79 (s, 2H), 4.30–4.25 (m, 1H), 3.41–3.33 (m, 1H), 3.30–3.26 (m, 1H), 3.11–3.05 (m, 1H), 3.03–2.93 (m, 2H), 2.11 (s, 3H), 2.10–2.01 (m, 2H), 1.83 (dtd, J = 14.1, 7.1, 3.5 Hz, 1H), 1.77–1.70 (m, 1H), 1.28 (d, J = 7.0 Hz, 6H). UPLC-MS (ESI) theoretical value is C ₂₂ H ₃₀ N ₈ O[M+H] ⁺ :423.25, found 423.40.

[C43] (R)-N-(4-(((2-(2-(Hydroxymethyl)pyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Using compound 3.3 as the raw material, referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with D-prolinol to prepare C43 with a yield of 25%. ¹ H NMR (500 MHz, Methanol-d4) δ7.88 (s, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 4.76 (s, 2H), 4.27–4.18 (m, 1H), 4.11–4.01 (m, 1H), 3.94–3.86 (m, 1H), 3.72 (dt, J = 11.8, 3.8 Hz, 2H), 3.02–2.88 (m, 1H), 2.30–2.23 (m, 1H), 2.11 (s, 3H), 2.00 (dq, J = 13.7, 7.0 Hz, 2H), 1.90–1.79 (m, 1H), 1.29 (d, J = 6.8 Hz, 6H). UPLC-MS (ESI) theoretical value was C ₂₂ H ₂₉ N ₇ O ₂ [M+H] ⁺ :424.24, found 424.36.

[C44](S)-N-(4-(((2-(2-(Hydroxymethyl)pyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Using compound 3.3 as the raw material, referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with L-prolinol to prepare C44 with a yield of 29%. ¹ H NMR (500MHz, Methanol-d4) δ7.88 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 4.77 (s, 2H), 4.26–4.18 (m, 1H), 4.07 (dt, J = 13.2, 7.0 Hz, 1H), 3.91 (d, J = 11.3 Hz, 1H), 3.72 (dt, J＝12.3, 6.5 Hz, 2H), 2.95 (q, J＝6.9 Hz, 1H), 2.28 (dd, J＝13.3, 7.3 Hz, 1H), 2.11 (s, 3H), 2.00 (dq, J＝13.5, 7.3, 6.7 Hz, 2H), 1.90–1.80 (m, 1H), 1.29 (d, J＝6.6 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₂ H ₂₉ N ₇ O ₂ [M+H] ⁺ : 424.24, found value is 424.39.

[C45] (R)-N-(4-(((2-(3-Hydroxypiperidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Using compound 3.3 as the raw material, referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced by (R)-3-piperidinol to prepare C45 with a yield of 36%. ¹ H NMR (500MHz, Methanol-d4) δ7.88 (s, 1H), 7.53 (d, J = 8.5Hz, 2H), 7.38 (d, J = 8.6Hz, 2H), 4.74 (d, J = 3.6Hz, 2H), 4.21–4.08 (m, 1H), 3.97–3.91 (m, 1H), 3.83 (td, J = 7.4, 6.7, 3.0Hz, 1H), 3.71 (dd , J＝15.9,7.0Hz,1H),3.59(dd,J＝13.3,7.1Hz,1H),3.19–3.14(m,1H),2.11(s,3H),2.02–1.98(m,1H),1.96–1.90(m,1H),1.70–1.59(m,2H),1.28(dd,J＝6.9,3.5Hz,6H).UPLC-MS(ESI) theoretical value for C ₂₂ H ₂₉ N ₇ O ₂ [M+H] ⁺ :424.24, found value is 424.46.

[C46] (S)-N-(4-(((2-(3-Hydroxypiperidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Using compound 3.3 as the raw material, referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with (S)-3-piperidinol to prepare C46 with a yield of 38%. ¹ H NMR (500MHz, Methanol-d4) δ7.89 (s, 1H), 7.55 (d, J = 8.5Hz, 2H), 7.40 (d, J = 8.6Hz, 2H), 4.76 (d, J = 3.4Hz, 2H), 4.20 (dd, J = 11.9, 5.2Hz, 1H), 4.01–3.96 (m, 1H), 3.83 (dt, J = 7.4, 3.8Hz, 1H), 3.69 (dd, J = 15. 5,7.5 Hz, 1H), 3.58 (dd, J＝13.2,7.3 Hz, 1H), 3.18 (p, J＝6.8 Hz, 1H), 2.13 (s, 3H), 2.05–1.99 (m, 1H), 1.94 (ddd, J＝13.5,7.0,3.7 Hz, 1H), 1.71–1.61 (m, 2H), 1.30 (dd, J＝6.9,3.3 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₂ H ₂₉ N ₇ O ₂ [M+H] ⁺ : 424.24, found value is 424.39.

[C47] (S)-N-(4-(((2-((1-Hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)aminomethyl)phenyl)acetamide

Using compound 3.3 as raw material and referring to the synthetic route of compound 2.2, C47 was prepared with a yield of 66%. ¹ H NMR (500 MHz, Methanol-d4) δ7.88 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 4.76 (d, J = 16.7 Hz, 2H), 4.16–4.09 (m, 1H), 3.65 (d, J = 4.9 Hz, 2H), 3.03–2.95 (m, 1H), 2.11 (s, 3H), 1.75–1.69 (m, 1H), 1.60 (dd, J = 14.3, 7.3 Hz, 1H), 1.29 (d, J = 6.9 Hz, 6H), 0.95 (d, J = 7.5 Hz, 3H). UPLC-MS (ESI) theoretical value is C ₂₁ H ₂₉ N ₇ O ₂ [M+H] ⁺ :412.24, the actual measured value is 412.89.

[C48] (R)-N-(4-(((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)aminomethyl)phenyl)acetamide

Using compound 3.3 as the raw material and referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with (R)-(-)-2-amino-1-butanol to prepare C48 with a yield of 64%. ¹ H NMR (500 MHz, Methanol-d4) δ7.88 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 4.76 (d, J = 16.9 Hz, 2H), 4.16–4.11 (m, 1H), 3.68–3.64 (m, 2H), 3.01–2.96 (m, 1H), 2.11 (s, 3H), 1.75–1.69 (m, 1H), 1.63–1.59 (m, 1H), 1.30 (d, J = 6.9 Hz, 6H), 0.96 (t, J = 6.8 Hz, 3H). UPLC-MS (ESI) theoretical value is C ₂₁ H ₂₉ N ₇ O ₂ [M+H] ⁺ :412.24, the measured value is 412.44.

[C49](S)-N-(4-(((8-isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Using compound 3.3 as the raw material and referring to the synthetic route of compound 1.6, C49 was prepared by replacing 1-methyl-4-piperidinol with (R)-3-hydroxypiperidine.

[C50] (R)-N-(4-(((8-isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Using compound 3.3 as the raw material and referring to the synthetic route of compound 1.6, C50 was prepared by replacing 1-methyl-4-piperidinol with (S)-3-hydroxypiperidine.

[C51] N-(4-(((8-isopropyl-2-(oxetan-3-ylamino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Using compound 3.3 as the raw material, referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with 3-oxetanamine to prepare C51 with a yield of 29%. ¹ H NMR (500MHz,

Methanol-d4)δ7.86(s,1H),7.54(d,J＝8.6Hz,2H),7.36(d,J＝8.6Hz,2H),5.12–5.07(m,1H),4.91–4.90(m,1H),4.75(d,J＝4.2Hz,2H),4.67–4.63(m,2H),3.81–3.65(m,1H),3.04(p,J＝6.9Hz,1H),2.11(s,3H),1.29(d,J＝6.9Hz,6H).UPLC-MS(ESI) theoretical value for C ₂₀ H ₂₅ N ₇ O ₂ [M+H] ⁺ :396.21, found value is 396.74.

[C52] N-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Using compound 3.3 as the raw material and referring to the synthetic route of compound 2.2, C52 was prepared with a yield of 64% by replacing (S)-(+)-2-amino-1-butanol with 4-aminotetrahydropyran. ¹ H NMR (500 MHz, Methanol-d4) δ7.89 (s, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 4.75 (s, 2H), 4.15–4.09 (m, 1H), 3.96 (d, J = 11.1 Hz, 2H), 3.51 (t, J = 11.4 Hz, 2H), 3.06–2.95 (m, 1H), 2.11 (s, 3H), 1.89–1.82 (m, 2H), 1.64–1.57 (m, 2H), 1.29 (d, J = 6.9 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₂ H ₂₉ N ₇ O ₂ [M+H] ⁺ : 424.24, found value 424.81.

[C53] N-(4-(((2-((1,3-dihydroxypropan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)aminomethoxy 4-( ...2-amino-1-nitrophenyl)acetamide

Using compound 3.3 as raw material and referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with 2-amino-1,3-propanediol to prepare C53 with a yield of 54%. ¹ H NMR (500 MHz, Methanol-d4) δ7.87 (s, 1H), 7.53 (d, J＝8.5 Hz, 2H), 7.39 (d, J＝8.2 Hz, 2H), 4.77 (s, 2H), 4.31–4.21 (m, 1H), 3.78–3.73 (m, 4H), 3.01–2.95 (m, 1H), 2.11 (s, 3H), 1.29 (d, J＝6.9 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₀ H ₂₇ N ₇ O ₃ [M+H] ⁺ : 414.22, found value 414.78.

[C54] N-(4-(((8-isopropyl-2-((1-methylpiperidin-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Using compound 3.3 as the raw material and referring to the synthetic route of compound 2.2, C54 was prepared with a yield of 53% by replacing (S)-(+)-2-amino-1-butanol with 4-amino-1-methylpiperidine. ¹ H NMR (500 MHz, Methanol-d4) δ7.89 (s, 1H), 7.52 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 4.77 (s, 2H), 4.17–4.08 (m, 1H), 3.58–3.53 (m, 2H), 3.16–3.10 (m, 2H), 3.06 (q, J = 7.0 Hz, 1H), 2.91 (s, 3H), 2.12 (s, 3H), 2.08–1.96 (m, 1H), 1.81–1.70 (m, 2H), 1.28 (d, J = 6.9 Hz, 6H). UPLC-MS (ESI) theoretical value is C ₂₃ H ₃₂ N ₈ O [M + H] ⁺ :437.27, the measured value is 437.41.

[C128] (R)-N-(4-(((2-(3-Hydroxypyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Using compound 3.3 as the raw material, referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with (R)-3-pyrrolidinol to prepare C128 with a yield of 62%. ¹ H NMR (400 MHz, DMSO-d6) δ9.91 (s, 1H), 9.38 (s, 1H), 7.87 (s, 1H), 7.57–7.46 (m, 2H), 7.33 (d, J=8.4 Hz, 2H), 4.56 (d, J=6.2 Hz, 2H), 4.38 (s, 1H), 3.65–3.40 (m, 4H), 3.06 (q, J=6.8 Hz, 1H), 2.01 (s, 3H), 1.94 (d, J=37.6 Hz, 2H), 1.21 (dd, J=6.9, 1.9 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₁ H ₂₇ N ₇ O ₂ [M+H] ⁺ : 410.49, found value 410.47.

[C129] (S)-N-(4-(((2-(3-Hydroxypyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Using compound 3.3 as the raw material and referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with (S)-3-pyrrolidinol to prepare C129 with a yield of 56%. ¹ H NMR (600 MHz, DMSO-d6) δ9.93 (s, 1H), 9.53 (s, 1H), 7.91 (s, 1H), 7.51 (d, J＝8.2 Hz, 2H), 7.33 (d, J＝8.1 Hz, 2H), 4.57 (d, J＝6.2 Hz, 2H), 4.39 (d, J＝21.8 Hz, 1H), 3.79–3.40 (m, 4H), 3.11 (dd, J＝13.7, 7.0 Hz, 1H), 2.01 (s, 3H), 1.90 (s, 2H), 1.21 (dd, J＝7.0, 3.2 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₁ H ₂₇ N ₇ O ₂ [M+H] ⁺ : 410.49, found value 410.47.

[C130] (S)-N-(4-(((2-(2-(2-hydroxyethyl)piperidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Using compound 3.3 as the raw material, referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with (S)-2-(2-piperidinyl)ethanol to prepare C130 with a yield of 47%. ¹ H NMR (500MHz, DMSO-d6) δ9.91 (s, 1H), 9.22 (s, 1H), 7.82 (s, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 4.93 (s, 1H), 4.55 (d, J = 6.3 Hz, 3H), 3.38 (dq, J = 15.1, 7.6, 6. 4 Hz, 2H), 2.94 (dd, J＝16.4, 10.0 Hz, 2H), 2.01 (s, 3H), 1.93 (s, 1H), 1.62 (dt, J＝41.9, 11.9 Hz, 6H), 1.33 (dd, J＝15.5, 9.6 Hz, 1H), 1.21 (d, J＝6.8 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₄ H ₃₃ N ₇ O ₂ [M+H] ⁺ :452.58, found value is 452.52.

Example 4

[C3] 7-Hydroxy-N-(4-(((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)heptylamide

Referring to the synthetic route of compound 3.3, acetic acid was replaced with 7-hydroxyheptanoic acid to prepare compound 4.3 with a yield of 65%.

Compound C3 was prepared with compound 4.3 and compound 1.5 as raw materials and referring to the synthetic route of compound 1.6, with a yield of 38%. ¹ H NMR (500MHz, Methanol-d4) δ7.85 (s, 1H), 7.52 (d, J = 8.5Hz, 2H), 7.34 (d, J = 8.6Hz, 2H), 4.73 (s, 2H), 3.54 (d, J = 6.6Hz, 2H), 3.30-3.25 (m, 2H), 3.19-3.09 (m, 2H), 3.05 (q, J = 7 .0Hz,1H),2.80(s,3H),2.36(t,J＝7.5Hz,2H),2.12(m,J＝11.3Hz,5H),1.70(t,J＝7.4Hz,2H),1.57–1.53(m,2H),1.42–1.39(m,4H),1.30(d,J＝7.0Hz,6H).UPLC-MS(ESI) theoretical value for C ₂₈ H ₄₁ N ₇ O ₃ [M+H] ⁺ :524.33, found value is 524.85.

[C4](S)-7-Hydroxy-N-(4-(((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)heptylamide

Using compound 4.3 as raw material, C4 was prepared according to the synthetic route of compound 2.2.

[C5](R)-7-Hydroxy-N-(4-(((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)heptylamide

Using compound 4.3 as the raw material, referring to the synthetic route of compound 2.2, C5 was prepared by replacing (S)-(+)-2-amino-1-butanol with (R)-(-)-2-amino-1-butanol.

[C6](R)-7-Hydroxy-N-(4-(((8-isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)heptylamide

Using compound 4.3 as the raw material and referring to the synthetic route of compound 1.6, C6 was prepared by replacing 1-methyl-4-piperidinol with (S)-3-hydroxypiperidine.

[C7](S)-7-Hydroxy-N-(4-(((8-isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)heptylamide

Using compound 4.3 as the raw material and referring to the synthetic route of compound 1.6, C7 was prepared by replacing 1-methyl-4-piperidinol with (R)-3-hydroxypiperidine.

Example 5

[C8] (S)-2-((4-(4-(ethylamino)benzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)butan-1-ol

N-ethyl-4-cyanoaniline (500 mg, 3.42 mmol, 1.0 equiv) was dissolved in dichloromethane (10 mL), cooled to 0°C, and di-tert-butyl dicarbonate (786 uL, 3.42 mmol, 1.0 equiv) was added. The mixture was reacted at room temperature for 5 h and the reaction was monitored to be complete. The solvent was dried and column chromatography was performed to obtain compound 5.1 (158 mg) with a yield of 19%. ¹ H NMR (500 MHz, DMSO-d6) δ7.29 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 3.69 (t, 2H), 3.56 (q, J = 7.0 Hz, 2H), 1.36 (s, 9H), 1.02 (t, J = 7.0 Hz, 3H).

Compound 5.1 was used as the raw material and the synthetic route of compound 1.2 was referred to to obtain compound 5.2 with a yield of 87%. ¹ H NMR (500 MHz, DMSO-d6) δ7.29 (d, J=8.3 Hz, 2H), 7.12 (d, J=8.3 Hz, 2H), 3.69 (t, 2H), 3.56 (q, J=7.0 Hz, 2H), 1.36 (s, 9H), 1.02 (t, J=7.0 Hz, 3H).

Compound 5.3 was obtained with the compound 1.3 and compound 5.2 as raw materials and with reference to the synthetic route of compound 1.4, with a yield of 22%. ¹ H NMR (400 MHz, DMSO-d6) δ10.01 (t, J = 5.1 Hz, 1H), 8.28 (s, 1H), 7.39 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 4.75 (d, J = 6.2 Hz, 2H), 3.56 (q, J = 7.2 Hz, 2H), 3.25 (s, 3H), 3.16–3.11 (m, 1H), 1.35 (s, 9H), 1.31 (d, J = 7.4 Hz, 6H), 1.01 (t, J = 6.7 Hz, 3H).

Compound C8 was prepared using compound 5.3 and compound 2.1 as raw materials and referring to the synthetic route of compound C38. Yield: 89%. ¹ H NMR (500 MHz, Methanol-d4) δ7.67 (s, 1H), 7.19 (d, J = 8.5 Hz, 2H), 6.64 (d, J = 8.3 Hz, 2H), 4.60 (d, J = 10.7 Hz, 2H), 4.09–3.90 (m, 1H), 3.65 (d, J = 5.4 Hz, 2H), 3.10 (q, J = 7.1 Hz, 2H), 2.99 (p, J = 6.9 Hz, 1H), 1.75–1.68 (m, 1H), 1.58 (dt, J = 14.5, 7.4 Hz, 1H), 1.27 (d, J = 6.9 Hz, 6H), 1.21 (t, J = 7.1 Hz, 3H), 0.99 (t, J = 7.3 Hz, 3H). UPLC-MS (ESI) theoretical value was C ₂₁ H ₃₁ N ₇ O[M+H] ⁺ :398.26, found:398.38.

Example 6

[C9](S)-2-Hydroxy-N-(4-(((2-((1-hydroxybutyl-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Compound p-aminobenzonitrile (1 g, 8.46 mmol, 1.0 equiv) and glycolic acid (634 mg, 8.46 mmol, 1.0 equiv) were mixed, heated to 130°C, heated and stirred for 4 h, then the mixture was cooled to room temperature, allowed to stand for 1 h, ether was added, solids were precipitated, filtered, and column chromatography was performed to obtain compound 6.1 (542 mg), with a yield of 36.4%. ¹ H NMR (400 MHz, DMSO-d6) δ10.13 (s, 1H), 7.92 (d, J = 7.1 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 5.72 (t, J = 5.3 Hz, 1H), 4.03 (d, J = 5.0 Hz, 2H).

Compound 6.1 (542 mg, 3.08 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL), cooled to 0°C, tert-butyldimethylsilyl chloride (558 mg, 3.70 mmol, 1.2 equiv) and imidazole (315 mg, 4.62 mmol, 1.5 equiv) were added, stirred at room temperature for 12 h, monitored for completion of the reaction, extracted three times with 150 mL of dichloromethane, washed three times with water, combined the organic phases, dried with anhydrous sodium sulfate, filtered and spin-dried, and column chromatography was performed to obtain compound 6.2 (411 mg) in a yield of 46%. ¹ H NMR (400 MHz, DMSO-d6) δ9.98 (s, 1H), 7.79 (q, J = 8.4 Hz, 4H), 4.26 (d, J = 2.2 Hz, 2H), 0.90 (s, 9H), 0.11 (s, 6H).

Compound 6.2 (411 mg, 1.0 mmol, 1.0 equiv) was dissolved in ammonia methanol (10 mL), two tubes of Raney nickel were added, nitrogen was replaced 3 times, and hydrogen was replaced 3 times, and the reaction was stirred at room temperature for 4 hours. After monitoring the completion of the reaction, the mixture was filtered through diatomaceous earth, and the filtered liquid was dried by spin drying to obtain compound 6.3 (152 mg), with a yield of 52%. ¹ H NMR (400 MHz, DMSO-d6) δ9.36 (s, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 4.19 (s, 2H), 3.66 (s, 2H), 0.91 (s, 9H), 0.12 (s, 6H).

Compound 6.4 was prepared with compound 1.3 and compound 6.3 as raw materials and with reference to the synthetic route of compound 1.4, with a yield of 26%. 1H NMR (400MHz, DMSO-d6) δ9.97 (s, 1H), 9.45 (s, 1H), 8.27 (s, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 4.70 (d, J = 5.8 Hz, 2H), 4.18 (s, 2H), 3.32 (d, J = 2.8 Hz, 3H), 3.14 (p, J = 6.9 Hz, 1H), 1.31 (d, J = 6.5 Hz, 6H), 0.90 (s, 9H), 0.10 (s, 6H).

Compound C9 was prepared with compound 6.4 and compound 2.1 as raw materials and referring to the synthetic route of compound C38, with a yield of 49%. ¹ H NMR (500 MHz, Methanol-d4) δ7.88 (s, 1H), 7.61 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 4.77 (d, J = 16.7 Hz, 2H), 4.14 (m, 1H), 4.10 (s, 2H), 3.65 (d, J = 4.8 Hz, 2H), 3.04–2.92 (m, 1H), 1.73 (ddd, J = 13.8, 7.6, 6.1 Hz, 1H), 1.61 (dt, J = 14.4, 7.4 Hz, 1H), 1.30 (d, J = 6.9 Hz, 6H), 1.00–0.89 (t, 3H). UPLC-MS (ESI) theoretical value is C ₂₁ H ₂₉ N ₇ O ₃ [M+H] ⁺ :428.23, the measured value is 428.38.

Example 7

[C10] (S)-2-((4-(4-(((2-hydroxyethyl)amino)benzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)butan-1-ol

Pour p-aminobenzonitrile (2 g, 16.93 mmol, 1.0 equiv) and 2-iodoethanol (2.91 g, 16.93 mmol, 1.0 equiv) into a round-bottom flask, replace with N ₂ for 3 times, and under N ₂ protection, heat to 90 ° C. and stir to react for 6 h. The reaction solution is extracted with 100 mL of ethyl acetate, and 2 M sodium hydroxide solution is added, followed by washing with saturated sodium chloride solution. The organic phases are combined, dried over anhydrous sodium sulfate, filtered and spin-dried, and column chromatography is performed to obtain compound 7.1 (1.038 g) with a yield of 38%.

Compound 7.1 (300 mg, 1.23 mmol, 1.0 equiv) was dissolved in 4 mL of dichloromethane, and tert-butyldimethylsilyl chloride (185 mg, 1.23 mmol, 1.0 equiv), triethylamine (359 μL, 2.58 mmol, 2.1 equiv) and 4-dimethylaminopyridine (15 mg, 0.123 mmol, 0.1 equiv) were added. The reaction was stirred at room temperature for 12 h. The reaction was monitored to be complete, diluted with water, extracted 3 times with 450 mL of dichloromethane, washed 3 times with saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and spin-dried, and column chromatography gave compound 7.2 (208 mg) with a yield of 61%. 1H NMR (400MHz, DMSO-d6) δ7.42(d,J＝8.3Hz,2H),6.66(d,J＝8.5Hz,3H),3.70(t,J＝5.2Hz,2H),3.22(q,J＝6.3Hz,2H),0.84(s,9H),0.01(s,6H).

Compound 7.3 was prepared with compound 7.2 as the starting material and referring to the synthetic route of compound 1.1, with a yield of 80%. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.58 (d, J=6.3 Hz, 2H), 7.48 (d, J=7.0 Hz, 2H), 3.78 (dt, J=13.0, 3.8 Hz, 4H), 1.47 (s, 9H), 0.85 (s, 9H), 0.02 (s, 6H).

Compound 7.4 was prepared with compound 7.3 as the starting material and referring to the synthetic route of compound 1.2, with a yield of 99%. ¹ H NMR (400 MHz, CDCl ₃ ) δ7.58 (d, J=6.3 Hz, 2H), 7.48 (d, J=7.0 Hz, 2H), 4.72 (q, J=6.3 Hz, 2H), 3.78 (dt, J=13.0, 3.8 Hz, 4H), 1.47 (s, 9H), 0.85 (s, 9H), 0.02 (s, 6H).

Compound 7.4 and compound 1.3 were used as raw materials, and the synthetic route of compound 1.4 was referred to to prepare compound 7.5 with a yield of 26%. ¹ H NMR (500 MHz, DMSO-d6) δ8.28 (s, 1H), 7.39 (d, J＝8.5 Hz, 2H), 7.22 (d,J＝8.4Hz,2H),5.76(t,1H),4.72(d,J＝6.3Hz,2H),3.64–3.61(m,4H),3.31(s,3H ),3.16–3.11(m,1H),1.35(s,9H),1.30(d,J=6.9Hz,6H),0.74(s,9H),0.07(s,6H).

Compound C10 was prepared with compound 7.5 and compound 2.1 as raw materials and referring to the synthetic route of compound C38, with a yield of 38%. ¹ H NMR (500 MHz, Methanol-d4) δ7.67 (s, 1H), 7.18 (d, J = 8.1 Hz, 2H), 6.64 (d, J = 8.6 Hz, 2H), 4.60 (d, J = 10.3 Hz, 2H), 4.15–3.94 (m, 1H), 3.70 (t, J = 5.8 Hz, 2H), 3.65 (d, J = 5.1 Hz, 2H), 3.21 (t, J = 5.7 Hz, 2H), 2.99 (p, J = 7.0 Hz, 1H), 1.75–1.69 (m, 1H), 1.58 (dt, J = 14.1, 7.3 Hz, 1H), 1.27 (d, J = 6.8 Hz, 6H), 0.99 (t, J = 7.4 Hz, 3H). UPLC-MS (ESI) theoretical value was C ₂₁ H ₃₁ N ₇ O ₂ [M+H] ⁺ :414.25, found 414.36.

Example 8

[C11] N-(4-(((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)tetrahydro-2H-pyran-4-carboxamide

Compound 8.1 was obtained with 4-(N-Boc-aminomethyl)aniline and tetrahydropyran-4-carboxylic acid as raw materials and with reference to the synthetic route of compound 3.1, with a yield of 95%. ¹ H NMR (400 MHz, DMSO-d6) δ9.84 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.33 (t, J = 6.1 Hz, 1H), 7.14 (d, J = 8.3 Hz, 2H), 4.04 (d, J = 6.2 Hz, 2H), 3.93–3.86 (m, 2H), 3.36 (d, J = 4.0 Hz, 1H), 3.31 (d, J = 5.5 Hz, 1H), 2.60–2.53 (m, 1H), 1.69–1.63 (m, 4H), 1.38 (s, 9H).

Compound 8.1 was used as the raw material and the synthetic route of compound 3.2 was referred to to obtain compound 8.2 in a yield of 99%. ¹ H NMR (400 MHz, DMSO-d6) δ9.99 (s, 1H), 8.06 (t, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 3.96 (d, J = 5.8 Hz, 2H), 3.90 (d, J = 11.6 Hz, 2H), 3.35 (td, J = 11.2, 3.5 Hz, 2H), 2.58 (dt, J = 10.2, 5.3 Hz, 1H), 1.72–1.62 (m, 4H).

Compound 8.2 and compound 1.3 were used as raw materials and the synthetic route of compound 1.4 was referred to to obtain compound 8.3 with a yield of 56%. ¹ H NMR (500 MHz, DMSO-d6) δ9.96 (t, 1H), 9.88 (s, 1H), 8.27 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 4.68 (d, 2H), 3.89 (dt, J = 11.5, 2.6 Hz, 2H), 3.35 (s, 3H), 3.32–3.26 (m, 2H), 3.17–3.11 (m, 1H), 2.57 (dd, J = 10.6, 4.8 Hz, 1H), 1.68–1.62 (m, 4H), 1.30 (d, J = 6.9 Hz, 6H).

Compound 8.3 and compound 1.5 were used as raw materials, and the synthetic route of compound 1.6 was referred to to obtain compound C11 with a yield of 45%. ¹ H NMR (500MHz, Methanol-d4) δ7.86 (s, 1H), 7.53 (d, J = 6.9 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 4.73 (d, J = 4.8 Hz, 2H), 4.02–3.98 (m, 2H), 3.59 (d, J = 13.0 Hz, 1H), 3.51–3.40 (m, 4H), 3.36–3.33 (m, 1H), 3.23–3.13 (m, 1H), 3.05 (dt, J = 13.8,6.9 Hz,1H),2.91(s,3H),2.61(ddt,J＝11.6,8.0,4.1 Hz,1H),2.33(dd,J＝29.7,14.6 Hz,2H),2.09(d,J＝14.2 Hz,1H),1.91–1.85(m,1H),1.85–1.78(m,2H),1.76–1.72(m,2H),1.31(d,J＝6.9 Hz,6H). UPLC-MS (ESI) theoretical value for C ₂₇ H ₃₇ N ₇ O ₃ [M+H] ⁺ :508.30, found value is 508.92.

[C12] N-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)tetrahydro-2H-pyran-4-carboxamide

Compound 8.3 was used as the raw material, and referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with 4-aminotetrahydropyran to prepare compound C12 with a yield of 27%. ¹ H NMR (500MHz, DMSO-d6) δ9.85 (s, 1H), 8.60 (t, 1H), 7.69 (s, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 22.1 Hz, 1H), 4.53 (s, 2H), 3.91–3.88 (m, 2H), 3.85–3.82 (m, 2H), 3.36 (d, J = 10.0 Hz, 2H), 3. 32 (d, J = 7.5 Hz, 2H), 2.93–2.85 (m, 1H), 2.56 (dt, J = 10.5, 5.3 Hz, 1H), 2.53 (d, J = 5.3 Hz, 1H), 1.89–1.80 (m, 1H), 1.71–1.64 (m, 4H), 1.63–1.58 (m, 1H), 1.51–1.40 (m, 2H), 1.22 (d, J = 8.4 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₆ H ₃₅ N ₇ O ₃ [M+H] ⁺ : 494.28, found value 494.89.

[C13] N-(4-(((2-((1,3-dihydroxypropan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)tetrahydro-2H-pyran-4-carboxamide

Using compound 8.3 as raw material and referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with 2-amino-1,3-propanediol to prepare compound C13 with a yield of 17%. ¹ H NMR (500 MHz, Methanol-d4) δ7.89 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 4.78 (s, 2H), 4.31–4.23 (m, 1H), 4.02–3.98 (m, 2H), 3.79–3.71 (m, 4H), 3.48 (td, J = 11.8, 2.3 Hz, 2H), 3.03–2.93 (m, 1H), 2.62 (td, J = 7.5, 3.8 Hz, 1H), 1.88–1.79 (m, 2H), 1.76–1.72 (m, 2H), 1.30 (d, J = 7.0 Hz, 6H). UPLC-MS (ESI) theoretical value is C ₂₄ H ₃₃ N ₇ O ₄ [M+H] ⁺ :484.26, found 484.41.

[C14] (S)-N-(4-(((2-((1-hydroxybutyl-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)tetrahydro-2H-pyran-4-carboxamide

Compound C14 was prepared with compound 8.3 as the raw material and referring to the synthetic route of compound 2.2 with a yield of 38%. ¹ H NMR (500MHz, Methanol-d4) δ7.88 (s, 1H), 7.56 (d, J = 8.5Hz, 2H), 7.38 (d, J = 8.6Hz, 2H), 4.77 (d, J = 18.0Hz, 2H), 4.14 (t, J = 6.9Hz, 1H), 4.00 (ddd, J = 11.5, 4.5, 2.0Hz, 2H), 3.66 (d, J = 4.9Hz, 2H), 3.50–3.45 (m, 2H), 3.04–2.96 (m, 1H), 2.62 (tt, J＝11.5, 4.0 Hz, 1H), 1.87–1.80 (m, 2H), 1.77–1.73 (m, 2H), 1.73–1.68 (m, 1H), 1.61 (dt, J＝14.4, 7.5 Hz, 1H), 1.29 (d, J＝7.0 Hz, 6H), 0.96 (t, J＝7.4 Hz, 3H). UPLC-MS (ESI) theoretical value for C _{2 5} H ₃₅ N ₇ O ₃ [M+H] ⁺ : 482.28, found value 482.87.

[C15] (R)-N-(4-(((2-((1-hydroxybutyl-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)tetrahydro-2H-pyran-4-carboxamide

Compound 8.3 was used as the raw material, and referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with (R)-(-)-2-amino-1-butanol to prepare compound C15 with a yield of 25%. ¹ H NMR (500MHz, Methanol-d4) δ7.88 (s, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 4.76 (d, J = 17.6 Hz, 2H), 4.17–4.10 (m, 1H), 4.01–3.97 (m, 2H), 3.65 (d, J = 4.9 Hz, 2H), 3.47 (td, J = 11.8, 2.4 Hz, 2H), 3.0 4–2.95(m,1H),2.62(td,J＝7.5,3.8Hz,1H),1.88–1.81(m,2H),1.75(tt,J＝4.7,1.8Hz,2H),1.72(d,J＝ 7.6Hz, 1H), 1.61 (dt, J＝14.2, 7.4Hz, 1H), 1.29 (d, J＝6.9Hz, 6H), 0.96 (t, J＝7.5Hz, 3H). UPLC-MS (ESI) theory The value is C ₂₅ H ₃₅ N ₇ O ₃ [M+H] ⁺ :482.28, and the measured value is 482.45.

[C16] N-(4-(((8-isopropyl-2-((1-methylpiperidin-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)tetrahydro-2H-pyran-4-carboxamide

Compound 8.3 was used as the raw material, and referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with 4-amino-1-methylpiperidine to prepare compound C16 with a yield of 9%. ¹ H NMR (500MHz, Methanol-d4) δ7.89 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 4.77 (s, 2H), 4.13 (tt, J = 11.7, 4.1 Hz, 1H), 4.02–3.98 (m, 2H), 3.59–3.53 (m, 2H), 3.50–3.46 (m, 2 H), 3.17–3.11 (m, 2H), 3.09–3.03 (m, 1H), 2.91 (s, 3H), 2.62 (td, J＝7.5, 3.8 Hz, 1H), 2.19–2.11 (m, 2H), 1.88–1.82 (m, 2H), 1.79–1.72 (m, 4H), 1.28 (d, J＝6.9 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₇ H ₃₈ N ₈ O ₂ [M+H] ⁺ :507.31, found value is 507.46.

[C17] (S)-N-(4-(((2-(3-hydroxypiperidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)tetrahydro-2H-pyran-4-carboxamide

Compound 8.3 was used as the raw material, and the synthetic route of compound 2.2 was referred to. (S)-(+)-2-amino-1-butanol was replaced with (S)-3-piperidinol to prepare compound C17 with a yield of 19%. ¹ H NMR (500MHz, Methanol-d4) δ7.91 (s, 1H), 7.55 (d, J = 8.5Hz, 2H), 7.39 (d, J = 8.6Hz, 2H), 4.75 (d, J = 4.4Hz, 2H), 4.18–4.04 (m, 1H), 4.02–3.98 (m, 2H), 3.87 (ddd, J = 13.7, 7.1, 3.5Hz, 2H), 3.83–3.72 (m, 1H), 3.66 (dd, J = 13.3, 7.0 Hz, 1H), 3.48 (td, J＝11.7, 2.3 Hz, 2H), 3.21–3.16 (m, 1H), 2.61 (ddt, J＝11.5, 8.0, 4.0 Hz, 1H), 2.05–1.94 (m, 2H), 1.87–1.80 (m, 2H), 1.76–1.72 (m, 2H), 1.71–1.61 (m, 2H), 1.28 (dd, J＝6.9, 3.9 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₆ H ₃₅ N ₇ O ₃ [M+H] ⁺ : 494.28, found value 494.44.

[C18] (R)-N-(4-(((2-(3-hydroxypiperidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)tetrahydro-2H-pyran-4-carboxamide

Compound 8.3 was used as the raw material, and referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with (R)-3-piperidinol to prepare compound C18 with a yield of 68%. ¹ H NMR (500MHz, Methanol-d4) δ7.91 (s, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 4.75 (d, J = 4.3 Hz, 2H), 4.11 (dd, J = 17.7, 11.2 Hz, 1H), 4.01–3.98 (m, 2H), 3.92–3.83 (m, 2H), 3.77 (dd, J = 15.0, 11.0 Hz, 1H), 3.65 ( dd, J＝13.3,7.0 Hz, 1H), 3.50–3.45 (m, 2H), 3.21–3.15 (m, 1H), 2.62 (tt, J＝11.6,4.1 Hz, 1H), 2.03–1.93 (m, 2H), 1.87–1.79 (m, 2H), 1.76–1.72 (m, 2H), 1.70–1.59 (m, 2H), 1.28 (dd, J＝6.9,3.9 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₆ H ₃₅ N ₇ O ₃ [M+H] ⁺ :494.28, found value is 494.47.

[C19] (S)-N-(4-(((2-(2-(hydroxymethyl)pyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)tetrahydro-2H-pyran-4-carboxamide

Using compound 8.3 as the raw material, referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with L-prolinol to prepare compound C19 with a yield of 77%. ¹ H NMR(500MHz, Methanol-d4)δ7.88(s,1H),7.55(d,J＝8.6Hz,2H),7.39(d,J＝8.0Hz,2H),4.77(s,2H),4.27–4.16(m,1H),4.11–4 .03(m,1H),4.02–3.98(m,2H),3.91(d,J＝11.3Hz,1H),3.72(dt,J＝12.4,6.5Hz,2H),3.50–3.45(m,2H),3.03–2.88(m,1H),2.62 (ddd, J = 11.6, 7.5, 4.1 Hz, 1H), 2.31–2.24 (m, 1H), 1.99 (dt, J = 13.5, 7.0 Hz, 2H), 1.87–1.79 (m, 3H), 1.76–1.72 (m, 2H), 1.29 (d, J = 6.9 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₆ H ₃₅ N ₇ O ₃ [M+H] ⁺ : 494.28, found value 494.45.

[C20] (R)-N-(4-(((2-(2-(hydroxymethyl)pyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)tetrahydro-2H-pyran-4-carboxamide

Compound 8.3 was used as the raw material, and the synthetic route of compound 2.2 was referred to. (S)-(+)-2-amino-1-butanol was replaced with D-prolinol to prepare compound C20 with a yield of 37%. ¹ H NMR (500MHz, Methanol-d4) δ7.66 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 4.69–4.68 (s, 2H), 4.21 (d, J = 5.9 Hz, 1H), 4.01 (dd, J = 4.5, 2.0 Hz, 1H), 3.99–3.98 (m, 1H), 3.73 (t, J = 8.4 Hz, 2H) ,3.60(dq,J＝11.4,5.9,5.4Hz,2H),3.50–3.46(m,2H),2.98(dd,J＝8.8,3.3Hz,1H),2.61(p,J＝3.5Hz,1H),1.99(m,2H),1.88–1.80(m,4H),1.76–1.73(m,2H),1.27–1.26(dd,6H).UPLC-MS(ESI) theoretical value is C ₂₆ H ₃₅ N ₇ O ₃ [M+H] ⁺ :494.28, found value is 494.38.

Embodiment 9

[C21] 1-Acetyl-N-(4-(((2-((1,3-dihydroxypropan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)piperidine-4-carboxamide

Compound 9.1 was prepared with 4-(N-Boc-aminomethyl)aniline and 1-acetyl-4-piperidinic acid as raw materials and with reference to the synthetic route of compound 3.1, with a yield of 69%. ¹ H NMR (400 MHz, DMSO-d6) δ9.88 (s, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.33 (t, J = 6.1 Hz, 1H), 7.14 (d, J = 8.3 Hz, 2H), 4.40 (d, J = 12.6 Hz, 1H), 4.04 (d, J = 6.2 Hz, 2H), 3.86 (d, J = 13.6 Hz, 1H ),3.05(td,J＝13.4,12.9,2.7Hz,1H),2.57(td,J＝11.5,10.5,4.9Hz,2H),2.00(s,3H) ,1.78(t,J＝12.7Hz,2H),1.58(td,J＝12.4,4.2Hz,1H),1.47–1.40(m,1H),1.38(s,9H).

Compound 9.2 was prepared with the compound 9.1 as the raw material and with reference to the synthetic route of compound 3.2, with a yield of 99%. ¹ H NMR (400 MHz, DMSO-d6) δ10.04 (s, 1H), 8.10 (s, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 4.40 (d, J = 12.7 Hz, 1H), 3.96 (q, J = 5.8 Hz, 2H), 3.86 (d, J = 13.6 Hz, 1H ),3.06(td,J＝13.6,13.0,2.7Hz,1H),2.57(td,J＝11.6,5.5Hz,2H),2.00(s,3H),1 .80(t,J＝12.6Hz,2H), 1.58(td,J＝12.4,4.2Hz,1H), 1.42(qd,J＝12.5,4.3Hz,1H).

Compound 9.3 was prepared with compound 9.2 and compound 1.3 as raw materials and with reference to the synthetic route of compound 1.4, with a yield of 65%. ¹ H NMR (500MHz, DMSO-d6) δ9.98 (t, J = 6.3 Hz, 1H), 9.92 (s, 1H), 8.27 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 4.68 (d, J = 6.2 Hz, 2H), 4.38 (d, J = 12.8 Hz, 1H), 3.85 (d, J = 13.5 Hz, 1H), 3.66–3.56 (m, 1H),3.33(s,3H),3.15–3.11(m,1H),3.04(td,J＝13.5,13.0,2.8Hz,1H),2.55(q,J＝4.1Hz,1H),1.99( s,3H),1.77(t,J＝14.1Hz,2H),1.60–1.51(m,1H),1.40(qd,J＝12.4,4.4Hz,1H),1.30(d,J＝7.0Hz,6H).

Compound C21 was prepared with compound 9.3 and compound 9.4 as raw materials and with reference to the synthetic route of compound 2.2, with a yield of 43%. ¹ H NMR (500MHz, Methanol-d4) δ7.89 (s, 1H), 7.55 (d, J = 7.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 4.78 (s, 2H), 4.58–4.54 (m, 1H), 4.31–4.24 (m, 1H), 4.02–3.98 (m, 1H), 3.78 (dd, J = 10.9, 5.0 Hz, 2H), 3.74 (d, J = 5.6 Hz, 2H), 3.21–3.15 (m, 1H), 3.01–2.93 (m, 1H), 2.72 (td, J=12.9, 2.9 Hz, 1H), 2.62 (ddt, J=11.5, 7.7, 3.9 Hz, 1H), 2.12 (s, 3H), 1.89 (t, J=15.2 Hz, 2H), 1.74 (qd, J=12.4, 4.3 Hz, 1H), 1.67–1.58 (m, 1H), 1.30 (d, J=6.9 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₆ H ₃₆ N ₈ O ₄ [M+H] ⁺ : 525.29, found value is 525.88.

[C22] 1-Acetyl-N-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)piperidine-4-carboxamide

Compound 9.3 was used as the raw material, and referring to the synthetic route of compound C21, 2-amino-1,3-propanediol was replaced with 4-aminotetrahydropyran to prepare compound C22 with a yield of 37%. ¹ H NMR (500MHz, Methanol-d4) δ7.90 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 4.75 (s, 2H), 4.58–4.53 (m, 1H), 4.16–4.09 (m, 1H), 4.02–3.98 (m, 1H), 3.95 (d, J = 11.7 Hz, 2H), 3.53–3.48 (m, 2H), 3.21–3.15 ( m, 1H), 3.07–2.97 (m, 1H), 2.75–2.69 (m, 1H), 2.63 (ddd, J＝11.5, 7.7, 3.9 Hz, 1H), 2.11 (s, 3H), 1.93–1.88 (m, 2H), 1.87–1.82 (m, 2H), 1.78–1.72 (m, 1H), 1.66–1.59 (m, 3H), 1.29 (d, J＝6.9 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₈ H ₃₈ N ₈ O ₃ [M+H] ⁺ : 535.31, found value is 535.43.

[C23] (R)-1-Acetyl-N-(4-(((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)piperidine-4-carboxamide

Compound 9.3 was used as the raw material, and the synthetic route of compound C21 was followed. 2-amino-1,3-propanediol was replaced with (R)-(-)-2-amino-1-butanol to prepare compound C23 with a yield of 33%. ¹ H NMR (500MHz, Methanol-d4) δ7.89 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.6 Hz, 2H), 4.77 (d, J = 18.5 Hz, 2H), 4.58–4.54 (m, 1H), 4.17–4.11 (m, 1H), 4.02–3.97 (m, 1H), 3.66 (d, J = 4.8 Hz, 2H), 3.21–3.15 (m, 1H), 2.99 (m, J = 6.9 Hz, 2H). z, 1H), 2.72 (td, J = 12.9, 3.0 Hz, 1H), 2.63 (ddt, J = 11.5, 7.7, 3.8 Hz, 1H), 2.11 (s, 3H), 1.92–1.86 (m, 2H), 1.77–1.70 (m, 2H), 1.63 (td, J = 13.4, 12.9, 8.2 Hz, 2H), 1.29 (d, J = 6.9 Hz, 6H), 0.96 (t, J = 7.5 Hz, 3H). UPLC-MS (ESI) theoretical value for C ₂₇ H ₃₈ N ₈ O ₃ [M+H] ⁺ : 523.31, found value is 523.89.

[C24](S)-1-Acetyl-N-(4-(((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)piperidine-4-carboxamide

Compound 9.3 was used as the raw material, and referring to the synthetic route of compound C21, 2-amino-1,3-propanediol was replaced with (S)-(+)-2-amino-1-butanol to prepare compound C24 with a yield of 31%. ¹ H NMR (500

MHz, Methanol-d4)δ7.89(s,1H),7.56(d,J＝8.6Hz,2H),7.38(d,J＝8.6Hz,2H),4.77(d,J＝18.2Hz,2H ),4.58–4.53(m,1H),4.18–4.10(m,1H),4.02–3.98(m,1H),3.66(d,J＝4.9Hz,2H),3.21–3.16(m,1H) ,3.00(m,J＝6.9Hz,1H),2.75–2.69(m,1H),2.63(ddt,J＝11.5,7.7,3.9Hz,1H),2.11(s,3H),1.93–1. 86(m,2H),1.78–1.70(m,2H),1.62(dt,J＝13.3,6.3Hz,2H),1.29(d,J＝6.9Hz,6H),0.96(t,J＝7.4Hz, 3H). UPLC-MS (ESI) theoretical value for C ₂₇ H ₃₈ N ₈ O ₃ [M+H] ⁺ :523.31, found value is 523.89.

[C25] (R)-1-Acetyl-N-(4-(((2-(2-(hydroxymethyl)pyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)piperidine-4-carboxamide

Compound 9.3 was used as the raw material, and the synthetic route of compound C21 was followed. 2-amino-1,3-propanediol was replaced with D-prolinol to prepare compound C25 with a yield of 51%. ¹ H NMR (500MHz, Methanol-d4) δ7.90 (s, 1H), 7.57 (d, J = 8.5Hz, 2H), 7.41 (d, J = 8.0Hz, 2H), 4.79 (s, 2H), 4.60–4.56 (m, 1H), 4.28–4.21 (m, 1H), 4.08 (q, J = 6.8, 6.2Hz, 1H), 4.02 (d, J = 13.8Hz, 1H), 3.93 (d, J = 11.2Hz, 1H), 3.74 (dd, J = 11.5, 5.7Hz, 2H), 3.20 (ddd, J = 7. 5,3.1,1.5Hz,1H),3.02–2.92(m,1H),2.76–2.71(m,1H),2.65(td,J＝7.7,3.8Hz,1H),2.34–2.27(m,1H),2.13(s,3H),2.07–1.97(m,2H),1.93–1.87(m,3H),1.76(dd,J＝12.5,4.1Hz,1H),1.65(dd,J＝12.3,4.2Hz,1H),1.31(d,J＝7.1Hz,6H). UPLC-MS (ESI) theoretical value for C ₂₈ H ₃₈ N ₈ O ₃ [M+H] ⁺ :535.31, found value is 535.43.

Example 10

[C26] N-(4-(((2-((1,3-dihydroxypropan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound 10.1 was prepared with 4-(N-Boc-aminomethyl)aniline and propionic acid as raw materials and with reference to the synthetic route of compound 3.1, with a yield of 95%. ¹ H NMR (400 MHz, DMSO-d6) δ9.79 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.30 (t, J = 6.1 Hz, 1H), 7.13 (d, J = 8.3 Hz, 2H), 4.05 (d, J = 6.3 Hz, 2H), 2.29 (q, J = 7.6 Hz, 2H), 1.38 (s, 9H), 1.07 (t, J = 7.5 Hz, 3H).

Compound 10.1 was used as the raw material and the synthetic route of compound 3.2 was followed to prepare compound 10.2 in a yield of 99%. ¹ H NMR (400 MHz, DMSO-d6) δ9.96 (s, 1H), 8.18–8.07 (m, 3H), 7.62 (d, J＝8.6 Hz, 2H), 7.36 (d, J＝8.6 Hz, 2H), 3.96 (q, J＝5.8 Hz, 2H), 2.32 (q, J＝7.5 Hz, 2H), 1.07 (t, J＝7.5 Hz, 3H).

Compound 10.2 and compound 1.3 were used as raw materials and the synthetic route of compound 1.4 was referred to to prepare compound 10.3 with a yield of 61%. ¹ H NMR (500 MHz, DMSO-d6) δ9.98 (t, J = 6.3 Hz, 1H), 9.85 (s, 1H), 8.27 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 4.68 (d, J = 6.2 Hz, 2H), 3.33 (s, 3H), 3.17–3.11 (m, 1H), 2.29 (d, J = 7.5 Hz, 2H), 1.30 (d, J = 6.9 Hz, 6H), 1.05 (t, J = 7.5 Hz, 3H).

Compound C26 was prepared with compound 10.3 and compound 9.4 as raw materials and with reference to the synthetic route of compound 2.2, with a yield of 62%. ¹ H NMR (500MHz, Methanol-d4) δ7.67 (s, 1H), 7.51 (d, J = 8.5Hz, 2H), 7.34 (d, J = 8.2Hz, 2H), 4.69 (s, 2H), 4.14–4.06 (m, 1H), 3.73 (q, J = 5.4Hz, 4H), 3.02–2.96 (m, 1H), 2.37 (q, J = 7.6Hz, 2H), 1.27 (d, J = 6.9Hz, 6H), 1.19 (t, J = 7.6Hz, 3H). UPLC-MS (ESI) theoretical value for C ₂₁ H ₂₉ N ₇ O ₃ [M+H] ⁺ :428.23, found value 428.41.

[C27] N-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Using compound 10.3 as the raw material and referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with 4-aminotetrahydropyran to prepare compound C27 with a yield of 42%. ¹ H NMR (500 MHz, Methanol-d4) δ7.68 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 4.68 (s, 2H), 4.04–3.98 (m, 1H), 3.94 (t, J = 11.8 Hz, 2H), 3.51 (t, J = 12.0 Hz, 2H), 3.03–2.97 (m, 1H), 2.37 (q, J = 7.6 Hz, 2H), 1.98–1.86 (m, 2H), 1.57–1.50 (m, 2H), 1.27 (d, J = 7.0 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H). UPLC-MS (ESI) theoretical value is C ₂₃ H ₃₁ N ₇ O ₂ [M+H] ⁺ :438.25, found 438.86.

[C28] N-(4-(((8-isopropyl-2-(oxetan-3-ylamino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Using compound 10.3 as the raw material and referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with 3-oxetanamine to prepare compound C28 with a yield of 15%. ¹ H NMR (500 MHz, Methanol-d4) δ7.84 (s, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 5.13–5.04 (m, 1H), 4.74 (d, J = 6.8 Hz, 2H), 4.65 (q, J = 6.7 Hz, 2H), 3.82–3.63 (m, 1H), 3.03 (td, J = 14.6, 14.1, 7.2 Hz, 1H), 2.37 (q, J = 7.6 Hz, 2H), 1.29 (d, J = 7.0 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H). UPLC-MS (ESI) theoretical value is C ₂₁ H ₂₇ N ₇ O ₂ [M+H] ⁺ :410.22, the measured value is 410.76.

[C29](S)-N-(4-(((2-((1-hydroxybutyl-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C29 was prepared with compound 10.3 as the raw material and referring to the synthetic route of compound 2.2, with a yield of 50%. ¹ H NMR (500MHz, Methanol-d4) δ7.70 (s, 1H), 7.52 (d, J = 8.5Hz, 2H), 7.35 (d, J = 8.2Hz, 2H), 4.70 (d, J = 12.8Hz, 2H), 4.04–3.90 (m, 1H), 3.63 (d, J = 5.0Hz, 2H), 2.99 (p, J = 6.9Hz, 1H), 2.37 (q, J = 7.6 Hz, 2H), 1.71 (ddd, J = 13.4, 7.6, 5.8 Hz, 1H), 1.56 (dt, J = 14.3, 7.4 Hz, 1H), 1.27 (d, J = 6.9 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H). UPLC-MS (ESI) theoretical value for C ₂₂ H ₃₁ N ₇ O ₂ [M+H] ⁺ : 426.25, found value is 426.45.

[C30] (R)-N-(4-(((2-((1-hydroxybutyl-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound 10.3 was used as the raw material, and referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with (R)-(-)-2-amino-1-butanol to prepare compound C30 with a yield of 64%. ¹ H NMR (500MHz, Methanol-d4) δ7.78 (s, 1H), 7.53 (d, J = 8.5Hz, 2H), 7.36 (d, J = 8.4Hz, 2H), 4.72 (d, J = 14.8Hz, 2H), 4.14–3.92 (m, 1H), 3.64 (d, J = 5.0Hz, 2H), 3.00 (p, J = 6.9Hz, 1H), 2.37 (q, J = 7.6 Hz, 2H), 1.71 (ddd, J = 13.5, 7.6, 5.9 Hz, 1H), 1.58 (dq, J = 14.3, 7.4 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H), 0.97 (t, 3H). UPLC-MS (ESI) theoretical value for C ₂₂ H ₃₁ N ₇ O ₂ [M+H] ⁺ : 426.25, found value is 426.77.

[C31] (R)-N-(4-(((8-isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound 10.3 was used as the raw material, and the synthetic route of compound 1.6 was followed. 1-methyl-4-piperidinol was replaced with (S)-3-hydroxypiperidine to prepare compound C31 with a yield of 55%. ¹ H NMR (500MHz, Methanol-d4) δ7.87 (s, 1H), 7.52 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 4.73 (d, J = 2.9 Hz, 2H), 3.48 (dd, J = 13.3, 3.9 Hz, 1H), 3.37–3.32 (m, 2H), 3.29 (d, J = 3.8 Hz, 1H), 3.19–3.0 9(m,1H),3.08–3.03(m,1H),2.37(t,J＝7.6Hz,2H),2.11(dt,J＝14.5,4.9Hz,2H),1.98–1.91(m,1H),1.84–1.78(m,1H),1.31(dd,J＝6.9,1.9Hz,6H),1.19(t,J＝7.6Hz,3H). UPLC-MS(ESI) theoretical value for C ₂₃ H ₃₁ N ₇ O ₂ [M+H] ⁺ :438.25, found value is 438.41.

[C32](S)-N-(4-(((8-isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound 10.3 was used as the raw material, and the synthetic route of compound 1.6 was followed. 1-methyl-4-piperidinol was replaced with (R)-3-hydroxypiperidine to prepare compound C32 with a yield of 59%. ¹ H NMR (500MHz, Methanol-d4) δ7.88 (s, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 4.74 (d, J = 2.9 Hz, 2H), 3.49 (dd, J = 13.3, 3.9 Hz, 1H), 3.36 (dd, J = 13.4, 2.5 Hz, 2H), 3.31–3.28 (m, 1H), 3.16–3.11 (m, 1H), 3.09–3.05 (m, 1H), 2.38 (q, J = 7.6 Hz, 2H), 2.14–2.08 (m, 2H), 1.95 (td, J = 12.3, 4.2 Hz, 1H), 1.83 (dt, J = 14.2, 3.7 Hz, 1H), 1.32 (dd, J = 6.9, 2.0 Hz, 6H), 1.20 (t, J = 7.6 Hz, 3H). UPLC-MS (ESI) theoretical value for C ₂₃ H ₃₁ N ₇ O ₂ [M+H] ⁺ : 438.25, found value 438.41.

[C33](S)-N-(4-(((8-isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound 10.3 was used as the raw material, and referring to the synthetic route of compound C38, (S)-(+)-2-amino-1-butanol was replaced with 1-tert-butyloxycarbonyl-4-aminopiperidine to prepare compound C33 with a yield of 37%. ¹ HNMR (500MHz, Methanol-d4) δ7.90 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 4.77 (s, 2H), 4.21 (dq, J = 10.5, 6.0, 4.9 Hz, 1H), 3.46–3.41 (m, 2H), 3.14 (dd, J = 12.0, 3.1Hz, 2H), 3.10–3.06(m, 1H), 2.38(q, J＝7.6Hz, 2H), 2.10(d, J＝13.8Hz, 2H), 1.77(td, J＝10.8,7.7Hz, 2H), 1.28(d, J＝6.9Hz, 6H), 1.19(t, J＝7.6Hz, 3H). UPLC-MS (ESI) theoretical value for C ₂₃ H ₃₂ N ₈ O[M+H] ⁺ :437.27, found value is 437.45.

[C34] N-(4-(((8-isopropyl-2-(piperidin-3-ylamino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Using compound 10.3 as the raw material, referring to the synthetic route of compound C38, (S)-(+)-2-amino-1-butanol was replaced with N-tert-butyloxycarbonyl-3-aminopiperidine to prepare compound C34 with ^a yield of 85%. HNMR (500MHz, Methanol-d4) δ7.88 (s, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 4.79 (s, 2H), 4.30–4.25 (m, 1H), 3.41–3.32 (m, 2H), 3.11–3.06 (m, 1H), 3.03–2.93 (m, 2H), 2.38 (q, J = 7.6 Hz, 2H), 2.11–2.04 (m, 2H), 1.84 (dt, J = 10.9, 3.7 Hz, 1H), 1.77–1.71 (m, 1H), 1.28 (d, J = 6.9 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H). UPLC-MS (ESI) theoretical value was C ₂₃ H ₃₂ N ₈ O[M+H] ⁺ :437.27, found 437.44.

[C35] N-(4-(((8-isopropyl-2-((1-methylpiperidin-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound 10.3 was used as the raw material, and referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with 4-amino-1-methylpiperidine to prepare compound C35 with a yield of 19%. ¹ H NMR (500MHz, Methanol-d4) δ7.91 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 4.77 (d, J = 4.1 Hz, 2H), 4.14 (tt, J = 11.8, 4.2 Hz, 1H), 3.56 (d, J = 12.5 Hz, 2H), 3.16–3.11 (m, 2H), 3.07 (q, J = 6.8 Hz, 1H), 2.91 (s, 3H), 2.38 (q, J = 7.6 Hz, 2H), 2.13 (d, J = 15.5 Hz, 2H), 1.84–1.72 (m, 2H), 1.28 (d, J = 6.9 Hz, 6H), 1.20 (t, J = 7.6 Hz, 3H). UPLC-MS (ESI) theoretical value for C ₂₄ H ₃₄ N ₈ O [M+H] ⁺ : 451.29, found value 451.43.

[C36] N-(4-(((8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Using compound 10.3 as raw material and referring to the synthetic route of compound 1.6, compound C36 was prepared with a yield of 62%. ¹ H NMR (500 MHz, Methanol-d4) δ7.84 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 5.19–5.12 (m, 1H), 4.72 (s, 2H), 3.10 (dd, J = 13.4, 7.4 Hz, 2H), 3.05 (q, J = 7.0 Hz, 1H), 2.96–2.79 (m, 2H), 2.63 (s, 3H), 2.37 (q, J = 7.6 Hz, 2H), 2.11 (d, J = 13.2 Hz, 2H), 2.00 (s, 2H), 1.29 (d, J = 6.9 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H). UPLC-MS (ESI) theoretical value is C ₂₄ H ₃₃ N ₇ O ₂ [M+H] ⁺ :452.27, found 452.81.

[C63] N-(4-(((8-isopropyl-2-((1-(prop-2-yn-1-yl)piperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Using compound 10.3 as the raw material, referring to the synthetic route of compound 1.6, replacing 1-methyl-4-piperidinol with 1-(prop-2-yn-1-yl)piperidin-4-ol, compound C63 was prepared.

[C131] (R)-N-(4-(((2-(3-hydroxypyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Using compound 10.3 as the raw material, referring to the synthetic route of compound 2.2, replacing (S)-(+)-2-amino-1-butanol with (R)-3-pyrrolidinol, C131 was prepared with a yield of 45%. ¹ H NMR (500 MHz, DMSO-d6) δ9.84 (s, 1H), 9.40 (s, 1H), 7.87 (s, 1H), 7.58–7.49 (m, 2H), 7.33 (d, J=8.3 Hz, 2H), 4.57 (d, J=6.3 Hz, 2H), 4.38 (s, 1H), 3.54 (d, J=58.8 Hz, 4H), 3.16–2.99 (m, 1H), 2.29 (q, J=7.5 Hz, 2H), 1.94 (d, J=53.6 Hz, 2H), 1.21 (dd, J=6.9, 2.2 Hz, 6H), 1.06 (t, J=7.6 Hz, 3H). UPLC-MS (ESI) theoretical value for C ₂₂ H ₂₉ N ₇ O ₂ [M+H] ⁺ :424.52, the measured value is 424.49.

[C132] (S)-N-(4-(((2-(3-Hydroxypyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Using compound 10.3 as the raw material and referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with (S)-3-pyrrolidinol to prepare C132 with a yield of 59%. ¹ H NMR (500 MHz, DMSO-d6) δ9.84 (s, 1H), 9.44 (s, 1H), 7.89 (s, 1H), 7.57–7.49 (m, 2H), 7.33 (d, J = 8.3 Hz, 2H), 4.57 (d, J = 6.3 Hz, 2H), 4.38 (s, 1H), 3.55 (d, J = 62.9 Hz, 4H), 3.09 (dt, J = 14.1, 7.2 Hz, 1H), 2.29 (q, J = 7.6 Hz, 2H), 2.00 (dd, J = 12.9, 5.4 Hz, 1H), 1.90 (s, 1H), 1.21 (dd, J = 6.9, 2.5 Hz, 6H), 1.06 (t, J = 7.6 Hz, 3H). UPLC-MS (ESI) theoretical value was C ₂₂ H ₂₉ N ₇ O ₂ [M+H] ⁺ :424.52, found 424.49.

[C133] (R)-N-(4-(((2-(2-(hydroxymethyl)pyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Using compound 10.3 as the raw material, referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with (R)-2-pyrrolidinemethanol to prepare C133 with a yield of 53%. ¹ H NMR (500 MHz, DMSO-d6) δ9.84 (s, 1H), 9.47 (s, 1H), 7.89 (s, 1H), 7.58–7.49 (m, 2H), 7.37–7.27 (m, 2H), 4.57 (dd, J=6.5, 3.3 Hz, 2H), 4.19 (s, 1H), 3.75–3.39 (m, 4H), 3.03 (d, J=74.9 Hz, 1H), 2.29 (q, J=7.5 Hz, 2H), 1.96 (d, J=58.2 Hz, 4H), 1.21 (dd, J=7.1, 3.4 Hz, 6H), 1.06 (t, J=7.5 Hz, 3H). UPLC-MS (ESI) theoretical value is C ₂₃ H ₃₁ N ₇ O ₂ [M+H] ⁺ :438.55, the actual measured value is 438.51.

[C134] (S)-N-(4-(((2-(2-(hydroxymethyl)pyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Using compound 10.3 as the raw material, referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with (S)-2-pyrrolidinemethanol to prepare C134 with a yield of 40%. ¹ H NMR (600 MHz, DMSO-d6) δ9.85 (s, 1H), 9.41 (s, 1H), 7.87 (d, J = 15.4 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 4.57 (s, 2H), 4.18 (s, 1H), 3.70–3.38 (m, 4H), 3.01 (d, J = 84.4 Hz, 1H), 2.29 (q, J = 7.6 Hz, 2H), 2.06–1.82 (m, 4H), 1.21 (d, J = 6.6 Hz, 6H), 1.06 (t, J = 7.5 Hz, 3H). UPLC-MS (ESI) theoretical value is C ₂₃ H ₃₁ N ₇ O ₂ [M+H] ⁺ :438.55, the actual measured value is 438.50.

[C135] (S)-N-(4-(((2-(2-(2-hydroxyethyl)piperidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound 10.3 was used as the raw material, and the synthetic route of compound 2.2 was followed. (S)-(+)-2-amino-1-butanol was replaced with (S)-2-(2-piperidinyl)ethanol to prepare C135 with a yield of 28%. ¹ H NMR (500MHz, DMSO-d6) δ9.83 (s, 1H), 9.13 (s, 1H), 7.80 (s, 1H), 7.57–7.47 (m, 2H), 7.36–7.29 (m, 2H), 4.91 (s, 1H), 4.55 (d, J=6.3 Hz, 3H), 3.39 (tt, J=12.4, 6.6 Hz, 2H), 2.92 (dd, J= 17.3,9.4Hz,2H),2.29(q,J＝7.5Hz,2H),1.96–1.87(m,1H),1.61(dt,J＝41.5,12.4Hz,6H),1.39–1.28(m,1H),1.21(dd,J＝7.0,0.9Hz,6H),1.06(t,J＝7.5Hz,3H). UPLC-MS(ESI)theoretical value C ₂₅ H ₃₅ N ₇ O ₂ [M+H] ⁺ : 466.60, found 466.47.

Embodiment 11

[C37] (S)-2-((7-((4-aminobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)butan-1-ol

Compound 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (369 mg, 1.61 mmol, 1.0 equiv), compound 1.2 (317 mg, 1.93 mmol, 1.2 equiv) and N,N-diisopropylethylamine (532 μL, 3.22 mmol, 2.0 equiv) were dissolved in 15 mL of ethanol. The reaction solution was refluxed at 90 ° C for 12 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was removed under reduced pressure. The remaining solid was dissolved in dichloromethane, washed several times with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed and purified by column chromatography to obtain compound 11.1 (524 mg) with a yield of 82%. ¹ H NMR(500MHz,DMSO-d6)δ9.33(s,1H),8.99(t,J＝6.6Hz,1H),8.06(s,1H),7.37(d,J＝8.4Hz,2H),7.14 (d,J＝8.4Hz,2H),6.00(s,1H),4.64(d,J＝6.5Hz,2H),3.09–3.07(m,1H),1.36(s,9H),1.27(dd,6H).

Compound 11.2 was prepared with a yield of 94% using compound 11.1 as the starting material and referring to the synthetic route of compound 1.1. ¹ H NMR (500 MHz, DMSO-d6) δ8.22 (s, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.13 (s, 1H), 7.07 (d, J = 8.4 Hz, 2H), 5.03 (s, 2H), 3.14–3.10 (m, 1H), 1.30 (s, 18H), 1.28 (d, J = 3.5 Hz, 6H).

Using compound 11.2 and compound 2.1 as raw materials and referring to the synthetic route of compound C38, compound C37 was prepared with a yield of 68%. ¹ H NMR (500 MHz, Methanol-d4) δ7.89 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 5.40 (s, 1H), 4.74–4.69 (s, 2H), 3.78–3.64 (m, 2H), 3.59 (dd, J = 11.0, 6.2 Hz, 1H), 3.06 (p, J = 7.0 Hz, 1H), 1.71–1.66 (m, 1H), 1.60–1.54 (m, 1H), 1.31 (dd, J = 6.9, 2.9 Hz, 6H), 0.97 (t, J = 7.4 Hz, 3H). UPLC-MS (ESI) theoretical value for C ₂₀ H ₂₈ N ₆ O [M+H] ⁺ :369.49, the actual measured value is 369.35.

Example 12

[C39](S)-N-(4-(((5-((1-hydroxybutan-2-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acetamide

Using 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine and compound 3.2 as raw materials, the synthetic route of compound 11.1 was used as reference. The compound 12.1 was prepared with a yield of 91%. ¹ H NMR (400 MHz, DMSO-d6) δ9.92 (s, 1H), 8.87 (t, J = 6.5 Hz, 1H), 8.04 (s, 1H), 7.52 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 6.05 (s, 1H), 4.55 (d, J = 6.5 Hz, 2H), 3.08 (p, J = 6.9 Hz, 1H), 2.01 (s, 3H), 1.27 (d, J = 6.9 Hz, 6H).

Compound 12.2 was prepared with a yield of 97% using compound 12.1 as the starting material and referring to the synthetic route of compound 1.1. ¹ H NMR (400 MHz, DMSO-d6) δ8.05 (s, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 6.02 (s, 1H), 5.76 (s, 2H), 3.08 (p, J = 6.8 Hz, 1H), 2.45 (s, 3H), 1.31 (s, 9H), 1.27 (d, J = 7.0 Hz, 6H).

Compound 12.3 (114 mg, 0.56 mmol, 2.0 equiv) was dissolved in 15 mL of toluene, and compound 12.2 (128 mg, 0.28 mmol, 1.0 equiv), Pd ₂ (dba) ₃ (13 mg, 0.014 mmol, 5 mol% equiv), rac BINAP (26 mg, 0.042 mmol, 15 mol% equiv) and Cs ₂ CO ₃ (137 mg, 0.42 mmol, 1.5 equiv) were added, and the mixture was purged with nitrogen three times. The temperature was raised to 100° C. and heated with stirring for 12 h. After the reaction was completed, the mixture was cooled to room temperature, toluene was removed under reduced pressure, and the residue was purified by column chromatography to obtain compound 12.4 (87 mg) with a yield of 50%. ¹ H NMR (400MHz, DMSO-d6) δ9.32 (s, 1H), 7.67 (s, 1H), 7.37 (d, J = 8.1Hz, 2H), 7.10 (d ,J＝8.2Hz,2H),6.91(d,J＝7.7Hz,1H),5.98(s,1H),5.75(s,2H),4.03(d,J＝7.1Hz ,1H),3.70–3.63(m,2H),3.01–2.95(m,1H),2.33(s,3H),1.68(s,2H),1.45(s,9 H), 1.32 (s, 6H), 1.25 (dd, J = 6.9, 3.2Hz, 6H), 1.17 (t, J = 7.2Hz, 3H), 0.81 (s, 9H).

Using compound 12.4 as raw material and referring to the synthetic route of compound C1, compound C39 was prepared with a yield of 99%. ¹ H NMR (500 MHz, Methanol-d4) δ7.88 (s, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 5.37 (s, 1H), 4.64 (s, 2H), 3.78–3.56 (m, 3H), 3.08–3.00 (m, 1H), 2.11 (s, 3H), 1.68 (ddd, J = 13.7, 7.6, 6.0 Hz, 1H), 1.60–1.49 (m, 1H), 1.31 (dd, J = 6.9, 3.6 Hz, 6H), 0.96 (t, J = 7.3 Hz, 3H). UPLC-MS (ESI) theoretical value is C ₂₂ H ₃₀ N ₆ O ₂ [M+H] ⁺ :411.24, the measured value is 411.85.

[C40] N-(4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acetamide

Using compound 12.2 as the raw material, referring to the synthetic route of compound C39, compound 12.3 was replaced with 4-aminotetrahydrofuran to prepare compound C40 with a yield of 45%. ¹ H NMR (500 MHz, Methanol-d4) δ7.90 (s, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 5.27 (s, 1H), 4.68 (d, 2H), 3.94 (dd, J = 9.5, 6.0 Hz, 2H), 3.84–3.74 (m, 1H), 3.51 (td, J = 11.7, 2.1 Hz, 2H), 3.12–3.06 (m, 1H), 2.11 (s, 3H), 1.82 (d, J = 13.0 Hz, 2H), 1.54 (qd, J = 11.6, 4.3 Hz, 2H), 1.30 (d, J = 6.9 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₃ H ₃₀ N ₆ O ₂ [M+H] ⁺ :423.24, found 423.85.

Embodiment 13

[C55] (S)-1-Fluoro-N-(4-(((2-(3-hydroxypyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)cyclopropane-1-carboxamide

Compound 13.1 was prepared with 4-(N-Boc-aminomethyl)aniline and 1-fluorocyclopropylcarboxylic acid as raw materials and with reference to the synthetic route of compound 3.1, with a yield of 98%. ¹ H NMR (500 MHz, DMSO-d6) δ10.20 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.37 (t, J = 6.2 Hz, 1H), 7.18 (d, J = 8.3 Hz, 2H), 4.08 (d, J = 6.2 Hz, 2H), 1.40 (s, 9H), 1.34–1.31 (m, 2H), 1.30 (d, J = 2.8 Hz, 1H), 1.19 (d, J = 6.7 Hz, 1H).

Compound 13.1 was used as the raw material and the synthetic route of compound 3.2 was referred to to prepare compound 13.2 with a yield of 99%. ¹ H NMR (500 MHz, DMSO-d6) δ10.33 (s, 1H), 8.17 (s, 3H), 7.74 (d, J＝8.6 Hz, 2H), 7.40 (d, J＝8.6 Hz, 2H), 3.99 (q, J＝5.8 Hz, 2H), 1.45–1.37 (m, 2H), 1.31 (td, J＝9.4, 8.9, 5.7 Hz, 2H).

Compound 13.2 and compound 1.3 were used as raw materials, and referring to the synthetic route of compound 1.4, compound 13.3 was prepared with a yield of 76%. ¹ H NMR (500MHz, DMSO-d6) δ10.22(s,1H),10.00(s,1H),8.28(s,1H),7.65(d,J＝8.6Hz,2H),7.37(d,J＝8.6Hz,2H),4.71(d,J＝5.6Hz,2H),3.3 2(s,3H),3.15–3.11(m,1H),1.42–1.40(m,1H),1.37(t,J＝3.9Hz,1H),1.30(d,J＝6.9Hz,6H),1.28(d,J＝2.9Hz,1H),1.23(d,J＝5.2Hz,1H).

Using compound 13.3 as raw material and referring to the synthetic route of compound 2.2, compound C55 was prepared with a yield of 32%. ¹ H NMR (500 MHz, Methanol-d4) δ7.92 (s, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 4.77 (s, 2H), 4.63–4.52 (m, 1H), 3.93 (dd, J = 26.2, 16.8 Hz, 1H), 3.79 (dd, J = 22.7, 11.2 Hz, 3H), 3.25–3.19 (m, 1H), 2.11 (d, J = 46.3 Hz, 2H), 1.40 (dd, J = 3.9, 2.1 Hz, 1H), 1.39–1.37 (m, 1H), 1.37 (d, 2H), 1.28 (dd, J = 6.9, 4.5 Hz, 6H). UPLC-MS (ESI) theoretical value was C ₂₃ H ₂₈ FN ₇ O ₂ [M+H] ⁺ : 454.23, found 454.32.

[C56] (R)-1-Fluoro-N-(4-(((2-(3-hydroxypyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)cyclopropane-1-carboxamide

Compound 13.3 was used as the raw material, and referring to the synthetic route of C55, (S)-3-pyrrolidinol was replaced with (R)-3-pyrrolidinol to prepare compound C56 with a yield of 47%. ¹ H NMR (500 MHz, Methanol-d4) δ1H NMR (500 MHz, Methanol-d4) δ7.69 (s, 1H), 7.57 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 4.70 (s, 2H), 4.48 (dd, J = 4.9, 2.6 Hz, 1H), 3.74 (t, J = 10.0 Hz, 1H), 3.70–3.59 (m, 3H), 3.07 (p, J = 6.9 Hz, 1H), 2.10 (dp, J = 13.4, 4.5 Hz, 1H), 1.99 (q, J = 10.2, 8.9 Hz, 1H), 1.39 (dq, J = 7.7, 2.8, 2.2 Hz, 2H), 1.36–1.35 (m, 2H), 1.27 (dd, J = 7.0, 3.7 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₃ H ₂₈ FN ₇ O ₂ [M+H] ⁺ : 454.23, found value 454.32.

[C57] 1-Fluoro-N-(4-(((8-isopropyl-2-(oxetan-3-ylamino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)cyclopropane-1-carboxamide

Using compound 13.3 as raw material and referring to the synthetic route of compound C55, (S)-3-pyrrolidinol was replaced with 3-oxetanamine to prepare compound C57 with a yield of 24%. ¹ H NMR (500 MHz, Methanol-d4) δ7.87 (s, 1H), 7.61 (d, J = 6.9 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 5.12–5.08 (m, 1H), 4.77 (d, J = 4.1 Hz, 2H), 4.66 (td, J = 6.5, 3.3 Hz, 2H), 4.48–4.30 (m, 1H), 3.82–3.65 (m, 1H), 3.08–3.01 (m, 1H), 1.40 (d, 2H), 1.37 (d, 2H), 1.29 (d, J = 7.0 Hz, 6H). UPLC-MS (ESI) theoretical value is C ₂₂ H ₂₆ FN ₇ O ₂ [M+H] ⁺ :440.21, the measured value is 440.76.

[C58] 1-Fluoro-N-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)cyclopropane-1-carboxamide

Using compound 13.3 as the raw material, referring to the synthetic route of compound C55, (S)-3-pyrrolidinol was replaced by 4-aminotetrahydropyran, and the yield was 59%. ¹ H NMR (500 MHz, Methanol-d4) δ7.89 (s, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 7.1 Hz, 2H), 4.77 (d, 2H), 4.12 (dt, J = 11.6, 5.3 Hz, 1H), 3.96 (d, J = 12.1 Hz, 2H), 3.51 (t, J = 11.6 Hz, 2H), 3.05–2.97 (m, 1H), 1.89–1.81 (m, 2H), 1.65–1.58 (m, 2H), 1.41–1.36 (m, 4H), 1.29 (d, J = 7.0 Hz, 6H). UPLC-MS (ESI) theoretical value is C ₂₄ H ₃₀ FN ₇ O ₂ [M+H] ⁺ :468.24, the measured value is 468.37.

[C59] (S)-1-Fluoro-N-(4-(((2-((1-hydroxybutyl-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)cyclopropane-1-carboxamide

Using compound 13.3 as raw material and referring to the synthetic route of compound C55, (S)-3-pyrrolidinol was replaced with (S)-(+)-2-amino-1-butanol to prepare compound C59 with a yield of 68%. ¹ H NMR (500 MHz, Methanol-d4) δ7.68 (s, 1H), 7.58 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 4.71 (d, J = 11.9 Hz, 2H), 4.03–3.91 (m, 1H), 3.66–3.57 (m, 2H), 3.00 (p, J = 6.9 Hz, 1H), 1.70 (ddd, J = 13.6, 7.7, 5.9 Hz, 1H), 1.59–1.50 (m, 1H), 1.40–1.37 (m, 2H), 1.37–1.35 (m, 2H), 1.27 (d, J = 7.0 Hz, 6H), 0.97 (t, J = 7.5 Hz, 3H). UPLC-MS (ESI) theoretical value was C ₂₃ H ₃₀ FN ₇ O ₂ [M+H] ⁺ : 456.24, found 456.38.

[C60] (R)-1-Fluoro-N-(4-(((2-((1-hydroxybutyl-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)cyclopropane-1-carboxamide

Using compound 13.3 as raw material and referring to the synthetic route of compound C55, (S)-3-pyrrolidinol was replaced with (R)-(-)-2-amino-1-butanol to prepare compound C60 with a yield of 56%. ¹ H NMR (500 MHz, Methanol-d4) δ7.67 (s, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 4.71 (d, J = 11.9 Hz, 2H), 4.02–3.91 (m, 1H), 3.66–3.56 (m, 2H), 3.03–2.96 (m, 1H), 1.70 (ddd, J = 13.6, 7.7, 5.9 Hz, 1H), 1.60–1.48 (m, 1H), 1.40–1.37 (m, 2H), 1.37–1.35 (m, 2H), 1.27 (d, J = 7.0 Hz, 6H), 0.98 (t, 3H). UPLC-MS (ESI) theoretical value for C ₂₃ H ₃₀ FN ₇ O ₂ [M+H] ⁺ : 456.24, found 456.38.

[C61] (R)-1-Fluoro-N-(4-(((2-(2-(hydroxymethyl)pyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)cyclopropane-1-carboxamide

Compound 13.3 was used as the raw material, and the synthetic route of compound C55 was followed. (S)-3-pyrrolidinol was replaced with D-prolinol to prepare compound C61 with a yield of 44%. ¹ H NMR (500MHz, Methanol-d4) δ7.88 (s, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 4.78 (d, 2H), 4.23 (dd, J = 10.2, 4.6 Hz, 1H), 4.10–4.03 (m, 1H), 3.91 (d, J = 11.3 Hz, 1H), 3.74–3.69 (m, 2H), 3.00–2.9 1(m,1H),2.31–2.24(m,1H),1.98(ddd,J＝26.8,12.7,5.7Hz,2H),1.85(dq,J＝12.1,6.9,6.3Hz,1H),1.41(t,J＝3.0Hz,1H),1.38(t,J＝2.0Hz,1H),1.37(d,2H),1.29(d,J＝6.3Hz,6H). UPLC-MS(ESI) theoretical value for C ₂₄ H ₃₀ FN ₇ O ₂ [M+H] ⁺ :468.24, found value 468.40.

[C62](S)-1-Fluoro-N-(4-(((2-(2-(hydroxymethyl)pyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)cyclopropane-1-carboxamide

Compound 13.3 was used as the raw material, and the synthetic route of compound C55 was followed. (S)-3-pyrrolidinol was replaced with L-prolinol to prepare compound C62 with a yield of 35%. ¹ H NMR (500MHz, Methanol-d4) δ7.89 (s, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), 4.78 (d, 2H), 4.29–4.15 (m, 1H), 4.07 (dd, J = 16.1, 9.2 Hz, 1H), 3.91 (d, J = 11.2 Hz, 1H), 3.72 (d t, J = 12.4, 6.3 Hz, 2H), 3.06–2.84 (m, 1H), 2.31–2.24 (m, 1H), 2.07–1.94 (m, 2H), 1.93–1.79 (m, 1H), 1.41–1.38 (m, 2H), 1.38–1.36 (m, 2H), 1.29 (d, J = 6.5 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₄ H ₃₀ FN ₇ O ₂ [M+H] ⁺ : 468.24, found value 468.34.

[C136] (S)-1-Fluoro-N-(4-(((2-(2-(2-hydroxyethyl)piperidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)cyclopropane-1-carboxamide

Using compound 13.3 as the raw material, referring to the synthetic route of compound C55, (S)-3-pyrrolidinol was replaced with (S)-2-(2-piperidinyl)ethanol to prepare C136 with a yield of 38%. ¹ H NMR (500 MHz, DMSO-d6) δ10.19 (d, J＝2.3 Hz, 1H), 9.14 (s, 1H), 7.79 (s, 1H), 7.66–7.60 (m, 2H), 7.40–7.31 (m, 2H), 4.91 (s, 1H), 4.57 (d, J＝6.3 Hz, 3H), 3.38 (tt, J＝12.9, 6.6 Hz, 2H), 3.01–2.84 (m, 2H), 1.91 (s, 1H), 1.74–1.50 (m, 6H), 1.43–1.25 (m, 5H), 1.21 (d, J＝6.9 Hz, 6H). UPLC-MS (ESI) theoretical value is C ₂₆ H ₃₄ FN ₇ O ₂ [M+H] ⁺ :496.60, the measured value is 496.53.

Embodiment 14

[C106] 8-isopropyl-N4-(4-(4-methyl-1H-imidazol-1-yl)benzyl)-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound 14.2 was prepared using compound 14.1 and compound 1.3 as raw materials and referring to the synthetic route of compound 1.4 with a yield of 63%.

Using compound 14.2 and compound 14.3 as raw materials and referring to the synthetic route of compound C55, C106 was prepared with a yield of 35%. ¹ H NMR (600 MHz, DMSO-d6) δ9.17–8.66 (m, 1H), 8.62 (s, 1H), 7.72 (s, 1H), 7.62–7.57 (m, 3H), 7.54–7.49 (m, 2H), 6.92 (d, J=65.2 Hz, 1H), 4.64 (s, 2H), 3.93–3.78 (m, 3H), 3.35 (tt, J=12.5, 6.6 Hz, 2H), 2.90 (s, 1H), 2.24–2.20 (m, 3H), 1.74 (d, J=127.2 Hz, 2H), 1.52–1.38 (m, 2H), 1.24–1.20 (m, 6H). UPLC-MS (ESI) theoretical value for C ₂₄ H ₃₀ N ₈ O[M+H] ⁺ :447.56, found value is 447.39.

[C108] 5-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-1-methylpyridin-2(1H)-one

Compound 1.3 and compound 14.3 were used as raw materials, and the synthetic route of compound C106 was referred to, (4-(4-methyl-1H-imidazol-1-yl)phenyl)methylamine was replaced with 5-(4-(aminomethyl)phenyl)pyridin-2(1H)-one to prepare compound C108 with a yield of 48%. 1H NMR (500MHz, DMSO-d6) δ8.08 (d, J＝2.7Hz, 1H), 7.78 (dd, J＝9.5, 2.7Hz, 2H), 7.55–7.48 (m, 2H), 7.41 (d, J＝8.0Hz, 2H), 6.46 (d, J＝9.4Hz, 1H), 4.62 (d, J＝6.2Hz, 2H), 3.96–3.88 (m, 1H), 3.84 (d, J = 11.3 Hz, 2H), 3.49 (s, 3H), 3.36 (td, J = 11.6, 2.1 Hz, 2H), 2.97–2.84 (m, 1H), 1.76 (d, J = 73.7 Hz, 2H), 1.46 (s, 2H), 1.22 (d, J = 6.4 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₆ H ₃₁ N ₇ O ₂ [M+H] ⁺ : 474.58, found value 474.38.

[C122] 8-Isopropyl-N4-(4-(pyridazin-3-yl)benzyl)-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound 1.3 and compound 14.3 were used as raw materials, and the synthetic route of compound C106 was referred to. (4-(4-methyl-1H-imidazol-1-yl)phenyl)methylamine was replaced with (4-(pyridazin-3-yl)phenyl)methylamine to prepare compound C122 with a yield of 40%. ¹ H NMR (500MHz, DMSO-d6) δ9.19 (dd, J＝4.9,1.6Hz,1H), 8.19 (dd, J＝8.7,1.6Hz,1H), 8.15–8.08 (m,2H), 7.76 (dd, J＝8.7,4.9Hz,1H), 7.54 (d, J＝7.9Hz,2H), 7.11 (d, J＝201.7Hz,1H), 4.7 0 (d, J = 6.3 Hz, 2H), 3.85 (d, J = 33.2 Hz, 3H), 3.35 (t, J = 11.7 Hz, 2H), 2.92 (t, J = 7.1 Hz, 1H), 1.74 (d, J = 100.3 Hz, 2H), 1.42 (d, J = 37.7 Hz, 2H), 1.22 (t, J = 5.1 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₄ H ₂₈ N ₈ O [M + H] ⁺ : 445.54, found value is 445.35.

[C107] 1-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)pyridin-2(1H)-one

Compound 1.3 and compound 14.3 were used as raw materials, and the synthetic route of compound C106 was referred to. (4-(4-methyl-1H-imidazol-1-yl)phenyl)methylamine was replaced with 1-(4-(aminomethyl)phenyl)pyridin-2(1H)-one to prepare compound C107 with a yield of 52%. ¹ H NMR (800MHz, DMSO-d6) δ7.73 (s, 1H), 7.60 (d, J＝8.3Hz, 1H), 7.48 (ddd, J＝14.3, 7.0, 3.7Hz, 3H), 7.35–7.32 (m, 2H), 6.46 (dt, J＝9.3, 0.9Hz, 1H), 6.29 (td, J＝6.7, 1.4Hz, 1H), 4.66 (d , J＝16.8Hz, 2H), 3.93–3.86(m, 1H), 3.84(d, J＝10.9Hz, 2H), 3.35(s, 2H), 2.91(s, 1H), 1.95–1.52(m, 2H), 1.45(d, J＝45.6Hz, 2H), 1.23(dd, J＝12.1, 6.1Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₅ H ₂₉ N ₇ O ₂ [M+H] ⁺ :460.55, found value is 460.36.

[C114] 8-isopropyl-N4-(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Using compound 1.3 and compound 14.3 as raw materials, referring to the synthetic route of compound C106, (4-(4-methyl-1H-imidazol-1-yl)phenyl)methanamine was replaced with (4-(1-methyl-1H-pyrazol-4-yl)phenyl)methanamine to prepare compound C114 with a yield of 37%. ¹ H NMR (500 MHz, DMSO-d6) δ8.78 (d, J = 153.1 Hz, 1H), 8.08 (d, J = 0.7 Hz, 1H), 7.81 (d, J = 0.8 Hz, 1H), 7.71 (s, 1H), 7.49 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 6.86 (s, 1H), 4.58 (s, 2H), 3.84 (s, 6H), 3.34 (d, J = 11.2 Hz, 2H), 2.91 (d, J = 12.5 Hz, 1H), 1.93–1.58 (m, 2H), 1.46 (s, 2H), 1.22 (d, J = 6.9 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₄ H ₃₀ N ₈ O[M+H] ⁺ :447.56, found value is 447.38.

[C115] 8-isopropyl-N4-(4-(oxazol-5-yl)benzyl)-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Using compound 1.3 and compound 14.3 as raw materials, referring to the synthetic route of compound C106, (4-(4-methyl-1H-imidazol-1-yl)phenyl)methanamine was replaced with (4-(oxazol-5-yl)phenyl)methanamine to prepare compound C115 with a yield of 48%. ¹ H NMR (500MHz, DMSO-d6) δ9.03(s,1H),8.41(s,1H),7.72(s,1H),7.68(d,J＝8.0Hz,2H),7.64(s,1H),7.46(d,J＝8.1Hz,2H),6.92 (d,J＝52.1Hz,1H),4.63(s,2H),3.83(s,3H),3.34(s,2H),2.90(s,1H),1.92–1.56(m,2H),1.45(s,2H),1.22(d,J＝7.5Hz,6H).

The theoretical value of UPLC-MS (ESI) was C ²³ H ²⁷ N ⁷ O ² [M+H] ⁺ :434.52, and the measured value was 434.25.

[C87] 8-Isopropyl-N4-(4-phenoxybenzyl)-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound 1.3 and compound 14.3 were used as raw materials, and the synthetic route of compound C106 was referred to. (4-(4-methyl-1H-imidazol-1-yl)phenyl)methylamine was replaced with (4-phenoxyphenyl)methylamine to prepare compound C87 with a yield of 44%. ¹ H NMR (500MHz, DMSO-d6) δ9.99 (s, 1H), 8.21 (d, J＝244.0Hz, 2H), 7.41 (d, J＝8.1Hz, 2H), 7.39–7.34 (m, 2H), 7.12 (t, J＝7.4Hz, 1H), 6.96 (dd, J＝8.8, 6.8Hz, 4H), 4.63 (d, J＝6.1Hz, 2H), 3 .99(s,1H),3.83(d,J＝11.3Hz,2H),3.37(td,J＝11.6,2.2Hz,2H),2.97(p,J＝6.9Hz,1H),1.91–1.66(m,2H),1.51(dt,J＝12.3,6.2Hz,2H),1.21(d,J＝6.9Hz,6H).UPLC-MS(ESI) theoretical value for C ₂₆ H ₃₀ N ₆ O ₂ [M+H] ⁺ :459.57, found value is 459.40.

[C93] N4-(4-(4-chlorophenoxy)benzyl)-8-isopropyl-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Using compound 1.3 and compound 14.3 as raw materials, referring to the synthetic route of compound C106, (4-(4-methyl-1H-imidazol-1-yl)phenyl)methanamine was replaced with (4-(4-chlorophenoxy)phenyl)methanamine to prepare compound C93 with a yield of 55%. ¹ H NMR (500 MHz, DMSO-d6) δ9.99 (s, 1H), 8.22 (d, J = 257.5 Hz, 2H), 7.47–7.37 (m, 4H), 7.04–6.92 (m, 4H), 4.63 (d, J = 6.2 Hz, 2H), 3.99 (s, 1H), 3.92–3.74 (m, 2H), 3.37 (td, J = 11.6, 2.2 Hz, 2H), 2.97 (p, J = 6.9 Hz, 1H), 1.77 (t, J = 27.6 Hz, 2H), 1.49 (qd, J = 11.4, 4.3 Hz, 2H), 1.21 (d, J = 6.9 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₆ H ₂₉ ClN ₆ O ₂ [M+H] ⁺ :494.01, found 493.33.

[C120] 8-isopropyl-N4-(4-(1-methyl-1H-imidazol-2-yl)benzyl)-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound 1.3 and compound 14.3 were used as raw materials, and the synthetic route of compound C106 was referred to. (4-(4-methyl-1H-imidazol-1-yl)phenyl)methylamine was replaced with (4-(1-methyl-1H-imidazol-2-yl)phenyl)methylamine to prepare compound C120 with a yield of 47%. ¹ H NMR (500MHz, DMSO-d6) δ9.99 (s, 1H), 8.81 (d, J＝107.7 Hz, 1H), 7.97 (s, 1H), 7.84 (d, J＝1.9 Hz, 1H), 7.80 (d, J＝2.0 Hz, 1H), 7.79–7.74 (m, 2H), 7.66 (d, J＝7.9 Hz, 2H), 4.77 (d , J＝6.3Hz,2H),3.94(s,1H),3.84(s,5H),3.44–3.28(m,2H),2.97(q, J＝6.9Hz,1H),1.93–1.64(m,2H),1.45(d, J＝12.9Hz,2H),1.21(d, J＝6.9Hz,6H). UPLC-MS (ESI) theoretical value for C ₂₄ H ₃₀ N ₈ O[M+H] ⁺ :447.56, found value is 447.39.

[C102] 1-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)pyrrolidin-2-one

Compound 1.3 and compound 14.3 were used as raw materials, and the synthetic route of compound C106 was referred to. (4-(4-methyl-1H-imidazol-1-yl)phenyl)methylamine was replaced with 1-(4-(aminomethyl)phenyl)pyrrolidin-2-one to prepare compound C102 with a yield of 39%. ¹ H NMR (500MHz, DMSO-d6) δ10.25–9.81 (m, 1H), 8.71 (d, J＝113.4 Hz, 1H), 7.86 (d, J＝101.7 Hz, 1H), 7.58 (d, J＝8.4 Hz, 2H), 7.38 (d, J＝8.2 Hz, 2H), 4.62 (d, J＝6.1 Hz, 2H), 4.03–3.96 (m, 1H), 3.87–3.82 (m, 2H), 3.79 (t, J = 7.0 Hz, 2H), 3.38 (t, J = 11.5 Hz, 2H), 2.97 (hept, J = 6.9 Hz, 1H), 2.47 (t, J = 8.0 Hz, 2H), 2.04 (p, J = 7.6 Hz, 2H), 1.92–1.65 (m, 2H), 1.48 (dt, J = 11.9, 5.5 Hz, 2H), 1.20 (d, J = 6.8 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₄ H ₃₁ N ₇ O ₂ [M+H] ⁺ : 450.56, found value 450.50.

Embodiment 15

[C123] 4'-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)-[1,1'-biphenyl]-3-carboxylic acid

Compound 15.2 was prepared using compound 15.1 and compound 1.3 as raw materials and referring to the synthetic route of compound 1.4 with a yield of 51%.

Using compound 15.2 and compound 14.3 as raw materials, referring to the synthetic route of compound C55, 15.3 was prepared with a yield of 40%.

Compound 15.3 was dissolved in dichloromethane, trifluoroacetic acid was added, and the mixture was reacted at room temperature for 6 h. After concentration under reduced pressure, the residue was washed with a small amount of water and acetonitrile, respectively, to obtain compound C123 with a yield of 95%. ¹ H NMR (800 MHz, DMSO-d6) δ10.05 (s, 1H), 8.16 (d, J = 1.9 Hz, 1H), 7.98 (s, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.91–7.87 (m, 1H), 7.67 (d, J = 7.8 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.51 (s, 2H), 4.71 ( d, J＝6.2 Hz, 2H), 3.99(s, 1H), 3.89–3.75(m, 2H), 3.38(t, J＝11.6 Hz, 2H), 2.98(p, J＝6.9 Hz, 1H), 1.90–1.67(m, 2H), 1.47(d, J＝12.5 Hz, 2H), 1.21(d, J＝7.3 Hz, 6H). UPLC-MS (ESI) theoretical value for C ₂₇ H ₃₀ N ₆ O ₃ [M+H] ⁺ :487.58, found value is 487.34.

Example 16

[C111] 8-Bromo-N2-(tetrahydro-2H-pyran-4-yl)-N4-(4-(thiophen-2-yl)benzyl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound 16.3 was prepared using compound 16.1 and compound 16.2 as raw materials and referring to the synthetic route of compound 1.4 with a yield of 58%.

Compound 16.3 (72 mg, 0.167 mmol, 1.0 equiv.) was dissolved in dichloromethane, and m-chloroperbenzoic acid (108 mg, 80%, 0.500 mmol, 3.0 equiv.) was added in batches under an ice bath. The mixture was transferred to room temperature for reaction for 5 h. After the reaction was completed, it was concentrated under reduced pressure and purified by column chromatography to obtain compound 16.4 (65 mg) with a yield of 84%.

C111 was prepared with compound 16.4 and compound 14.3 as raw materials and referring to the synthetic route of compound C55, with a yield of 38%. ¹ H NMR (500MHz, DMSO-d6) δ9.07 (d, J = 148.1 Hz, 1H), 7.95 (s, 1H), 7.64–7.57 (m, 2H), 7.51 (dd, J = 5.1, 1.2 Hz, 1H), 7.46 (d, J = 3.6 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.7 Hz, 1H), 7.11 (dd, J = 5.1, 3.6 Hz, 1H), 4.70–4.54 (m, 2H), 4.04–3.76 (m, 3H), 3.35 (dt, J＝23.9, 11.6 Hz, 2H), 1.71 (dd, J＝101.3, 12.5 Hz, 2H), 1.56–1.33 (m, 2H). UPLC-MS (ESI) theoretical value for C ₂₁ H ₂₁ BrN ₆ OS [M+H] ⁺ : 486.40, found value 485.17, 487.16.

[C110] 8-Bromo-N4-(4-(pyridin-2-yl)benzyl)-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Using compound 16.1 and compound 14.3 as raw materials, referring to the synthetic route of compound C111, (4-(thiophen-2-yl)phenyl)methanamine was replaced with (4-(pyridin-2-yl)phenyl)methanamine to prepare compound C110 with a yield of 42%. ¹ H NMR (500 MHz, DMSO-d6) δ9.16 (d, J = 182.7 Hz, 1H), 8.70 (dt, J = 5.0, 1.4 Hz, 1H), 8.07–8.00 (m, 4H), 7.97 (s, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 4.4 Hz, 1H), 4.69 (d, J = 13.7 Hz, 2H), 4.06–3.72 (m, 3H), 3.43–3.26 (m, 2H), 1.88–1.57 (m, 2H), 1.57–1.30 (m, 2H). UPLC-MS (ESI) theoretical value is C ₂₂ H ₂₂ BrN ₇ O [M+H] ⁺ :481.37, the actual measured values are 480.21,482.20.

[C124] 1-(4-(((8-bromo-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)pyridin-2(1H)-one

Using compound 16.1 and compound 14.3 as raw materials, referring to the synthetic route of compound C111, (4-(thiophen-2-yl)phenyl)methanamine was replaced with 1-(4-(aminomethyl)phenyl)pyridin-2(1H)-one to prepare compound C124 with a yield of 37%. ¹ H NMR (500 MHz, DMSO-d6) δ9.24 (d, J = 227.3 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.72–7.41 (m, 5H), 7.36–7.33 (m, 2H), 6.46 (dt, J = 9.3, 0.9 Hz, 1H), 6.29 (td, J = 6.7, 1.4 Hz, 1H), 4.77–4.61 (m, 2H), 3.93 (d, J = 24.4 Hz, 1H), 3.83 (d, J = 11.3 Hz, 2H), 3.36 (t, J = 11.3 Hz, 2H), 1.74 (d, J = 64.7 Hz, 2H), 1.46 (d, J = 32.5 Hz, 2H). UPLC-MS (ESI) theoretical value was C ₂₂ H ₂₂ BrN ₇ O ₂ [M+H] ⁺ :497.37, found 496.26,498.24.

[C125] 8-Bromo-N4-(4-(4-methyl-1H-imidazol-1-yl)benzyl)-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound 16.1 and compound 14.3 were used as raw materials, and the synthetic route of compound C111 was referred to. (4-(4-methyl-1H-imidazol-1-yl)phenyl)methylamine was replaced with (4-(4-methyl-1H-imidazol-1-yl)phenyl)methylamine to prepare compound C125 with a yield of 25%. ¹ H NMR (500MHz, DMSO-d6) δ9.51 (s, 1H), 9.13 (d, J＝130.4Hz, 1H), 7.96 (s, 2H), 7.70 (d, J＝8.2Hz, 2H), 7.61 (d, J＝8.2Hz, 2H), 7.49–7.22 (m, 1H), 4.68 (s, 2H), 4.00 (d, J＝7.2 Hz, 3H), 3.36 (dt, J＝20.5, 11.2 Hz, 2H), 2.34 (s, 3H), 1.81 (d, J＝12.7 Hz, 1H), 1.61 (d, J＝12.6 Hz, 1H), 1.49 (d, J＝13.0 Hz, 1H), 1.38 (d, J＝12.0 Hz, 1H). UPLC-MS (ESI) theoretical value for C ₂₁ H ₂₃ BrN ₈ O[M+H] ⁺ : 484.37, found values are 483.24, 485.21.

Embodiment 17

[C127] N-(4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)propanamide

Compound 17.1 was prepared with a yield of 78% using 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine and compound 10.2 as raw materials and referring to the synthetic route of compound 11.1.

Compound 17.1 was used as the raw material and the synthetic route of compound 11.2 was referred to to prepare compound 17.2 with a yield of 85%.

Compound 17.2 and compound 14.3 were used as raw materials, and referring to the synthetic route of compound 11.3, compound 17.3 was prepared with a yield of 51%.

Compound C127 was prepared with compound 17.3 as the raw material and with reference to the synthetic route of compound C37, with a yield of 93%. ¹ H NMR (500MHz, DMSO-d6) δ9.87 (s, 1H), 9.37 (s, 1H), 8.20 (s, 1H), 7.99 (s, 1H), 7.59–7.52 (m, 2H), 7.33 (d, J＝8.3Hz, 2H), 5.37 (s, 1H), 4.58 (d, J＝6.2Hz, 2H), 3.88–3.84 (m, 3H ),3.41(td,J＝11.6,2.1Hz,2H),3.09(s,1H),2.29(q,J＝7.6Hz,2H),1.80–1.69(m,2H),1.50–1.37(m,2H),1.21(d,J＝6.9Hz,6H),1.06(t,J＝7.5Hz,3H).UPLC-MS(ESI) theoretical value for C ₂₄ H ₃₂ N ₆ O ₂ [M+H] ⁺ :437.56, found value is 437.50.

Embodiment 18

[C126] 1-Fluoro-N-(4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)cyclopropane-1-carboxamide

Compound 18.1 was prepared using 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine and compound 13.2 as raw materials and referring to the synthetic route of compound 11.1 with a yield of 70%.

Compound 18.1 was used as the raw material and the synthetic route of compound 11.2 was referred to to prepare compound 18.2 with a yield of 82%.

Compound 18.2 and compound 14.3 were used as raw materials, and referring to the synthetic route of compound 11.3, compound 18.3 was prepared with a yield of 42%.

Compound C126 was prepared with compound 18.3 as the starting material and referring to the synthetic route of compound C37, with a yield of 90%. ¹ H NMR (500MHz, DMSO-d6) δ10.24 (d, J＝2.2Hz, 1H), 9.31 (s, 1H), 8.11 (s, 1H), 7.97 (s, 1H), 7.69–7.62 (m, 2H), 7.37 (d, J＝8.3Hz, 2H), 5.37 (s, 1H), 4.60 (d, J＝6.2Hz, 2H), 3.93–3.81 (m, 3H), 3.44–3.38 (m, 2H), 3.08 (p, J＝7.2Hz, 1H), 1.84–1.70 (m, 2H), 1.42 (dddd, J＝ 23.0,18.1,9.5,4.6Hz,4H),1.32–1.25(m,2H),1.21(d,J＝6.9Hz,6H).UPLC-MS(ESI) theoretical value for C ₂₅ H ₃₁ FN ₆ O ₂ [M+H] ⁺ :467.56, found value is 467.74.

Embodiment 19

[C137] (R)-N-(4-(((8-Bromo-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Compound 19.1 was prepared using compound 16.1 and compound 3.2 as raw materials and referring to the synthetic route of compound 16.3, with a yield of 55%.

Compound 19.2 was prepared using compound 19.1 as raw material and referring to the synthetic route of compound 16.4 with a yield of 88%.

Compound C137 was prepared with compound 19.2 and (R)-2-pyrrolidinemethanol as raw materials and referring to the synthetic route of compound C111 with a yield of 45%. ¹ H NMR (500 MHz, DMSO-d6) δ9.90 (s, 1H), 9.19–8.96 (m, 1H), 7.94 (d, J＝4.4 Hz, 1H), 7.55–7.46 (m, 2H), 7.32 (d, J＝8.1 Hz, 2H), 4.55 (t, J＝5.2 Hz, 2H), 4.12 (d, J＝9.5 Hz, 1H), 3.63 (dd, J＝10.4, 3.9 Hz, 1H), 3.60–3.29 (m, 3H), 2.01 (s, 3H), 1.99–1.74 (m, 4H). UPLC-MS (ESI) theoretical value for C ₁₉ H ₂₂ BrN ₇ O ₂ [M+H] ⁺ : 461.34, found values are 460.33, 462.33.

[C138] (S)-N-(4-(((8-Bromo-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Compound C138 was prepared with compound 19.2 and (S)-2-pyrrolidinemethanol as raw materials and referring to the synthetic route of compound C137 with a yield of 49%. ¹ H NMR (500 MHz, DMSO-d6) δ9.90 (s, 1H), 9.16–9.00 (m, 1H), 7.94 (d, J=4.1 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 4.55 (d, J=5.6 Hz, 2H), 4.12 (d, J=6.3 Hz, 1H), 3.63 (dd, J=10.4, 3.9 Hz, 1H), 3.60–3.29 (m, 3H), 2.01 (s, 3H), 2.00–1.78 (m, 4H). UPLC-MS (ESI) theoretical value is C ₁₉ H ₂₂ BrN ₇ O ₂ [M+H] ⁺ :461.34, the actual measured values are 460.34,462.34.

[C139] (S)-N-(4-(((8-bromo-2-(2-(2-hydroxyethyl)piperidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

Compound C139 was prepared with compound 19.2 and (S)-2-(2-piperidinyl)ethanol as raw materials and referring to the synthetic route of compound C137 with a yield of 39%. ¹ H NMR (500 MHz, DMSO-d6) δ9.91 (s, 1H), 9.01 (s, 1H), 7.93 (s, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 4.99 (s, 1H), 4.70–4.59 (m, 1H), 4.53 (d, J = 6.2 Hz, 2H), 3.35 (t, J = 6.6 Hz, 2H), 2.87 (t, J = 12.1 Hz, 1H), 2.01 (s, 3H), 1.88 (s, 1H), 1.74–1.58 (m, 4H), 1.58–1.44 (m, 2H), 1.35–1.25 (m, 1H). UPLC-MS (ESI) theoretical value is C ₂₁ H ₂₆ BrN ₇ O ₂ [M+H] ⁺ :489.39, found values are 488.37, 490.36.

Embodiment 20

[C140] (R)-N-(4-(((8-Bromo-2-(3-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound 20.1 was prepared using compound 16.1 and compound 10.2 as raw materials and referring to the synthetic route of compound 16.3 with a yield of 60%.

Compound 20.2 was prepared using compound 20.1 as raw material and referring to the synthetic route of compound 16.4 with a yield of 83%.

Compound C140 was prepared with compound 20.2 and (R)-3-pyrrolidinol as raw materials and referring to the synthetic route of compound C111 with a yield of 49%. ¹ H NMR (600 MHz, DMSO-d6) δ9.84 (s, 1H), 9.05 (d, J = 6.6 Hz, 1H), 7.94 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.35–7.29 (m, 2H), 4.54 (d, J = 6.3 Hz, 2H), 4.36–4.31 (m, 1H), 3.69–3.41 (m, 4H), 2.29 (q, J = 7.5 Hz, 2H), 2.01–1.92 (m, 1H), 1.88–1.83 (m, 1H), 1.06 (t, J = 7.5 Hz, 3H). UPLC-MS (ESI) theoretical value is C ₁₉ H ₂₂ BrN ₇ O ₂ [M+H] ⁺ :461.34, the measured values are 460.37,462.35.

[C141] (S)-N-(4-(((8-Bromo-2-(3-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C141 was prepared with a yield of 53% using compound 20.2 and (S)-3-pyrrolidinol as raw materials and referring to the synthetic route of compound C140. ¹ H NMR (600 MHz, DMSO-d6) δ9.84 (s, 1H), 9.09 (d, J = 6.7 Hz, 1H), 7.94 (s, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 4.55 (d, J = 6.3 Hz, 2H), 4.34 (dt, J = 6.1, 2.8 Hz, 1H), 3.69–3.41 (m, 4H), 2.29 (q, J = 7.5 Hz, 2H), 1.97 (q, J = 3.9 Hz, 1H), 1.86 (dt, J = 8.9, 4.3 Hz, 1H), 1.06 (t, J = 7.6 Hz, 3H). UPLC-MS (ESI) theoretical value: C ₁₉ H ₂₂ BrN ₇ O ₂ [M+H] ⁺ :461.34, found values are 460.37,462.36.

[C142] (R)-N-(4-(((8-bromo-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C142 was prepared with compound 20.2 and (R)-2-pyrrolidinemethanol as raw materials and referring to the synthetic route of compound C140 with a yield of 55%. ¹ H NMR (500 MHz, DMSO-d6) δ9.82 (s, 1H), 9.14–9.00 (m, 1H), 7.94 (d, J=4.1 Hz, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 4.54 (t, J=5.7 Hz, 2H), 4.11 (s, 1H), 3.63 (dd, J=10.5, 3.8 Hz, 1H), 3.60–3.30 (m, 3H), 2.29 (q, J=7.5 Hz, 2H), 1.92 (ddd, J=56.2, 32.2, 10.3 Hz, 4H), 1.06 (t, J=7.6 Hz, 3H). UPLC-MS (ESI) theoretical value for C ₂₀ H ₂₄ BrN ₇ O ₂ [M+H] ⁺ :475.36, found values are 474.35,476.35.

[C143] (S)-N-(4-(((8-bromo-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C143 was prepared with compound 20.2 and (S)-2-pyrrolidinemethanol as raw materials and referring to the synthetic route of compound C140 with a yield of 40%. ¹ H NMR (500 MHz, DMSO-d6) δ9.82 (s, 1H), 9.16–9.00 (m, 1H), 7.94 (d, J=4.6 Hz, 1H), 7.52 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 4.55 (t, J=5.7 Hz, 2H), 4.16–4.06 (m, 1H), 3.63 (dd, J=10.4, 3.9 Hz, 1H), 3.61–3.30 (m, 3H), 2.29 (q, J=7.5 Hz, 2H), 1.92 (ddd, J=55.6, 35.0, 8.7 Hz, 4H), 1.06 (t, J=7.5 Hz, 3H). UPLC-MS (ESI) theoretical value for C ₂₀ H ₂₄ BrN ₇ O ₂ [M+H] ⁺ :475.36, found values are 474.35, 476.34.

[C144] (S)-N-(4-(((8-bromo-2-(2-(2-hydroxyethyl)piperidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C144 was prepared with compound 20.2 and (S)-2-(2-piperidinyl)ethanol as raw materials and referring to the synthetic route of compound C140 with a yield of 37%. ¹ H NMR (600 MHz, DMSO-d6) δ9.83 (s, 1H), 9.03 (s, 1H), 7.94 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 4.97 (s, 1H), 4.57–4.50 (m, 3H), 3.36 (d, J = 6.6 Hz, 2H), 2.87 (t, J = 13.4 Hz, 1H), 2.29 (q, J = 7.5 Hz, 2H), 1.87 (s, 1H), 1.74–1.45 (m, 6H), 1.36–1.25 (m, 1H), 1.05 (t, J = 7.5 Hz, 3H). UPLC-MS (ESI) theoretical value is C ₂₂ H ₂₈ BrN ₇ O ₂ [M+H] ⁺ :503.42, found values are 502.38,504.37.

Embodiment 21

[C145] (R)-N-(4-(((8-Bromo-2-(3-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-1-fluorocyclopropane-1-carboxamide

Compound 21.1 was prepared using compound 16.1 and compound 13.2 as raw materials and referring to the synthetic route of compound 16.3 with a yield of 47%.

Compound 21.2 was prepared using compound 21.1 as raw material and referring to the synthetic route of compound 16.4 with a yield of 76%.

Compound C145 was prepared with a yield of 31% using compound 21.2 and (R)-3-pyrrolidinol as raw materials and referring to the synthetic route of compound C111. ¹ H NMR (500 MHz, DMSO-d6) δ10.24–10.15 (m, 1H), 9.08 (d, J = 5.5 Hz, 1H), 7.94 (s, 1H), 7.68–7.60 (m, 2H), 7.35 (d, J = 8.1 Hz, 2H), 4.57 (d, J = 6.3 Hz, 2H), 4.38–4.31 (m, 1H), 3.69–3.42 (m, 4H), 1.96 (qd, J = 8.7, 4.4 Hz, 1H), 1.85 (dq, J = 12.7, 3.5 Hz, 1H), 1.43–1.34 (m, 2H), 1.33–1.25 (m, 2H). UPLC-MS (ESI) theoretical value for C ₂₀ H ₂₁ BrFN ₇ O ₂ [M+H] ⁺ :491.34, found values are 490.32,492.32.

[C146] (S)-N-(4-(((8-Bromo-2-(3-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-1-fluorocyclopropane-1-carboxamide

Compound C146 was prepared using compound 21.2 and (S)-3-pyrrolidinol as raw materials and referring to the synthetic route of compound C145 with a yield of 50%. ¹ H NMR (500 MHz, DMSO-d6) δ10.19 (s, 1H), 9.03 (d, J = 6.2 Hz, 1H), 7.93 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.39–7.30 (m, 2H), 4.57 (d, J = 6.3 Hz, 2H), 4.33 (s, 1H), 3.61–3.42 (m, 4H), 1.96 (dtd, J = 13.2, 8.7, 4.3 Hz, 1H), 1.84 (dd, J = 14.3, 6.1 Hz, 1H), 1.43–1.25 (m, 4H). UPLC-MS (ESI) theoretical value for C ₂₀ H ₂₁ BrFN ₇ O ₂ [M+H] ⁺ :491.34, the measured values are 490.33,492.32.

[C147] (R)-N-(4-(((8-bromo-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-1-fluorocyclopropane-1-carboxamide

Compound C147 was prepared with compound 21.2 and (R)-2-pyrrolidinemethanol as raw materials and referring to the synthetic route of compound C145 with a yield of 39%. ¹ H NMR (500 MHz, DMSO-d6) δ10.19 (d, J＝2.3 Hz, 1H), 9.14–8.99 (m, 1H), 7.94 (d, J＝3.8 Hz, 1H), 7.63 (d, J＝8.4 Hz, 2H), 7.35 (d, J＝8.1 Hz, 2H), 4.62–4.52 (m, 2H), 4.11 (s, 1H), 3.63 (dd, J＝10.5, 3.8 Hz, 1H), 3.60–3.28 (m, 3H), 1.92 (td, J＝42.9, 41.8, 11.2 Hz, 4H), 1.43–1.25 (m, 4H). UPLC-MS (ESI) theoretical value is C ₂₁ H ₂₃ BrFN ₇ O ₂ [M+H] ⁺ :505.36, the actual measured values are 504.31,506.30.

[C148] (S)-N-(4-(((8-Bromo-2-(2-(hydroxymethyl)pyrrolidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-1-fluorocyclopropane-1-carboxamide

Compound C148 was prepared with a yield of 42% using compound 21.2 and (S)-2-pyrrolidinemethanol as raw materials and referring to the synthetic route of compound C145. ¹ H NMR (500 MHz, DMSO-d6) δ10.19 (d, J = 2.2 Hz, 1H), 9.19–9.01 (m, 1H), 7.94 (d, J = 3.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 4.57 (t, J = 5.3 Hz, 2H), 4.10 (d, J = 7.6 Hz, 1H), 3.62 (dd, J = 10.4, 3.9 Hz, 1H), 3.59–3.29 (m, 3H), 1.91 (tdd, J = 36.5, 17.5, 8.5 Hz, 4H), 1.43–1.24 (m, 4H). UPLC-MS (ESI) theoretical value: C ₂₁ H ₂₃ BrFN ₇ O ₂ [M+H] ⁺ :505.36, found values are 504.31,506.30.

[C149] (S)-N-(4-(((8-bromo-2-(2-(2-hydroxyethyl)piperidin-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-1-fluorocyclopropane-1-carboxamide

Compound C149 was prepared with compound 21.2 and (S)-2-(2-piperidinyl)ethanol as raw materials and referring to the synthetic route of compound C145 with a yield of 40%. ¹ H NMR (500 MHz, DMSO-d6) δ10.19 (d, J＝2.2 Hz, 1H), 9.05 (s, 1H), 7.94 (s, 1H), 7.66–7.60 (m, 2H), 7.35 (d, J＝8.2 Hz, 2H), 5.00 (s, 1H), 4.60 (dd, J＝40.8, 9.4 Hz, 3H), 3.35 (t, J＝6.6 Hz, 2H), 2.87 (td, J＝13.6, 12.7, 4.3 Hz, 1H), 1.87 (s, 1H), 1.75–1.45 (m, 6H), 1.43–1.25 (m, 5H). UPLC-MS (ESI) theoretical value is C ₂₃ H ₂₇ BrFN ₇ O ₂ [M+H] ⁺ :533.42, the actual measured values are 532.36,534.34.

[C64] N-(4-(((8-cyclopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C64 can be synthesized according to the above synthetic route.

[C65] N-(4-(((8-isopropyl-2-morpholinylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C65 can be synthesized according to the above synthetic route.

[C66] N-(4-(((8-cyclopropyl-2-morpholinylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C66 can be synthesized according to the above synthetic route.

[C67] N-(4-(((8-bromo-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C67 can be synthesized according to the above synthetic route.

[C68] N-(4-(((8-(1-methyl-1H-pyrazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C68 can be synthesized according to the above synthetic route.

[C69] N-(4-(((2-((tetrahydro-2H-pyran-4-yl)amino)-8-(trifluoromethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C69 can be synthesized according to the above synthetic route.

[C70] N-(4-(((8-cyano-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C70 can be synthesized according to the above synthetic route.

[C71] N-(4-(((8-cyclobutyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C71 can be synthesized according to the above synthetic route.

[C72] N-(4-(((2-((tetrahydro-2H-pyran-4-yl)amino)-8-(2,2,2-trifluoroethyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C72 can be synthesized according to the above synthetic route.

[C73] N-(4-(((8-(oxetan-3-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C73 can be synthesized according to the above synthetic route.

[C74] N-(4-(((8-(2,2-difluorocyclopropyl)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C74 can be synthesized according to the above synthetic route.

[C75] N-(4-(((8-(tetrahydro-2H-pyran-4-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C75 can be synthesized according to the above synthetic route.

[C76] N-(4-(((8-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C76 can be synthesized according to the above synthetic route.

[C77] N-(4-(((8-(pyridazin-4-yl)-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C77 can be synthesized according to the above synthetic route.

[C78] N-(4-(((2-((tetrahydro-2H-pyran-4-yl)amino)-8-(thiazol-2-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C78 can be synthesized according to the above synthetic route.

[C79] N-(4-(((2-((tetrahydro-2H-pyran-4-yl)amino)-8-(thiazol-4-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C79 can be synthesized according to the above synthetic route.

[C80] N-(4-(((2-((tetrahydro-2H-pyran-4-yl)amino)-8-(thiazol-5-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C80 can be synthesized according to the above synthetic route.

[C81] N-(2-Fluoro-4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C81 can be synthesized according to the above synthetic route.

[C82] N-(2,3,5,6-tetrafluoro-4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C82 can be synthesized according to the above synthetic route.

[C83] N-(3,5-difluoro-4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C83 can be synthesized according to the above synthetic route.

[C84] N-(2,6-difluoro-4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C84 can be synthesized according to the above synthetic route.

[C85] N-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl-2,3,5,6-d ₄ )propanamide

Compound C85 can be synthesized according to the above synthetic route.

[C86] N-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

Compound C86 can be synthesized according to the above synthetic route.

[C87] 8-Isopropyl-N4-(4-phenoxybenzyl)-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C87 can be synthesized according to the above synthetic route.

[C88] N ⁴ -(4-(3-fluorophenoxy)benzyl)-8-isopropyl-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C88 can be synthesized according to the above synthetic route.

[C89] N ⁴ -(4-(4-fluorophenoxy)benzyl)-8-isopropyl-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C89 can be synthesized according to the above synthetic route.

[C90] N ⁴ -(4-(2-fluorophenoxy)benzyl)-8-isopropyl-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C90 can be synthesized according to the above synthetic route.

[C91] N ⁴ -(4-(3-chloro-4-fluorophenoxy)benzyl)-8-isopropyl-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C91 can be synthesized according to the above synthetic route.

[C92] N ⁴ -(4-(3,4-difluorophenoxy)benzyl)-8-isopropyl-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C92 can be synthesized according to the above synthetic route.

[C93] N4-(4-(4-chlorophenoxy)benzyl)-8-isopropyl-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C93 can be synthesized according to the above synthetic route.

[C94] N ⁴ -(4-(3,4-dichlorophenoxy)benzyl)-8-isopropyl-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C94 can be synthesized according to the above synthetic route.

[C95] 8-isopropyl-N ² -(tetrahydro-2H-pyran-4-yl)-N ⁴ -(4-((tetrahydrofuran-3-yl)oxy)benzyl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C95 can be synthesized according to the above synthetic route.

[C96] 8-isopropyl-N ⁴ -(4-(pyridin-4-yloxy)benzyl)-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C96 can be synthesized according to the above synthetic route.

[C97] 4-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)morpholin-3-one

Compound C97 can be synthesized according to the above synthetic route.

[C98] 1-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)piperidin-2-one

Compound C98 can be synthesized according to the above synthetic route.

[C99] 8-isopropyl-N ⁴ -(4-(piperazin-1-yl)benzyl)-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazol Oxazine-2,4-diamine

Compound C99 can be synthesized according to the above synthetic route.

[C100] 8-isopropyl-N ⁴ -(4-morpholinobenzyl)-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C100 can be synthesized according to the above synthetic route.

[C101] 8-isopropyl-N ⁴ -(4-(4-methylpiperazin-1-yl)benzyl)-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C101 can be synthesized according to the above synthetic route.

[C102] 1-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)pyrrolidin-2-one

Compound C102 can be synthesized according to the above synthetic route.

[C103] N ⁴ -(4-(4,7-diazaspiro[2.5]octan-7-yl)benzyl)-8-isopropyl-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C103 can be synthesized according to the above synthetic route.

[C104] 4'-(((8-Bromo-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)-[1,1'-biphenyl]-3-carboxylic acid

Compound C104 can be synthesized according to the above synthetic route.

[C105] N ⁴ -(4-(2H-tetrazolyl-5-yl)benzyl)-8-isopropyl-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C105 can be synthesized according to the above synthetic route.

[C106] 8-isopropyl-N ⁴ -(4-(4-methyl-1H-imidazol-1-yl)benzyl)-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C106 can be synthesized according to the above synthetic route.

[C107] 1-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)pyridin-2(1H)-one

Compound C107 can be synthesized according to the above synthetic route.

[C108] 5-(4-(((8-isopropyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)-1-methylpyridin-2(1H)-one

Compound C108 can be synthesized according to the above synthetic route.

[C109] 8-Bromo-N ² -(tetrahydro-2H-pyran-4-yl)-N ⁴ -(4-(thiophen-3-yl)benzyl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C109 can be synthesized according to the above synthetic route.

[C110] 8-Bromo-N ⁴ -(4-(pyridin-2-yl)benzyl)-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C110 can be synthesized according to the above synthetic route.

[C111] 8-Bromo-N ² -(tetrahydro-2H-pyran-4-yl)-N ⁴ -(4-(thiophen-2-yl)benzyl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C111 can be synthesized according to the above synthetic route.

[C112] N ⁴ -(4-(1H-pyrazol-4-yl)benzyl)-8-isopropyl-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C112 can be synthesized according to the above synthetic route.

[C113] N ⁴ -(4-(1H-imidazol-1-yl)benzyl)-8-isopropyl-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C113 can be synthesized according to the above synthetic route.

[C114] 8-isopropyl-N ⁴ -(4-(1-methyl-1H-pyrazol-4-yl)benzyl)-N ² -(tetrahydro-2H-pyrazol-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C114 can be synthesized according to the above synthetic route.

[C115] 8-isopropyl-N ⁴ -(4-(oxazol-5-yl)benzyl)-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C115 can be synthesized according to the above synthetic route.

[C116] 8-isopropyl-N ⁴ -(4-(isoxazol-4-yl)benzyl)-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C116 can be synthesized according to the above synthetic route.

[C117] 8-isopropyl-N ² -(tetrahydro-2H-pyran-4-yl)-N ⁴ -(4-(thiazol-5-yl)benzyl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C117 can be synthesized according to the above synthetic route.

[C118] N ⁴ -(4-(1H-imidazol-2-yl)benzyl)-8-isopropyl-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C118 can be synthesized according to the above synthetic route.

[C119] N ⁴ -(4-(1H-imidazol-4-yl)benzyl)-8-isopropyl-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C119 can be synthesized according to the above synthetic route.

[C120] 8-isopropyl-N ⁴ -(4-(1-methyl-1H-imidazol-2-yl)benzyl)-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C120 can be synthesized according to the above synthetic route.

[C121] 8-isopropyl-N ⁴ -(4-(pyridazin-4-yl)benzyl)-N ² -(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C121 can be synthesized according to the above synthetic route.

[C122] 8-isopropyl-N ⁴ -(4-(pyridazin-3-yl)benzyl)-N ² -(tetrahydro-2H-pyrazin-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

Compound C122 can be synthesized according to the above synthetic route.

Example 22: Proliferation and growth inhibition activity of the compound on triple-negative breast cancer cells

1. Experimental methods

The human triple-negative breast cancer cells MDA-MB-231, MDA-MB-468 and BT549 used in the present invention were purchased from the Shanghai Cell Bank, and the MDA-MB-231 and MDA-MB-468 cells were cultured in a 37°C, _CO2- free incubator in Leibovitzs (L-15) medium supplemented with 10% fetal bovine serum (FBS) and penicillin-streptomycin (PS) antibiotics. 468 cells and BT549 cells were cultured in RPMI 1640 medium supplemented with 10% FBS, 1% penicillin-streptomycin (PS) antibiotics and recombinant human insulin solution (Insulin) at 37°C in an incubator containing 5% CO ₂ .

In the cell activity test experiment, according to the cell growth, 90 μL of cell suspension of appropriate concentration was added to a 96-well cell culture plate, each compound to be tested was gradiently diluted with the corresponding culture medium, 10 μL of the diluted compound was added to 90 μL of cell solution, and then cultured at 37°C, 5% CO ₂ for 4 days. Cell proliferation was analyzed by WST-8, which can be reduced to yellow formazan by lactate dehydrogenase in the cells. 10 μL of WST-8 reagent (DOJINDO) was added to the cells and reacted at 37°C for more than 1 hour. Cells treated with DMSO were used as positive controls, OD450nm was read by a microplate reader, and the data were processed using GraphPad Prism6 software. Activity results: A represents cell activity IC ₅₀ <1μM, B represents cell activity 1μM <IC ₅₀ <3μM, and C represents cell activity IC ₅₀ >3μM.

2. Experimental results

Based on the above compound cell growth inhibition activity test method, in triple-negative breast cancer cell lines MDA-MB-231, MDA-MB-468 and BT549, compared with the positive compound Control compound, the compound of the present invention has a good inhibitory activity on cell growth inhibition. Therefore, the compound of the present invention can be used as a new inhibitor of related targets in triple-negative breast cancer cells.

Example 23: In vitro kinase inhibitory activity of compounds against CDK

1. Experimental methods

In the in vitro kinase activity test, the LANCE Ultra KinaSelect Ser/Thr detection kit of Perkin Elmer was used to determine the kinase activity of CDK9. The reaction of this method was carried out in a 384-well plate, and the total reaction volume was 10 μL. CDK9 protein (final concentration of 1 ng/μL), 4EBP-1 peptide substrate (final concentration of 50 nM) and ATP (final concentration of 2.5 μM) were reacted in a buffer solution: 50 mM HEPES-KOH (pH 7.5), 10 mM MgCl ₂ , 2 mM DTT, 1 mM EGTA for 1 h, and the corresponding Eu-labeled anti-phosphorylation antibody Eu-anti-P-4E-BP1 (final concentration of 2 nM) was added and incubated for 30 min, and then the phosphorylation was detected, and the laser ratio at 620 nM and 665 nM wavelengths was detected by the fluorescence detector Envision (PerkinElmer, USA). Activity results: A indicates cell activity IC ₅₀ <100nM, B indicates cell activity 100nM<IC ₅₀ <1000nM, C indicates cell activity 1μM<IC ₅₀ <20μM, and D indicates cell activity IC ₅₀ >20μM.

2. Experimental results

In vitro kinase inhibitory activity of compounds against CDK9

Based on the in vitro kinase inhibitory activity of the above compounds on CDK9, most of the compounds of the present invention have good in vitro kinase inhibitory activity on CDK9. Therefore, the compounds of the present invention can be used as new inhibitors of CDK9 targets.

Using a similar kinase assay as described above, the in vitro kinase inhibitory activity of related kinases such as CDK2, CDK4, CDK6, CDK7, CDK12, and CDK13 was tested.

2. Experimental methods

In the in vitro kinase activity test, the LANCE Ultra KinaSelect Ser/Thr detection kit of Perkin Elmer was used to determine the CDK2 kinase activity. The reaction of this method was in a 384-well plate, and the total reaction volume was 10μL. CDK2 protein (final concentration of 1ng/μL), 4EBP-1 peptide substrate (final concentration of 50nM) and ATP (final concentration of 2.5μM) were reacted in a buffer solution: 50mM HEPES-KOH (pH 7.5), 10mM MgCl ₂ , 2mM DTT, 1mM EGTA for 1h, and the corresponding Eu-labeled anti-phosphorylation antibody Eu-anti-P-4E-BP1 (final concentration of 2nM) was added and incubated for 30min, and then the phosphorylation was detected, and the laser ratio at 620nM and 665nM wavelengths was detected by the fluorescence detector Envision (PerkinElmer, USA). Activity results:

A indicates cell activity IC ₅₀ <100nM, B indicates cell activity 100nM<IC ₅₀ <1000nM, C indicates cell activity 1μM<IC ₅₀ <20μM, and D indicates cell activity IC ₅₀ >20μM.

In vitro kinase inhibitory activity of compounds against CDK2

Based on the in vitro kinase inhibitory activity of the above compounds on CDK2, most of the compounds of the present invention have certain inhibitory activity on the in vitro kinase of CDK2, while some compounds have much higher in vitro kinase activity on CDK9, so these compounds have good CDK9/CDK2 selectivity. The compounds of the present invention can be used as novel selective inhibitors of CDK9 or CDK2 targets, or they can be used as inhibitors of dual targets.

3. Experimental methods

In the in vitro kinase activity test, the LANCE Ultra KinaSelect Ser/Thr detection kit of Perkin Elmer was used to determine the kinase activity of CDK12. The reaction of this method was carried out in a 384-well plate, and the total reaction volume was 10 μL. CDK12 protein (final concentration of 1 ng/μL), 4EBP-1 peptide substrate (final concentration of 50 nM) and ATP (final concentration of 2.5 μM) were reacted in a buffer solution: 50 mM HEPES-KOH (pH 7.5), 10 mM MgCl ₂ , 2 mM DTT, 1 mM EGTA for 1 h, and the corresponding Eu-labeled anti-phosphorylation antibody Eu-anti-P-4E-BP1 (final concentration of 2 nM) was added and incubated for 30 min, and then the phosphorylation was detected, and the laser ratio at 620 nM and 665 nM wavelengths was detected by the fluorescence detector Envision (PerinElmer, USA). Activity results: In vitro kinase inhibition rate (10 μM) A indicates kinase inhibition rate >40%, B indicates kinase inhibition rate 10% <IC ₅₀ <40%, C indicates kinase inhibition rate 1% <IC ₅₀ <10%, and D indicates kinase inhibition rate IC ₅₀ <1%.

In vitro kinase inhibitory activity of compounds against CDK12

Based on the in vitro kinase inhibitory activity of the above compounds on CDK12, most of the compounds of the present invention have good in vitro kinase inhibitory activity on CDK12. Therefore, the compounds of the present invention can be used as new inhibitors of CDK12 targets.

Example 24: Pharmacokinetic Characterization of Compounds

1. Experimental methods

Twenty-four male ICR mice (6-8 weeks old, 18-22 g, Beijing Weitong Lihua Experimental Animal Science Technology Co., Ltd., China) were randomly divided into 8 groups, 3 mice in each group. The mice were administered a single oral gavage (20 mg/kg) and intravenous injection (5 mg/kg) with a single dose of compounds C27, C44, C58 and C59 dissolved in DMSO/solutol HS-15/normal saline (5, 5 and 90%). The oral gavage group fasted for 10-14 hours before administration, but was not allowed to drink water. They were allowed to eat freely 4 hours after administration, and then blood (50 μL) was collected from the eye sockets before administration and at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The intravenous group did not fast before administration, and then blood was collected from the eye sockets before administration and at 0.083, 0.5, 1, 2, 4, 8, and 24 hours after administration. Blood (50 μL) was collected. The sample was centrifuged at 12000 rpm for 5 min to obtain plasma, which was stored at -20°C before analysis. LC-MS/MS technology was used for analysis to evaluate the pharmacokinetics of compounds C27, C44, C58 and C59 in plasma.

2. Experimental results

The compounds (C27, C44, C58 and C59) of the present invention have good absorption, bioavailability greater than 40%, and good pharmacokinetic properties. Since the compounds are inhibitors of a completely new structure, they have great potential in the development of new drugs and can be used as new CDK9 inhibitors.

Example 25: An experiment in which compounds act on CDK to cause degradation of its interacting proteins.

In the present invention, we also unexpectedly discovered that some of the compounds can lead to the degradation of its interacting proteins, such as Cyclin K protein, after acting on CDK. Therefore, the development of compounds that selectively weaken the function of CDK12/Cyclin K can be used to treat cancer and other diseases. CDK12 inhibitors have the problem of poor restriction. The compounds in the present invention can achieve the functions of other proteins in the RNA polymerase II complex or the function of the pre-mRNA splicing complex by inducing the hydrolysis of CDK12/Cyclin K protein. Therefore, the compounds in the present invention can weaken the function of CDK/Cyclin K, while preserving the selectivity for other CDKs, achieving effective treatment of diseases, and reducing undesirable side effects, providing clinical effectiveness. Therefore, the compounds of the present invention can achieve the function of weakening CDK12/Cyclin K, and can therefore be used in drugs for treating or preventing abnormal CDK12 activity or regulating diseases or symptoms related to CDK activity.

1. Experimental methods

MDA-MB-231 cells were inoculated in 6-well plates, and the corresponding compounds or DMSO blank controls were added. After incubation for the corresponding time, the cells were lysed on ice with lysis buffer (RIPA:PI=6:1, RIPA+PI:PMSF=200:1) for 10 min, centrifuged at 15000g for 30 min at 4°C, and the protein supernatant was taken for protein quantification and normalization using BCA reagent. After 8% SDS-PAGE gel electrophoresis, the protein was transferred to a PVDF membrane, blocked with 5% skim milk and incubated with the primary antibody (Cyclin K), washed with 5% skim milk and incubated with the secondary antibody (rabbit antibody), and washed and exposed after incubation.

The experimental results are shown in Figure 1. The results show that after treating MDA-MB-231 cells with compounds at a concentration of 50nM for 2 hours, compared with the positive compound Cyclin K degrader CR8, most of the compounds of the present invention have a more significant degradation effect on Cyclin K. Therefore, the patented compounds can be used to treat triple-negative breast cancer or other diseases related to abnormal cyclin K activity by degrading Cyclin K.

discuss

The inventors of the present invention obtained the following important information by analyzing the complex crystal structure of CDK9 and the complex crystal structure of other CDKs (PDB ID: IQMZ, 3BLR, 1UA2, 3BLH): The hydrogen bonds between the ligand and the hinge residues Asp104 and Cys106 in the CDK9 protein are crucial for the activity of the ligand. For example, the core scaffold of the CDK9 inhibitor in clinical trials forms hydrogen bonds with residues in the hinge region, which greatly contributes to its CDK9 potency. The activation loop (T loop) is the location of a threonine residue whose phosphorylation is crucial for the activity of the enzyme, which is Thr186 in CDK9. In addition, residues Asp149, Lys151 and Thr191 of CDK9 form a catalytic loop that is directly involved in the phosphotransfer reaction. It is worth noting that some less conserved regions in the CDK9 binding site, including hydrophobic regions and solvent-exposed regions, may provide opportunities for the design of selective CDK9 inhibitors. Through structural analysis, we also obtained important information from the docking results of CDK9 and other small molecule inhibitors (PDB ID: 3LQ5): the 4-amino group and N6 of pyrazoline [1,5-a] [1,3,5] triazine interact with the hinge region and form hydrogen bonds with the amide nitrogen and carbonyl moieties of the Cys106 residue, respectively. This interaction leads to its inhibitory effect on the kinase activity of CDK9. In addition, the benzene ring points to the solvent region, and the isopropyl group is located in the hydrophobic region composed of Ala46 and Val79. Therefore, these characteristics will mainly serve as the starting point for our design of small molecule inhibitors of CDK9. Based on the molecular docking of the crystal structure, the inventors mainly designed and synthesized CDK9 small molecule inhibitors targeting transcriptional regulation, and conducted activity tests and screening in the CDK kinase family (including CDK2, 4, 6, 7, 9) and triple-negative breast cancer cell lines (including MDA-MB-231 and BT549); the test results showed that this type of molecule has very high anti-proliferation activity in triple-negative breast cancer cells, very high kinase inhibitory activity against CDK9, and very high selectivity for other CDK subtypes. At the same time, through relevant testing methods, it was found that most of the compounds of this type of molecule have good transmembrane absorption, are highly permeable compounds, and have good pharmacokinetic data. Preliminary studies on the mechanism found that the compound promotes cell apoptosis and inhibits cancer cell proliferation, thereby achieving effective disease treatment based on the CDK9 target.

The present invention unexpectedly found that the substituents in the compound of formula (I) and The selection of different CDKs has different effects. By changing and The structure of can also achieve the activity of targeting CDK12. The compounds in the present invention are also unexpectedly found to have the activity of targeting CDK12 and regulate the degradation of CyclinK protein. The development of compounds that selectively weaken the function of CDK12/Cyclin K can be used to treat cancer and other diseases. CDK12 inhibitors have the problem of poor restriction. The compounds in the present invention can achieve the function of other proteins in the RNA polymerase II complex or the function of the pre-mRNA splicing complex by inducing the hydrolysis of CDK12/Cyclin K protein. Therefore, the compound in the present invention can weaken the function of CDK/Cyclin K, while preserving the selectivity for other CDKs, achieving effective treatment of diseases, and reducing undesirable side effects, providing the effectiveness in clinical practice. Therefore, the compounds of the present invention can achieve the function of weakening CDK12/Cyclin K, so they can be used in drugs for treating or preventing abnormal CDK12 activity or regulating diseases or symptoms related to CDK activity.

All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims (13)

A compound represented by general formula (I), and its tautomers, stereoisomers, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof,
Wherein, X is CH or N; Y is selected from -NH-, -O- or absent; R ¹ is selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the following group: hydroxyl, C ₁ -C ₃ alkyl, propynyl, C ₁ -C ₃ alkylhydroxyl, C ₁ -C ₃ alkylcarbonyl, halogen, 3-8 membered heterocyclyl, amino, (C ₁ -C ₃ alkyl) _1-2amino , methylsulfonyl; Selected from hydrogen, halogen, cyano, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the following group: deuterium, halogen, cyano, nitro, hydroxyl, amino, C ₁ -C ₃ alkyl, halogen-substituted C ₁ -C ₃ alkyl; R ² is selected from hydrogen, deuterium, halogen and unsubstituted or halogenated C ₁ -C ₃ alkyl; R ³ is selected from deuterium, halogen, cyano, hydroxyl, nitro, unsubstituted or halogenated C ₁ -C ₃ alkyl; n is 1 or 2; m is 0, 1, 2, 3 or 4; Z is selected from NH, N, O or absent; When Z is selected from NH or N, each independently selected from hydrogen, -C(O)R ⁴ , C ₁ -C ₃ alkyl substituted with R ⁵ , wherein R ⁴ is selected from C ₁ -C ₆ alkyl substituted with R ⁶ , 3-6 membered heterocycloalkyl substituted with R ⁶ , and C ₃ -C ₆ cycloalkyl substituted with R ⁶ , wherein each R ⁶ is independently selected from hydrogen, hydroxy, C ₁ -C ₃ alkyl-C(O)-, halogen, and carboxyl; R ⁵ is selected from hydrogen, hydroxy, halogen, and carboxyl; When Z is selected from O or Z is absent, each Independently selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 3-8 membered heterocyclyl, wherein the substitution means that one or more H on the group is substituted by a substituent independently selected from the group consisting of deuterium, oxo (=O), halogen, cyano, nitro, hydroxyl, amino, carboxyl, formylamino, C ₁ -C ₃ alkyl, halogen-substituted C ₁ -C ₃ alkyl; The premise is that when Z does not exist, Not simultaneously selected from the following substituents: is phenyl, pyridyl, thienyl, furyl, thiazolyl, pyrrolyl and pyrimidinyl, It is an unsubstituted C ₁ -C ₆ alkyl group or an unsubstituted C ₃ -C ₆ cycloalkyl group. The compound according to claim 1, and its tautomers, stereoisomers, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, wherein the compound has a structure shown in formula (I-1)-(I-4):
Among them, (I-2) Can be the same or different, X is CH or N; Y is selected from -NH-, -O- or absent; R ¹ is selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the following group: hydroxyl, C ₁ -C ₃ alkyl, propynyl, -C ₁ -C ₃ alkylhydroxyl, C ₁ -C ₃ alkylcarbonyl, halogen, 3-8 membered heterocyclyl, amino, (C ₁ -C ₃ alkyl) _1-2amino , methylsulfonyl; R ² , R ³ , m, Same as definition in claim 1. The compound according to claim 1, and its tautomer, stereoisomer, isotope compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof, wherein the compound has a structure shown in formula (I-5)-(I-8):
Among them, (I-6) and (I-8) Can be the same or different, Y is selected from -NH-, -O- or absent; R ¹ is selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the following group: hydroxyl, C ₁ -C ₃ alkyl, propynyl, -C ₁ -C ₃ alkylhydroxyl, C ₁ -C ₃ alkylcarbonyl, halogen, 3-8 membered heterocyclyl, amino, (C ₁ -C ₃ alkyl) _1-2amino , methylsulfonyl; Selected from hydrogen, halogen, cyano, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, amino, C ₁ -C ₃ alkyl, halogen-substituted C ₁ -C ₃ alkyl; each independently selected from hydrogen, -C(O)R ⁴ , C ₁ -C ₃ alkyl substituted with R ⁵ , wherein R ⁴ is selected from C ₁ -C ₆ alkyl substituted with R ⁶ , R ⁶ substituted 3-6 membered heterocycloalkyl and R ⁶ substituted C ₃ -C ₆ cycloalkyl, wherein each R ⁶ is independently selected from hydrogen, hydroxy, C ₁ -C ₃ alkylcarbonyl, halogen and carboxyl, and R ⁵ is selected from hydrogen, hydroxy, halogen and carboxyl; R ² , R ³ and m are the same as defined in claim 1. The compound according to claim 1, and its tautomer, stereoisomer, isotope compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof, wherein the compound has a structure shown in formula (I-9)-(I-10):
wherein Y is selected from -NH-, -O- or absent; R ¹ is selected from substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, wherein the aforementioned substitution refers to substitution by one or more of the following substituents: hydroxyl, C ₁ -C ₃ alkyl, propynyl, hydroxyC ₁ -C ₃ alkyl, C ₁ -C ₃ alkylcarbonyl, halogen, heterocyclyl, amino, alkylamino, methylsulfonyl; Selected from hydrogen, halogen, cyano, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the group consisting of deuterium, halogen, hydroxyl, C ₁ -C ₃ alkyl, halogen-substituted C ₁ -C ₃ alkyl; Selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, wherein the substitution means that one or more H on the group is independently selected from the following group: deuterium, oxo (=O), halogen, cyano, nitro, hydroxyl, amino, carboxyl, formylamino, C ₁ -C ₃ alkyl, halogen-substituted C ₁ -C ₃ alkyl; R ² , R ³ and m are the same as defined in claim 1. The compound according to claim 1, and its tautomer, stereoisomer, isotope compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof, wherein the compound has a structure shown in formula (I-11)-(I-12):
wherein Y is selected from -NH-, -O- or absent; is selected from hydrogen, halogen, cyano, substituted C ₁ -C ₆ alkyl, substituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution refers to one or more H on the group being independently is substituted with a substituent selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxy, amino, C ₁ -C ₃ alkyl, and halogen-substituted C ₁ -C ₃ alkyl; is selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, wherein the substitution means that one or more H on the group is independently selected from the following group: deuterium, oxo (=O), halogen, cyano, nitro, hydroxyl, amino, carboxyl, formylamino, C ₁ -C ₃ alkyl, halogen-substituted C ₁ -C ₃ alkyl, R ¹ , R ² , R ³ and m are the same as defined in claim 1. The compound according to claim 1, and its tautomer, stereoisomer, isotope compound, pharmaceutically acceptable salt, ester, prodrug or hydrate thereof, wherein the compound has a structure shown in formula (I-13)-(I-41):

Wherein, X is CH or N; _R1 and Y are as defined in claim 1. The compound according to claim 1, and its tautomers, stereoisomers, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, wherein R ₁ -Y is selected from:

A compound as claimed in claim 1, and its tautomers, stereoisomers, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, wherein the compound is selected from the group consisting of:











A method for preparing the compound according to any one of claims 1 to 8, wherein the method is selected from one of the following methods: Synthesis method 1:
Step 1-1: Compound 1A reacts with Boc anhydride to obtain compound 1B; Step 1-2: Compound 1B is subjected to hydrogenation reaction with Raney nickel to obtain compound 1C; Step 1-3: Compound 1C and compound 1D are subjected to phosphorus oxychloride and N,N-dimethylbenzylamine to obtain a halogenated product, which is then subjected to nucleophilic substitution under alkaline conditions to obtain compound 1E; Step 1-4: Compound 1E and compound 1F react under sodium hydrogen and anhydrous N,N-dimethylformamide to obtain Compound 1H; Step 1-5: Compound 1E and compound 1G react under 1-methyl-2-pyrrolidone to obtain compound 1J; Step 1-6: Compound 1H is reacted in the presence of dioxane hydrochloride to obtain compound 1I; Step 1-7: Compound 1J is reacted in the presence of dioxane hydrochloride to obtain compound 1K; R ₁ is the same as defined in claim 1; Synthesis method 2:
Step 2-1: Compound 2A reacts with compound 2B in the presence of HATU and DIPEA to obtain compound 2C; Step 2-2: Compound 2C is reacted in the presence of dioxane hydrochloride to obtain compound 2D; Step 2-3: Compound 2D and compound 1D are reacted in the presence of phosphorus oxychloride and N,N-dimethylbenzylamine to obtain a halogenated product, which is then subjected to nucleophilic substitution under alkaline conditions to obtain compound 2E; Step 2-4: Compound 2E and compound 2F react under the conditions of sodium hydrogen and anhydrous N,N-dimethylformamide to obtain compound 2I; Step 2-5: Compound 2E and compound 2G react under 1-methyl-2-pyrrolidone to obtain compound 2J; Step 2-6: Compound 2E and compound 2H react under 1-methyl-2-pyrrolidone to obtain compound 2K; R ₃ is selected from -CH ₃ , -CH ₂ CH ₃ , R ₁ is the same as defined in claim 1; Synthesis method three:
Step 3-1: Compound 3A and compound 1D are reacted in the presence of phosphorus oxychloride and N,N-dimethylbenzylamine to obtain a halogenated product, which is then subjected to nucleophilic substitution under alkaline conditions to obtain compound 3C; Step 3-2: Compound 3B and compound 1D are reacted in the presence of phosphorus oxychloride and N,N-dimethylbenzylamine to obtain a halogenated product, which is then subjected to nucleophilic substitution under alkaline conditions to obtain compound 3D; Step 3-3: Compound 3C and compound 3E react under 1-methyl-2-pyrrolidone to obtain compound 3F; Step 3-4: Compound 3D and compound 3E react under 1-methyl-2-pyrrolidone to obtain compound 3G; Step 3-5: Compound 3F is reacted in the presence of dioxane hydrochloride to obtain compound 3H; Step 3-6: Compound 3G is reacted in the presence of dioxane hydrochloride to obtain compound 3I; R ₁ is the same as defined in claim 3; Synthesis method 4:
Step 4-1: Compound 4A and compound 1C react under the conditions of N,N-diisopropylethylamine and ethanol to obtain compound 4B; Step 4-2: Compound 4A and compound 2D react under the conditions of N,N-diisopropylethylamine and ethanol to obtain compound 4C; Step 4-3: Compound 4B reacts with Boc anhydride to obtain compound 4D; Step 4-4: Compound 4C reacts with Boc anhydride to obtain compound 4E; Step 4-5: Compound 4D and compound 4F react under 1-methyl-2-pyrrolidone to obtain compound 4G; Step 4-6: Compound 4E and compound 4F react under 1-methyl-2-pyrrolidone to obtain compound 4H; Step 4-7: Compound 4G is reacted in the presence of dioxane hydrochloride to obtain compound 4I; Step 4-8: Compound 4H is reacted in the presence of dioxane hydrochloride to obtain compound 4J; R ₁ has the same meaning as defined in claim 1. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, and one or more of its tautomers, stereoisomers, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, and pharmaceutically acceptable excipients. Use of the compound as described in any one of claims 1 to 8, and its tautomers, stereoisomers, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, or the pharmaceutical composition as described in claim 10 in the preparation of a medicament for preventing and/or treating diseases or symptoms associated with abnormal activity of CDK or Cyclin K. The use as described in claim 11 is characterized in that the disease associated with abnormal activity of CDK or Cyclin K is cancer, pain, central nervous system disease or immune system disease. The use according to claim 11, characterized in that the disease associated with abnormal activity of CDK or Cyclin K is a solid tumor or a blood tumor, preferably, the disease is selected from: myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, myelofibrosis, Burkitt's lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, ciliary body and chronic melanoma, iris melanoma, recurrent interocular melanoma, T-cell lymphoma, erythroid lymphoma, monocytic and monocytic leukemia, myeloid leukemia, central nervous system lymphoma, brain Meningioma, spinal cord tumor, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, astrocytoma, amyloidosis, complex regional pain syndrome type I, malignant melanoma, radiculopathy, glioblastoma, gliosarcoma, malignant glioma, refractory plasmacytoma, melanoma with extraocular extension, papillary and follicular thyroid cancer, breast cancer, prostate cancer, colorectal cancer, ovarian cancer, endometrial cancer, cervical cancer, hepatocellular carcinoma, stomach cancer, esophageal cancer, bladder cancer, small cell lung cancer, non-small cell lung cancer, Ewing sarcoma, glioblastoma, pancreatic cancer, or primary macroglobulinemia.