Pyrazolotriazine and pyrazolopyrimidine derivatives, preparation method therefor, pharmaceutical composition, and use thereof

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

[0001] The present invention relates to the field of medicinal chemistry, and specifically, to a class of compounds represented by general formula (I), methods for preparing the same, pharmaceutical compositions, and their use in the preparation of degraders targeting cyclin-dependent kinases (CDKs) for preventing and / or treating diseases or symptoms associated with abnormal activity of cyclin-dependent kinases, as well as for treating diseases or conditions associated with selective transcription of CDKs. The present invention also provides pharmaceutical compositions comprising the compounds of the present invention and methods for using the compositions to treat diseases or conditions associated with selective transcription of CDKs. Background Art

[0002] Cyclin-dependent kinases (CDKs) are important targets for cancer therapy. Cyclin-dependent kinases (CDKs) are a class of serine / threonine kinases, typically heterodimeric complexes composed of a cell cycle catalytic kinase subunit and a regulatory subunit. They are activated by binding to cyclins, thereby regulating the cell cycle and transcription. Dysregulation of CDK activity can directly or indirectly lead to uncontrolled cell proliferation, increased DNA mutations, chromosomal deletions, and chromosomal changes, contributing to tumor development and progression. CDK family proteins participate in mitosis and transcription, playing a crucial role in cell proliferation. Due to the abnormally active proliferation of tumor cells, aberrant CDK activation is often observed in tumor cells, promoting tumor growth. The CDK family has long been considered an important target for cancer therapy. However, due to the high conservation of amino acid sequences at the ATP-binding pocket among different CDK proteins, it has been difficult to identify small molecule inhibitors with high selectivity across the CDK family. Currently available 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.

[0003] In the CDK family, CDK7 and CDK9 have recently attracted widespread attention from academia and major pharmaceutical companies. CDK7 has the dual function of affecting the cell cycle and regulating the transcription process. CDK7 is the catalytic subunit of the CDK activating enzyme complex (cyclinactivating kinase complex, CAK), which is composed of CDK7, cyclin H and MAT1. CAK can activate CDK proteins related to the cell cycle by threonine phosphorylation, including CDK1, CDK2, CDK4, CDK6, thereby affecting cell cycle progression. 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.

[0004] CDK9 / Cyclin T1 (or T2) is a subunit of the positive transcription elongation factor b (P-TEFb) complex. It activates RNA polymerase II by phosphorylating the carboxyl-terminal domain (CTD) of RNA polymerase, initiating gene transcription elongation. CDK9 is located upstream of key molecules closely associated with tumors, such as anti-apoptotic proteins Bcl-2, Mcl-1, and XIAP, as well as cell cycle regulatory proteins and mitotic regulatory kinases. Regulating CDK9 can directly or indirectly regulate these proteins. For example, in chronic lymphocytic leukemia (CLL), inhibiting CDK9 activity can downregulate key Bcl-2 family proteins, leading to therapeutic effects. CDK9, on the other hand, does not affect cell cycle regulation. This specific regulation of transcription makes it one of the most promising anti-tumor targets in the CDK family. Furthermore, studies have shown that the CDK7 / cyclin H and CDK9 / cyclin T complexes can inhibit HIV and HSV RNA replication, suggesting potential applications in the antiviral field.

[0005] CDK7 and CDK9 are important targets for tumor treatment, and several CDK7 and CDK9 inhibitors have entered clinical trials. However, due to the highly conserved structure of CDKs, most are non-selective inhibitors. Representative small molecule inhibitors include flavopiridol, roscovitine, SNS-032, R547, TG-02, and AT-7519. However, relatively few small molecule inhibitors have been studied that selectively target either CDK7 or CDK9, or both. Using small molecule inhibitors to block the cell cycle, induce apoptosis, and regulate transcription through CDK7 and CDK9 has become an important anti-tumor approach. However, most known CDK9 inhibitors suffer from drawbacks such as non-selectivity or unexpected toxicity, which may lead to unforeseen side effects.

[0006] Cyclin-dependent kinases (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. The CDK12 / CyclinK complex, CDK12, regulates transcriptional, co-transcriptional, and post-transcriptional processes by phosphorylating Ser within the CTD of the RNA polymerase II complex. CDK13, a closely related kinase to CDK12, forms a complex with CyclinK and regulates the transcription of a diverse set of genes. The amplification and high expression levels of CDK12 suggest that the tumor-promoting effects of CDK12 are at least partially based on alternatively spliced ​​mRNAs, increased DNA repair capacity, and enhanced stress tolerance. This information suggests that CDK12 is a potential target for drug development in cancer and other diseases.

[0007] 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 of CDKs, thereby regulating RNA polymerase II-mediated transcription initiation and elongation, 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 CDKs. Therefore, the development of inhibitors and degraders targeting CDKs has important scientific significance and research value.

[0008] Summary of the Invention

[0009] One object of the present invention is to provide a compound represented by general formula (I) and its tautomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, pharmaceutical compositions containing the same, and uses thereof.

[0010] Another object of the present invention is to provide a method for preparing the compound represented by general formula (I), an important intermediate for preparing the compound and a method for preparing the same.

[0011] 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.

[0012] Wherein, X is CH or N;

[0013] Y is selected from -NH-, -O- or absent;

[0014] R 1 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 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 group consisting of hydroxy, C1-C3 alkyl, propynyl, -C1-C3 alkylhydroxy, C1-C3 alkylcarbonyl, halogen, 3-8 membered heterocyclyl, amino, (C1-C3 alkyl) 1-2 amino, methylsulfonyl;

[0015] Selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 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, C1-C3 alkyl, halogen-substituted C1-C3 alkyl;

[0016] R 2 is selected from hydrogen, deuterium, halogen and unsubstituted or halogenated C1-C3 alkyl;

[0017] R 3 is selected from deuterium, halogen, cyano, hydroxy, nitro, unsubstituted or halogenated C1-C3 alkyl;

[0018] n is 1 or 2;

[0019] m is 0, 1, 2, 3 or 4;

[0020] Z is selected from NH, N, O or absent;

[0021] When Z is selected from NH or N, each are independently selected from hydrogen, -C(O)R 4 、R 5 Substituted C1-C3 alkyl, wherein R 4 Selected from R6 Substituted C1-C6 alkyl, R 6 Substituted 3-6 membered heterocycloalkyl and R 6 Substituted C3-C6 cycloalkyl, wherein each R 6 R is independently selected from hydrogen, hydroxy, C1-C3 alkyl-C(O)-, halogen and carboxyl; 5 is selected from hydrogen, hydroxy, halogen and carboxyl;

[0022] 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, C1-C3 alkyl, and halogen-substituted C1-C3 alkyl;

[0023] The premise is that when Z does not exist, and are not simultaneously selected from the following substituents: is phenyl, pyridyl, thienyl, furyl, thiazolyl, pyrrolyl and pyrimidinyl, is an unsubstituted C1-C6 alkyl group or an unsubstituted C3-C6 cycloalkyl group.

[0024] 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 replaced by a substituent independently selected from the following group: deuterium, oxo (=O), halogen, cyano, nitro, hydroxyl, amino, carboxyl, formylamino, C1-C3 alkyl, halogen-substituted C1-C3 alkyl.

[0025] In another preferred embodiment, the compound of general formula (I) has the structure shown in formula (I-1)-(I-4):

[0026] Among them, (I-2) Can be the same or different,

[0027] X is CH or N;

[0028] Y is selected from -NH-, -O- or absent;

[0029] R 1is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 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 group consisting of hydroxy, C1-C3 alkyl, propynyl, -C1-C3 alkylhydroxy, C1-C3 alkylcarbonyl, halogen, 3-8 membered heterocyclyl, amino, (C1-C3 alkyl) 1-2 amino, methylsulfonyl;

[0030] R 2 、R 3 、m、 and As defined in the present invention.

[0031] In another preferred embodiment, the compound of general formula (I) has the structure shown in formula (I-5)-(I-8):

[0032] Among them, (I-6) and (I-8) Can be the same or different,

[0033] Y is selected from -NH-, -O- or absent;

[0034] R 1 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 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 group consisting of hydroxy, C1-C3 alkyl, propynyl, -C1-C3 alkylhydroxy, C1-C3 alkylcarbonyl, halogen, 3-8 membered heterocyclyl, amino, (C1-C3 alkyl) 1-2 amino, methylsulfonyl;

[0035] Selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 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 replaced by a substituent selected from the group: deuterium, halogen, cyano, nitro, hydroxyl, amino, C1-C3 alkyl, halogen-substituted C1-C3 alkyl;

[0036] each are independently selected from hydrogen, -C(O)R 4 、R 5 Substituted C1-C3 alkyl, wherein R 4 Selected from R 6 Substituted C1-C6 alkyl, R 6 Substituted 3-6 membered heterocycloalkyl and R 6Substituted C3-C6 cycloalkyl, wherein each R 6 R is independently selected from hydrogen, hydroxy, C1-C3 alkylcarbonyl, halogen and carboxyl, 5 is selected from hydrogen, hydroxy, halogen and carboxyl;

[0037] R 2 、R 3 , m are as defined in the present invention.

[0038] In another preferred embodiment, the compound of general formula (I) has the structure shown in formula (I-9)-(I-10):

[0039] wherein Y is selected from -NH-, -O- or absent;

[0040] R 1 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, wherein the aforementioned substitution refers to substitution with one or more of the following substituents: hydroxy, C1-C3 alkyl, propynyl, hydroxyC1-C3 alkyl, C1-C3 alkylcarbonyl, halogen, heterocyclyl, amino, alkylamino, methylsulfonyl;

[0041] Selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 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 replaced by a substituent selected from the group: deuterium, halogen, hydroxyl, C1-C3 alkyl, halogen-substituted C1-C3 alkyl;

[0042] 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, C1-C3 alkyl, halogen-substituted C1-C3 alkyl;

[0043] R 2 、R 3 , m are as defined in the present invention.

[0044] In another preferred embodiment, the compound of general formula (I) has the structure shown in formula (I-11)-(I-12):

[0045] wherein Y is selected from -NH-, -O- or absent;

[0046] Selected from hydrogen, halogen, cyano, substituted C1-C6 alkyl, substituted C3-C6 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 replaced by a substituent selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, amino, C1-C3 alkyl, halogen-substituted C1-C3 alkyl;

[0047] 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, C1-C3 alkyl, halogen-substituted C1-C3 alkyl,

[0048] R 1 、R 2 、R 3 , m are as defined in the present invention.

[0049] In another preferred embodiment, the compound of general formula (I) has the structure shown in formula (I-13)-(I-41):

[0050] wherein X is CH or N; and R1 and Y are as defined in the present invention.

[0051] In another preferred embodiment, the compound of general formula (I) is characterized in that R1-Y is selected from:

[0052] In another preferred embodiment, the compound is selected from the following group:

[0053] In another preferred embodiment, n, m, X, Y, Z, R 1 、R 2 、R 3 、 and Optionally, each independently represents any corresponding group from C1 to C149.

[0054] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound as described in the first aspect of the present invention and one or more of its tautomers, stereoisomers, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, and pharmaceutically acceptable excipients.

[0055] In a third aspect, the present invention provides the use of the compound as described in the first aspect of the present invention and its tautomers, stereoisomers, isotopic 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 medicament for preventing and / or treating diseases or symptoms associated with abnormal activity of CDK or Cyclin K.

[0056] In another preferred embodiment, the CDK is selected from: CDK2, CDK9, CDK12, or Cyclin K, or a combination thereof.

[0057] In another preferred embodiment, the disease associated with abnormal activity of CDK or Cyclin K is cancer, pain, central nervous system disease or immune system disease.

[0058] 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, monoblastic and monocytic leukemia, myeloid leukemia, and 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.

[0059] 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, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof in the preparation of CDK or Cyclin K inhibitors.

[0060] In another preferred embodiment, the CDK is selected from: CDK2, CDK9, CDK12, or a combination thereof.

[0061] 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 the compound as described in the first aspect of the present invention, and its tautomers, stereoisomers, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, or the pharmaceutical composition as described in the second aspect of the present invention.

[0062] In another preferred embodiment, the subject is a human or non-human mammal, such as a rat or a mouse.

[0063] The present invention also encompasses any novel intermediates disclosed herein.

[0064] Another aspect of the present invention provides 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:

[0065] Synthesis method 1:

[0066] Step 1-1: Compound 1A reacts with Boc anhydride to obtain compound 1B;

[0067] Step 1-2: Compound 1B is subjected to hydrogenation reaction with Raney nickel to obtain compound 1C;

[0068] Step 1-3: Compound 1C 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 1E;

[0069] Step 1-4: Compound 1E and compound 1F react in the presence of sodium bicarbonate and anhydrous N,N-dimethylformamide to obtain compound 1H;

[0070] Step 1-5: Compound 1E and compound 1G react in 1-methyl-2-pyrrolidone to obtain compound 1J;

[0071] Step 1-6: Compound 1H is reacted in the presence of dioxane hydrochloride to obtain compound 1I.

[0072] Step 1-7: Compound 1J is reacted in the presence of dioxane hydrochloride to obtain compound 1K.

[0073] R1 is the same as defined in the first aspect of the present invention;

[0074] Synthesis method 2:

[0075] Step 2-1: Compound 2A reacts with compound 2B in the presence of HATU and DIPEA to obtain compound 2C;

[0076] Step 2-2: Compound 2C is reacted in the presence of dioxane hydrochloride to obtain compound 2D;

[0077] 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;

[0078] Step 2-4: Compound 2E and compound 2F react under sodium hydrogen sulfide and anhydrous N,N-dimethylformamide to obtain compound 2I;

[0079] Step 2-5: Compound 2E and compound 2G react in 1-methyl-2-pyrrolidone to obtain compound 2J;

[0080] Step 2-6: Compound 2E and compound 2H react in 1-methyl-2-pyrrolidone to obtain compound 2K.

[0081] R3 is selected from -CH3, -CH2CH3,

[0082] R1 is the same as defined in the first aspect of the present invention;

[0083] Synthesis method three:

[0084] 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;

[0085] 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;

[0086] Step 3-3: Compound 3C and compound 3E react in 1-methyl-2-pyrrolidone to obtain compound 3F;

[0087] Step 3-4: Compound 3D and compound 3E react in 1-methyl-2-pyrrolidone to obtain compound 3G;

[0088] Step 3-5: Compound 3F is reacted in the presence of dioxane hydrochloride to obtain compound 3H;

[0089] Step 3-6: Compound 3G is reacted in the presence of dioxane hydrochloride to obtain compound 3I;

[0090] R1 is the same as defined in the first aspect of the present invention;

[0091] Synthesis method 4:

[0092] Step 4-1: Compound 4A and compound 1C react in the presence of N,N-diisopropylethylamine and ethanol to obtain compound 4B;

[0093] Step 4-2: Compound 4A and compound 2D react in the presence of N,N-diisopropylethylamine and ethanol to obtain compound 4C;

[0094] Step 4-3: Compound 4B reacts with Boc anhydride to obtain compound 4D;

[0095] Step 4-4: Compound 4C reacts with Boc anhydride to obtain compound 4E;

[0096] Step 4-5: Compound 4D and compound 4F react in 1-methyl-2-pyrrolidone to obtain compound 4G;

[0097] Step 4-6: Compound 4E and compound 4F react in 1-methyl-2-pyrrolidone to obtain compound 4H;

[0098] Step 4-7: Compound 4G is reacted in the presence of dioxane hydrochloride to obtain compound 4I;

[0099] Step 4-8: Compound 4H is reacted in the presence of dioxane hydrochloride to obtain compound 4J;

[0100] R1 is the same as defined in the first aspect of the present invention.

[0101] 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 in the embodiments) can be combined with each other to form new or preferred technical solutions. The above description is not intended to limit the aspects of the present invention in any form. BRIEF DESCRIPTION OF THE DRAWINGS

[0102] FIG1 is a Western blot analysis result showing the Cyclin K degradation activity of some compounds of the present invention. DETAILED DESCRIPTION

[0103] After extensive and in-depth research, and through a large number of screening and testing, the present inventors have provided a class of CDK inhibitor compounds with novel structures and excellent anti-tumor activity.

[0104] the term

[0105] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0106] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0107] The compounds of formula (I) may contain one or more asymmetric or chiral centers and may therefore 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 (e.g., racemates), which are all included within the scope of the present invention.

[0108] The term "substituted" refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Specific substituents are those described above or appearing in the examples. Unless otherwise indicated, an optionally substituted group may have a substituent selected from the specified group at any substitutable position on the group, where the substituents 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 ring system, e.g., where both rings share a single carbon atom. Unless otherwise specified, substitution may refer to a group being substituted by one or more groups selected from the group consisting of 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 C1-C6 alkoxy.

[0109] Those skilled in the art will understand that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. References to substitutions in the relevant structures herein include both substitution and non-substitution, and references to "optionally" being substituted with a substituent include references to being substituted or non-substituted with a substituent.

[0110] 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.

[0111] The term "substituted" only applies to sites that can be substituted by substituents and does not include substitutions that are not achievable based on existing chemical knowledge.

[0112] The compounds represented by general formula (I) may also exist in different tautomeric forms, all of which are included within the scope of the present invention.

[0113] 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.

[0114] 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.

[0115] "Diastereomers" refer to stereoisomers that have two or more chiral neutralities and are not mirror images.

[0116] "Racemate" refers to two stereoisomers that are mirror images of each other, with opposite optical rotations that cancel each other out.

[0117] "Pharmaceutically acceptable salts" refer to salts formed by drug molecules with corresponding organic acids, inorganic acids or organic bases, inorganic bases, such as hydrochloric acid, formic acid, trifluoroacetic acid, succinic acid, methanesulfonate, etc.

[0118] "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 the body to exert their pharmacological effects.

[0119] "Hydrate" refers to a compound containing water.

[0120] The present invention also includes isotopically labeled compounds that 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. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, 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 3 H and14 Radioisotopes of C are also included and are useful in tissue distribution experiments of drugs and substrates. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2 H, due to its excellent metabolic stability, has advantages in certain therapies, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in certain circumstances. Isotope-labeled compounds can be prepared using conventional methods by replacing readily available isotope-labeled reagents with non-isotopic reagents, using the protocols disclosed in the examples. Preferably, the isotope compound is a deuterated compound, and more preferably, the isotope compound has one or more carbon atoms substituted with deuterium.

[0121] The term "plurality" refers to two or more, such as 2, 3, 4, 5 or 6.

[0122] The term "halogen" includes fluorine, chlorine, bromine or iodine.

[0123] 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.

[0124] The term "C1-C6 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 in this article 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 and the like.

[0125] The term "C1-C6 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.

[0126] The term "C1-C6 alkoxycarbonyl" includes, but is not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

[0127] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. For example, "C3-C8 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, fused, and bridged cycloalkyl groups.

[0128] The term "heterocyclyl" refers to a cyclic group 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. Heterocyclyl groups may include 3-8 membered heterocyclyls, preferably 5-6 membered heterocyclyls, such as oxetane, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. Heterocyclyl groups may be fused to aryl, heteroaryl, or cycloalkyl rings, and the ring connected to the parent structure is the heterocyclyl group. Heterocyclyl groups include spirocyclic, fused, and bridged heterocyclyls.

[0129] The term "aryl" refers to a 6-14 membered all-carbon monocyclic or fused polycyclic group having a conjugated p-electron system, preferably a 6- to 10-membered ring, more preferably a 6- to 10-membered ring, more preferably a phenyl and naphthyl ring, and most preferably a phenyl ring. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring.

[0130] 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 atoms, wherein the heteroatoms include oxygen, sulfur, and nitrogen. Preferably, the heteroaryl group is 5-10 membered. The heteroaryl group 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 the heteroaryl ring.

[0131] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the rings share a common atom (called a spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen, sulfur, or S(O)m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. The spiroheterocycle may be fused to a 6-10 membered aryl or 5-10 membered heteroaryl ring, wherein the ring attached to the parent structure is the spiroheterocycle.

[0132] 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.

[0133] The term "alkenyl" refers to an alkenyl group that can be 2-10 carbons, such as ethenyl, propenyl, butenyl, styryl, phenylpropenyl.

[0134] The term "alkynyl" refers to an alkynyl group that can be 2-10 carbon atoms, such as ethynyl, propynyl, butynyl, phenylethynyl, phenylpropenyl.

[0135] 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.

[0136] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0137] The present invention also encompasses any novel intermediates disclosed herein.

[0138] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0139] The term "treat" refers to therapeutic treatment. When referring to a specific condition, treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.

[0140] The present invention provides a compound having a structure as shown in formula (I) or a crystalline hydrate and solvate thereof, and its use in preparing a drug for preventing and / or treating diseases or symptoms associated with abnormal activity of CDK.

[0141] When the compounds of the present invention contain basic groups, they can be prepared into pharmaceutically acceptable salts, including inorganic and organic acid salts. Suitable acids for forming salts include (but are not limited to): inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as 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, phenylmethanesulfonic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

[0142] One aspect of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by 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.

[0143] A typical formulation is prepared by mixing the compound represented by general formula (I) of the present invention with a carrier, diluent, or excipient. Suitable carriers, diluents, or excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, and the like.

[0144] The specific carrier, diluent or excipient used will depend on 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, flavorings, flavorings or other known additives to allow the compound represented by formula (I) to be manufactured or used in an acceptable form.

[0145] As used herein, a "pharmaceutical composition" refers to a formulation of a compound of the present invention and a medium generally accepted in the art for delivering a biologically active compound to a mammal (e.g., a human), the medium including a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to an organism, thereby facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0146] When the compound of formula (I) of the present invention is used in combination with at least one other drug, the two or more drugs can be used separately or in combination, preferably administered 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 form.

[0147] 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, flavorings, flavorings or other known additives so that the pharmaceutical compositions can be manufactured or used in an acceptable form.

[0148] The medicament of the present invention is preferably administered orally. Solid dosage forms for oral administration may include capsules, tablets, powders, or granular formulations. 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.; humectants 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 enhancers 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, for example, lactose and high molecular weight polyethylene glycols as excipients.

[0149] 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 sorbitan; or mixtures of several of these substances.

[0150] In addition to these inert diluents, the composition may also include excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0151] 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.

[0152] 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.

[0153] 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 preservatives, buffers, or propellants. Ophthalmic formulations, ophthalmic ointments, powders, and solutions are also intended to be encompassed within the scope of this invention.

[0154] Another aspect of the present invention provides the use of a 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 a drug for preventing and / or treating diseases or symptoms associated with abnormal activity of CDK.

[0155] 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 lymphoblastic leukemia, acute lymphoblastic leukemia, cellular lymphoma, cellular lymphoma, myeloma, acute and chronic myeloid leukemia, and promyelocytic leukemia.

[0156] 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 treating diseases such as tumors, central nervous system diseases and immune diseases.

[0157] 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.

[0158] 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 essential macroglobulinemia.

[0159] The compounds provided by the present invention are also effective against hematological tumors and myelomas, such as 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.

[0160] 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.

[0161] The main advantages of the present invention are:

[0162] 1. The compounds of the present invention have excellent cancer cell inhibitory activity, especially the inhibitory activity against triple-negative breast cancer cells, which is superior to clinical research drugs and can be used to treat a variety of malignant tumors.

[0163] 2. The compounds of the present invention are used as CDK kinase inhibitors, preferably having good selectivity and kinase activity for inhibiting CDK9.

[0164] 3. In addition to having CDK kinase inhibitory activity, the compounds of the present invention unexpectedly found that some of the compounds can act as Cyclin K degraders and have a good degradation effect in tumor cells.

[0165] 4. The compounds of the present invention have excellent pharmacokinetic properties.

[0166] Specific implementation methods

[0167] The present invention will be further described below with reference to specific examples, but these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, where specific conditions are not specified, were generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0168] In all embodiments, 1 H NMR spectra were measured using 400 MHz Bruker and 500 MHz Bruker nuclear magnetic resonance instruments, with chemical shifts expressed in δ (ppm). Mass spectra were determined using MS UPLC-MS (ESI). The UPLC model was Waters HPLC H-CLASS, and the MS (ESI) model was Waters SQ Detector 2. Anhydrous tetrahydrofuran was prepared by reflux drying and deoxygenation of benzophenone / sodium metal, and anhydrous toluene and anhydrous dichloromethane were prepared by reflux drying of calcium chloride. Solvents used for column chromatography mobile phases, such as petroleum ether, ethyl acetate, and dichloromethane, were purchased from Sinopharm Chemical Reagent Co., Ltd. The thin layer chromatography silica gel plates (HSGF254) used in reaction detection were from Sinopharm Chemical Reagent Co., Ltd. Compound separation used 200-300 mesh silica gel from Sinopharm Chemical Reagent Co., Ltd. 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 known in the art, or prepared according to the methods described in the present invention.

[0169] EtOH: ethanol; DCM: dichloromethane; ACN: acetonitrile; TFA: trifluoroacetic acid; TEA: triethylamine; 1,4-dioxane: 1,4-dioxane; NaH: sodium hydride; H2O: 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)2O: di-tert-butyl dicarbonate; NaCl: sodium chloride; Na2SO4: sodium sulfate; POCl3: phosphorus oxychloride; PhNMe2: N,N-dimethylaniline; DMSO: dimethyl sulfoxide; N2: nitrogen; toluene: toluene; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; rac-BINAP: 1,1'-binaphthyl-2,2'-bis(diphenylphosphine); Cs2CO3: cesium carbonate; NaOH: sodium hydroxide.

[0170] 1. Preparation Example

[0171] [Control compound] N-benzyl-8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin-4-amine

[0172] Referring to the synthetic route of compound 1.6, compound 1.2 was replaced with benzylamine to prepare the control compound.

[0173] Example 1

[0174] [C1] N-(4-aminobenzyl)-8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazin-4-amine

[0175] 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. Once the reaction is complete, dilute the solution with dichloromethane and wash three times with saturated sodium chloride. The combined organic layers are dried over anhydrous sodium sulfate, filtered, and then purified by column chromatography to yield 1.1 (14.31 g) as a white solid in a 77% yield. 1 H NMR (500MHz, DMSO-d6) δ9.90 (s, 1H), 7.71 (d, J = 8.8Hz, 2H), 7.62 (d, J = 8.7Hz, 2H), 1.48 (s, 9H).

[0176] Compound 1.1 (14.31 g, 65.56 mmol, 1.0 equiv) was dissolved in ammonia methanol, and two tubes of Raney nickel were added. The atmosphere was evacuated with nitrogen three times and hydrogen three times. After 4 h at room temperature, the reaction was complete. Methanol was added to dilute the reaction solution, which was filtered through celite and dried to give product 1.2 (14.28 g) in a 98% yield. 1 H NMR (400MHz, DMSO-d6) δ9.21 (s, 1H), 7.35 (d, J = 8.4Hz, 2H), 7.18 (d, J = 8.5Hz, 2H), 3.61 (t, 2H), 1.46 (s, 9H).

[0177] 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. The reaction was allowed to proceed at 100°C for 2 hours. After the reaction was completed, the mixture 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, the acetonitrile solution from the previous step and N,N-dimethylbenzylamine (258 μL, 1.56 mmol, 2.0 equiv) were added, and the mixture was heated to 50°C and reacted for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted three times with 150 mL of ethyl acetate, washed three times with saturated aqueous NaCl, and dried over anhydrous sodium sulfate. The ethyl acetate was removed by filtration, and the residue was purified by column chromatography to afford compound 1.4 (280 mg) in a 78% yield. 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).

[0178] 1-Methyl-4-piperidinol (248 mg, 2.15 mmol, 5.0 equiv) was dissolved in 2 mL of anhydrous N,N-dimethylformamide. 60% (w / w) sodium hydroxide (86 mg, 2.15 mmol, 5.0 equiv) was added at 0°C. Compound 1.4 (200 mg, 0.43 mmol, 1.0 equiv) in 2 mL of anhydrous N,N-dimethylformamide was then added. The mixture was heated to 50°C and allowed to react for 3 h. After completion of the reaction, the mixture was cooled to room temperature, quenched with water, diluted with ethyl acetate, and washed with saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate, filtered, dried, and purified by column chromatography to afford compound 1.6 (132 mg) in a 62% yield. 1H 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).

[0179] Compound 1.6 (132 mg, 0.27 mmol, 1.0 equiv) was dissolved in 4 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 1 h, dried by rotation, and purified by HPLC to obtain compound C1 (107 mg) in a yield of 99%. 1 H NMR(500MHz,DMSO-d6)δ9.39(t,J=3.8Hz,1H),7.97(s,1H),7.42(d,J=8.3Hz,2H),7 .27(d,J=4.0Hz,2H),5.07–4.96(m,1H),4.65(d,J=6.3Hz,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, 4.1 Hz, 1H), 1.80–1.74 (m, 1H), 1.26 (d, J = 6.9 Hz, 6H). UPLC-MS (ESI) theoretical value was C 21 H 29 N7O[M+H] + :396.24, the measured value is 396.33.

[0180] Example 2

[0181] [C38](S)-2-((4-((4-Aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)butan-1-ol

[0182] Compound 1.4 (30 mg, 0.065 mmol, 1.0 equiv) was dissolved in 2 mL of 1-methyl-2-pyrrolidone, and (S)-(+)-2-amino-1-butanol (25 μL, 0.26 mmol, 4.0 equiv) was added. The temperature was raised to 120°C and the reaction was allowed to react for 5 h. After the reaction, the mixture was cooled to room temperature and extracted with 60 mL of ethyl acetate. The mixture was washed with saturated sodium chloride solution, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, dried, and purified by column chromatography to afford compound 2.2 (22 mg) in a 71% yield. 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).

[0183] 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, dried by rotation, and purified by HPLC to obtain compound C38 (19 mg) in a yield of 99%. 1 H NMR (400 MHz, Methanol-d4) δ 7.89 (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) requires C 19 H 27 N7O[M+H] + :370.23, the measured value is 370.32.

[0184] Example 3

[0185] [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

[0186] 4-(N-Boc-aminomethyl)aniline (3 g, 13.50 mmol, 1.0 equiv) was dissolved in anhydrous DMF, and acetic acid (927 μL, 16.20 mmol, 1.2 equiv) and DIPEA (23.5 mL, 135.0 mmol, 10.0 equiv) were added. The mixture was allowed to react at room temperature for 1 h, then diluted with ethyl acetate and washed with saturated sodium chloride. The combined organic phases were dried over anhydrous sodium sulfate. Filtered, dried, and purified by column chromatography to afford 3.1 (3.25 g) as a white solid in a 91% yield. 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).

[0187] Compound 3.1 (3.25 g, 12.29 mmol, 1.0 equiv) was dissolved in 20 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 1 h, dried by rotation, and purified by HPLC to obtain compound 3.2 (1.92 g) in a yield of 95%. 1 H NMR (400MHz, DMSO-d6) δ 10.05 (s, 1H), 8.13 (s, 3H), 7.60 (d, J = 8.2Hz, 2H), 7.36 (d, J = 8.4Hz, 2H), 3.96 (q, J = 5.8Hz, 2H), 2.04 (s, 3H).

[0188] Compound C2 was prepared using compound 3.2 as the starting material and referring to the synthesis of compound 1.6 with a yield of 62%. 1HNMR (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) requires C 23 H 31 N7O2[M+H] + :438.25, the measured value is 438.34.

[0189] [C41]N-(4-(((8-Isopropyl-2-(piperidin-4-ylamino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0190]

[0191] Using compound 3.3 as the raw material, referring to the synthetic route of compound C38, C41 was prepared in a yield of 37% by replacing (S)-(+)-2-amino-1-butanol with 1-tert-butyloxycarbonyl-4-aminopiperidine. 1 H NMR (500 MHz, Methanol-d4) δ 7.87 (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) requires C 22 H 30 N8O[M+H] + :423.25, the actual measured value is 423.40.

[0192] [C42]N-(4-(((8-Isopropyl-2-(piperidin-3-ylamino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0193]

[0194] Using compound 3.3 as the raw material, referring to the synthetic route of compound C38, C42 was prepared in a yield of 35% by replacing (S)-(+)-2-amino-1-butanol with 1-tert-butyloxycarbonyl-3-aminopiperidine. 1 H NMR (500 MHz, Methanol-d4) δ 7.89 (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) requires C 22 H 30 N8O[M+H] + :423.25, the actual measured value is 423.40.

[0195] [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

[0196]

[0197] Using compound 3.3 as the raw material, referring to the synthetic route of compound 2.2, C43 was prepared in a yield of 25% by replacing (S)-(+)-2-amino-1-butanol with D-prolinol. 1 H NMR (500 MHz, Methanol-d4) δ 7.88 (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) requires C 22 H29 N7O2[M+H] + :424.24, the measured value is 424.36.

[0198] [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

[0199]

[0200] Using compound 3.3 as the raw material, referring to the synthetic route of compound 2.2, C44 was prepared in a yield of 29% by replacing (S)-(+)-2-amino-1-butanol with L-prolinol. 1 H NMR(500MHz,Methanol-d4)δ7.88(s,1H),7.54(d,J=8.6Hz,2H),7.39(d,J=8.2Hz,2H),4.7 7(s,2H),4.26–4.18(m,1H),4.07(dt,J=13.2,7.0Hz,1H),3.91(d,J=11.3Hz,1H),3.72(dt, J=12.3,6.5Hz,2H),2.95(q,J=6.9Hz,1H),2.28(dd,J=13.3,7.3Hz,1H),2.11(s,3H),2.00(dq,J=13.5,7.3,6.7Hz,2H),1.90–1.80(m,1H),1.29(d,J=6.6Hz,6H). UPLC-MS (ESI) theoretical value is C 22 H 29 N7O2[M+H] + :424.24, the measured value is 424.39.

[0201] [C45](R)-N-(4-(((2-(3-Hydroxypiperidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0202]

[0203] Using compound 3.3 as the starting material, referring to the synthetic route of compound 2.2, C45 was prepared in a yield of 36% by replacing (S)-(+)-2-amino-1-butanol with (R)-3-piperidinol. 1H 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 was C 22 H 29 N7O2[M+H] + :424.24, the measured value is 424.46.

[0204] [C46](S)-N-(4-(((2-(3-Hydroxypiperidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0205]

[0206] Using compound 3.3 as the starting material, referring to the synthetic route of compound 2.2, C46 was prepared in a yield of 38% by replacing (S)-(+)-2-amino-1-butanol with (S)-3-piperidinol. 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=3.4 Hz,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. 5,7.5Hz,1H),3.58(dd,J=13.2,7.3Hz,1H),3.18(p,J=6.8Hz,1H),2.13(s,3H),2.05–1.99(m,1H),1.94(ddd,J=13.5,7.0,3.7Hz,1H),1.71–1.61(m,2H),1.30(dd,J=6.9,3.3Hz,6H). UPLC-MS (ESI) theoretical value was C 22 H 29N7O2[M+H] + :424.24, the measured value is 424.39.

[0207] [C47](S)-N-(4-(((2-((1-Hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)aminomethyl)phenyl)acetamide

[0208]

[0209] 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) δ 7.88 (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) requires C 21 H 29 N7O2[M+H] + :412.24, the measured value is 412.89.

[0210] [C48](R)-N-(4-(((2-((1-Hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)aminomethyl)phenyl)acetamide

[0211]

[0212] Using compound 3.3 as the starting material, referring to the synthetic route of compound 2.2, C48 was prepared in a yield of 64% by replacing (S)-(+)-2-amino-1-butanol with (R)-(-)-2-amino-1-butanol. 1H NMR (500 MHz, Methanol-d4) δ 7.88 (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) requires C 21 H 29 N7O2[M+H] + :412.24, the measured value is 412.44.

[0213] [C49](S)-N-(4-(((8-Isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0214]

[0215] Compound 3.3 was used as the starting material, and C49 was prepared by referring to the synthetic route of compound 1.6, except that 1-methyl-4-piperidinol was replaced with (R)-3-hydroxypiperidine.

[0216] [C50](R)-N-(4-(((8-Isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0217]

[0218] Compound C50 was prepared using compound 3.3 as the starting material and referring to the synthetic route of compound 1.6, except that 1-methyl-4-piperidinol was replaced with (S)-3-hydroxypiperidine.

[0219] [C51]N-(4-(((8-Isopropyl-2-(oxetan-3-ylamino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0220]

[0221] Using compound 3.3 as the raw material, referring to the synthetic route of compound 2.2, C51 was prepared in a yield of 29% by replacing (S)-(+)-2-amino-1-butanol with 3-oxetanamine. 1 H NMR (500 MHz,

[0222] Methanol-d4) δ7.86 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 5.12–5.07 (m, 1H), 4.91–4.90 (m, 1H), 4.75 (d, J = 4.2 Hz, 2H), 4.67–4.63 (m, 2H), 3.81–3.65 (m, 1H), 3.04 (p, J = 6.9 Hz, 1H), 2.11 (s, 3H), 1.29 (d, J = 6.9 Hz, 6H). UPLC-MS (ESI) theoretical value is C 20 H 25 N7O2[M+H] + :396.21, the measured value is 396.74.

[0223] [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

[0224]

[0225] Using compound 3.3 as the starting material, referring to the synthetic route of compound 2.2, C52 was prepared in a yield of 64% by replacing (S)-(+)-2-amino-1-butanol with 4-aminotetrahydropyran. 1 H NMR (500 MHz, Methanol-d4) δ 7.89 (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) requires C 22 H 29 N7O2[M+H] + :424.24, the measured value is 424.81.

[0226] [C53]N-(4-(((2-((1,3-Dihydroxypropan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)aminomethyl)phenyl)acetamide

[0227]

[0228] Using compound 3.3 as the raw material, referring to the synthetic route of compound 2.2, C53 was prepared in a yield of 54% by replacing (S)-(+)-2-amino-1-butanol with 2-amino-1,3-propanediol. 1 H NMR (500 MHz, Methanol-d4) δ 7.87 (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) calculated for C 20 H 27 N7O3[M+H] + :414.22, the measured value is 414.78.

[0229] [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

[0230]

[0231] Using compound 3.3 as the starting material, referring to the synthetic route of compound 2.2, C54 was prepared in a yield of 53% by replacing (S)-(+)-2-amino-1-butanol with 4-amino-1-methylpiperidine. 1 H NMR (500 MHz, Methanol-d4) δ 7.89 (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) requires C 23 H 32 N8O[M+H] + :437.27, the measured value is 437.41.

[0232] [C128] (R)-N-(4-(((2-(3-Hydroxypyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0233]

[0234] Using compound 3.3 as the starting material, referring to the synthetic route of compound 2.2, C128 was prepared in a yield of 62% by replacing (S)-(+)-2-amino-1-butanol with (R)-3-pyrrolidinol. 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (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) requires C 21 H 27 N7O2[M+H] + :410.49, the measured value is 410.47.

[0235] [C129](S)-N-(4-(((2-(3-Hydroxypyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0236]

[0237] Using compound 3.3 as the starting material, referring to the synthetic route of compound 2.2, C129 was prepared in a yield of 56% by replacing (S)-(+)-2-amino-1-butanol with (S)-3-pyrrolidinol. 1H 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) requires C 21 H 27 N7O2[M+H] + :410.49, the measured value is 410.47.

[0238] [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

[0239]

[0240] Using compound 3.3 as the starting material, referring to the synthetic route of compound 2.2, C130 was prepared in a yield of 47% by replacing (S)-(+)-2-amino-1-butanol with (S)-2-(2-piperidinyl)ethanol. 1 H NMR(500MHz,DMSO-d6)δ9.91(s,1H),9.22(s,1H),7.82(s,1H),7.51(d,J=8.3Hz,2H) ,7.32(d,J=8.2Hz,2H),4.93(s,1H),4.55(d,J=6.3Hz,3H),3.38(dq,J=15.1,7.6,6. 4Hz,2H),2.94(dd,J=16.4,10.0Hz,2H),2.01(s,3H),1.93(s,1H),1.62(dt,J=41.9,11.9Hz,6H),1.33(dd,J=15.5,9.6Hz,1H),1.21(d,J=6.8Hz,6H). UPLC-MS (ESI) theoretical value is C 24 H 33 N7O2[M+H] + :452.58, the actual measured value is 452.52.

[0241] Example 4

[0242] [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

[0243] 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%.

[0244] Compound C3 was prepared using compound 4.3 and compound 1.5 as raw materials, 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 is C 28 H 41 N7O3[M+H] + :524.33, the measured value is 524.85.

[0245] [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

[0246]

[0247] Using compound 4.3 as the raw material, C4 was prepared according to the synthetic route of compound 2.2.

[0248] [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

[0249]

[0250] Compound 4.3 was used as the starting material, and C5 was prepared by referring to the synthetic route of compound 2.2, except that (S)-(+)-2-amino-1-butanol was replaced with (R)-(-)-2-amino-1-butanol.

[0251] [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

[0252]

[0253] Using compound 4.3 as the starting material, referring to the synthetic route of compound 1.6, C6 was prepared by replacing 1-methyl-4-piperidinol with (S)-3-hydroxypiperidine.

[0254] [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

[0255]

[0256] Compound 4.3 was used as the starting material, and C7 was prepared by referring to the synthetic route of compound 1.6, except that 1-methyl-4-piperidinol was replaced with (R)-3-hydroxypiperidine.

[0257] Example 5

[0258] [C8](S)-2-((4-(4-(ethylamino)benzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)butan-1-ol

[0259] 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 μL, 3.42 mmol, 1.0 equiv) was added. The mixture was allowed to react at room temperature for 5 h, monitoring the reaction for completion. The solvent was evaporated, and the product was purified by column chromatography to afford Compound 5.1 (158 mg) in a 19% yield. 1 H NMR (500MHz, 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).

[0260] Using compound 5.1 as the starting material and referring to the synthetic route of compound 1.2, compound 5.2 was obtained with a yield of 87%. 1 H NMR (500MHz, 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).

[0261] Using compound 1.3 and compound 5.2 as raw materials, referring to the synthetic route of compound 1.4, compound 5.3 was obtained with a yield of 22%. 1 H NMR (400MHz, DMSO-d6) δ10.01(t,J=5.1Hz,1H),8.28(s,1H),7.39(d,J=7.9Hz,2H),7.17(d,J=8.0Hz,2H),4.75(d,J=6.2 Hz,2H),3.56(q,J=7.2Hz,2H),3.25(s,3H),3.16–3.11(m,1H),1.35(s,9H),1.31(d,J=7.4Hz,6H),1.01(t,J=6.7Hz,3H).

[0262] Compound C8 was prepared using compound 5.3 and compound 2.1 as raw materials with reference to the synthetic route of compound C38, with a yield of 89%. 1 H NMR (500 MHz, Methanol-d4) δ 7.67 (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) requires C 21 H 31 N7O[M+H] + :398.26, the measured value is 398.38.

[0263] Example 6

[0264] [C9](S)-2-Hydroxy-N-(4-(((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0265] 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, and heated with stirring for 4 h. The mixture was then cooled to room temperature and allowed to stand for 1 h. Ether was added to precipitate a solid, which was filtered and purified by column chromatography to obtain compound 6.1 (542 mg) in a yield of 36.4%. 1 H NMR (400MHz, DMSO-d6) δ 10.13 (s, 1H), 7.92 (d, J = 7.1Hz, 2H), 7.77 (d, J = 8.3Hz, 2H), 5.72 (t, J = 5.3Hz, 1H), 4.03 (d, J = 5.0Hz, 2H).

[0266] Compound 6.1 (542 mg, 3.08 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL), cooled to 0°C, and tert-butyldimethylsilyl chloride (558 mg, 3.70 mmol, 1.2 equiv) and imidazole (315 mg, 4.62 mmol, 1.5 equiv) were added. The mixture was stirred at room temperature for 12 h. After monitoring the completion of the reaction, the mixture was extracted three times with 150 mL of dichloromethane and washed three times with water. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Compound 6.2 (411 mg) was obtained by column chromatography in a yield of 46%. 1 H NMR (400MHz, DMSO-d6) δ9.98 (s, 1H), 7.79 (q, J = 8.4Hz, 4H), 4.26 (d, J = 2.2Hz, 2H), 0.90 (s, 9H), 0.11 (s, 6H).

[0267] Compound 6.2 (411 mg, 1.0 mmol, 1.0 equiv) was dissolved in ammonia methanol (10 mL), and two tubes of Raney nickel were added. The atmosphere was evacuated with nitrogen three times, and then with hydrogen three times. The reaction was stirred at room temperature for 4 h. After monitoring the reaction completion, the mixture was filtered through celite and the filtered liquid was dried to give compound 6.3 (152 mg) in a yield of 52%. 1 H NMR (400MHz, DMSO-d6) δ 9.36 (s, 1H), 7.52 (d, J = 8.1Hz, 2H), 7.26 (d, J = 8.1Hz, 2H), 4.19 (s, 2H), 3.66 (s, 2H), 0.91 (s, 9H), 0.12 (s, 6H).

[0268] Compound 6.4 was prepared in 26% yield using compounds 1.3 and 6.3 as starting materials, following the synthetic route of compound 1.4. 1H NMR (400 MHz, DMSO-d6) δ 9.97 (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).

[0269] Compound C9 was prepared using compound 6.4 and compound 2.1 as raw materials with reference to the synthetic route of compound C38 in a yield of 49%. 1 H NMR (500 MHz, Methanol-d4) δ 7.88 (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) requires C 21 H 29 N7O3[M+H] + :428.23, the measured value is 428.38.

[0270] Example 7

[0271] [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

[0272] p-Aminobenzonitrile (2 g, 16.93 mmol, 1.0 equiv) and 2-iodoethanol (2.91 g, 16.93 mmol, 1.0 equiv) were poured into a round-bottom flask. The atmosphere was purged with N2 three times. Under N2 protection, the temperature was raised to 90°C and the reaction was stirred for 6 h. The reaction solution was extracted with 100 mL of ethyl acetate, 2 M sodium hydroxide solution was added, and the mixture was washed with saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. Compound 7.1 (1.038 g) was obtained by column chromatography in a yield of 38%.

[0273] 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. After monitoring the reaction completion, the mixture was diluted with water and extracted three times with 450 mL of dichloromethane. The mixture was washed three times with saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give compound 7.2 (208 mg) in a yield of 61%. 1H NMR (400MHz, DMSO-d6) δ7.42 (d, J = 8.3 Hz, 2H), 6.66 (d, J = 8.5 Hz, 3H), 3.70 (t, J = 5.2 Hz, 2H), 3.22 (q, J = 6.3 Hz, 2H), 0.84 (s, 9H), 0.01 (s, 6H).

[0274] Compound 7.3 was prepared using 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 (400MHz, CDCl3) 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).

[0275] Compound 7.4 was prepared using 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 (400MHz, CDCl3) δ7.58(d,J=6.3Hz,2H),7.48(d,J=7.0Hz,2H),4.72(q,J=6 .3Hz,2H),3.78(dt,J=13.0,3.8Hz,4H),1.47(s,9H),0.85(s,9H),0.02(s,6H).

[0276] Compound 7.5 was prepared using compound 7.4 and compound 1.3 as raw materials with reference to the synthetic route of compound 1.4 in a yield of 26%. 1 H NMR (500MHz, DMSO-d6) δ8.28 (s, 1H), 7.39 (d, J = 8.5Hz, 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).

[0277] Compound C10 was prepared using compound 7.5 and compound 2.1 as raw materials with reference to the synthetic route of compound C38 in a yield of 38%. 1 H NMR (500 MHz, Methanol-d4) δ 7.67 (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) requires C 21 H 31 N7O2[M+H] + :414.25, the measured value is 414.36.

[0278] Example 8

[0279] [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

[0280] Compound 8.1 was obtained using 4-(N-Boc-aminomethyl)aniline and tetrahydropyran-4-carboxylic acid as starting materials and referring to the synthetic route of compound 3.1 in a yield of 95%. 1H NMR (400MHz, DMSO-d6) δ9.84(s,1H),7.52(d,J=8.2Hz,2H),7.33(t,J=6.1Hz,1H),7.14(d,J=8.3Hz,2H),4.04(d,J=6.2Hz ,2H),3.93–3.86(m,2H),3.36(d,J=4.0Hz,1H),3.31(d,J=5.5Hz,1H),2.60–2.53(m,1H),1.69–1.63(m,4H),1.38(s,9H).

[0281] Compound 8.1 was used as the starting material, and referring to the synthetic route of compound 3.2, compound 8.2 was obtained in a yield of 99%. 1 H NMR (400MHz, DMSO-d6) δ9.99(s,1H),8.06(t,2H),7.63(d,J=8.5Hz,2H),7.36(d,J=8.5Hz,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).

[0282] Using compound 8.2 and compound 1.3 as raw materials, referring to the synthetic route of compound 1.4, compound 8.3 was obtained with a yield of 56%. 1 H NMR (500MHz, DMSO-d6) δ9.96(t,1H),9.88(s,1H),8.27(s,1H),7.54(d,J=8.6Hz,2H),7.34(d,J=8.6Hz,2H),4.68(d,2H),3.89(dt,J=11. 5,2.6Hz,2H),3.35(s,3H),3.32–3.26(m,2H),3.17–3.11(m,1H),2.57(dd,J=10.6,4.8Hz,1H),1.68–1.62(m,4H),1.30(d,J=6.9Hz,6H).

[0283] 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 in a yield of 45%. 1H NMR(500MHz,Methanol-d4)δ7.86(s,1H),7.53(d,J=6.9Hz,2H),7.34(d,J=8.5Hz,2H),4.73(d,J=4.8Hz,2H),4 .02–3.98(m,2H),3.59(d,J=13.0Hz,1H),3.51–3.40(m,4H),3.36–3.33(m,1H),3.23–3.13(m,1H),3.05(dt,J= 13.8,6.9Hz,1H),2.91(s,3H),2.61(ddt,J=11.6,8.0,4.1Hz,1H),2.33(dd,J=29.7,14.6Hz,2H),2.09(d,J=14.2Hz,1H),1.91–1.85(m,1H),1.85–1.78(m,2H),1.76–1.72(m,2H),1.31(d,J=6.9Hz,6H). UPLC-MS (ESI) theoretical value was C 27 H 37 N7O3[M+H] + :508.30, the measured value is 508.92.

[0284] [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

[0285]

[0286] Compound 8.3 was used as the starting 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 in a yield of 27%. 1H NMR(500MHz,DMSO-d6)δ9.85(s,1H),8.60(t,1H),7.69(s,1H),7.52(d,J=8.1Hz,2H),7.28(d,J=8.1Hz,2 H),6.87(d,J=22.1Hz,1H),4.53(s,2H),3.91–3.88(m,2H),3.85–3.82(m,2H),3.36(d,J=10.0Hz,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 was C 26 H 35 N7O3[M+H] + :494.28, the measured value is 494.89.

[0287] [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

[0288]

[0289] Compound 8.3 was used as the starting 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 in a yield of 17%. 1 H NMR (500 MHz, Methanol-d4) δ 7.89 (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) requires C 24 H 33 N7O4[M+H]+ :484.26, the measured value is 484.41.

[0290] [C14](S)-N-(4-(((2-((1-Hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)tetrahydro-2H-pyran-4-carboxamide

[0291]

[0292] Compound C14 was prepared using compound 8.3 as the starting 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=18.0 Hz,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 was C 25 H 35 N7O3[M+H] + :482.28, the measured value is 482.87.

[0293] [C15](R)-N-(4-(((2-((1-Hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)tetrahydro-2H-pyran-4-carboxamide

[0294]

[0295] Compound 8.3 was used as the starting 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 in a yield of 25%. 1H NMR (500MHz, Methanol-d4) δ7.88(s,1H),7.56(d,J=8.6Hz,2H),7.38(d,J=8.5Hz,2H),4.76(d,J=17.6H z,2H),4.17–4.10(m,1H),4.01–3.97(m,2H),3.65(d,J=4.9Hz,2H),3.47(td,J=11.8,2.4Hz,2H),3.04– 2.95 (m, 1H), 2.62 (td, J = 7.5, 3.8 Hz, 1H), 1.88–1.81 (m, 2H), 1.75 (tt, J = 4.7, 1.8 Hz, 2H), 1.72 (d, J = 7.6 Hz, 1H), 1.61 (dt, J = 14.2, 7.4 Hz, 1H), 1.29 (d, J = 6.9 Hz, 6H), 0.96 (t, J = 7.5 Hz, 3H). UPLC-MS (ESI) theoretical value was C 25 H 35 N7O3[M+H] + :482.28, the measured value is 482.45.

[0296] [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

[0297]

[0298] Compound C16 was prepared using compound 8.3 as the starting material and following the synthetic route of compound 2.2, except that (S)-(+)-2-amino-1-butanol was replaced with 4-amino-1-methylpiperidine. The yield of the compound C16 was 9%. 1 H NMR(500MHz,Methanol-d4)δ7.89(s,1H),7.54(d,J=8.6Hz,2H),7.37(d,J=8.6Hz,2H),4.77 (s,2H),4.13(tt,J=11.7,4.1Hz,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 is C 27H 38 N8O2[M+H] + :507.31, the measured value is 507.46.

[0299] [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

[0300]

[0301] Compound 8.3 was used as the starting material, and referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with (S)-3-piperidinol to prepare compound C17 in 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 was C 26 H 35 N7O3[M+H] + :494.28, the measured value is 494.44.

[0302] [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

[0303]

[0304] Compound 8.3 was used as the starting 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 in a yield of 68%. 1 H NMR (500MHz, Methanol-d4) δ7.91(s,1H),7.55(d,J=8.7Hz,2H),7.39(d,J=8.7Hz,2H),4.75(d,J=4.3Hz,2H ),4.11(dd,J=17.7,11.2Hz,1H),4.01–3.98(m,2H),3.92–3.83(m,2H),3.77(dd,J=15.0,11.0Hz,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 was C 26 H 35 N7O3[M+H] + :494.28, the measured value is 494.47.

[0305] [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

[0306]

[0307] Compound 8.3 was used as the starting material, and referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with L-prolinol to prepare compound C19 in a yield of 77%. 1H 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 is C 26 H 35 N7O3[M+H] + :494.28, the measured value is 494.45.

[0308] [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

[0309]

[0310] Compound 8.3 was used as the starting material, and referring to the synthetic route of compound 2.2, (S)-(+)-2-amino-1-butanol was replaced with D-prolinol to prepare compound C20 in a yield of 37%. 1H NMR(500MHz, Methanol-d4)δ7.66(s,1H),7.52(d,J=8.5Hz,2H),7.36(d,J=8.5Hz,2H),4.69–4.68( s,2H),4.21(d,J=5.9Hz,1H),4.01(dd,J=4.5,2.0Hz,1H),3.99–3.98(m,1H),3.73(t,J=8.4Hz,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 was C 26 H 35 N7O3[M+H] + :494.28, the actual measured value is 494.38.

[0311] Example 9

[0312] [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

[0313] Compound 9.1 was prepared using 4-(N-Boc-aminomethyl)aniline and 1-acetyl-4-piperidinic acid as raw materials, following the synthetic route of compound 3.1, with a yield of 69%. 1 H NMR (400MHz, DMSO-d6) δ9.88 (s, 1H), 7.51 (d, J = 8.3Hz, 2H), 7.33 (t, J = 6.1Hz, 1H), 7.1 4(d,J=8.3Hz,2H),4.40(d,J=12.6Hz,1H),4.04(d,J=6.2Hz,2H),3.86(d,J=13.6Hz,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).

[0314] Compound 9.2 was prepared using compound 9.1 as the starting material and referring to the synthetic route of compound 3.2 with a yield of 99%. 1 H NMR (400MHz, DMSO-d6) δ10.04(s,1H),8.10(s,2H),7.62(d,J=8.5Hz,2H),7.36(d, J=8.6Hz,2H),4.40(d,J=12.7Hz,1H),3.96(q,J=5.8Hz,2H),3.86(d,J=13.6Hz,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).

[0315] Compound 9.2 and compound 1.3 were used as raw materials, and referring to the synthetic route of compound 1.4, compound 9.3 was prepared in a yield of 65%. 1 H NMR (500MHz, DMSO-d6) δ9.98(t,J=6.3Hz,1H),9.92(s,1H),8.27(s,1H),7.54(d,J=8.6Hz,2H),7.34( d,J=8.6Hz,2H),4.68(d,J=6.2Hz,2H),4.38(d,J=12.8Hz,1H),3.85(d,J=13.5Hz,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).

[0316] Compound C21 was prepared using compound 9.3 and compound 9.4 as raw materials with reference to the synthetic route of compound 2.2 in a yield of 43%. 1H NMR(500MHz,Methanol-d4)δ7.89(s,1H),7.55(d,J=7.2Hz,2H),7.40(d,J=8.2Hz,2H),4.78(s,2H),4.58–4.5 4(m,1H),4.31–4.24(m,1H),4.02–3.98(m,1H),3.78(dd,J=10.9,5.0Hz,2H),3.74(d,J=5.6Hz,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 is C 26 H 36 N8O4[M+H] + :525.29, the measured value is 525.88.

[0317] [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

[0318]

[0319] Compound 9.3 was used as the starting material, and referring to the synthetic route of compound C21, 2-amino-1,3-propanediol was replaced with 4-aminotetrahydropyran to prepare compound C22 in a yield of 37%. 1H NMR(500MHz,Methanol-d4)δ7.90(s,1H),7.55(d,J=8.6Hz,2H),7.37(d,J=8.5Hz,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=11.7Hz,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=11.5,7.7,3.9Hz,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=6.9Hz,6H). UPLC-MS (ESI) theoretical value is C 28 H 38 N8O3[M+H] + :535.31, the measured value is 535.43.

[0320] [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

[0321]

[0322] Compound 9.3 was used as the starting material, and referring to the synthetic route of compound C21, 2-amino-1,3-propanediol was replaced with (R)-(-)-2-amino-1-butanol to prepare compound C23 in a yield of 33%. 1H NMR(500MHz,Methanol-d4)δ7.89(s,1H),7.56(d,J=8.4Hz,2H),7.38(d,J=8.6Hz,2H),4.77(d,J=18.5Hz,2H),4 .58–4.54(m,1H),4.17–4.11(m,1H),4.02–3.97(m,1H),3.66(d,J=4.8Hz,2H),3.21–3.15(m,1H),2.99(m,J=6.9H 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 is C 27 H 38 N8O3[M+H] + :523.31, the measured value is 523.89.

[0323] [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

[0324]

[0325] Compound 9.3 was used as the starting 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 in a yield of 31%. 1 H NMR (500

[0326] 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 was C 27 H 38 N8O3[M+H] + :523.31, the measured value is 523.89.

[0327] [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

[0328]

[0329] Compound 9.3 was used as the starting material, and referring to the synthetic route of compound C21, 2-amino-1,3-propanediol was replaced with D-prolinol to prepare compound C25 with a yield of 51%. 1H 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),4.28–4.2 1(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 was C 28 H 38 N8O3[M+H] + :535.31, the measured value is 535.43.

[0330] Example 10

[0331] [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

[0332] Compound 10.1 was prepared using 4-(N-Boc-aminomethyl)aniline and propionic acid as raw materials, following the synthetic route of compound 3.1, with a yield of 95%. 1 H NMR (400MHz, DMSO-d6) δ9.79(s,1H),7.50(d,J=8.2Hz,2H),7.30(t,J=6.1Hz,1H),7.13(d,J= 8.3Hz, 2H), 4.05 (d, J = 6.3Hz, 2H), 2.29 (q, J = 7.6Hz, 2H), 1.38 (s, 9H), 1.07 (t, J = 7.5Hz, 3H).

[0333] Compound 10.2 was prepared using compound 10.1 as the starting material and referring to the synthetic route of compound 3.2 with a yield of 99%. 1H NMR (400MHz, DMSO-d6) δ9.96 (s, 1H), 8.18–8.07 (m, 3H), 7.62 (d, J = 8.6Hz, 2H), 7.36 ( d, J=8.6Hz, 2H), 3.96 (q, J=5.8Hz, 2H), 2.32 (q, J=7.5Hz, 2H), 1.07 (t, J=7.5Hz, 3H).

[0334] Compound 10.2 and compound 1.3 were used as raw materials, and referring to the synthetic route of compound 1.4, compound 10.3 was prepared in a yield of 61%. 1 H NMR (500MHz, DMSO-d6) δ9.98(t,J=6.3Hz,1H),9.85(s,1H),8.27(s,1H),7.53(d,J=8.4Hz,2H),7.34(d,J=8.5Hz,2H),4. 68(d,J=6.2Hz,2H),3.33(s,3H),3.17–3.11(m,1H),2.29(d,J=7.5Hz,2H),1.30(d,J=6.9Hz,6H),1.05(t,J=7.5Hz,3H).

[0335] Compound C26 was prepared using compound 10.3 and compound 9.4 as raw materials and referring to the synthetic route of compound 2.2 in a yield of 62%. 1 H NMR (500 MHz, Methanol-d4) δ 7.67 (s, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 4.69 (s, 2H), 4.14–4.06 (m, 1H), 3.73 (q, J = 5.4 Hz, 4H), 3.02–2.96 (m, 1H), 2.37 (q, J = 7.6 Hz, 2H), 1.27 (d, J = 6.9 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H). UPLC-MS (ESI) requires C 21 H 29 N7O3[M+H] + :428.23, the measured value is 428.41.

[0336] [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

[0337]

[0338] Compound 10.3 was used as the starting 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 in a yield of 42%. 1 H NMR (500 MHz, Methanol-d4) δ 7.68 (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) requires C 23 H 31 N7O2[M+H] + :438.25, the measured value is 438.86.

[0339] [C28]N-(4-(((8-Isopropyl-2-(oxetan-3-ylamino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0340]

[0341] Compound 10.3 was used as the starting 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 in a yield of 15%. 1 H NMR (500 MHz, Methanol-d4) δ 7.84 (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) requires C 21 H 27 N7O2[M+H] + :410.22, the measured value is 410.76.

[0342] [C29](S)-N-(4-(((2-((1-Hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0343]

[0344] Compound C29 was prepared using compound 10.3 as the starting 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 was C 22 H 31 N7O2[M+H] + :426.25, the measured value is 426.45.

[0345] [C30](R)-N-(4-(((2-((1-Hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0346]

[0347] Compound 10.3 was used as the starting 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 in a yield of 64%. 1H 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 is C 22 H 31 N7O2[M+H] + :426.25, the measured value is 426.77.

[0348] [C31](R)-N-(4-(((8-Isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0349]

[0350] Compound 10.3 was used as the starting material, and referring to the synthetic route of compound 1.6, 1-methyl-4-piperidinol was replaced with (S)-3-hydroxypiperidine to prepare compound C31 in a yield of 55%. 1 H NMR (500MHz, Methanol-d4) δ7.87(s,1H),7.52(d,J=8.6Hz,2H),7.33(d,J=8.6Hz,2H),4.73(d, J=2.9Hz,2H),3.48(dd,J=13.3,3.9Hz,1H),3.37–3.32(m,2H),3.29(d,J=3.8Hz,1H),3.19–3.0 9 (m, 1H), 3.08–3.03 (m, 1H), 2.37 (t, J = 7.6 Hz, 2H), 2.11 (dt, J = 14.5, 4.9 Hz, 2H), 1.98–1.91 (m, 1H), 1.84–1.78 (m, 1H), 1.31 (dd, J = 6.9, 1.9 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H). UPLC-MS (ESI) theoretical value was C 23 H 31 N7O2[M+H] + :438.25, the measured value is 438.41.

[0351] [C32](S)-N-(4-(((8-Isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0352]

[0353] Compound 10.3 was used as the starting material, and referring to the synthetic route of compound 1.6, 1-methyl-4-piperidinol was replaced with (R)-3-hydroxypiperidine to prepare compound C32 in a yield of 59%. 1 H NMR (500MHz, Methanol-d4) δ7.88(s,1H),7.53(d,J=8.5Hz,2H),7.34(d,J=8.6Hz,2H),4.74(d,J=2 .9Hz,2H),3.49(dd,J=13.3,3.9Hz,1H),3.36(dd,J=13.4,2.5Hz,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 is C 23 H 31 N7O2[M+H] + :438.25, the measured value is 438.41.

[0354] [C33](S)-N-(4-(((8-Isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0355]

[0356] Using compound 10.3 as the starting material, referring to the synthetic route of compound C38, replacing (S)-(+)-2-amino-1-butanol with 1-tert-butyloxycarbonyl-4-aminopiperidine, compound C33 was prepared in a yield of 37%. 1HNMR(500MHz,Methanol-d4)δ7.90(s,1H),7.54(d,J=8.5Hz,2H),7.36(d,J=8.5Hz,2H ),4.77(s,2H),4.21(dq,J=10.5,6.0,4.9Hz,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 was C 23 H 32 N8O[M+H] + :437.27, the measured value is 437.45.

[0357] [C34]N-(4-(((8-Isopropyl-2-(piperidin-3-ylamino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0358]

[0359] Using compound 10.3 as the starting material, referring to the synthetic route of compound C38, replacing (S)-(+)-2-amino-1-butanol with N-tert-butyloxycarbonyl-3-aminopiperidine, compound C34 was prepared in 85% yield. 1 HNMR (500 MHz, 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) requires C 23 H 32 N8O[M+H] + :437.27, the measured value is 437.44.

[0360] [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

[0361]

[0362] Compound 10.3 was used as the starting 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 in a yield of 19%. 1 H NMR(500MHz,Methanol-d4)δ7.91(s,1H),7.54(d,J=8.6Hz,2H),7.37(d,J=8.6Hz,2H), 4.77(d,J=4.1Hz,2H),4.14(tt,J=11.8,4.2Hz,1H),3.56(d,J=12.5Hz,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 is C 24 H 34 N8O[M+H] + :451.29, the measured value is 451.43.

[0363] [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

[0364]

[0365] Compound C36 was prepared using compound 10.3 as the starting material and referring to the synthetic route of compound 1.6 in a yield of 62%. 1H NMR (500 MHz, Methanol-d4) δ 7.84 (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) requires C 24 H 33 N7O2[M+H] + :452.27, the measured value is 452.81.

[0366] [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

[0367]

[0368] Compound C63 was prepared using compound 10.3 as the starting material and referring to the synthetic route of compound 1.6, except that 1-methyl-4-piperidinol was replaced with 1-(prop-2-yn-1-yl)piperidin-4-ol.

[0369] [C131] (R)-N-(4-(((2-(3-Hydroxypyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0370]

[0371] Using compound 10.3 as the starting material, referring to the synthetic route of compound 2.2, C131 was prepared in a yield of 45% by replacing (S)-(+)-2-amino-1-butanol with (R)-3-pyrrolidinol. 1H 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) requires C 22 H 29 N7O2[M+H] + :424.52, the measured value is 424.49.

[0372] [C132](S)-N-(4-(((2-(3-Hydroxypyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0373]

[0374] Using compound 10.3 as the starting material, referring to the synthetic route of compound 2.2, C132 was prepared in a yield of 59% by replacing (S)-(+)-2-amino-1-butanol with (S)-3-pyrrolidinol. 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) requires C 22 H 29 N7O2[M+H] + :424.52, the measured value is 424.49.

[0375] [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

[0376]

[0377] Using compound 10.3 as the starting material, referring to the synthetic route of compound 2.2, C133 was prepared in a yield of 53% by replacing (S)-(+)-2-amino-1-butanol with (R)-2-pyrrolidinemethanol. 1 H NMR (500 MHz, DMSO-d6) δ 9.84 (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) requires C 23 H 31 N7O2[M+H] + :438.55, the measured value is 438.51.

[0378] [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

[0379]

[0380] Using compound 10.3 as the starting material, referring to the synthetic route of compound 2.2, C134 was prepared in 40% yield by replacing (S)-(+)-2-amino-1-butanol with (S)-2-pyrrolidinemethanol. 1H NMR (600 MHz, DMSO-d6) δ 9.85 (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) requires C 23 H 31 N7O2[M+H] + :438.55, the actual measured value is 438.50.

[0381] [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

[0382]

[0383] Using compound 10.3 as the starting material, referring to the synthetic route of compound 2.2, C135 was prepared in a yield of 28% by replacing (S)-(+)-2-amino-1-butanol with (S)-2-(2-piperidinyl)ethanol. 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=6.3Hz,3H),3.39(tt,J=12.4,6.6Hz,2H),2.92(dd,J=1 7.3,9.4Hz,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 was C 25 H 35 N7O2[M+H] + :466.60, the measured value is 466.47.

[0384] Example 11

[0385] [C37] (S)-2-((7-((4-Aminobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)butan-1-ol

[0386] 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 mixture was refluxed at 90°C for 12 h. After completion of the reaction, 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 solution, and dried over anhydrous sodium sulfate. After filtration and removal of the solvent, the product was purified by column chromatography to afford compound 11.1 (524 mg) in an 82% yield. 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).

[0387] Compound 11.2 was prepared using compound 11.1 as the starting material and referring to the synthetic route of compound 1.1 in a yield of 94%. 1 H NMR(500MHz,DMSO-d6)δ8.22(s,1H),7.32(d,J=8.4Hz,2H),7.13(s,1H),7.07(d,J =8.4Hz,2H),5.03(s,2H),3.14–3.10(m,1H),1.30(s,18H),1.28(d,J=3.5Hz,6H).

[0388] Compound C37 was prepared using compound 11.2 and compound 2.1 as raw materials, referring to the synthetic route of compound C38, with a yield of 68%. 1H NMR (500 MHz, Methanol-d4) δ 7.89 (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) requires C 20 H 28 N6O[M+H] + :369.49, the measured value is 369.35.

[0389] Example 12

[0390] [C39](S)-N-(4-(((5-((1-Hydroxybutan-2-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acetamide

[0391] Compound 12.1 was prepared using 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine and compound 3.2 as starting materials, following the synthetic route of compound 11.1, in a yield of 91%. 1 H NMR (400MHz, DMSO-d6) δ9.92(s,1H),8.87(t,J=6.5Hz,1H),8.04(s,1H),7.52(d,J=8.3Hz,2H),7.30(d,J= 8.3Hz, 2H), 6.05 (s, 1H), 4.55 (d, J = 6.5Hz, 2H), 3.08 (p, J = 6.9Hz, 1H), 2.01 (s, 3H), 1.27 (d, J = 6.9Hz, 6H).

[0392] Compound 12.2 was prepared using compound 12.1 as starting material and referring to the synthetic route of compound 1.1 in a yield of 97%. 1 H NMR (400MHz, DMSO-d6) δ8.05(s,1H),7.38(d,J=8.2Hz,2H),7.10(d,J=8.2Hz,2H),6.02(s ,1H),5.76(s,2H),3.08(p,J=6.8Hz,1H),2.45(s,3H),1.31(s,9H),1.27(d,J=7.0Hz,6H).

[0393] 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(dba) (13 mg, 0.014 mmol, 5 mol% equiv), rac BINAP (26 mg, 0.042 mmol, 15 mol% equiv), and CsCO (137 mg, 0.42 mmol, 1.5 equiv) were added. The mixture was purged with nitrogen three times. The temperature was raised to 100°C and heated with stirring for 12 h. After completion of the reaction, the mixture was cooled to room temperature, the toluene was removed under reduced pressure, and the residue was purified by column chromatography to afford compound 12.4 (87 mg) in a 50% yield. 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).

[0394] Compound C39 was prepared using compound 12.4 as the starting material and referring to the synthetic route of compound C1 with a yield of 99%. 1 H NMR (500 MHz, Methanol-d4) δ 7.88 (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) requires C 22 H 30 N6O2[M+H] + :411.24, the measured value is 411.85.

[0395] [C40]N-(4-(((3-Isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acetamide

[0396]

[0397] Using compound 12.2 as the starting material, referring to the synthetic route of compound C39, compound 12.3 was replaced with 4-aminotetrahydrofuran to prepare compound C40 in a yield of 45%. 1 H NMR (500 MHz, Methanol-d4) δ 7.90 (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) requires C 23 H 30 N6O2[M+H] + :423.24, the measured value is 423.85.

[0398] Example 13

[0399] [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

[0400] Compound 13.1 was prepared using 4-(N-Boc-aminomethyl)aniline and 1-fluorocyclopropylcarboxylic acid as starting materials, following the synthetic route of compound 3.1, with a yield of 98%. 1 H NMR (500MHz, DMSO-d6) δ10.20(s,1H),7.62(d,J=8.4Hz,2H),7.37(t,J=6.2Hz,1H),7.18(d,J=8.3Hz,2 H), 4.08 (d, J = 6.2Hz, 2H), 1.40 (s, 9H), 1.34–1.31 (m, 2H), 1.30 (d, J = 2.8Hz, 1H), 1.19 (d, J = 6.7Hz, 1H).

[0401] Compound 13.2 was prepared using compound 13.1 as the starting material and referring to the synthetic route of compound 3.2 with a yield of 99%. 1 H NMR (500MHz, DMSO-d6) δ10.33(s,1H),8.17(s,3H),7.74(d,J=8.6Hz,2H),7.40(d,J=8 .6Hz,2H),3.99(q,J=5.8Hz,2H),1.45–1.37(m,2H),1.31(td,J=9.4,8.9,5.7Hz,2H).

[0402] Compound 13.2 and compound 1.3 were used as raw materials and the synthetic route of compound 1.4 was referred to to prepare compound 13.3 in 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).

[0403] Compound C55 was prepared using compound 13.3 as the starting material and referring to the synthetic route of compound 2.2 in a yield of 32%. 1 H NMR (500 MHz, Methanol-d4) δ 7.92 (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) requires C 23 H 28 FN7O2[M+H] + :454.23, the measured value is 454.32.

[0404] [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

[0405]

[0406] Using compound 13.3 as the starting material, referring to the synthetic route of C55, replacing (S)-3-pyrrolidinol with (R)-3-pyrrolidinol, compound C56 was prepared in a yield of 47%. 1 H NMR(500MHz,Methanol-d4)δ1H NMR(500MHz,Methanol-d4)δ7.69(s,1H),7.57(d,J=8.6Hz,2H),7.41(d,J=8.7Hz,2H),4 .70(s,2H),4.48(dd,J=4.9,2.6Hz,1H),3.74(t,J=10.0Hz,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 is C 23 H 28 FN7O2[M+H] + :454.23, the measured value is 454.32.

[0407] [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

[0408]

[0409] Using compound 13.3 as the starting material, referring to the synthetic route of compound C55, replacing (S)-3-pyrrolidinol with 3-oxetanamine, compound C57 was prepared in a yield of 24%. 1H NMR (500 MHz, Methanol-d4) δ 7.87 (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) requires C 22 H 26 FN7O2[M+H] + :440.21, the measured value is 440.76.

[0410] [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

[0411]

[0412] Using compound 13.3 as the starting material, referring to the synthetic route of compound C55, (S)-3-pyrrolidinol was replaced with 4-aminotetrahydropyran, and the yield was 59%. 1 H NMR (500 MHz, Methanol-d4) δ 7.89 (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) requires C 24 H 30 FN7O2[M+H] + :468.24, the measured value is 468.37.

[0413] [C59](S)-1-Fluoro-N-(4-(((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)cyclopropane-1-carboxamide

[0414]

[0415] Using compound 13.3 as the starting material, referring to the synthetic route of compound C55, (S)-3-pyrrolidinol was replaced with (S)-(+)-2-amino-1-butanol to prepare compound C59 in a yield of 68%. 1 H NMR (500 MHz, Methanol-d4) δ 7.68 (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) requires C 23 H 30 FN7O2[M+H] + :456.24, the measured value is 456.38.

[0416] [C60](R)-1-Fluoro-N-(4-(((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)cyclopropane-1-carboxamide

[0417]

[0418] Using compound 13.3 as the starting material, referring to the synthetic route of compound C55, (S)-3-pyrrolidinol was replaced with (R)-(-)-2-amino-1-butanol to prepare compound C60 in a yield of 56%. 1H NMR (500 MHz, Methanol-d4) δ 7.67 (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) requires C 23 H 30 FN7O2[M+H] + :456.24, the measured value is 456.38.

[0419] [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

[0420]

[0421] Using compound 13.3 as the starting material, referring to the synthetic route of compound C55, (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=8.6Hz,2H),7.42(d,J=8.1Hz,2H),4.78(d,2H), 4.23(dd,J=10.2,4.6Hz,1H),4.10–4.03(m,1H),3.91(d,J=11.3Hz,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)theoretic value was C 24 H 30 FN7O2[M+H] +:468.24, the measured value is found 468.40.

[0422] [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

[0423]

[0424] Using compound 13.3 as the raw material, referring to the synthetic route of compound C55, replacing (S)-3-pyrrolidinol with L-prolinol, compound C62 was prepared in a yield of 35%. 1 H NMR (500MHz, Methanol-d4) δ7.89 (s, 1H), 7.60 (d, J = 8.3Hz, 2H), 7.42 (d, J = 8.1Hz, 2H), 4. 78(d,2H),4.29–4.15(m,1H),4.07(dd,J=16.1,9.2Hz,1H),3.91(d,J=11.2Hz,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 was C 24 H 30 FN7O2[M+H] + :468.24, the measured value is 468.34.

[0425] [C136](S)-1-Fluoro-N-(4-(((2-(2-hydroxyethyl)piperidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)cyclopropane-1-carboxamide

[0426]

[0427] Using compound 13.3 as the starting 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%. 1H NMR (500 MHz, DMSO-d6) δ 10.19 (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) requires C 26 H 34 FN7O2[M+H] + :496.60, the measured value is 496.53.

[0428] Example 14

[0429] [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

[0430] 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 in a yield of 63%.

[0431] Using compounds 14.2 and 14.3 as raw materials, referring to the synthetic route of compound C55, C106 was prepared in 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) requires C 24 H 30 N8O[M+H] + :447.56, the measured value is 447.39.

[0432] [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

[0433]

[0434] Compound C108 was prepared using compounds 1.3 and 14.3 as starting materials, following the synthetic route of compound C106, except that (4-(4-methyl-1H-imidazol-1-yl)phenyl)methanamine was replaced with 5-(4-(aminomethyl)phenyl)pyridin-2(1H)-one in a 48% yield. 1H NMR (500 MHz, DMSO-d6) δ 8.08 (d, J = 2.7 Hz, 1H), 7.78 (dd, J = 9.5, 2.7 Hz, 2H), 7.55–7.48 (m, 2H), 7.41 (d, J = 8.0 Hz, 2H), 6.46 (d, J = 9.4 Hz, 1H), 4.62 (d, J = 6.2 Hz, 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 is C 26 H 31 N7O2[M+H] + :474.58, the actual measured value is 474.38.

[0435] [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

[0436]

[0437] Compound 1.3 and compound 14.3 were used as raw materials, and referring to the synthetic route of compound C106, (4-(4-methyl-1H-imidazol-1-yl)phenyl)methanamine was replaced with (4-(pyridazin-3-yl)phenyl)methanamine to prepare compound C122 in a yield of 40%. 1H 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 was C 24 H 28 N8O[M+H] + :445.54, the measured value is 445.35.

[0438] [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

[0439]

[0440] Compound 1.3 and compound 14.3 were used as raw materials, and referring to the synthetic route of compound C106, (4-(4-methyl-1H-imidazol-1-yl)phenyl)methanamine was replaced with 1-(4-(aminomethyl)phenyl)pyridin-2(1H)-one to prepare compound C107 in 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 was C 25 H 29 N7O2[M+H]+ :460.55, the measured value is 460.36.

[0441] [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

[0442]

[0443] Compound 1.3 and compound 14.3 were used as raw materials, and 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 in a yield of 37%. 1 H NMR (500 MHz, DMSO-d6) δ 8.78 (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) requires C 24 H 30 N8O[M+H] + :447.56, the measured value is 447.38.

[0444] [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

[0445]

[0446] Compound 1.3 and compound 14.3 were used as raw materials, and 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 in a yield of 48%. 1H 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).

[0447] The theoretical value of UPLC-MS (ESI) is C 23 H 27 N 7 O 2 [M+H] + :434.52, the measured value is 434.25.

[0448] [C87]8-Isopropyl-N4-(4-phenoxybenzyl)-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

[0449]

[0450] Compound 1.3 and compound 14.3 were used as raw materials, and referring to the synthetic route of compound C106, (4-(4-methyl-1H-imidazol-1-yl)phenyl)methanamine was replaced with (4-phenoxyphenyl)methanamine to prepare compound C87 in 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 was C 26 H 30 N6O2[M+H] + :459.57, the actual measured value is 459.40.

[0451] [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

[0452]

[0453] Using compounds 1.3 and 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 in 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) requires C 26 H 29 ClN6O2[M+H] + :494.01, the measured value is 493.33.

[0454] [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

[0455]

[0456] Compound 1.3 and compound 14.3 were used as raw materials, and referring to the synthetic route of compound C106, (4-(4-methyl-1H-imidazol-1-yl)phenyl)methanamine was replaced with (4-(1-methyl-1H-imidazol-2-yl)phenyl)methanamine to prepare compound C120 in a yield of 47%. 1H NMR(500MHz,DMSO-d6)δ9.99(s,1H),8.81(d,J=107.7Hz,1H),7.97(s,1H),7.84(d,J =1.9Hz,1H),7.80(d,J=2.0Hz,1H),7.79–7.74(m,2H),7.66(d,J=7.9Hz,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 was C 24 H 30 N8O[M+H] + :447.56, the measured value is 447.39.

[0457] [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

[0458]

[0459] Compound 1.3 and compound 14.3 were used as raw materials, and referring to the synthetic route of compound C106, (4-(4-methyl-1H-imidazol-1-yl)phenyl)methanamine was replaced with 1-(4-(aminomethyl)phenyl)pyrrolidin-2-one to prepare compound C102 in a yield of 39%. 1 H NMR (500MHz, DMSO-d6) δ10.25–9.81(m,1H),8.71(d,J=113.4Hz,1H),7.86(d,J=101.7Hz,1H),7.58(d, J=8.4Hz,2H),7.38(d,J=8.2Hz,2H),4.62(d,J=6.1Hz,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 is C 24 H31 N7O2[M+H] + :450.56, the actual measured value is 450.50.

[0460] Example 15

[0461] [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

[0462] 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 in a yield of 51%.

[0463] 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%.

[0464] 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 in a yield of 95%. 1 H NMR (800MHz, DMSO-d6) δ10.05(s,1H),8.16(d,J=1.9Hz,1H),7.98(s,1H),7.92(d,J=7.7H z,1H),7.91–7.87(m,1H),7.67(d,J=7.8Hz,2H),7.58(t,J=7.7Hz,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 was C 27 H 30 N6O3[M+H] + :487.58, the measured value is 487.34.

[0465] Example 16

[0466] [C111]8-Bromo-N2-(tetrahydro-2H-pyran-4-yl)-N4-(4-(thien-2-yl)benzyl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

[0467] 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 in a yield of 58%.

[0468] Compound 16.3 (72 mg, 0.167 mmol, 1.0 equiv.) was dissolved in dichloromethane. m-Chloroperbenzoic acid (108 mg, 80%, 0.500 mmol, 3.0 equiv.) was added portionwise under ice-cooling. The mixture was allowed to react at room temperature for 5 h. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by column chromatography to afford compound 16.4 (65 mg) in an 84% yield.

[0469] Using compound 16.4 and compound 14.3 as raw materials, referring to the synthetic route of compound C55, C111 was prepared in a yield of 38%. 1 H NMR (500MHz, DMSO-d6) δ9.07(d,J=148.1Hz,1H),7.95(s,1H),7.64–7.57(m,2H),7.51(dd,J=5.1,1.2Hz,1H),7.46(d,J=3.6 Hz,1H),7.40(d,J=8.0Hz,2H),7.25(d,J=7.7Hz,1H),7.11(dd,J=5.1,3.6Hz,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 is C 21 H 21 BrN6OS[M+H] + :486.40, the measured values ​​are 485.17,487.16.

[0470] [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

[0471]

[0472] Compound 16.1 and compound 14.3 were used as raw materials, and 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 in a yield of 42%. 1H 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) requires C 22 H 22 BrN7O[M+H] + :481.37, the measured values ​​are 480.21,482.20.

[0473] [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

[0474]

[0475] Compound 16.1 and compound 14.3 were used as raw materials, and 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 in 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) requires C 22 H 22 BrN7O2[M+H] + :497.37, the measured values ​​are 496.26,498.24.

[0476] [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

[0477]

[0478] Compound C125 was prepared using compound 16.1 and compound 14.3 as raw materials and referring to the synthetic route of compound C111, except that (4-(thiophen-2-yl)phenyl)methanamine was replaced with (4-(4-methyl-1H-imidazol-1-yl)phenyl)methanamine. The yield of the compound C125 was 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 is C 21 H 23 BrN8O[M+H] + :484.37, the measured values ​​are 483.24,485.21.

[0479] Example 17

[0480] [C127] N-(4-(((3-Isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)propanamide

[0481] Compound 17.1 was prepared using 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine and compound 10.2 as starting materials, following the synthetic route of compound 11.1, in a yield of 78%.

[0482] Compound 17.2 was prepared using compound 17.1 as starting material and referring to the synthetic route of compound 11.2 in a yield of 85%.

[0483] Compound 17.2 and compound 14.3 were used as raw materials and the synthetic route of compound 11.3 was referred to to prepare compound 17.3 in a yield of 51%.

[0484] Compound C127 was prepared using compound 17.3 as raw material and referring 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 is C 24 H 32 N6O2[M+H] + :437.56, the actual measured value is 437.50.

[0485] Example 18

[0486] [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

[0487] Compound 18.1 was prepared using 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine and compound 13.2 as starting materials, following the synthetic route of compound 11.1, in a yield of 70%.

[0488] Compound 18.2 was prepared using compound 18.1 as starting material and referring to the synthetic route of compound 11.2 in a yield of 82%.

[0489] Compound 18.2 and compound 14.3 were used as raw materials and the synthetic route of compound 11.3 was referred to to prepare compound 18.3 in a yield of 42%.

[0490] Compound C126 was prepared using compound 18.3 as starting material and referring to the synthetic route of compound C37 with a yield of 90%. 1H 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= 23.0,18.1,9.5,4.6 Hz,4H),1.32–1.25 (m,2H),1.21 (d,J=6.9 Hz,6H). UPLC-MS (ESI) theoretical value is C 25 H 31 FN6O2[M+H] + :467.56, the measured value is 467.74.

[0491] Example 19

[0492] [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

[0493] Compound 19.1 was prepared using compound 16.1 and compound 3.2 as raw materials, referring to the synthetic route of compound 16.3, with a yield of 55%.

[0494] Compound 19.2 was prepared using compound 19.1 as starting material and referring to the synthetic route of compound 16.4 in a yield of 88%.

[0495] Compound C137 was prepared using compound 19.2 and (R)-2-pyrrolidinemethanol as raw materials with reference to the synthetic route of compound C111 in 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) requires C 19 H22 BrN7O2[M+H] + :461.34, the measured values ​​are 460.33,462.33.

[0496] [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

[0497]

[0498] Compound C138 was prepared using compound 19.2 and (S)-2-pyrrolidinemethanol as raw materials with reference to the synthetic route of compound C137 in 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) requires C 19 H 22 BrN7O2[M+H] + :461.34, the measured values ​​are 460.34,462.34.

[0499] [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

[0500]

[0501] Compound C139 was prepared using compound 19.2 and (S)-2-(2-piperidinyl)ethanol as raw materials with reference to the synthetic route of compound C137. The yield was 39%. 1H 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) requires C 21 H 26 BrN7O2[M+H] + :489.39, the measured values ​​are 488.37,490.36.

[0502] Example 20

[0503] [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

[0504] 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 in a yield of 60%.

[0505] Compound 20.2 was prepared using compound 20.1 as starting material and referring to the synthetic route of compound 16.4 in a yield of 83%.

[0506] Compound C140 was prepared using compound 20.2 and (R)-3-pyrrolidinol as raw materials with reference to the synthetic route of compound C111 in 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) requires C 19 H 22BrN7O2[M+H] + :461.34, the measured values ​​are 460.37,462.35.

[0507] [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

[0508]

[0509] Compound C141 was prepared using compound 20.2 and (S)-3-pyrrolidinol as raw materials with reference to the synthetic route of compound C140 in a yield of 53%. 1 H NMR (600 MHz, DMSO-d6) δ 9.84 (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) requires C 19 H 22 BrN7O2[M+H] + :461.34, the measured values ​​are 460.37,462.36.

[0510] [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

[0511]

[0512] Compound C142 was prepared using compound 20.2 and (R)-2-pyrrolidinemethanol as raw materials with reference to the synthetic route of compound C140 in a yield of 55%. 1H 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) requires C 20 H 24 BrN7O2[M+H] + :475.36, the measured values ​​are 474.35,476.35.

[0513] [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

[0514]

[0515] Compound C143 was prepared using compound 20.2 and (S)-2-pyrrolidinemethanol as raw materials with reference to the synthetic route of compound C140 in 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) requires C 20 H 24 BrN7O2[M+H] + :475.36, the measured values ​​are 474.35,476.34.

[0516] [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

[0517]

[0518] Compound C144 was prepared using compound 20.2 and (S)-2-(2-piperidinyl)ethanol as raw materials with reference to the synthetic route of compound C140 in 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) requires C 22 H 28 BrN7O2[M+H] + :503.42, the measured values ​​are 502.38,504.37.

[0519] Example 21

[0520] [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

[0521] 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 in a yield of 47%.

[0522] Compound 21.2 was prepared using compound 21.1 as starting material and referring to the synthetic route of compound 16.4 in a yield of 76%.

[0523] Compound C145 was prepared using compound 21.2 and (R)-3-pyrrolidinol as raw materials with reference to the synthetic route of compound C111 in a yield of 31%. 1H NMR (500 MHz, DMSO-d6) δ 10.24–10.15 (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) required C 20 H 21 BrFN7O2[M+H] + :491.34, the measured values ​​are 490.32,492.32.

[0524] [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

[0525]

[0526] Compound C146 was prepared using compound 21.2 and (S)-3-pyrrolidinol as raw materials with reference to the synthetic route of compound C145 in a yield of 50%. 1 H NMR (500 MHz, DMSO-d6) δ 10.19 (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) required C 20 H 21 BrFN7O2[M+H] + :491.34, the measured values ​​are 490.33,492.32.

[0527] [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

[0528]

[0529] Compound C147 was prepared using compound 21.2 and (R)-2-pyrrolidinemethanol as raw materials with reference to the synthetic route of compound C145 in a yield of 39%. 1 H NMR (500 MHz, DMSO-d6) δ 10.19 (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) requires C 21 H 23 BrFN7O2[M+H] + :505.36, the measured values ​​are 504.31,506.30.

[0530] [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

[0531]

[0532] Compound C148 was prepared using compound 21.2 and (S)-2-pyrrolidinemethanol as raw materials with reference to the synthetic route of compound C145 in a yield of 42%. 1 H NMR (500 MHz, DMSO-d6) δ 10.19 (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) requires C 21 H 23BrFN7O2[M+H] + :505.36, the measured values ​​are 504.31,506.30.

[0533] [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

[0534]

[0535] Compound C149 was prepared using compound 21.2 and (S)-2-(2-piperidinyl)ethanol as raw materials with reference to the synthetic route of compound C145 in a yield of 40%. 1 H NMR (500 MHz, DMSO-d6) δ 10.19 (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) requires C 23 H 27 BrFN7O2[M+H] + :533.42, the measured values ​​are 532.36,534.34.

[0536] [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

[0537] Compound C64 can be synthesized according to the above synthetic route.

[0538] [C65]N-(4-(((8-Isopropyl-2-morpholinylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0539] Compound C65 can be synthesized according to the above synthetic route.

[0540] [C66]N-(4-(((8-Cyclopropyl-2-morpholinylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0541] Compound C66 can be synthesized according to the above synthetic route.

[0542] [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

[0543] Compound C67 can be synthesized according to the above synthetic route.

[0544] [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

[0545] Compound C68 can be synthesized according to the above synthetic route.

[0546] [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

[0547] Compound C69 can be synthesized according to the above synthetic route.

[0548] [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

[0549] Compound C70 can be synthesized according to the above synthetic route.

[0550] [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

[0551] Compound C71 can be synthesized according to the above synthetic route.

[0552] [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

[0553] Compound C72 can be synthesized according to the above synthetic route.

[0554] [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

[0555] Compound C73 can be synthesized according to the above synthetic route.

[0556] [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

[0557] Compound C74 can be synthesized according to the above synthetic route.

[0558] [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

[0559] Compound C75 can be synthesized according to the above synthetic route.

[0560] [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

[0561] Compound C76 can be synthesized according to the above synthetic route.

[0562] [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

[0563] Compound C77 can be synthesized according to the above synthetic route.

[0564] [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

[0565] Compound C78 can be synthesized according to the above synthetic route.

[0566] [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

[0567] Compound C79 can be synthesized according to the above synthetic route.

[0568] [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

[0569] Compound C80 can be synthesized according to the above synthetic route.

[0570] [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

[0571] Compound C81 can be synthesized according to the above synthetic route.

[0572] [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

[0573] Compound C82 can be synthesized according to the above synthetic route.

[0574] [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

[0575] Compound C83 can be synthesized according to the above synthetic route.

[0576] [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

[0577] Compound C84 can be synthesized according to the above synthetic route.

[0578] [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-d4)propanamide

[0579] Compound C85 can be synthesized according to the above synthetic route.

[0580] [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

[0581] Compound C86 can be synthesized according to the above synthetic route.

[0582] [C87]8-Isopropyl-N4-(4-phenoxybenzyl)-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

[0583] Compound C87 can be synthesized according to the above synthetic route.

[0584] [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

[0585] Compound C88 can be synthesized according to the above synthetic route.

[0586] [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

[0587] Compound C89 can be synthesized according to the above synthetic route.

[0588] [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

[0589] Compound C90 can be synthesized according to the above synthetic route.

[0590] [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

[0591] Compound C91 can be synthesized according to the above synthetic route.

[0592] [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

[0593] Compound C92 can be synthesized according to the above synthetic route.

[0594] [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

[0595] Compound C93 can be synthesized according to the above synthetic route.

[0596] [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

[0597] Compound C94 can be synthesized according to the above synthetic route.

[0598] [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

[0599] Compound C95 can be synthesized according to the above synthetic route.

[0600] [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

[0601] Compound C96 can be synthesized according to the above synthetic route.

[0602] [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

[0603] Compound C97 can be synthesized according to the above synthetic route.

[0604] [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

[0605] Compound C98 can be synthesized according to the above synthetic route.

[0606] [C99]8-Isopropyl-N 4 -(4-(piperazin-1-yl)benzyl)-N 2 -(Tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

[0607] Compound C99 can be synthesized according to the above synthetic route.

[0608] [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

[0609] Compound C100 can be synthesized according to the above synthetic route.

[0610] [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

[0611] Compound C101 can be synthesized according to the above synthetic route.

[0612] [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

[0613] Compound C102 can be synthesized according to the above synthetic route.

[0614] [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

[0615] Compound C103 can be synthesized according to the above synthetic route.

[0616] [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

[0617] Compound C104 can be synthesized according to the above synthetic route.

[0618] [C105]N 4 -(4-(2H-tetrazol-5-yl)benzyl)-8-isopropyl-N 2 -(Tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

[0619] Compound C105 can be synthesized according to the above synthetic route.

[0620] [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

[0621] Compound C106 can be synthesized according to the above synthetic route.

[0622] [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

[0623] Compound C107 can be synthesized according to the above synthetic route.

[0624] [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

[0625] Compound C108 can be synthesized according to the above synthetic route.

[0626] [C109]8-Bromo-N 2 -(tetrahydro-2H-pyran-4-yl)-N 4 -(4-(Thien-3-yl)benzyl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

[0627] Compound C109 can be synthesized according to the above synthetic route.

[0628] [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

[0629] Compound C110 can be synthesized according to the above synthetic route.

[0630] [C111]8-Bromo-N 2 -(tetrahydro-2H-pyran-4-yl)-N 4 -(4-(Thien-2-yl)benzyl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

[0631] Compound C111 can be synthesized according to the above synthetic route.

[0632] [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

[0633] Compound C112 can be synthesized according to the above synthetic route.

[0634] [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

[0635] Compound C113 can be synthesized according to the above synthetic route.

[0636] [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

[0637] Compound C114 can be synthesized according to the above synthetic route.

[0638] [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

[0639] Compound C115 can be synthesized according to the above synthetic route.

[0640] [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

[0641] Compound C116 can be synthesized according to the above synthetic route.

[0642] [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

[0643] Compound C117 can be synthesized according to the above synthetic route.

[0644] [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

[0645] Compound C118 can be synthesized according to the above synthetic route.

[0646] [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

[0647] Compound C119 can be synthesized according to the above synthetic route.

[0648] [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

[0649] Compound C120 can be synthesized according to the above synthetic route.

[0650] [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

[0651] Compound C121 can be synthesized according to the above synthetic route.

[0652] [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

[0653] Compound C122 can be synthesized according to the above synthetic route.

[0654] Example 22: Inhibitory activity of the compound on the proliferation and growth of triple-negative breast cancer cells

[0655] 1. Experimental methods

[0656] 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. MDA-MB-231 and MDA-MB-468 cells were cultured in Leibovitz's (L-15) medium supplemented with 10% fetal bovine serum (FBS) and penicillin-streptomycin (PS) antibiotics at 37°C in a CO2-free incubator, while 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 a 5% CO2 incubator.

[0657] In the cell activity test experiment, 90 μL of cell suspension of appropriate concentration was added to a 96-well cell culture plate according to the cell growth situation. Each compound to be tested was diluted with the corresponding culture medium in a gradient manner. 10 μL of the diluted compound was added to 90 μL of cell solution, and then cultured at 37°C and 5% CO2 for 4 days. Cell proliferation was analyzed by WST-8. WST-8 can be reduced to a yellow formazan product 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 was processed using GraphPad Prism6 software. Activity results: A represents cell activity IC 50 <1μM, B indicates cell viability 1μM <IC 50 <3 μM, C represents the IC of cell viability 50 >3μM.

[0658] 2. Experimental results

[0659] Based on the above-mentioned assay for compound cell growth inhibition, the compounds of the present invention exhibited superior cell growth inhibition activity in triple-negative breast cancer cell lines MDA-MB-231, MDA-MB-468, and BT549, compared to the positive control compound. Therefore, the compounds of the present invention may serve as novel inhibitors of relevant targets in triple-negative breast cancer cells.

[0660] Example 23: In vitro kinase inhibitory activity of compounds against CDK

[0661] 1. Experimental methods

[0662] In the in vitro kinase activity assay, CDK9 kinase activity was measured using Perkin Elmer's LANCE Ultra KinaSelect Ser / Thr Assay Kit. The reaction was performed in a 384-well plate in a total volume of 10 μL. CDK9 protein (final concentration 1 ng / μL), 4EBP-1 peptide substrate (final concentration 50 nM), and ATP (final concentration 2.5 μM) were reacted in a buffer solution consisting of 50 mM HEPES-KOH (pH 7.5), 10 mM MgCl2, 2 mM DTT, and 1 mM EGTA for 1 hour. The corresponding Eu-labeled anti-phosphoantibody, Eu-anti-P-4E-BP1, was added (final concentration 2 nM) and incubated for 30 minutes. Phosphorylation was then detected using the Envision fluorescence detector (Perkin Elmer, USA) to measure the ratio of laser light at wavelengths of 620 nM and 665 nM. Activity results: A represents cell activity (IC). 50 <100nM, B indicates cell viability 100nM <IC 50 <1000nM, C indicates cell viability 1μM <IC 50 <20μM, D represents the IC value of cell viability 50 >20μM.

[0663] 2. Experimental results

[0664] In vitro kinase inhibitory activity of compounds against CDK9

[0665] Based on the in vitro kinase inhibitory activity of the above compounds against CDK9, most of the compounds of the present invention have good in vitro kinase inhibitory activity against CDK9. Therefore, the compounds of the present invention can be used as new inhibitors of the CDK9 target.

[0666] 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.

[0667] 2. Experimental methods

[0668] In the in vitro kinase activity assay, CDK2 kinase activity was determined using Perkin Elmer's LANCE Ultra KinaSelect Ser / Thr Assay Kit. The reaction was performed in a 384-well plate in a total volume of 10 μL. CDK2 protein (final concentration 1 ng / μL), 4EBP-1 peptide substrate (final concentration 50 nM), and ATP (final concentration 2.5 μM) were reacted in a buffer solution of 50 mM HEPES-KOH (pH 7.5), 10 mM MgCl2, 2 mM DTT, and 1 mM EGTA for 1 hour. The corresponding Eu-labeled anti-phosphoantibody, Eu-anti-P-4E-BP1 (final concentration 2 nM), was added and incubated for 30 minutes. Phosphorylation was then detected using a fluorescence detector, Envision (Perkin Elmer, USA), to measure the laser ratio at wavelengths of 620 nM and 665 nM. Activity results:

[0669] A represents cell activity IC 50 <100nM, B indicates cell viability 100nM <IC 50 <1000nM, C indicates cell viability 1μM <IC 50 <20μM, D represents the IC value of cell viability 50 >20μM.

[0670] In vitro kinase inhibitory activity of compounds against CDK2

[0671] Based on the in vitro kinase inhibitory activity of the above compounds against CDK2, most of the compounds of the present invention have some inhibitory activity against CDK2 in vitro, while some compounds have much higher in vitro kinase activity against CDK9, thus exhibiting excellent CDK9 / CDK2 selectivity. Therefore, the compounds of the present invention can be used as novel selective inhibitors of either CDK9 or CDK2, depending on their activity and selectivity against CDK targets, or as dual-target inhibitors.

[0672] 3. Experimental methods

[0673] In vitro kinase activity assays were performed using the Perkin Elmer LANCE Ultra KinaSelect Ser / Thr Assay Kit to measure CDK12 kinase activity. The reaction was performed in a 384-well plate in a total volume of 10 μL. CDK12 protein (final concentration 1 ng / μL), 4EBP-1 peptide substrate (final concentration 50 nM), and ATP (final concentration 2.5 μM) were reacted in a buffer containing 50 mM HEPES-KOH (pH 7.5), 10 mM MgCl2, 2 mM DTT, and 1 mM EGTA for 1 h. The corresponding Eu-labeled anti-phosphoantibody, Eu-anti-P-4E-BP1, was added (final concentration 2 nM) and incubated for 30 min. Phosphorylation was then detected using an Envision fluorescence detector (Perkin Elmer, USA) to measure the ratio of laser light at wavelengths of 620 nM and 665 nM. Activity results: In vitro kinase inhibition rate (10μM) A indicates kinase inhibition rate >40%, B indicates kinase inhibition rate 10% <IC 50 <40%, C represents kinase inhibition rate 1% <IC 50 <10%, D represents the kinase inhibition rate IC 50 <1%.

[0674] In vitro kinase inhibitory activity of compounds against CDK12

[0675] Based on the in vitro kinase inhibitory activity of the above compounds against CDK12, most of the compounds of the present invention have good in vitro kinase inhibitory activity against CDK12. Therefore, the compounds of the present invention can be used as novel inhibitors of the CDK12 target.

[0676] Example 24: Pharmacokinetic Characterization of Compounds

[0677] 1. Experimental methods

[0678] Twenty-four male ICR mice (6-8 weeks old, 18-22 g, Beijing Weitonglihua Laboratory Animal Science Technology Co., Ltd., China) were randomly divided into eight groups of three mice each. Mice were administered single doses of compounds C27, C44, C58, and C59 dissolved in DMSO / solutol HS-15 / normal saline (5, 5, and 90%) via oral gavage (20 mg / kg) and intravenous injection (5 mg / kg). The oral group fasted for 10-14 hours before dosing but was allowed to drink water. Four hours after dosing, blood was collected from the eye sockets (50 μL) before dosing and at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after dosing. The intravenous group fasted before dosing and blood was collected from the eye sockets (50 μL) before dosing and at 0.083, 0.5, 1, 2, 4, 8, and 24 hours after dosing. The samples were centrifuged at 12,000 rpm for 5 minutes to obtain plasma, which was stored at -20°C before analysis. LC-MS / MS was used to evaluate the pharmacokinetics of compounds C27, C44, C58, and C59 in plasma.

[0679] 2. Experimental results

[0680] The compounds (C27, C44, C58, and C59) of the present invention are well absorbed, with bioavailabilities exceeding 40% and good pharmacokinetic properties. Because these compounds are novel inhibitors, they have great potential for new drug development and can be used as novel CDK9 inhibitors.

[0681] Example 25: An experiment in which compounds act on CDKs to cause degradation of their interacting proteins.

[0682] In the present invention, we unexpectedly discovered that some compounds, after acting on CDKs, can lead to the degradation of their interacting proteins, such as Cyclin K. Therefore, the development of compounds that selectively weaken CDK12 / Cyclin K function can be used to treat cancer and other diseases. CDK12 inhibitors have limited efficacy. The compounds of the present invention can induce the hydrolysis of CDK12 / Cyclin K, thereby affecting the functions of other proteins in the RNA polymerase II complex or the pre-mRNA splicing complex. Therefore, the compounds of the present invention can weaken the function of CDK / Cyclin K while maintaining selectivity for other CDKs, achieving effective treatment of diseases while reducing undesirable side effects and providing clinical efficacy. Therefore, the compounds of the present invention can weaken the function of CDK12 / Cyclin K and are therefore useful in treating or preventing diseases or symptoms associated with abnormal CDK12 activity or modulation of CDK activity.

[0683] 1. Experimental methods

[0684] MDA-MB-231 cells were seeded in 6-well plates and the corresponding compounds or DMSO blank control were added. After incubation for the corresponding time, the cells were lysed on ice for 10 minutes using lysis buffer (RIPA:PI = 6:1, RIPA+PI:PMSF = 200:1). The cells were centrifuged at 15,000 g for 30 minutes at 4°C. The protein supernatant was collected and quantified and normalized using BCA reagent. After electrophoresis on an 8% SDS-PAGE gel, the proteins were transferred to a PVDF membrane, blocked with 5% skim milk, and incubated with the primary antibody (Cyclin K). The membrane was washed and blocked with 5% skim milk and incubated with the secondary antibody (rabbit anti-antibody). After incubation, the membrane was washed and exposed to light.

[0685] The experimental results are shown in Figure 1. After treating MDA-MB-231 cells for 2 hours at a 50 nM concentration, the vast majority of the compounds disclosed herein exhibited a more significant degradation effect on cyclin K than the positive compound, cyclin K degrader CR8. Therefore, the compounds disclosed herein may be useful in treating triple-negative breast cancer or other diseases associated with abnormal cyclin K activity by degrading cyclin K.

[0686] discuss

[0687] By analyzing the crystal structures of CDK9 complexes and other CDKs (PDB IDs: IQMZ, 3BLR, 1UA2, 3BLH), the inventors of the present invention obtained the following important information: 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 CDK9 inhibitors in clinical trials forms hydrogen bonds with residues in the hinge region, which greatly contributes to their CDK9 potency. The activation loop (T loop) is the location of a threonine residue whose phosphorylation is crucial for enzyme activity, which is Thr186 in CDK9. In addition, residues Asp149, Lys151, and Thr191 of CDK9 form a catalytic loop that is directly involved in the phosphotransferase reaction. Notably, 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 docking results with CDK9 and other small molecule inhibitors (PDB ID: 3LQ5): The 4-amino group and N6 group of the pyrazo[1,5-a][1,3,5]triazine interact with the hinge region and form hydrogen bonds with the amide nitrogen and carbonyl groups of Cys106, respectively. These interactions lead to its inhibitory effect on CDK9 kinase activity. Furthermore, the phenyl ring points toward the solvent region, and the isopropyl group is located in the hydrophobic region bounded by Ala46 and Val79. Therefore, these characteristics will serve as a key starting point for the design of small molecule inhibitors of CDK9. Based on the molecular docking of the crystal structure, the inventors mainly designed and synthesized small molecule inhibitors of CDK9 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-proliferative 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 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.

[0688] 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 the present invention can also achieve the activity of targeting CDK12. The compounds of the present invention have also unexpectedly been found to have the activity of targeting CDK12 and regulating the degradation of Cyclin K 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 limitations. The compounds of the present invention can induce the hydrolysis of CDK12 / Cyclin K protein, thereby affecting the functions of other proteins in the RNA polymerase II complex or the function of the pre-mRNA splicing complex. Therefore, the compounds of the present invention can weaken the function of CDK / Cyclin K while maintaining selectivity for other CDKs, achieving effective treatment of diseases while reducing undesirable side effects and providing clinical effectiveness. Therefore, the compounds of the present invention can achieve the function of weakening CDK12 / Cyclin K and are therefore used in drugs to treat or prevent diseases or symptoms related to abnormal CDK12 activity or regulation of CDK activity.

[0689] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound represented by general formula (I), and its tautomers, stereoisomers, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, in, X is CH or N; Y is selected from -NH-, -O- or absent; R 1 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 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, C1-C3 alkyl, propynyl, C1-C3 alkylhydroxyl, C1-C3 alkylcarbonyl, halogen, 3-8 membered heterocyclyl, amino, (C1-C3 alkyl) 1-2 amino, methylsulfonyl; Selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution refers to 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, C1-C3 alkyl, halogen substituted C1-C3 alkyl; R 2 is selected from hydrogen, deuterium, halogen and unsubstituted or halogenated C1-C3 alkyl; R 3 Selected from deuterium, halogen, cyano, hydroxyl, nitro, unsubstituted or halogenated C1-C3 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 are independently selected from hydrogen, -C(O)R 4 , R 5 Substituted C1-C3 alkyl, wherein R 4 Selected from R 6 Substituted C1-C6 alkyl, R 6 Substituted 3-6 membered heterocycloalkyl and R 6 Substituted C3-C6 cycloalkyl, wherein each R 6 R is independently selected from hydrogen, hydroxy, C1-C3 alkyl-C(O)-, halogen and carboxyl; 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 following group: deuterium, oxo (=O), halogen, cyano, nitro, hydroxyl, amino, carboxyl, formylamino, C1-C3 alkyl, halogen-substituted C1-C3 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 C1-C6 alkyl group or an unsubstituted C3-C6 cycloalkyl group.

2. 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): in, (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 C1-C6 alkyl, substituted or unsubstituted C3-C6 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, C1-C3 alkyl, propynyl, -C1-C3 alkylhydroxyl, C1-C3 alkylcarbonyl, halogen, 3-8 membered heterocyclyl, amino, (C1-C3 alkyl) 1-2 amino, methylsulfonyl; R 2 、R 3 、m、 Same as definition in claim 1.

3. 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): in, (I-6) Japanese (I-8) Chinese Can be the same or different, Y is selected from -NH-, -O- or absent; R 1 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 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, C1-C3 alkyl, propynyl, -C1-C3 alkylhydroxyl, C1-C3 alkylcarbonyl, halogen, 3-8 membered heterocyclyl, amino, (C1-C3 alkyl) 1-2 amino, methylsulfonyl; Selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution refers to 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, C1-C3 alkyl, halogen substituted C1-C3 alkyl; each are independently selected from hydrogen, -C(O)R 4 , R 5 Substituted C1-C3 alkyl, wherein R 4 Selected from R 6 Substituted C1-C6 alkyl, R 6 Substituted 3-6 membered heterocycloalkyl and R 6 Substituted C3-C6 cycloalkyl, wherein each R 6 are independently selected from hydrogen, hydroxy, C1-C3 alkylcarbonyl, halogen and carboxyl, R 5 is selected from hydrogen, hydroxy, halogen and carboxyl; R 2 , R 3 , m are the same as defined in claim 1.

4. 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): in, Y is selected from -NH-, -O- or absent; R 1 Selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, wherein the aforementioned substitution refers to substitution by one or more of the following substituents: hydroxyl, C1-C3 alkyl, propynyl, hydroxyC1-C3 alkyl, C1-C3 alkylcarbonyl, halogen, heterocyclyl, amino, alkylamino, methylsulfonyl; Selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl, wherein the substitution refers to that one or more H on the group is independently substituted by a substituent selected from the group consisting of deuterium, halogen, hydroxyl, C1-C3 alkyl, halogen substituted C1-C3 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 refers to one or more H on the group being independently selected from the following group: deuterium, oxo (=O), halogen, cyano, nitro, hydroxyl, amino, carboxyl, formylamino, C1-C3 alkyl, halogen-substituted C1-C3 alkyl; R 2 , R 3 , m are the same as defined in claim 1.

5. 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): in, Y is selected from -NH-, -O- or absent; is selected from hydrogen, halogen, cyano, substituted C1-C6 alkyl, substituted C3-C6 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 independently is substituted by a substituent selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, amino, C1-C3 alkyl, halogen-substituted C1-C3 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 refers to one or more H on the group being independently selected from the following group: deuterium, oxo (=O), halogen, cyano, nitro, hydroxyl, amino, carboxyl, formylamino, C1-C3 alkyl, halogen-substituted C1-C3 alkyl, R 1 , R 2 , R 3 , m are the same as defined in claim 1.

6. 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): in, X is CH or N; R1 and Y are as defined in claim 1.

7. The compound according to claim 1, and its tautomers, stereoisomers, isotopic compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, wherein R1-Y is selected from:

8. 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:

9. A method for preparing the compound according to any one of claims 1 to 8, the method being 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; R1 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; R3 is selected from -CH3, -CH2CH3, R1 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; R1 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; R1 is the same as defined in claim 1.

10. 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.

11. Use of the compound according to 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 according to claim 10 in the preparation of a medicament for preventing and / or treating a disease or symptom associated with abnormal activity of CDK or Cyclin K.

12. The use according to claim 11, 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.

13. 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 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, 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.

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