Pyrazolotriazine and pyrazolopyrimidine derivatives, and preparation method, pharmaceutical composition and application thereof

Abstract

The invention provides pyrazolotriazine and pyrazolopyrimidine derivatives as well as a preparation method, a pharmaceutical composition and application thereof. Specifically, the invention provides pyrazolo [1, 5-a] [1, 3, 5] triazine and pyrazolo [1, 5-a] pyrimidine derivatives as shown in a general formula (I) and / or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and application of the derivatives as pharmaceutical active agents in drugs for preventing and / or treating diseases related to abnormal activity of CDKs, it is indicated that the compound has a good cell proliferation inhibition effect on solid tumors and hematologic tumors, and potential for treating related cancers and autoimmune diseases is achieved. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular, to a class of compounds as shown in general formula (I), preparation methods thereof, pharmaceutical compositions and their use in the preparation of degradation agents targeting cell cycle-dependent kinases (CDKs) for preventing and / or treating diseases or symptoms associated with abnormal activity of cell cycle-dependent kinases, and drugs for treating diseases or conditions associated with selective transcription of CDKs. The present invention also provides a pharmaceutically acceptable composition comprising the compound of the present invention and a method for using the composition to treat diseases or conditions associated with selective transcription of CDKs. Background Art

[0002] Cyclic-dependent kinases (CDKs) are important targets for tumor therapy. Cyclic-dependent kinases (CDKs) are a class of serine / threonine kinases, mostly heterodimeric complexes composed of cell cycle catalytic kinase subunits and regulatory subunits. They are activated by binding to cell cycle proteins, thereby regulating the cell cycle and transcription process. Disturbance of CDK activity can directly or indirectly cause uncontrolled cell proliferation, increased DNA mutations, chromosome deletions and chromosome changes, etc., leading to the occurrence and development of tumors. CDK family proteins participate in cell mitosis and transcription processes and play an important role in cell proliferation. Due to the abnormally active proliferation of tumor cells, abnormal activation of CDKs is often observed in tumor cells, thereby promoting the growth of tumor cells. The CDK family has always been considered an important target in tumor therapy, but due to the highly conserved amino acid sequence of the ATP binding pocket between different CDK proteins, it is difficult to find small molecule inhibitors with high selectivity between CDK families. Currently on the market, drugs targeting the CDK family include Pfizer's Palbociclib, Novartis' Ribociclib, Eli Lilly's Abemaciclib, Hengrui's Dalpiciclib and G1 Therapeutics' Trilaciclib. Except for Trilaciclib, which is used to reduce the frequency of bone marrow suppression in patients with small cell lung cancer after chemotherapy, the indications of the other drugs are all 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 gradually 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), and the CDK activating enzyme complex is composed of CDK7, cyclinH and MAT1. CAK can activate CDK proteins related to the cell cycle by threonine phosphorylation, including CDK1, CDK2, CDK4, CDK6, thereby affecting the cell cycle progress. In terms of transcriptional regulation, CDK7, as a component of the basic transcription factor TFIIH complex, can activate RNA polymerase II by the C-terminal domain of serine phosphorylation RNA polymerase II, thereby regulating the transcription initiation and extension mediated by RNA polymerase II.

[0004] CDK9 / Cyclin T1 (or T2) is part of the subunit of the positive transcription elongation factor b (P-TEFb) complex. It activates RNA polymerase II to initiate gene transcription elongation regulation by phosphorylating the carboxyl terminal domain (CTD) of RNA polymerase. CDK9 is upstream of key molecules such as anti-apoptotic proteins Bcl-2, Mcl-1, XIAP, cell cycle regulatory proteins, and mitotic regulatory kinases that are closely related to tumors. CDK9 can be directly or indirectly regulated. For example, in chronic lymphocytic leukemia (CLL), the key proteins of the Bcl-2 family can be downregulated by inhibiting the activity of CDK9 to achieve a therapeutic effect. CDK9 does not affect the regulation of the cell cycle. This specific regulation of the transcription process by CDK9 makes it one of the most potential anti-tumor targets in the CDK family. In addition, there are literature reports that CDK7 / cyclin H and CDK9 / cyclin T complexes also show the ability to inhibit the replication of RNA of HIV and HSV viruses, so there will be certain application prospects in the antiviral field.

[0005] CDK7 and CDK9 are important targets for the treatment of tumors. Currently, several CDK7 and CDK9 inhibitors have entered clinical research. However, due to the highly conservative structure of CDKs, most of them are non-selective inhibitors. Representative small molecule inhibitors include Flavopiridol, Roscovitine, SNS-032, R547, TG-02, AT-7519, etc., but there are relatively few studies on small molecule inhibitors that highly selectively target CDK7 or CDK9, or target CDK7 and CDK9 dual targets. Blocking the cell cycle by small molecule inhibitors on CDK7 and CDK9 to induce apoptosis and regulate transcription has become an important anti-tumor method. Since most of the known CDK9 inhibitors have disadvantages such as non-selectivity or unexpected toxicity, they may cause unforeseen side effects.

[0006] Cyclin-dependent kinase (CDK) 12 and CDK13 are important targets for disease treatment. CDK12 is a member of a subset of the CDK serine / threonine kinase family that phosphorylates the C-terminal domain (CTD) of RNA polymerase II. CDK12 in the CDK12 / CyclinK complex regulates transcriptional, co-transcriptional, and post-transcriptional processes by phosphorylating Ser of the CTD of the RNA polymerase II complex. CDK13 is a kinase closely related to CDK12 that forms a complex with CyclinK and regulates the transcription of a different set of genes. CDK12 amplification and high expression levels suggest that the tumor-promoting effects of CDK12 are at least in part based on alternatively spliced ​​mRNAs, increased DNA repair capacity, and increased stress tolerance. This information suggests that CDK12 is a potential target for the development of drugs to treat cancer and other diseases.

[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 CDKs, thereby regulating RNA polymerase II-mediated transcription initiation and extension, and effectively inhibiting the proliferation of tumor cells. The purpose of the present invention is to provide a class of compounds that can be used to treat and / or prevent or improve such diseases and / or conditions by designing and synthesizing new inhibitors or degraders targeting CDK. Therefore, the development of inhibitors and degraders targeting CDK has important scientific significance and research value. Summary of the invention

[0008] One object of the present invention is to provide a compound as represented by the general formula (I) and its tautomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, pharmaceutical compositions containing the same, and uses thereof.

[0009] Another object of the present invention is to provide a method for preparing the compound represented by the general formula (I), an important intermediate for preparing the compound and a method for preparing the compound.

[0010] 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.

[0011]

[0012]

[0013] Wherein, X is CH or N;

[0014] Y is selected from -NH-, -O- or absent;

[0015] 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;

[0016] 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;

[0017] R 2 is selected from hydrogen, deuterium, halogen and unsubstituted or halogenated C1-C3 alkyl;

[0018] R 3 Selected from deuterium, halogen, cyano, hydroxyl, nitro, unsubstituted or halogenated C1-C3 alkyl;

[0019] n is 1 or 2;

[0020] m is 0, 1, 2, 3 or 4;

[0021] Z is selected from NH, N, O or absent;

[0022] 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 6Substituted 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;

[0023] 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;

[0024] The premise is 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.

[0025] 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.

[0026] In another preferred embodiment, the compound of general formula (I) has a structure shown in formula (I-1)-(I-4):

[0027]

[0028] Among them, (I-2) Can be the same or different,

[0029] X is CH or N;

[0030] Y is selected from -NH-, -O- or absent;

[0031] 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 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;

[0032] R 2 , R 3 、m、 As defined in the present invention.

[0033] In another preferred embodiment, the compound of general formula (I) has a structure shown in formula (I-5)-(I-8):

[0034]

[0035] Among them, (I-6) and (I-8) Can be the same or different,

[0036] Y is selected from -NH-, -O- or absent;

[0037] 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;

[0038] 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;

[0039] 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 R6 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;

[0040] R 2 , R 3 , m are as defined in the present invention.

[0041] In another preferred embodiment, the compound of general formula (I) has the structure shown in formula (I-9)-(I-10):

[0042]

[0043] wherein Y is selected from -NH-, -OO- or absent;

[0044] 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;

[0045] 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;

[0046] 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;

[0047] R 2 , R 3 , m are as defined in the present invention.

[0048] In another preferred embodiment, the compound of general formula (I) has a structure shown by formula (I-11)-(I-12):

[0049]

[0050] wherein Y is selected from -NH-, -O- or absent;

[0051] 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 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;

[0052] 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,

[0053] R 1 , R 2 , R 3 , m are as defined in the present invention.

[0054] In another preferred embodiment, the compound of general formula (I) has a structure shown in formula (I-13)-(I-41):

[0055]

[0056] Wherein, X is CH or N; R1 and Y are as defined in the present invention.

[0057] In another preferred embodiment, the compound of the general formula (I) is characterized in that R1-Y is selected from:

[0058]

[0059] In another preferred embodiment, the compound is selected from the following group:

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072] In another preferred embodiment, n, m, X, Y, Z, R 1 , R 2 , R 3 , and Optionally, it is independently any corresponding group of C1-C149.

[0073] The second aspect of the present invention provides a pharmaceutical composition, which comprises the compound as described in the first aspect of the present invention and one or more of its tautomers, stereoisomers, isotope compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, and pharmaceutically acceptable excipients.

[0074] The third aspect of the present invention provides the use of the compound as described in the first aspect of the present invention and its tautomers, stereoisomers, isotope compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof or the pharmaceutical composition as described in the second aspect of the present invention in the preparation of a drug for preventing and / or treating diseases or symptoms associated with abnormal activity of CDK or Cyclin K.

[0075] In another preferred embodiment, the CDK is selected from: CDK2, CDK9, CDK12, or Cyclin K, or a combination thereof.

[0076] 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.

[0077] 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, 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.

[0078] In addition, the present invention also provides the use of the compound as described in the first aspect of the present invention and its tautomers, stereoisomers, isotope compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof in the preparation of CDK or Cyclin K inhibitors.

[0079] In another preferred embodiment, the CDK is selected from: CDK2, CDK9, CDK12, or a combination thereof.

[0080] The present invention also provides a method for preventing and / or treating diseases or symptoms associated with abnormal activity of CDK or Cyclin K, comprising the steps of administering to a subject in need thereof a compound as described in the first aspect of the present invention and its tautomers, stereoisomers, isotope compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, or a pharmaceutical composition as described in the second aspect of the present invention.

[0081] In another preferred embodiment, the subject is a human or non-human mammal, such as a rat or a mouse.

[0082] The present invention also encompasses any novel intermediates disclosed herein.

[0083] In another aspect of the present invention, there is provided a method for preparing the compound according to the first aspect of the present invention, wherein the method is selected from one of the following methods:

[0084] Synthesis method 1:

[0085]

[0086] Step 1-1: Compound 1A reacts with Boc anhydride to obtain compound 1B;

[0087] Step 1-2: Compound 1B is subjected to hydrogenation reaction with Raney nickel to obtain compound 1C;

[0088] 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;

[0089] Step 1-4: Compound 1E and compound 1F react under the conditions of sodium hydrogen and anhydrous N,N-dimethylformamide to obtain compound 1H;

[0090] Step 1-5: Compound 1E and compound 1G react under 1-methyl-2-pyrrolidone to obtain compound 1J;

[0091] Step 1-6: Compound 1H is reacted in the presence of dioxane hydrochloride to obtain compound 1I.

[0092] Step 1-7: Compound 1J is reacted in the presence of dioxane hydrochloride to obtain compound 1K.

[0093] R1 is the same as defined in the first aspect of the present invention;

[0094] Synthesis method 2:

[0095]

[0096] Step 2-1: Compound 2A reacts with compound 2B in the presence of HATU and DIPEA to obtain compound 2C;

[0097] Step 2-2: Compound 2C is reacted in the presence of dioxane hydrochloride to obtain compound 2D;

[0098] 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;

[0099] Step 2-4: Compound 2E and compound 2F react under the conditions of sodium hydrogen and anhydrous N,N-dimethylformamide to obtain compound 2I;

[0100] Step 2-5: Compound 2E and compound 2G react under 1-methyl-2-pyrrolidone to obtain compound 2J;

[0101] Step 2-6: Compound 2E and compound 2H react in 1-methyl-2-pyrrolidone to obtain compound 2K.

[0102] R3 is selected from -CH3, -CH2CH3,

[0103] R1 is the same as defined in the first aspect of the present invention;

[0104] Synthesis method three:

[0105]

[0106] 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;

[0107] 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;

[0108] Step 3-3: Compound 3C and compound 3E react under 1-methyl-2-pyrrolidone to obtain compound 3F;

[0109] Step 3-4: Compound 3D and compound 3E react under 1-methyl-2-pyrrolidone to obtain compound 3G;

[0110] Step 3-5: Compound 3F is reacted in the presence of dioxane hydrochloride to obtain compound 3H;

[0111] Step 3-6: Compound 3G is reacted in the presence of dioxane hydrochloride to obtain compound 3I;

[0112] R1 is the same as defined in the first aspect of the present invention;

[0113] Synthesis method 4:

[0114]

[0115] Step 4-1: Compound 4A and compound 1C react under the conditions of N,N-diisopropylethylamine and ethanol to obtain compound 4B;

[0116] Step 4-2: Compound 4A and compound 2D react under the conditions of N,N-diisopropylethylamine and ethanol to obtain compound 4C;

[0117] Step 4-3: Compound 4B reacts with Boc anhydride to obtain compound 4D;

[0118] Step 4-4: Compound 4C reacts with Boc anhydride to obtain compound 4E;

[0119] Step 4-5: Compound 4D and compound 4F react under 1-methyl-2-pyrrolidone to obtain compound 4G;

[0120] Step 4-6: Compound 4E and compound 4F react under 1-methyl-2-pyrrolidone to obtain compound 4H;

[0121] Step 4-7: Compound 4G is reacted in the presence of dioxane hydrochloride to obtain compound 4I;

[0122] Step 4-8: Compound 4H is reacted in the presence of dioxane hydrochloride to obtain compound 4J;

[0123] R1 is the same as defined in the first aspect of the present invention.

[0124] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. The above description does not mean to limit the aspects of the present invention in any form. BRIEF DESCRIPTION OF THE DRAWINGS

[0125] Figure 1 The results of Western blotting experiments are shown to show the Cyclin K degradation activity of some compounds of the present invention. DETAILED DESCRIPTION

[0126] The present inventors have provided a class of CDK inhibitor compounds with novel structures and excellent anti-tumor activity through extensive and in-depth research, a large number of screenings and tests.

[0127] the term

[0128] When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0129] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0130] The compounds shown in general formula (I) may contain one or more asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. The compounds of the present invention include all stereoisomeric forms, including but not limited to diastereomers, enantiomers and atropisomers and mixtures thereof (such as racemates), which are all included within the scope of the present invention.

[0131] The term "substituted" refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is a substituent described above or a substituent appearing in the examples. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different at each position. A cyclic substituent, such as a heterocycloalkyl, may be attached to another ring, such as a cycloalkyl, to form a spirobicyclic system, for example, two rings sharing one carbon atom. Unless otherwise specified, substitution may refer to a group being replaced by one or more groups selected from the following: hydrogen, halogen, cyano, nitro, hydroxyl, carboxyl, 4-10 membered heterocyclyl, C1-C6 alkyl, C1-C6 alkoxy, halogen-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkoxy, C2-C6 alkenyl, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy-substituted C1-C6 alkoxy, and C1-C6 alkoxy substituted by C1-C6 alkoxy.

[0132] Those skilled in the art will appreciate that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. The substitutions on the relevant structures in the present invention include substitution and non-substitution, such as "optionally" substituted with a certain substituent, which means including substitution or non-substitution with a certain substituent.

[0133] 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.

[0134] The term "substituted" applies only to sites that can be substituted by substituents and does not include substitutions that are not achievable based on existing chemical knowledge.

[0135] The compounds represented by the general formula (I) may also exist in different tautomeric forms, all of which are included within the scope of the present invention.

[0136] 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.

[0137] 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.

[0138] "Diastereomers" refer to stereoisomers that have two or more chiral neutrals and are not mirror images.

[0139] "Racemate" refers to two stereoisomers that are mirror images of each other, with opposite optical rotations that cancel each other out.

[0140] "Pharmaceutically acceptable salts" refer to salts formed by drug molecules and corresponding organic acids, inorganic acids or organic bases, inorganic bases, such as hydrochloric acid, formic acid, trifluoroacetic acid, succinic acid, methanesulfonate, etc.

[0141] "Prodrug" refers to a class of compounds that are inactive or have low activity in vitro, but release active drugs through enzymatic or non-enzymatic conversion in vivo to exert their pharmacological effects.

[0142] "Hydrate" refers to a compound containing water.

[0143] 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 than the original atoms. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 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, wherein the isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention. Certain isotope-labeled compounds of the present invention, such as 3 H and 14 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 good metabolic stability, has advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore, can be given priority in certain cases. Isotope-labeled compounds can be prepared by general methods by replacing readily available isotope-labeled reagents with non-isotope reagents and using the scheme disclosed in the examples. Preferably, the isotope compound is a deuterated compound, and more preferably, one or more H on carbon in the isotope compound is replaced by deuterium.

[0144] The term "plurality" refers to two or more, such as 2, 3, 4, 5 or 6.

[0145] The term "halogen" includes fluorine, chlorine, bromine or iodine.

[0146] 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.

[0147] 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 other groups 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.

[0148] The term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.

[0149] 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.

[0150] 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 having 3 to 8 carbon atoms in the ring. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentenyl, and cyclohexyl. Polycyclic cycloalkyls include spirocyclic, condensed, and bridged cycloalkyls.

[0151] The term "heterocyclic group" refers to a cyclic substituent containing one or more saturated and / or partially saturated monocyclic or polycyclic substituents, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur, oxo (=O) or S(O)m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon; the heterocyclic group may include a 3-8-membered heterocyclic group, preferably a 5-6-membered heterocyclic group, for example, propylene oxide, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl; the heterocyclic group may be fused to an aryl, heteroaryl, or cycloalkyl ring, and the ring connected to the parent structure is a heterocyclic group. Heterocyclic groups include spirocyclic, fused ring, and bridged heterocyclic groups.

[0152] The term "aryl" refers to a 6-14-membered all-carbon monocyclic or fused polycyclic group with a conjugated p-electron system, preferably a 6- to 10-membered ring, preferably a 6- to 10-membered ring, more preferably a phenyl and a naphthyl, and most preferably a phenyl. The aryl ring may be fused to a heteroaryl, a heterocyclic or a cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring.

[0153] The term "heteroaryl" refers to a 5-14-membered aromatic group having 1 to 4 (e.g., 2 or 3) heteroatoms as ring atoms, with the remaining ring atoms being carbon, wherein the heteroatoms include oxygen, sulfur, and nitrogen. Preferably, it is 5-10 members. Heteroaryl is preferably 5-membered or 6-membered, such as thienyl, pyridyl, pyrrolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring,

[0154] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen, sulfur or S(O)m (wherein m is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are carbon. The spiroheterocycle can be fused to a 6-10-membered aryl or 5-10-membered heteroaryl ring, wherein the ring connected to the parent structure is a spiroheterocycle.

[0155] 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.

[0156] The term "alkenyl" refers to an alkenyl group which may be of 2 to 10 carbons, such as ethenyl, propenyl, butenyl, styryl, phenylpropenyl.

[0157] The term "alkynyl" refers to an alkynyl group which may be 2-10 carbons, such as ethynyl, propynyl, butynyl, phenylethynyl, phenylpropenyl.

[0158] 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.

[0159] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0160] The present invention also encompasses any novel intermediates disclosed herein.

[0161] The term "prevent" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0162] 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 leading to or causing 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.

[0163] The present invention provides a compound or a crystalline hydrate and a solvate with a structure as formula (I), and use thereof in preparing a drug for preventing and / or treating a disease or symptom associated with abnormal activity of CDK.

[0164] When the compound of the present invention contains a basic group, it can be prepared into a pharmaceutically acceptable salt, including inorganic acid salts and organic acid salts. Acids suitable for forming salts include (but are not limited to): inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid.

[0165] One aspect of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the general formula (I), and one or more of its stereoisomers, pharmaceutically acceptable salts, prodrugs, solvates, hydrates and crystalline forms, and at least one excipient, diluent or carrier.

[0166] A typical formulation is prepared by mixing the compound represented by the general formula (I) of the present invention and a carrier, diluent or excipient. Suitable carriers, diluents or excipients are well known to those skilled in the art, and include substances such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, and the like.

[0167] The specific carrier, diluent or excipient used will be determined according to the mode of use and purpose of the compound of the present invention. Solvents are generally selected based on solvents that are considered safe and effective for administration to mammals by those skilled in the art. Generally speaking, safe solvents are non-toxic aqueous solvents such as pharmaceutical water, and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300), etc. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents or other known additives to make the compound represented by formula (I) in an acceptable form for manufacture or use.

[0168] In this application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human), the medium including a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0169] When the compound of formula (I) of the present invention is used in combination with at least one other drug, the two drugs or multiple drugs can be used separately or in combination, preferably in the form of a pharmaceutical composition. The compound of formula (I) or pharmaceutical composition of the present invention can be administered to a subject separately or together in any known oral, intravenous, rectal, vaginal, transdermal, or other topical or systemic administration forms.

[0170] These pharmaceutical compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, flavoring agents, flavoring agents or other known additives so that the pharmaceutical compositions can be manufactured or used in an acceptable form.

[0171] The drug of the present invention is preferably administered orally. Solid dosage forms for oral administration may include capsules, tablets, powders or granular preparations. In the solid dosage form, the compound or pharmaceutical composition of the present invention is mixed with at least one inert excipient, diluent or carrier. Suitable excipients, diluents or carriers include substances such as sodium citrate or dicalcium phosphate, or starch, lactose, sucrose, mannitol, silicic acid, etc.; binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, gum arabic, etc.; wetting agents such as glycerol, etc.; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, specific complex silicates, sodium carbonate, etc.; solution retardants such as paraffin, etc.; absorption promoters such as quaternary ammonium compounds, etc.; adsorbents such as kaolin, bentonite, etc.; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc. In the case of capsules and tablets, the dosage form may also include a buffer. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or other excipients such as high molecular weight polyethylene glycols.

[0172] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the compound of the present invention or its composition, the liquid dosage form may contain an inert diluent commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide; oils (such as cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, etc.); glycerol; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and dehydrated sorbitan; or a mixture of several of these substances, etc.

[0173] In addition to these inert diluents, the composition may also include excipients such as one or more of wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, and perfuming agents.

[0174] 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.

[0175] 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.

[0176] The compounds or pharmaceutical compositions of the present invention may be administered in other topical dosage forms, including creams, powders, sprays and inhalants. The drug may be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent or carrier and any desired preservative, buffer or propellant. Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be included within the scope of the present invention.

[0177] Another aspect of the present invention provides the use of the compound represented by general formula (I) and its tautomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or the above-mentioned pharmaceutical compositions in the preparation of drugs for preventing and / or treating diseases or symptoms associated with abnormal activity of CDK.

[0178] The diseases associated with abnormal CDK activity include solid tumors such as breast cancer, colon cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer, and blood tumors such as acute lymphocytic leukemia, acute lymphocytic leukemia, cellular lymphoma, cellular lymphoma, myeloma, acute and chronic myeloid leukemia, and promyelocytic leukemia.

[0179] Another aspect of the present invention also provides the use of the compound represented by general formula (I) and its tautomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating diseases such as tumors, central nervous system diseases and immune diseases.

[0180] 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.

[0181] In another preferred embodiment, the cancer includes (but is not limited to): the disease is a solid tumor, a blood tumor, preferably, the disease is selected from: myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, myelofibrosis, Burkitt's lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, ciliary body and chronic melanoma, iris melanoma, recurrent interocular melanoma, T-cell lymphoma, erythroid lymphoma, monocytic and monocytic leukemia, myeloid leukemia, Central nervous system lymphoma, meningioma, spinal cord tumor, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, astrocytoma, amyloidosis, complex regional pain syndrome type I, malignant melanoma, radiculopathy, glioblastoma, gliosarcoma, malignant glioma, refractory plasmacytoma, melanoma with extraocular extension, papillary and follicular thyroid cancer, breast cancer, prostate cancer, colorectal cancer, ovarian cancer, endometrial cancer, cervical cancer, hepatocellular carcinoma, stomach cancer, esophageal cancer, bladder cancer, small cell lung cancer, non-small cell lung cancer, Ewing sarcoma, glioblastoma, pancreatic cancer, or primary macroglobulinemia.

[0182] The compounds provided by the present invention are also effective against blood tumors and myelomas, such as being useful for treating multiple myeloma and acute and chronic leukemia. The compounds provided by the present invention can be used to prevent or treat primary tumors and metastatic tumors.

[0183] 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.

[0184] The main advantages of the present invention are:

[0185] 1. The compounds of the present invention have excellent cancer cell inhibitory activity, especially the inhibitory activity on triple-negative breast cancer cells, which is superior to the drugs under clinical research and can be used to treat a variety of malignant tumors.

[0186] 2. The compounds of the present invention are used as CDK kinase inhibitors, preferably having good selectivity and kinase activity for inhibiting CDK9.

[0187] 3. In addition to the inhibitory activity of CDK kinase, it is unexpectedly found that some of the compounds of the present invention can be used as degraders of Cyclin K and have a good degradation effect in tumor cells.

[0188] 4. The compounds of the present invention have excellent pharmacokinetic properties.

[0189] Specific implementation methods

[0190] The present invention will be further described below in conjunction with specific examples, but these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0191] In all embodiments, 1 H NMR spectrum test instruments are 400MHz Bruker and 500MHz Bruker nuclear magnetic resonance instruments, and chemical shifts are expressed in δ (ppm); mass spectra are measured by MS mass spectrometry UPLC-MS (ESI); wherein the UPLC model is WatersHPLC H-CLASS, and the MS (ESI) model is Waters SQ Detector 2; anhydrous tetrahydrofuran is prepared by benzophenone / metallic sodium reflux drying and deoxygenation, and anhydrous toluene and anhydrous dichloromethane are prepared by calcium chloride reflux drying; petroleum ether, ethyl acetate, dichloromethane and other solvents used for column chromatography mobile phase are all purchased from Sinopharm Chemical Reagent Co., Ltd.; the thin layer chromatography silica gel plate (HSGF254) used in reaction detection comes from Sinopharm Chemical Reagent Co., Ltd.; and the 200-300 mesh silica gel of Sinopharm Chemical Reagent Co., Ltd. is selected for compound separation. The raw materials in the present invention can be obtained from commercial sources, such as the main reagents purchased from Sinopharm Chemical Reagent Co., Ltd., or prepared by the method inhibited in the art, or prepared according to the method described in the present invention.

[0192] 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.

[0193] 1. Preparation Example

[0194] [Control compound] N-Benzyl-8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazine-4-amine

[0195] Referring to the synthetic route of compound 1.6, compound 1.2 was replaced with benzylamine to prepare compound Control compound.

[0196]

[0197] Example 1

[0198] [C1] N-(4-aminobenzyl)-8-isopropyl-2-((1-methylpiperidin-4-yl)oxy)pyrazolo[1,5-a][1,3,5]triazine-4-amine

[0199]

[0200] Dissolve p-cyanoaniline (10 g, 84.65 mmol, 1.0 equiv) and 4-dimethylaminopyridine (2.07 g, 16.93 mmol, 0.2 equiv) in dichloromethane, cool to 0°C, add di-tert-butyl dicarbonate (19.45 mL, 84.65 mmol, 1.0 equiv), and warm to room temperature for 4 hours. After the reaction is complete, dichloromethane is added to dilute the reaction solution, and the solution is washed three times with a saturated sodium chloride aqueous solution. The organic layers are combined, dried with anhydrous sodium sulfate, filtered and dried, and then column chromatography is performed to obtain a white solid 1.1 (14.31 g) with a yield of 77%. 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).

[0201] 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 nitrogen gas was replaced 3 times, and the hydrogen gas was replaced 3 times. After reacting at room temperature for 4 hours, the reaction was completed. Methanol was added to dilute the reaction solution, filtered through diatomaceous earth, and dried to obtain product 1.2 (14.28 g) with a yield of 98%. 1 H NMR (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).

[0202] Compound 1.3 (200 mg, 0.78 mmol, 1.0 equiv) was dissolved in 4 mL of phosphorus oxychloride, and N, N-dimethylbenzylamine (297 μL, 2.34 mmol, 3.0 equiv) was added and reacted at 100 ° C for 2 hours. After the reaction was completed, it was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in 4 mL of acetonitrile. Compound 1.2 (209 mg, 0.94 mmol, 1.2 equiv) was dissolved in 6 mL of acetonitrile, and the acetonitrile solution of the previous step and N, N-dimethylbenzylamine (258 μL, 1.56 mmol, 2.0 equiv) were added, and the temperature was raised to 50 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature, extracted with 150 mL of ethyl acetate 3 times, washed with saturated NaCl aqueous solution 3 times, and dried over anhydrous sodium sulfate. Filter, remove ethyl acetate, and obtain compound 1.4 (280 mg) by column chromatography with a yield of 78%. 1 H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.30(s,1H),8.28–8.24(m,1H),7.39(d,J=8.4Hz,2H),7.31( d,J=8.6Hz,2H),4.66(d,2H),3.27(s,3H),3.18–3.15(m,1H),1.45(s,9H),1.30(d,J=7.0Hz,6H).

[0203] 1-Methyl-4-piperidinol (248 mg, 2.15 mmol, 5.0 equiv) was dissolved in 2 mL of anhydrous N, N-dimethylformamide, and 60% (w / w) sodium hydrogen (86 mg, 2.15 mmol, 5.0 equiv) was added at 0°C, and a 2 mL anhydrous N, N-dimethylformamide solution of compound 1.4 (200 mg, 0.43 mmol, 1.0 equiv) was added, and the mixture was heated to 50°C and reacted for 3 h. After the reaction was completed, the mixture was cooled to room temperature, quenched with water, diluted with ethyl acetate, washed with a saturated sodium chloride aqueous solution, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, dried by spin drying, and column chromatography was performed to obtain compound 1.6 (132 mg) with a yield of 62%. 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).

[0204] 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, and then dried by spin drying. Compound C1 (107 mg) was obtained by HPLC purification with 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 is C 21 H 29 N7O[M+H] + :396.24, the measured value is 396.33.

[0205] Example 2

[0206] [C38] (S)-2-((4-((4-aminobenzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)butan-1-ol

[0207]

[0208] Compound 1.4 (30 mg, 0.065 mmol, 1.0 equiv) was dissolved in 2 mL of 1-methyl-2-pyrrolidone, (S)-(+)-2-amino-1-butanol (25 μL, 0.26 mmol, 4.0 equiv) was added, and the temperature was raised to 120°C for 5 h. After the reaction, the mixture was cooled to room temperature, and 60 mL of ethyl acetate was added for extraction, and the mixture was washed with saturated sodium chloride aqueous solution, and the organic phases were combined and dried with anhydrous sodium sulfate. The mixture was filtered, dried by spin drying, and column chromatography was performed to obtain compound 2.2 (22 mg) with a yield of 71%. 1 H NMR (500MHz, DMSO-d6) δ9.29(s,1H),7.67(s,1H),7.37(d,J=8.2Hz,2H),7.26(d,J=8.0Hz,2H),6.58–6.46(m,1H),4.52(d,J=6.5Hz,2H),3.87–3. 78(m,1H),3.46(d,2H),2.89(dt,J=13.2,6.6Hz,1H),1.93–1.86(m,1H), 1.65–1.59(m,1H),1.45(s,9H),1.22(d,J=7.3Hz,6H),0.87–0.82(m,3H).

[0209] Compound 2.2 (22 mg, 0.047 mmol, 1.0 equiv) was dissolved in 2 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 1 h, and then dried by spin drying. Compound C38 (19 mg) was obtained by HPLC purification with a yield of 99%. 1 H NMR (400 MHz, Methanol-d4) δ7.89 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 4.85–4.78 (m, 2H), 4.16–4.07 (m, 1H), 3.63 (d, J = 5.2 Hz, 2H), 3.06–2.97 (m, 1H), 1.72 (ddd, J = 13.5, 7.5, 5.8 Hz, 1H), 1.59 (dt, J = 14.4, 7.4 Hz, 1H), 1.29 (d, J = 7.0 Hz, 6H), 0.94 (t, J = 7.4 Hz, 3H). UPLC-MS (ESI) theoretical value was C 19 H 27 N7O[M+H] + :370.23, the actual measured value is 370.32.

[0210] Example 3

[0211] [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

[0212]

[0213] 4-(N-Boc-aminomethyl)aniline (3 g, 13.50 mmol, 1.0 equiv) was dissolved in anhydrous DMF, acetic acid (927 μL, 16.20 mmol, 1.2 equiv) and DIPEA (23.5 mL, 135.0 mmol, 10.0 equiv) were added, reacted at room temperature for 1 h, diluted with ethyl acetate, washed with saturated sodium chloride aqueous solution, combined organic phases, dried over anhydrous sodium sulfate, filtered, dried by spin drying, and column chromatography to obtain a white solid 3.1 (3.25 g) with a yield of 91%. 1 H NMR (400MHz, DMSO-d6) δ9.90 (s, 1H), 7.49 (d, J = 8.1Hz, 2H), 7.32 (t, J = 6.3Hz ,1H),7.13(d,J=8.2Hz,2H),4.04(d,J=6.2Hz,2H),2.02(s,3H),1.38(s,9H).

[0214] 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, and then dried by spin drying. Compound 3.2 (1.92 g) was obtained by HPLC purification with 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).

[0215] Using compound 3.2 as raw material and referring to the synthesis of compound 1.6, compound C2 was prepared with a yield of 62%. 1HNMR (500MHz, Methanol-d4) δ7.84 (s, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 5.21–5.14 (m, 1H), 4.72 (s, 2H), 3.18–3.12 (m, 2H), 3.08–3.03 (m, 1H), 3.01–2.88 (m, 2H), 2.67 (s, 3H), 2.15–2.11 (m, 1H), 2.11 (s, 3H), 2.10–2.07 (m, 1H), 2.02 (dd, J = 9.3, 3.8 Hz, 2H), 1.29 (d, J = 6.9 Hz, 6H). UPLC-MS (ESI) theoretical value is C 23 H 31 N7O2[M+H] + :438.25, the actual measured value is 438.34.

[0216] [C41]N-(4-(((8-isopropyl-2-(piperidin-4-ylamino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0217] (d, J = 6.9 Hz, 6H). UPLC-MS (ESI) theoretical value is C 22 H 30 N8O[M+H] + :423.25, the actual measured value is 423.40.

[0218] [C42] N-(4-(((8-isopropyl-2-(piperidin-3-ylamino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0219] 1.83 (dtd, J = 14.1, 7.1, 3.5 Hz, 1H), 1.77–1.70 (m, 1H), 1.28 (d, J = 7.0 Hz, 6H). UPLC-MS (ESI) theoretical value is C 22 H 30 N8O[M+H] + :423.25, the actual measured value is 423.40.

[0220] [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

[0221] 7.0Hz, 2H), 1.90–1.79 (m, 1H), 1.29 (d, J=6.8Hz, 6H). UPLC-MS (ESI) theoretical value is C 22 H 29 N7O2[M+H] + :424.24, the measured value is 424.36.

[0222] [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

[0223] 2.11 (s, 3H), 2.00 (dq, J = 13.5, 7.3, 6.7 Hz, 2H), 1.90–1.80 (m, 1H), 1.29 (d, J = 6.6 Hz, 6H). UPLC-MS (ESI) theoretical value is C 22 H 29 N7O2[M+H] + :424.24, the measured value is 424.39.

[0224] [C45] (R)-N-(4-(((2-(3-Hydroxypiperidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0225] 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, 3.5 Hz, 6H). UPLC-MS (ESI) theoretical value is C 22 H 29 N7O2[M+H] + :424.24, the measured value is 424.46.

[0226] [C46] (S)-N-(4-(((2-(3-Hydroxypiperidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0227] 1H), 3.18 (p, J = 6.8 Hz, 1H), 2.13 (s, 3H), 2.05–1.99 (m, 1H), 1.94 (ddd, J = 13.5, 7.0, 3.7 Hz, 1H), 1.71–1.61 (m, 2H), 1.30 (dd, J = 6.9, 3.3 Hz, 6H). UPLC-MS (ESI) theoretical value is C 22 H 29 N7O2[M+H] + :424.24, the measured value is 424.39.

[0228] [C47] (S)-N-(4-(((2-((1-Hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)aminomethyl)phenyl)acetamide

[0229] Hz, 3H). UPLC-MS (ESI) theoretical value is C 21 H 29 N7O2[M+H] + :412.24, the actual measured value is 412.89.

[0230] [C48] (R)-N-(4-(((2-((1-hydroxybutan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)aminomethyl)phenyl)acetamide

[0231] Hz, 6H), 0.96 (t, J = 6.8 Hz, 3H). UPLC-MS (ESI) theoretical value is C 21 H 29 N7O2[M+H] + :412.24, the measured value is 412.44.

[0232] [C49](S)-N-(4-(((8-isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0233]

[0234] [C50] (R)-N-(4-(((8-isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0235] amino)methyl)phenyl)acetamide

[0236] 396.74.

[0237] [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

[0238] 1.57 (m, 2H), 1.29 (d, J = 6.9 Hz, 6H). UPLC-MS (ESI) theoretical value is C 22 H 29 N7O2[M+H] + :424.24, the measured value is 424.81.

[0239] [C53] N-(4-(((2-((1,3-dihydroxypropan-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)aminomethyl)phenyl)acetamide

[0240] H] + :414.22, the measured value is 414.78.

[0241] [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

[0242] (m, 2H), 1.28 (d, J = 6.9 Hz, 6H). UPLC-MS (ESI) theoretical value is C 23 H 32 N8O[M+H] + :437.27, the measured value is 437.41.

[0243] [C128] (R)-N-(4-(((2-(3-Hydroxypyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0244] C 21 H 27 N7O2[M+H] + :410.49, the actual measured value is 410.47.

[0245] [C129] (S)-N-(4-(((2-(3-Hydroxypyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0246] C 21 H 27 N7O2[M+H] + :410.49, the actual measured value is 410.47.

[0247] [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

[0248] 1H), 1.21 (d, J = 6.8 Hz, 6H). UPLC-MS (ESI) theoretical value is C 24 H 33 N7O2[M+H] + :452.58, the actual measured value is 452.52.

[0249] Example 4

[0250] [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

[0251]

[0252] 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%.

[0253] Compound C3 was prepared with compound 4.3 and compound 1.5 as raw materials and referring to the synthetic route of compound 1.6, with a yield of 38%. 1H 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.

[0254] [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

[0255] a) [1,3,5]triazin-4-yl)amino)methyl)phenyl)heptylamide

[0256] (4-oxazin-4-yl)amino)methyl)phenyl)heptylamide

[0257] -4-yl)amino)methyl)phenyl)heptylamide

[0258]

[0259] [C8] (S)-2-((4-(4-(ethylamino)benzyl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-2-yl)amino)butan-1-ol

[0260]

[0261] N-ethyl-4-cyanoaniline (500 mg, 3.42 mmol, 1.0 equiv) was dissolved in dichloromethane (10 mL), cooled to 0°C, and di-tert-butyl dicarbonate (786 uL, 3.42 mmol, 1.0 equiv) was added, and the mixture was reacted at room temperature for 5 h, and the reaction was monitored to be complete. The solvent was dried and column chromatography was performed to obtain compound 5.1 (158 mg), with a yield of 19%. 1H 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).

[0262] Using compound 5.1 as raw 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).

[0263] Using compound 1.3 and compound 5.2 as raw materials and 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).

[0264] Compound C8 was prepared with compound 5.3 and compound 2.1 as raw materials and referring to the synthetic route of compound C38, with a yield of 89%. 1 H NMR (500 MHz, Methanol-d4) δ7.67 (s, 1H), 7.19 (d, J = 8.5 Hz, 2H), 6.64 (d, J = 8.3 Hz, 2H), 4.60 (d, J = 10.7 Hz, 2H), 4.09–3.90 (m, 1H), 3.65 (d, J = 5.4 Hz, 2H), 3.10 (q, J = 7.1 Hz, 2H), 2.99 (p, J = 6.9 Hz, 1H), 1.75–1.68 (m, 1H), 1.58 (dt, J = 14.5, 7.4 Hz, 1H), 1.27 (d, J = 6.9 Hz, 6H), 1.21 (t, J = 7.1 Hz, 3H), 0.99 (t, J = 7.3 Hz, 3H). UPLC-MS (ESI) theoretical value was C 21 H31 N7O[M+H] + :398.26, the measured value is 398.38.

[0265] Example 6

[0266] [C9](S)-2-Hydroxy-N-(4-(((2-((1-hydroxybutyl-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)acetamide

[0267]

[0268] Compound p-aminobenzonitrile (1 g, 8.46 mmol, 1.0 equiv) and glycolic acid (634 mg, 8.46 mmol, 1.0 equiv) were mixed, heated to 130 ° C, heated and stirred for 4 h, then the mixture was cooled to room temperature, allowed to stand for 1 h, ether was added, solids precipitated, filtered, and column chromatography was performed to obtain compound 6.1 (542 mg) with 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).

[0269] Compound 6.1 (542 mg, 3.08 mmol, 1.0 equiv) was dissolved in dichloromethane (2 mL), cooled to 0 ° C, tert-butyldimethylsilyl chloride (558 mg, 3.70 mmol, 1.2 equiv) and imidazole (315 mg, 4.62 mmol, 1.5 equiv) were added, and stirred at room temperature for 12 h. The reaction was monitored to be complete, and 150 mL of dichloromethane was added to extract 3 times, washed with water 3 times, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried, and column chromatography was performed to obtain compound 6.2 (411 mg) with 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).

[0270] 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 nitrogen gas was replaced 3 times, and then the hydrogen gas was replaced 3 times. The reaction was stirred at room temperature for 4 h. After the reaction was monitored to be complete, it was filtered through diatomaceous earth and the filtered liquid was spin-dried to obtain compound 6.3 (152 mg) with a yield of 52%. 1H NMR (400MHz, DMSO-d6) δ9.36 (s, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 4.19 (s, 2H), 3.66 (s, 2H), 0.91 (s, 9H), 0.12 (s, 6H).

[0271] Compound 6.4 was prepared with compound 1.3 and compound 6.3 as raw materials and with reference to the synthetic route of compound 1.4, with a yield of 26%. 1H NMR (400MHz, DMSO-d6) δ9.97 (s, 1H), 9.45 (s, 1H), 8.27 (s, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 4.70 (d, J = 5.8 Hz, 2H), 4.18 (s, 2H), 3.32 (d, J = 2.8 Hz, 3H), 3.14 (p, J = 6.9 Hz, 1H), 1.31 (d, J = 6.5 Hz, 6H), 0.90 (s, 9H), 0.10 (s, 6H).

[0272] Compound C9 was prepared with compound 6.4 and compound 2.1 as raw materials and referring to the synthetic route of compound C38, with a yield of 49%. 1 H NMR (500 MHz, Methanol-d4) δ7.88 (s, 1H), 7.61 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 4.77 (d, J = 16.7 Hz, 2H), 4.14 (m, 1H), 4.10 (s, 2H), 3.65 (d, J = 4.8 Hz, 2H), 3.04–2.92 (m, 1H), 1.73 (ddd, J = 13.8, 7.6, 6.1 Hz, 1H), 1.61 (dt, J = 14.4, 7.4 Hz, 1H), 1.30 (d, J = 6.9 Hz, 6H), 1.00–0.89 (t, 3H). UPLC-MS (ESI) theoretical value was C 21 H 29 N7O3[M+H] + :428.23, the measured value is 428.38.

[0273] Example 7

[0274] [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

[0275]

[0276] Pour p-aminobenzonitrile (2 g, 16.93 mmol, 1.0 equiv) and 2-iodoethanol (2.91 g, 16.93 mmol, 1.0 equiv) into a round-bottom flask, replace with N2 three times, and under the protection of N2, heat to 90 ° C. and stir to react for 6 h. The reaction solution is extracted with 100 mL of ethyl acetate, and 2 M sodium hydroxide solution is added, followed by washing with saturated sodium chloride solution. The organic phases are combined, dried over anhydrous sodium sulfate, filtered and spin-dried, and column chromatography is performed to obtain compound 7.1 (1.038 g) with a yield of 38%.

[0277] Compound 7.1 (300 mg, 1.23 mmol, 1.0 equiv) was dissolved in 4 mL of dichloromethane, and tert-butyldimethylsilyl chloride (185 mg, 1.23 mmol, 1.0 equiv), triethylamine (359 μL, 2.58 mmol, 2.1 equiv) and 4-dimethylaminopyridine (15 mg, 0.123 mmol, 0.1 equiv) were added. The reaction was stirred at room temperature for 12 h. The reaction was monitored to be complete, diluted with water, extracted 3 times with 450 mL of dichloromethane, washed 3 times with saturated sodium chloride solution, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and spin-dried, and column chromatography gave compound 7.2 (208 mg) with a yield of 61%. 1H NMR (400MHz, DMSO-d6) δ7.42 (d, J = 8.3 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).

[0278] Compound 7.2 was used as the raw material, and referring to the synthetic route of compound 1.1, compound 7.3 was prepared with a yield of 80%. 1 HNMR (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).

[0279] Compound 7.4 was prepared using compound 7.3 as raw material and referring to the synthetic route of compound 1.2 with a yield of 99%. 1 HNMR(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).

[0280] Compound 7.4 and compound 1.3 were used as raw materials, and referring to the synthetic route of compound 1.4, compound 7.5 was prepared with 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).

[0281] Compound C10 was prepared with compound 7.5 and compound 2.1 as raw materials and referring to the synthetic route of compound C38, with a yield of 38%. 1 H NMR (500 MHz, Methanol-d4) δ7.67 (s, 1H), 7.18 (d, J = 8.1 Hz, 2H), 6.64 (d, J = 8.6 Hz, 2H), 4.60 (d, J = 10.3 Hz, 2H), 4.15–3.94 (m, 1H), 3.70 (t, J = 5.8 Hz, 2H), 3.65 (d, J = 5.1 Hz, 2H), 3.21 (t, J = 5.7 Hz, 2H), 2.99 (p, J = 7.0 Hz, 1H), 1.75–1.69 (m, 1H), 1.58 (dt, J = 14.1, 7.3 Hz, 1H), 1.27 (d, J = 6.8 Hz, 6H), 0.99 (t, J = 7.4 Hz, 3H). UPLC-MS (ESI) theoretical value was C 21 H 31 N7O2[M+H] + :414.25, the measured value is 414.36.

[0282] Example 8

[0283] [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

[0284]

[0285] Using 4-(N-Boc-aminomethyl)aniline and tetrahydropyran-4-carboxylic acid as raw materials and referring to the synthetic route of compound 3.1, compound 8.1 was obtained with 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).

[0286] Using compound 8.1 as raw material and referring to the synthetic route of compound 3.2, compound 8.2 was obtained with 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).

[0287] Using compound 8.2 and compound 1.3 as raw materials and 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).

[0288] Using compound 8.3 and compound 1.5 as raw materials and referring to the synthetic route of compound 1.6, compound C11 was obtained with 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 is C 27 H 37 N7O3[M+H] + :508.30, the actual measured value is 508.92.

[0289] [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

[0290] (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 is C 26 H 35 N7O3[M+H] + :494.28, the actual measured value is 494.89.

[0291] [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

[0292] 1.88–1.79 (m, 2H), 1.76–1.72 (m, 2H), 1.30 (d, J=7.0 Hz, 6H). UPLC-MS (ESI) theoretical value is C 24 H 33 N7O4[M+H] + :484.26, the measured value is 484.41.

[0293] [C14] (S)-N-(4-(((2-((1-hydroxybutyl-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)tetrahydro-2H-pyran-4-carboxamide

[0294] (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 is C 25 H 35 N7O3[M+H] + :482.28, the actual measured value is 482.87.

[0295] [C15] (R)-N-(4-(((2-((1-hydroxybutyl-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)tetrahydro-2H-pyran-4-carboxamide

[0296] 3.8Hz,1H),1.88–1.81(m,2H),1.75(tt,J=4.7,1.8Hz,2H),1.72(d,J=7.6Hz,1H),1.61(dt,J=14.2,7.4Hz,1H),1.29(d,J=6.9Hz,6H),0.96(t,J=7.5Hz,3H). UPLC-MS(ESI)theoretical value is C 25 H 35 N7O3[M+H] + :482.28, the actual measured value is 482.45.

[0297] [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

[0298] 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 27 H 38 N8O2[M+H] + :507.31, the actual 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] (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 is C 26 H 35 N7O3[M+H] + :494.28, the actual measured value is 494.44.

[0301] [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

[0302] 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 is C 26 H 35 N7O3[M+H] + :494.28, the actual measured value is 494.47.

[0303] [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

[0304] (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.

[0305] [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

[0306] 2.98 (dd, J = 8.8, 3.3 Hz, 1H), 2.61 (p, J = 3.5 Hz, 1H), 1.99 (m, 2H), 1.88–1.80 (m, 4H), 1.76–1.73 (m, 2H), 1.27–1.26 (dd, 6H). UPLC-MS (ESI) theoretical value is C 26 H 35 N7O3[M+H] + :494.28, the actual measured value is 494.38.

[0307] Example 9

[0308] [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

[0309]

[0310] Compound 9.1 was prepared with 4-(N-Boc-aminomethyl)aniline and 1-acetyl-4-piperidinic acid as raw materials and referring to the synthetic route of compound 3.1, with a yield of 69%. 1H 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).

[0311] Compound 9.2 was prepared using compound 9.1 as raw material and referring to the synthetic route of compound 3.2 with a yield of 99%. 1 HNMR(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,1 H),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).

[0312] 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 with a yield of 65%. 1H 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).

[0313] 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, with a yield of 43%. 1 H 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 actual measured value is 525.88.

[0314] [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

[0315] –2.69 (m, 1H), 2.63 (ddd, J = 11.5, 7.7, 3.9 Hz, 1H), 2.11 (s, 3H), 1.93–1.88 (m, 2H), 1.87–1.82 (m, 2H), 1.78–1.72 (m, 1H), 1.66–1.59 (m, 3H), 1.29 (d, J = 6.9 Hz, 6H). UPLC-MS (ESI) theoretical value is C 28 H 38 N8O3[M+H] + :535.31, the measured value is 535.43.

[0316] [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

[0317] 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 actual measured value is 523.89.

[0318] [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

[0319] 1H), 2.75–2.69 (m, 1H), 2.63 (ddt, J = 11.5, 7.7, 3.9 Hz, 1H), 2.11 (s, 3H), 1.93–1.86 (m, 2H), 1.78–1.70 (m, 2H), 1.62 (dt, J = 13.3, 6.3 Hz, 2H), 1.29 (d, J = 6.9 Hz, 6H), 0.96 (t, J = 7.4 Hz, 3H). UPLC-MS (ESI) theoretical value is C 27 H38 N8O3[M+H] + :523.31, the actual measured value is 523.89.

[0320] [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

[0321] Hz, 2H), 3.20 (ddd, J = 7.5, 3.1, 1.5 Hz, 1H), 3.02–2.92 (m, 1H), 2.76–2.71 (m, 1H), 2.65 (td, J = 7.7, 3.8 Hz, 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, 4.1 Hz, 1H), 1.65 (dd, J = 12.3, 4.2 Hz, 1H), 1.31 (d, J = 7.1 Hz, 6H). UPLC-MS (ESI) theoretical value is C 28 H 38 N8O3[M+H] + :535.31, the actual measured value is 535.43.

[0322] Example 10

[0323] [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

[0324]

[0325] Compound 10.1 was prepared with 4-(N-Boc-aminomethyl)aniline and propionic acid as raw materials and referring to 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).

[0326] Compound 10.1 was used as the raw material and the synthetic route of compound 3.2 was referred to to prepare compound 10.2 with a yield of 99%. 1 HNMR(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).

[0327] 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 with 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).

[0328] 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 with a yield of 62%. 1 H NMR (500 MHz, Methanol-d4) δ7.67 (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) theoretical value was C 21 H 29 N7O3[M+H] + :428.23, the measured value is 428.41.

[0329] [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

[0330] 1.50 (m, 2H), 1.27 (d, J = 7.0 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H). UPLC-MS (ESI) theoretical value is C 23 H 31 N7O2[M+H] + :438.25, the measured value is 438.86.

[0331] [C28] N-(4-(((8-isopropyl-2-(oxetan-3-ylamino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0332] C 21 H 27 N7O2[M+H] + :410.22, the measured value is 410.76.

[0333] [C29](S)-N-(4-(((2-((1-hydroxybutyl-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0334] 1.19 (t, J = 7.6 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H). UPLC-MS (ESI) theoretical value is C 22 H 31 N7O2[M+H] + :426.25, the actual measured value is 426.45.

[0335] [C30] (R)-N-(4-(((2-((1-hydroxybutyl-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0336] 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.

[0337] [C31] (R)-N-(4-(((8-isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0338] 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 is C 23 H 31 N7O2[M+H] + :438.25, the actual measured value is 438.41.

[0339] [C32](S)-N-(4-(((8-isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0340] (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 actual measured value is 438.41.

[0341] [C33](S)-N-(4-(((8-isopropyl-2-(piperidin-3-yloxy)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0342] 2.10 (d, J = 13.8 Hz, 2H), 1.77 (td, J = 10.8, 7.7 Hz, 2H), 1.28 (d, J = 6.9 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H). UPLC-MS (ESI) theoretical value is C 23 H 32 N8O[M+H] + :437.27, the measured value is 437.45.

[0343] [C34] N-(4-(((8-isopropyl-2-(piperidin-3-ylamino)pyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0344] (dt, J = 10.9, 3.7 Hz, 1H), 1.77–1.71 (m, 1H), 1.28 (d, J = 6.9 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H). UPLC-MS (ESI) theoretical value is C 23 H 32 N8O[M+H] + :437.27, the actual measured value is 437.44.

[0345] [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

[0346] 7.6Hz, 2H), 2.13 (d, J = 15.5Hz, 2H), 1.84–1.72 (m, 2H), 1.28 (d, J = 6.9Hz, 6H), 1.20 (t, J = 7.6Hz, 3H). UPLC-MS (ESI) theoretical value is C 24 H 34 N8O[M+H] + :451.29, the measured value is 451.43.

[0347] [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

[0348] Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H). UPLC-MS (ESI) theoretical value is C 24 H 33 N7O2[M+H] + :452.27, the measured value is 452.81.

[0349] [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

[0350]

[0351] [C131] (R)-N-(4-(((2-(3-hydroxypyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0352] The theoretical value of UPLC-MS (ESI) is C 22 H 29 N7O2[M+H] + :424.52, the actual measured value is 424.49.

[0353] [C132] (S)-N-(4-(((2-(3-Hydroxypyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0354] 1.06 (t, J = 7.6 Hz, 3H). UPLC-MS (ESI) theoretical value is C 22 H 29 N7O2[M+H] + :424.52, the actual measured value is 424.49.

[0355] [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

[0356] The theoretical value of UPLC-MS (ESI) is C 23 H 31 N7O2[M+H] + :438.55, the measured value is 438.51. [C134] (S)-N-(4-(((2-(2-(hydroxymethyl)pyrrolidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0357] The theoretical value is C 23 H 31 N7O2[M+H] + :438.55, the actual measured value is 438.50.

[0358] [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

[0359] J=7.0,0.9Hz,6H),1.06(t,J=7.5Hz,3H). UPLC-MS (ESI) theoretical value is C 25 H 35 N7O2[M+H] +:466.60, the measured value is 466.47.

[0360] Embodiment 11

[0361] [C37] (S)-2-((7-((4-aminobenzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)butan-1-ol

[0362]

[0363] Compound 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (369 mg, 1.61 mmol, 1.0 equiv), compound 1.2 (317 mg, 1.93 mmol, 1.2 equiv) and N,N-diisopropylethylamine (532 μL, 3.22 mmol, 2.0 equiv) were dissolved in 15 mL of ethanol. The reaction solution was refluxed at 90 ° C for 12 h. After the reaction was completed, the mixture was cooled to room temperature and the solvent was removed under reduced pressure. The remaining solid was dissolved in dichloromethane, washed several times with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed and purified by column chromatography to obtain compound 11.1 (524 mg) with a yield of 82%. 1 H NMR(500MHz,DMSO-d6)δ9.33(s,1H),8.99(t,J=6.6Hz,1H),8.06(s,1H),7.37(d,J=8.4Hz,2H),7.14 (d,J=8.4Hz,2H),6.00(s,1H),4.64(d,J=6.5Hz,2H),3.09–3.07(m,1H),1.36(s,9H),1.27(dd,6H).

[0364] Using compound 11.1 as raw material and referring to the synthetic route of compound 1.1, compound 11.2 was prepared with a yield of 94%. 1 HNMR(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).

[0365] Compound C37 was prepared using compound 11.2 and compound 2.1 as raw materials and referring to the synthetic route of compound C38 with a yield of 68%. 1H NMR (500 MHz, Methanol-d4) δ7.89 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 5.40 (s, 1H), 4.74–4.69 (s, 2H), 3.78–3.64 (m, 2H), 3.59 (dd, J = 11.0, 6.2 Hz, 1H), 3.06 (p, J = 7.0 Hz, 1H), 1.71–1.66 (m, 1H), 1.60–1.54 (m, 1H), 1.31 (dd, J = 6.9, 2.9 Hz, 6H), 0.97 (t, J = 7.4 Hz, 3H). UPLC-MS (ESI) theoretical value was C 20 H 28 N6O[M+H] + :369.49, the actual measured value is 369.35.

[0366] Example 12

[0367] [C39] (S)-N-(4-(((5-((1-hydroxybutan-2-yl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acetamide

[0368]

[0369] Compound 12.1 was prepared with a yield of 91% using 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine and compound 3.2 as raw materials and referring to the synthetic route of compound 11.1. 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).

[0370] Using compound 12.1 as raw material and referring to the synthetic route of compound 1.1, compound 12.2 was prepared with a yield of 97%. 1HNMR(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).

[0371] 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), Pd2(dba)3 (13 mg, 0.014 mmol, 5 mol% equiv), rac BINAP (26 mg, 0.042 mmol, 15 mol% equiv) and Cs2CO3 (137 mg, 0.42 mmol, 1.5 equiv) were added, and the mixture was purged with nitrogen three times. The temperature was raised to 100°C, and the mixture was heated and stirred for 12 h. After the reaction was completed, the mixture was cooled to room temperature, toluene was removed under reduced pressure, and the residue was purified by column chromatography to obtain compound 12.4 (87 mg) with a yield of 50%. 1 H NMR (400MHz, DMSO-d6) δ9.32 (s, 1H), 7.67 (s, 1H), 7.37 (d, J = 8.1Hz, 2H), 7.10 (d ,J=8.2Hz,2H),6.91(d,J=7.7Hz,1H),5.98(s,1H),5.75(s,2H),4.03(d,J=7.1Hz ,1H),3.70–3.63(m,2H),3.01–2.95(m,1H),2.33(s,3H),1.68(s,2H),1.45(s,9 H), 1.32 (s, 6H), 1.25 (dd, J = 6.9, 3.2Hz, 6H), 1.17 (t, J = 7.2Hz, 3H), 0.81 (s, 9H).

[0372] Using compound 12.4 as raw material and referring to the synthetic route of compound C1, compound C39 was prepared with a yield of 99%. 1HNMR (500MHz, Methanol-d4) δ7.88 (s, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 5.37 (s, 1H), 4.64 (s, 2H), 3.78–3.56 (m, 3H), 3.08–3.00 (m, 1H), 2.11 (s, 3H), 1.68 (ddd, J = 13.7, 7.6, 6.0 Hz, 1H), 1.60–1.49 (m, 1H), 1.31 (dd, J = 6.9, 3.6 Hz, 6H), 0.96 (t, J = 7.3 Hz, 3H). UPLC-MS (ESI) theoretical value is C 22 H 30 N6O2[M+H] + :411.24, the measured value is 411.85.

[0373] [C40] N-(4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)acetamide

[0374] 2H), 1.54 (qd, J = 11.6, 4.3 Hz, 2H), 1.30 (d, J = 6.9 Hz, 6H). UPLC-MS (ESI) theoretical value is C 23 H 30 N6O2[M+H] + :423.24, the measured value is 423.85.

[0375] Example 13

[0376] [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

[0377]

[0378] Compound 13.1 was prepared with a yield of 98% using compound 4-(N-Boc-aminomethyl)aniline and 1-fluorocyclopropylcarboxylic acid as raw materials and referring to the synthetic route of compound 3.1. 1H 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).

[0379] Compound 13.1 was used as the raw material and the synthetic route of compound 3.2 was referred to to prepare compound 13.2 with a yield of 99%. 1 HNMR(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).

[0380] Compound 13.2 and compound 1.3 were used as raw materials, and referring to the synthetic route of compound 1.4, compound 13.3 was prepared with a yield of 76%. 1 H NMR (500MHz, DMSO-d6) δ10.22(s,1H),10.00(s,1H),8.28(s,1H),7.65(d,J=8.6Hz,2H),7.37(d,J=8.6Hz,2H),4.71(d,J=5.6Hz,2H),3.3 2(s,3H),3.15–3.11(m,1H),1.42–1.40(m,1H),1.37(t,J=3.9Hz,1H),1.30(d,J=6.9Hz,6H),1.28(d,J=2.9Hz,1H),1.23(d,J=5.2Hz,1H).

[0381] Using compound 13.3 as raw material and referring to the synthetic route of compound 2.2, compound C55 was prepared with a yield of 32%. 1H NMR (500 MHz, Methanol-d4) δ7.92 (s, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 4.77 (s, 2H), 4.63–4.52 (m, 1H), 3.93 (dd, J = 26.2, 16.8 Hz, 1H), 3.79 (dd, J = 22.7, 11.2 Hz, 3H), 3.25–3.19 (m, 1H), 2.11 (d, J = 46.3 Hz, 2H), 1.40 (dd, J = 3.9, 2.1 Hz, 1H), 1.39–1.37 (m, 1H), 1.37 (d, 2H), 1.28 (dd, J = 6.9, 4.5 Hz, 6H). UPLC-MS (ESI) theoretical value was C 23 H 28 FN7O2[M+H] + :454.23, the measured value is 454.32.

[0382] [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

[0383] 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.

[0384] [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

[0385] 1.29 (d, J = 7.0 Hz, 6H). UPLC-MS (ESI) theoretical value is C 22 H 26 FN7O2[M+H] + :440.21, the measured value is 440.76.

[0386] [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

[0387] =7.0Hz,6H). UPLC-MS (ESI) theoretical value is C 24 H 30 FN7O2[M+H] + :468.24, the measured value is 468.37. [C59] (S)-1-Fluoro-N-(4-(((2-((1-hydroxybutyl-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)cyclopropane-1-carboxamide

[0388] 1.37 (m, 2H), 1.37–1.35 (m, 2H), 1.27 (d, J = 7.0 Hz, 6H), 0.97 (t, J = 7.5 Hz, 3H). UPLC-MS (ESI) theoretical value is C 23 H 30 FN7O2[M+H] + :456.24, the measured value is 456.38.

[0389] [C60] (R)-1-Fluoro-N-(4-(((2-((1-hydroxybutyl-2-yl)amino)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)cyclopropane-1-carboxamide

[0390] 1.37 (m, 2H), 1.37–1.35 (m, 2H), 1.27 (d, J=7.0 Hz, 6H), 0.98 (t, 3H). UPLC-MS (ESI) theoretical value is C 23 H 30 FN7O2[M+H] + :456.24, the measured value is 456.38.

[0391] [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

[0392] J=2.0Hz,1H),1.37(d,2H),1.29(d,J=6.3Hz,6H). UPLC-MS(ESI)theoretical value is C 24 H 30 FN7O2[M+H] + :468.24, the measured value is found 468.40.

[0393] [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

[0394] Hz, 6H). UPLC-MS (ESI) theoretical value is C 24 H 30 FN7O2[M+H] + :468.24, the actual measured value is 468.34.

[0395] [C136] (S)-1-Fluoro-N-(4-(((2-(2-(2-hydroxyethyl)piperidin-1-yl)-8-isopropylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)cyclopropane-1-carboxamide

[0396] C 26 H 34 FN7O2[M+H] + :496.60, the measured value is 496.53.

[0397] Embodiment 14

[0398]

[0399] [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

[0400] Compound 14.2 was prepared using compound 14.1 and compound 1.3 as raw materials and referring to the synthetic route of compound 1.4 with a yield of 63%.

[0401] Using compound 14.2 and compound 14.3 as raw materials and referring to the synthetic route of compound C55, C106 was prepared with a yield of 35%. 1H NMR (600 MHz, DMSO-d6) δ9.17–8.66 (m, 1H), 8.62 (s, 1H), 7.72 (s, 1H), 7.62–7.57 (m, 3H), 7.54–7.49 (m, 2H), 6.92 (d, J = 65.2 Hz, 1H), 4.64 (s, 2H), 3.93–3.78 (m, 3H), 3.35 (tt, J = 12.5, 6.6 Hz, 2H), 2.90 (s, 1H), 2.24–2.20 (m, 3H), 1.74 (d, J = 127.2 Hz, 2H), 1.52–1.38 (m, 2H), 1.24–1.20 (m, 6H). UPLC-MS (ESI) theoretical value was C 24 H 30 N8O[M+H] + :447.56, the measured value is 447.39.

[0402] [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

[0403] 474.58, the measured value is 474.38.

[0404] [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

[0405] 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 is C 24 H 28 N8O[M+H] + :445.54, the actual measured value is 445.35.

[0406] [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

[0407] 2H), 3.35 (s, 2H), 2.91 (s, 1H), 1.95–1.52 (m, 2H), 1.45 (d, J = 45.6 Hz, 2H), 1.23 (dd, J = 12.1, 6.1 Hz, 6H). UPLC-MS (ESI) theoretical value is C 25 H 29 N7O2[M+H] + :460.55, the actual measured value is 460.36.

[0408] [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

[0409]

[0410] The theoretical value is C 24 H 30 N8O[M+H] + :447.56, the actual measured value is 447.38.

[0411] [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

[0412]

[0413] The theoretical value of UPLC-MS (ESI) is C 23 H 27 N7O2[M+H] + :434.52, the measured value is 434.25. [C87] 8-isopropyl-N4-(4-phenoxybenzyl)-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

[0414] 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 is C 26 H 30 N6O2[M+H] + :459.57, the measured value is 459.40. [C93] N4-(4-(4-chlorophenoxy)benzyl)-8-isopropyl-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

[0415] C 26 H 29 ClN6O2[M+H] + :494.01, the actual measured value is 493.33.

[0416] [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

[0417] =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 is C 24 H 30 N8O[M+H] + :447.56, the measured value is 447.39.

[0418] [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

[0419] 11.5Hz,2H),2.97(hept,J=6.9Hz,1H),2.47(t,J=8.0Hz,2H),2.04(p,J=7.6Hz,2H),1.92–1.65(m,2H),1.48(dt,J=11.9,5.5Hz,2H),1.20(d,J=6.8Hz,6H). UPLC-MS(ESI)theoretical value is C 24 H 31 N7O2[M+H] + :450.56, the actual measured value is 450.50.

[0420] Embodiment 15

[0421]

[0422] [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

[0423] Compound 15.2 was prepared using compound 15.1 and compound 1.3 as raw materials and referring to the synthetic route of compound 1.4 with a yield of 51%.

[0424] 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%.

[0425] Compound 15.3 was dissolved in dichloromethane, trifluoroacetic acid was added, and the mixture was reacted at room temperature for 6 h. After concentration under reduced pressure, the residue was washed with a small amount of water and acetonitrile respectively to obtain compound C123 with a yield of 95%. 1 H NMR (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 is C 27 H 30 N6O3[M+H] + :487.58, the actual measured value is 487.34.

[0426] Example 16

[0427]

[0428] [C111] 8-Bromo-N2-(tetrahydro-2H-pyran-4-yl)-N4-(4-(thiophen-2-yl)benzyl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

[0429] Compound 16.3 was prepared using compound 16.1 and compound 16.2 as raw materials and referring to the synthetic route of compound 1.4 with a yield of 58%.

[0430] Compound 16.3 (72 mg, 0.167 mmol, 1.0 equiv.) was dissolved in dichloromethane, and m-chloroperbenzoic acid (108 mg, 80%, 0.500 mmol, 3.0 equiv.) was added in batches under an ice bath. The mixture was transferred to room temperature for reaction for 5 h. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by column chromatography to obtain compound 16.4 (65 mg) with a yield of 84%.

[0431] Using compound 16.4 and compound 14.3 as raw materials and referring to the synthetic route of compound C55, C111 was prepared with 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=3.6Hz,1H),7.40(d,J=8.0Hz,2H),7.25(d,J=7.7Hz, 1H), 7.11 (dd, J = 5.1, 3.6 Hz, 1H), 4.70–4.54 (m, 2H), 4.04–3.76 (m, 3H), 3.35 (dt, J = 23.9, 11.6 Hz, 2H), 1.71 (dd, J = 101.3, 12.5 Hz, 2H), 1.56–1.33 (m, 2H). UPLC-MS (ESI) theoretical value is C 21 H 21 BrN6OS[M+H] + :486.40, the actual measured values ​​are 485.17,487.16.

[0432] [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

[0433] The theoretical value of UPLC-MS (ESI) is C 22 H 22 BrN7O[M+H] + :481.37, the actual measured values ​​are 480.21,482.20.

[0434] [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

[0435] Hz, 2H), 1.74 (d, J = 64.7 Hz, 2H), 1.46 (d, J = 32.5 Hz, 2H). UPLC-MS (ESI) theoretical value is C 22 H 22 BrN7O2[M+H] + :497.37, the measured values ​​are 496.26,498.24.

[0436] [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

[0437] 12.6Hz,1H),1.49(d,J=13.0Hz,1H),1.38(d,J=12.0Hz,1H). UPLC-MS(ESI)theoretical value is C 21 H 23 BrN8O[M+H] + :484.37, the measured values ​​are 483.24,485.21.

[0438] Embodiment 17

[0439]

[0440] [C127] N-(4-(((3-isopropyl-5-((tetrahydro-2H-pyran-4-yl)amino)pyrazolo[1,5-a]pyrimidin-7-yl)amino)methyl)phenyl)propanamide

[0441] Compound 17.1 was prepared with a yield of 78% using 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine and compound 10.2 as raw materials and referring to the synthetic route of compound 11.1.

[0442] Compound 17.1 was used as the raw material and the synthetic route of compound 11.2 was referred to to prepare compound 17.2 with a yield of 85%.

[0443] Compound 17.2 and compound 14.3 were used as raw materials, and referring to the synthetic route of compound 11.3, compound 17.3 was prepared with a yield of 51%.

[0444] 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%. 1HNMR(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.

[0445] Embodiment 18

[0446]

[0447] [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

[0448] Compound 18.1 was prepared using 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine and compound 13.2 as raw materials and referring to the synthetic route of compound 11.1 with a yield of 70%.

[0449] Compound 18.1 was used as the raw material and the synthetic route of compound 11.2 was referred to to prepare compound 18.2 with a yield of 82%.

[0450] Compound 18.2 and compound 14.3 were used as raw materials, and referring to the synthetic route of compound 11.3, compound 18.3 was prepared with a yield of 42%.

[0451] Compound C126 was prepared using compound 18.3 as raw material and referring to the synthetic route of compound C37 with a yield of 90%. 1HNMR(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),3.93–3.8 1(m,3H),3.44–3.38(m,2H),3.08(p,J=7.2Hz,1H),1.84–1.70(m,2H),1.42(dddd,J=23.0,18.1,9.5,4.6Hz,4H),1.32–1.25(m,2H),1.21(d,J=6.9Hz,6H). UPLC-MS(ESI)theoretical value is C 25 H 31 FN6O2[M+H] + :467.56, the actual measured value is 467.74.

[0452] Embodiment 19

[0453]

[0454] [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

[0455] Compound 19.1 was prepared using compound 16.1 and compound 3.2 as raw materials and referring to the synthetic route of compound 16.3, with a yield of 55%.

[0456] Compound 19.2 was prepared using compound 19.1 as raw material and referring to the synthetic route of compound 16.4 with a yield of 88%.

[0457] Compound C137 was prepared with compound 19.2 and (R)-2-pyrrolidinemethanol as raw materials and referring to the synthetic route of compound C111 with a yield of 45%. 1H NMR (500 MHz, DMSO-d6) δ9.90 (s, 1H), 9.19–8.96 (m, 1H), 7.94 (d, J = 4.4 Hz, 1H), 7.55–7.46 (m, 2H), 7.32 (d, J = 8.1 Hz, 2H), 4.55 (t, J = 5.2 Hz, 2H), 4.12 (d, J = 9.5 Hz, 1H), 3.63 (dd, J = 10.4, 3.9 Hz, 1H), 3.60–3.29 (m, 3H), 2.01 (s, 3H), 1.99–1.74 (m, 4H). UPLC-MS (ESI) theoretical value was C 19 H 22 BrN7O2[M+H] + :461.34, the actual measured values ​​are 460.33,462.33.

[0458] [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

[0459]

[0460] The values ​​are 460.34,462.34.

[0461] [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

[0462] C 21 H 26 BrN7O2[M+H] + :489.39, the actual measured values ​​are 488.37,490.36.

[0463] Embodiment 20

[0464]

[0465] [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

[0466] Compound 20.1 was prepared using compound 16.1 and compound 10.2 as raw materials and referring to the synthetic route of compound 16.3 with a yield of 60%.

[0467] Compound 20.2 was prepared using compound 20.1 as raw material and referring to the synthetic route of compound 16.4 with a yield of 83%.

[0468] Compound C140 was prepared with compound 20.2 and (R)-3-pyrrolidinol as raw materials and referring to the synthetic route of compound C111 with a yield of 49%. 1 H NMR (600 MHz, DMSO-d6) δ9.84 (s, 1H), 9.05 (d, J = 6.6 Hz, 1H), 7.94 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.35–7.29 (m, 2H), 4.54 (d, J = 6.3 Hz, 2H), 4.36–4.31 (m, 1H), 3.69–3.41 (m, 4H), 2.29 (q, J = 7.5 Hz, 2H), 2.01–1.92 (m, 1H), 1.88–1.83 (m, 1H), 1.06 (t, J = 7.5 Hz, 3H). UPLC-MS (ESI) theoretical value was C 19 H 22 BrN7O2[M+H] + :461.34, the measured values ​​are 460.37,462.35.

[0469] [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

[0470] The value is C 19 H 22 BrN7O2[M+H] + :461.34, the measured values ​​are 460.37,462.36.

[0471] [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

[0472] The theoretical value is C 20 H 24 BrN7O2[M+H] + :475.36, the actual measured values ​​are 474.35,476.35.

[0473] [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

[0474] The theoretical value is C 20 H 24 BrN7O2[M+H] + :475.36, the measured values ​​are 474.35,476.34.

[0475] [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

[0476] C 22 H 28 BrN7O2[M+H] + :503.42, the actual measured values ​​are 502.38,504.37.

[0477] Embodiment 21

[0478]

[0479] [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

[0480] Compound 21.1 was prepared using compound 16.1 and compound 13.2 as raw materials and referring to the synthetic route of compound 16.3 with a yield of 47%.

[0481] Compound 21.2 was prepared using compound 21.1 as raw material and referring to the synthetic route of compound 16.4 with a yield of 76%.

[0482] Compound C145 was prepared with a yield of 31% using compound 21.2 and (R)-3-pyrrolidinol as raw materials and referring to the synthetic route of compound C111. 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) theoretical value was C 20 H 21 BrFN7O2[M+H] + :491.34, the measured values ​​are 490.32,492.32.

[0483] [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

[0484] 491.34, the measured values ​​are 490.33, 492.32.

[0485] [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

[0486] C 21 H 23 BrFN7O2[M+H] + :505.36, the actual measured values ​​are 504.31,506.30.

[0487] [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

[0488] C 21 H 23 BrFN7O2[M+H] + :505.36, the actual measured values ​​are 504.31,506.30.

[0489] [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

[0490] The actual measured values ​​are 532.36,534.34.

[0491] [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

[0492] Compound C64 can be synthesized according to the above synthetic route.

[0493] [C65] N-(4-(((8-isopropyl-2-morpholinylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0494] Compound C65 can be synthesized according to the above synthetic route.

[0495] [C66] N-(4-(((8-cyclopropyl-2-morpholinylpyrazolo[1,5-a][1,3,5]triazin-4-yl)amino)methyl)phenyl)propanamide

[0496] Compound C66 can be synthesized according to the above synthetic route.

[0497] [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

[0498] Compound C67 can be synthesized according to the above synthetic route.

[0499] [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

[0500] Compound C68 can be synthesized according to the above synthetic route.

[0501] [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

[0502] Compound C69 can be synthesized according to the above synthetic route.

[0503] [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

[0504] Compound C70 can be synthesized according to the above synthetic route.

[0505] [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

[0506] Compound C71 can be synthesized according to the above synthetic route.

[0507] [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

[0508] Compound C72 can be synthesized according to the above synthetic route.

[0509] [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

[0510] Compound C73 can be synthesized according to the above synthetic route.

[0511] [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

[0512] Compound C74 can be synthesized according to the above synthetic route.

[0513] [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

[0514] Compound C75 can be synthesized according to the above synthetic route.

[0515] [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

[0516] Compound C76 can be synthesized according to the above synthetic route.

[0517] [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

[0518] Compound C77 can be synthesized according to the above synthetic route.

[0519] [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

[0520] Compound C78 can be synthesized according to the above synthetic route.

[0521] [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

[0522] Compound C79 can be synthesized according to the above synthetic route.

[0523] [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

[0524] Compound C80 can be synthesized according to the above synthetic route.

[0525] [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

[0526] Compound C81 can be synthesized according to the above synthetic route.

[0527] [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

[0528] Compound C82 can be synthesized according to the above synthetic route.

[0529] [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

[0530] Compound C83 can be synthesized according to the above synthetic route.

[0531] [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

[0532] Compound C84 can be synthesized according to the above synthetic route.

[0533] [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

[0534] Compound C85 can be synthesized according to the above synthetic route.

[0535] [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

[0536] Compound C86 can be synthesized according to the above synthetic route.

[0537] [C87] 8-Isopropyl-N4-(4-phenoxybenzyl)-N2-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

[0538] Compound C87 can be synthesized according to the above synthetic route.

[0539] [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

[0540] Compound C88 can be synthesized according to the above synthetic route.

[0541] [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

[0542] Compound C89 can be synthesized according to the above synthetic route.

[0543] [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

[0544] Compound C90 can be synthesized according to the above synthetic route.

[0545] [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

[0546] Compound C91 can be synthesized according to the above synthetic route.

[0547] [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

[0548] Compound C92 can be synthesized according to the above synthetic route.

[0549] [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

[0550] Compound C93 can be synthesized according to the above synthetic route.

[0551] [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

[0552] Compound C94 can be synthesized according to the above synthetic route.

[0553] [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

[0554] Compound C95 can be synthesized according to the above synthetic route.

[0555] [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

[0556] Compound C96 can be synthesized according to the above synthetic route.

[0557] [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

[0558] Compound C97 can be synthesized according to the above synthetic route.

[0559] [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

[0560] Compound C98 can be synthesized according to the above synthetic route.

[0561] [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

[0562] Compound C99 can be synthesized according to the above synthetic route.

[0563] [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

[0564] Compound C100 can be synthesized according to the above synthetic route.

[0565] [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

[0566] Compound C101 can be synthesized according to the above synthetic route.

[0567] [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

[0568] Compound C102 can be synthesized according to the above synthetic route.

[0569] [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

[0570] Compound C103 can be synthesized according to the above synthetic route.

[0571] [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

[0572] Compound C104 can be synthesized according to the above synthetic route.

[0573] [C105]N 4 -(4-(2H-tetrazolyl-5-yl)benzyl)-8-isopropyl-N 2 -(Tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a][1,3,5]triazine-2,4-diamine

[0574] Compound C105 can be synthesized according to the above synthetic route.

[0575] [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

[0576] Compound C106 can be synthesized according to the above synthetic route.

[0577] [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

[0578] Compound C107 can be synthesized according to the above synthetic route.

[0579] [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

[0580] Compound C108 can be synthesized according to the above synthetic route.

[0581] [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

[0582] Compound C109 can be synthesized according to the above synthetic route.

[0583] [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

[0584] Compound C110 can be synthesized according to the above synthetic route.

[0585] [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

[0586] Compound C111 can be synthesized according to the above synthetic route.

[0587] [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

[0588] Compound C112 can be synthesized according to the above synthetic route.

[0589] [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

[0590] Compound C113 can be synthesized according to the above synthetic route.

[0591] [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

[0592] Compound C114 can be synthesized according to the above synthetic route.

[0593] [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

[0594] Compound C115 can be synthesized according to the above synthetic route.

[0595] [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

[0596] Compound C116 can be synthesized according to the above synthetic route.

[0597] [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

[0598] Compound C117 can be synthesized according to the above synthetic route.

[0599] [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

[0600] Compound C118 can be synthesized according to the above synthetic route.

[0601] [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

[0602] Compound C119 can be synthesized according to the above synthetic route.

[0603] [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

[0604] Compound C120 can be synthesized according to the above synthetic route.

[0605] [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

[0606] Compound C121 can be synthesized according to the above synthetic route.

[0607] [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

[0608] Compound C122 can be synthesized according to the above synthetic route.

[0609] Example 22: Proliferation and growth inhibition activity of the compound on triple-negative breast cancer cells

[0610] 1. Experimental methods

[0611] 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 a 37° C., CO2-free incubator using Leibovitzs (L-15) medium supplemented with 10% fetal bovine serum (FBS) and penicillin-streptomycin (PS) antibiotics, and BT549 cells were cultured in a 37° C., CO2-free incubator using RPMI 1640 medium supplemented with 10% FBS, 1% penicillin-streptomycin (PS) antibiotics and recombinant human insulin solution (Insulin).

[0612] In the cell activity test experiment, according to the cell growth, 90 μL of cell suspension of appropriate concentration is added to the 96-well cell culture plate, each compound to be tested is diluted with the corresponding culture medium, 10 μL of the diluted compound is added to 90 μL of cell solution, and then cultured at 37°C, 5% CO2 for 4 days. Cell proliferation is analyzed by WST-8. WST-8 can be reduced to yellow formazan by lactate dehydrogenase in the cell. 10 μL of WST-8 reagent (DOJINDO) is added to the cells and reacted at 37°C for more than 1 hour. DMSO-treated cells are used as positive controls. The microplate reader reads OD450nm, and the data is processed with GraphPad Prism6 software. Activity results: A represents cell activity IC 50 <1μM, B indicates cell activity 1μM <IC 50 <3μM, C represents the IC of cell activity 50 >3μM.

[0613] 2. Experimental results

[0614]

[0615]

[0616]

[0617]

[0618] Based on the above compound cell growth inhibition activity test method, in triple-negative breast cancer cell lines MDA-MB-231, MDA-MB-468 and BT549, compared with the positive compound Control compound, the compound of the present invention has a good inhibitory activity on cell growth inhibition. Therefore, the compound of the present invention can be used as a new inhibitor of related targets in triple-negative breast cancer cells.

[0619] Example 23: In vitro kinase inhibitory activity of compounds against CDK

[0620] 1. Experimental methods

[0621] In the in vitro kinase activity test, the LANCE Ultra KinaSelectSer / Thr detection kit of Perkin Elmer was used to determine the CDK9 kinase activity. The reaction of this method was carried out in a 384-well plate, and the total reaction volume was 10 μL. CDK9 protein (final concentration of 1 ng / μL), 4EBP-1 peptide substrate (final concentration of 50 nM) and ATP (final concentration of 2.5 μM) were reacted in a buffer solution: 50 mM HEPES-KOH (pH 7.5), 10 mM MgCl2, 2 mM DTT, 1 mM EGTA for 1 h, and the corresponding Eu-labeled anti-phosphorylation antibody Eu-anti-P-4E-BP1 (final concentration of 2 nM) was added and incubated for 30 min, and then the phosphorylation was detected, and the laser ratio at 620 nM and 665 nM wavelengths was detected by the fluorescence detector Envision (PerkinElmer, USA). Activity results: A represents cell activity IC 50 <100nM, B indicates cell viability 100nM <IC 50 <1000nM, C indicates cell viability 1μM <IC 50 <20μM, D represents cell activity IC 50 >20μM.

[0622] 2. Experimental results

[0623] In vitro kinase inhibitory activity of compounds against CDK9

[0624]

[0625]

[0626]

[0627] Based on the in vitro kinase inhibitory activity of the above compounds on CDK9, most of the compounds of the present invention have good in vitro kinase inhibitory activity on CDK9. Therefore, the compounds of the present invention can be used as new inhibitors of CDK9 targets.

[0628] 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.

[0629] 2. Experimental methods

[0630] In the in vitro kinase activity test, the LANCE Ultra KinaSelectSer / Thr detection kit of Perkin Elmer was used to determine the CDK2 kinase activity. The reaction of this method was in a 384-well plate, and the total reaction volume was 10 μL. CDK2 protein (final concentration of 1 ng / μL), 4EBP-1 peptide substrate (final concentration of 50 nM) and ATP (final concentration of 2.5 μM) were reacted in a buffer solution: 50 mM HEPES-KOH (pH 7.5), 10 mM MgCl2, 2 mM DTT, 1 mM EGTA for 1 h, and the corresponding Eu-labeled anti-phosphorylation antibody Eu-anti-P-4E-BP1 (final concentration of 2 nM) was added and incubated for 30 min, and then the phosphorylation was detected, and the laser ratio at 620 nM and 665 nM wavelengths was detected by the fluorescence detector Envision (PerkinElmer, USA). Activity results:

[0631] 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 cell activity IC 50 >20μM.

[0632] In vitro kinase inhibitory activity of compounds against CDK2

[0633]

[0634]

[0635] Based on the in vitro kinase inhibitory activity of the above compounds on CDK2, most of the compounds of the present invention have certain inhibitory activity on the in vitro kinase of CDK2, and some compounds have much higher in vitro kinase activity on CDK9, so these compounds have good CDK9 / CDK2 selectivity. Therefore, the compounds of the present invention can be used as novel selective inhibitors of CDK9 or CDK2 targets, respectively, according to the activity and selectivity characteristics of the compounds on CDK targets, or the compounds of the present invention can also be used as inhibitors of their dual targets.

[0636] 3. Experimental methods

[0637] In the in vitro kinase activity test, the LANCE Ultra KinaSelectSer / Thr detection kit of Perkin Elmer was used to determine the kinase activity of CDK12. The reaction of this method was carried out in a 384-well plate, and the total volume of the reaction was 10 μL. CDK12 protein (final concentration of 1 ng / μL), 4EBP-1 peptide substrate (final concentration of 50 nM) and ATP (final concentration of 2.5 μM) were reacted in a buffer solution: 50 mM HEPES-KOH (pH 7.5), 10 mM MgCl2, 2 mM DTT, 1 mM EGTA for 1 h, and the corresponding Eu-labeled anti-phosphorylation antibody Eu-anti-P-4E-BP1 (final concentration of 2 nM) was added and incubated for 30 min, and then the phosphorylation was detected, and the laser ratio at 620 nM and 665 nM wavelengths was detected by the fluorescence detector Envision (PerinElmer, USA). Activity results: In vitro kinase inhibition rate (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 kinase inhibition rate IC 50 <1%.

[0638] In vitro kinase inhibitory activity of compounds against CDK12

[0639]

[0640] Based on the in vitro kinase inhibitory activity of the above compounds on CDK12, most of the compounds of the present invention have good in vitro kinase inhibitory activity on CDK12. Therefore, the compounds of the present invention can be used as new inhibitors of CDK12 targets.

[0641] Example 24: Pharmacokinetic Characterization of Compounds

[0642] 1. Experimental methods

[0643] Twenty-four male ICR mice (6-8 weeks old, 18-22 g, Beijing Weitong Lihua Experimental Animal Science Technology Co., Ltd., China) were randomly divided into 8 groups, 3 mice in each group. Mice were administered a single oral gavage (20 mg / kg) and intravenous injection (5 mg / kg) with a single dose of compound C27, C44, C58 and C59 dissolved in DMSO / solutol HS-15 / normal saline (5, 5 and 90%). The oral gavage group fasted for 10-14 hours before administration, but was not allowed to drink water. After 4 hours of administration, they were allowed to eat freely, and then blood (50 μL) was collected from the eye sockets before administration and at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The intravenous group was not fasted before administration, and then blood (50 μL) was collected from the eye sockets before administration and at 0.083, 0.5, 1, 2, 4, 8, and 24 hours after administration. The sample was centrifuged at 12000 rpm for 5 min to obtain plasma, which was stored at -20°C before analysis. LC-MS / MS technology was used to analyze and evaluate the pharmacokinetics of compounds C27, C44, C58 and C59 in plasma.

[0644] 2. Experimental results

[0645]

[0646] The compounds (C27, C44, C58 and C59) of the present invention have good absorption, bioavailability greater than 40%, and good pharmacokinetic properties. Since the compounds are inhibitors of a completely new structure, they have great potential in the development of new drugs and can be used as new CDK9 inhibitors.

[0647] Example 25: An experiment in which compounds act on CDK to cause degradation of its interacting proteins.

[0648] In the present invention, we also unexpectedly found that some of the compounds can lead to the degradation of its interacting proteins, such as CyclinK protein, after acting on CDK. Therefore, the development of compounds that selectively weaken the function of CDK12 / Cyclin K can be used to treat cancer and other diseases. CDK12 inhibitors have the problem of poor restriction. The compounds in the present invention can achieve the function of other proteins in the RNA polymerase II complex or the function of the pre-mRNA splicing complex by inducing the hydrolysis of CDK12 / Cyclin K protein. Therefore, the compounds in the present invention can weaken the function of CDK / Cyclin K, while preserving the selectivity for other CDKs, achieving effective treatment of diseases, and reducing undesirable side effects, providing clinical effectiveness. Therefore, the compounds of the present invention can achieve the function of weakening CDK12 / Cyclin K, and therefore can be used in drugs for treating or preventing abnormal CDK12 activity or regulating diseases or symptoms related to CDK activity.

[0649] 1. Experimental methods

[0650] MDA-MB-231 cells were inoculated in 6-well plates, and the corresponding compounds or DMSO blank controls were added. After incubation for the corresponding time, the cells were lysed on ice with lysis buffer (RIPA:PI=6:1, RIPA+PI:PMSF=200:1) for 10 min, centrifuged at 15000g for 30 min at 4°C, and the protein supernatant was taken for protein quantification and normalization using BCA reagent. After 8% SDS-PAGE gel electrophoresis, the proteins were transferred to PVDF membranes, blocked with 5% skim milk and incubated with primary antibodies (Cyclin K), washed with 5% skim milk, blocked with secondary antibodies (rabbit antibodies), and washed and exposed after incubation.

[0651] The experimental results are as follows Figure 1 As shown, the results show that after treating MDA-MB-231 cells with compounds at a concentration of 50nM for 2 hours, compared with the positive compound Cyclin K degrader CR8, most of the compounds of the present invention have a more significant degradation effect on Cyclin K. Therefore, the patented compounds can be used to treat triple-negative breast cancer or other diseases related to abnormal cyclin K activity by degrading Cyclin K.

[0652] discuss

[0653] The inventors of the present invention obtained the following important information by analyzing the complex crystal structure of CDK9 and the complex crystal structure of other CDKs (PDB ID: IQMZ, 3BLR, 1UA2, 3BLH): The hydrogen bonds between the ligand and the hinge residues Asp104 and Cys106 in the CDK9 protein are crucial to the activity of the ligand. For example, the core scaffold of the CDK9 inhibitor in clinical trials forms hydrogen bonds with residues in the hinge region, which greatly contributes to its CDK9 potency. The activation loop (T loop) is the location of a threonine residue whose phosphorylation is crucial for the activity of the enzyme, which is Thr186 in CDK9. In addition, residues Asp149, Lys151 and Thr191 of CDK9 form a catalytic loop that is directly involved in the phosphotransfer reaction. It is worth noting that some less conserved regions in the CDK9 binding site, including hydrophobic regions and solvent-exposed regions, may provide opportunities for the design of selective CDK9 inhibitors. Through structural analysis, we also obtained important information from the docking results of CDK9 and other small molecule inhibitors (PDBID: 3LQ5): the 4-amino group and N6 of pyrazoline [1,5-a] [1,3,5] triazine interact with the hinge region, and form hydrogen bonds with the amide nitrogen and carbonyl moieties of the Cys106 residue, which leads to its inhibitory effect on CDK9 kinase activity. In addition, the benzene ring points to the solvent region, and the isopropyl group is located in the hydrophobic region composed of Ala46 and Val79. Therefore, these characteristics will mainly serve as the starting point for our design of small molecule inhibitors of CDK9. Based on the molecular docking of the crystal structure, the inventors mainly designed and synthesized CDK9 small molecule inhibitors targeting transcriptional regulation, and conducted activity tests and screening in the CDK kinase family (including CDK2, 4, 6, 7, 9) and triple-negative breast cancer cell lines (including MDA-MB-231 and BT549); the test results showed that this type of molecule has very high anti-proliferation activity in triple-negative breast cancer cells, very high kinase inhibitory activity against CDK9, and very high selectivity for other CDK subtypes. At the same time, through relevant testing methods, it was found that most of the compounds of this type of molecule have good transmembrane absorption, are highly permeable compounds, and have good pharmacokinetic data. Preliminary studies on the mechanism found that the compound promotes cell apoptosis and inhibits cancer cell proliferation, thereby achieving effective disease treatment based on the CDK9 target.

[0654] The present invention unexpectedly found that the substituents in the compound of general formula (I) The selection of different CDKs has different effects. By changing The structure of can also achieve the activity of targeting CDK12. The compounds in the present invention are also unexpectedly found to have the activity of targeting CDK12 and regulate the degradation of CyclinK protein. The development of compounds that selectively weaken the function of CDK12 / Cyclin K can be used to treat cancer and other diseases. CDK12 inhibitors have the problem of poor restriction. The compounds in the present invention can achieve the function of other proteins in the RNA polymerase II complex or the function of the pre-mRNA splicing complex by inducing the hydrolysis of CDK12 / Cyclin K protein. Therefore, the compound in the present invention can weaken the function of CDK / Cyclin K, while preserving the selectivity for other CDKs, achieving effective treatment of diseases, and reducing undesirable side effects, providing the effectiveness in clinical practice. Therefore, the compounds of the present invention can achieve the function of weakening CDK12 / Cyclin K, so they can be used in drugs for treating or preventing abnormal CDK12 activity or regulating diseases or symptoms related to CDK activity.

[0655] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

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 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) Medium 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, In (I-6) and (I-8) Can be the same or different, Y is selected from -NH-, -O- or absent; R 1 is selected from substituted or unsubstituted 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; 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 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; 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 the conditions of sodium hydrogen and anhydrous N,N-dimethylformamide to obtain compound 1H; Step 1-5: Compound 1E and compound 1G react under 1-methyl-2-pyrrolidone to obtain compound 1J; Step 1-6: Compound 1H is reacted in the presence of dioxane hydrochloride to obtain compound 1I; Step 1-7: Compound 1J is reacted in the presence of dioxane hydrochloride to obtain compound 1K; 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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