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WO2025067540A1 - 吡唑并三嗪及吡唑并嘧啶衍生物、其制备方法、药物组合物及其用途 - Google Patents

吡唑并三嗪及吡唑并嘧啶衍生物、其制备方法、药物组合物及其用途 Download PDF

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WO2025067540A1
WO2025067540A1 PCT/CN2024/122446 CN2024122446W WO2025067540A1 WO 2025067540 A1 WO2025067540 A1 WO 2025067540A1 CN 2024122446 W CN2024122446 W CN 2024122446W WO 2025067540 A1 WO2025067540 A1 WO 2025067540A1
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amino
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French (fr)
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陈小华
李佳
王文静
孟心宇
聂辉军
高立信
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Shanghai Institute of Materia Medica of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • 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.
  • CDKs cell cycle-dependent kinases
  • 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.
  • Cyclin-dependent kinase is an important target for tumor treatment.
  • Cyclin-dependent kinase is a type of serine/threonine kinase, which is mostly a heterodimeric complex composed of cell cycle catalytic kinase subunits and regulatory subunits. It is activated by binding to cell cycle proteins, thereby regulating the cell cycle and transcription process. Disturbance of CDK activity can directly or indirectly cause uncontrolled cell proliferation, increased DNA mutations, chromosome deletions and chromosome changes, etc., leading to the occurrence and development of tumors. CDK family proteins are involved in cell mitosis and transcription processes and play an important role in cell proliferation.
  • CDK Due to the abnormally active proliferation of tumor cells, abnormal activation of CDK is often observed in tumor cells, thereby promoting the growth of tumor cells.
  • the CDK family has always been considered an important target in tumor treatment, but due to the highly conserved amino acid sequence of the ATP binding pocket between different CDK proteins, it is difficult to find small molecule inhibitors with high selectivity between CDK families.
  • drugs targeting the CDK family include Pfizer's Palbociclib, Novartis' Ribociclib, Eli Lilly's Abemaciclib, Hengrui's Dalpiciclib and G1 Therapeutics' Trilaciclib.
  • Trilaciclib which is used to reduce the frequency of bone marrow suppression in patients with small cell lung cancer after chemotherapy
  • the indications of the other drugs are all for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) recurrent or metastatic breast cancer.
  • Drugs targeting other targets of the CDK family are mostly in the clinical or preclinical research stage.
  • CDK7 has the dual functions of affecting the cell cycle and regulating the transcription process.
  • CDK7 is the catalytic subunit of the CDK activating enzyme complex (CAK), which is composed of CDK7, cyclin H and MAT1.
  • CAK can activate CDK proteins related to the cell cycle, including CDK1, CDK2, CDK4, and CDK6, through threonine phosphorylation, thereby affecting the progression of the cell cycle.
  • CDK9/Cyclin T1 (or T2) is part of the subunit of the positive transcription elongation factor b (P-TEFb) complex. It activates RNA polymerase II to initiate gene transcription elongation by phosphorylating the carboxyl terminal domain (CTD) of RNA polymerase.
  • CDK9 is upstream of key molecules such as anti-apoptotic proteins Bcl-2, Mcl-1, XIAP, cell cycle regulatory proteins, and mitosis regulatory kinases that are closely related to tumors.
  • CDK9 can be directly or indirectly regulated. For example, in chronic lymphocytic leukemia (CLL), downregulation of Bcl-2 can be achieved by inhibiting the activity of CDK9. 2 family to achieve therapeutic effects.
  • CLL chronic lymphocytic leukemia
  • CDK9 does not affect the regulation of the cell cycle. This specific regulation of CDK9 on the transcription process makes it one of the most promising anti-tumor targets in the CDK family.
  • CDK7/cyclin H and CDK9/cyclin T complexes can also inhibit the replication of HIV and HSV virus RNA, so there will be certain application prospects in the antiviral field.
  • CDK7 and CDK9 are important targets for the treatment of tumors.
  • CDK7 and CDK9 inhibitors have entered clinical research.
  • 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.
  • CDK12 Cyclin-dependent kinase 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.
  • CTD C-terminal domain
  • CDK12 in the CDK12/CyclinK complex regulates transcriptional, co-transcriptional, and post-transcriptional processes by phosphorylating Ser of the CTD of the RNA polymerase II complex.
  • CDK13 is a kinase closely related to CDK12 that forms a complex with CyclinK and regulates the transcription of a different set of genes.
  • CDK12 amplification and high expression levels suggest that the tumor-promoting effects of CDK12 are at least in part based on alternatively spliced mRNAs, increased DNA repair capacity, and increased stress tolerance. This information suggests that CDK12 is a potential target for the development of drugs to treat cancer and other diseases.
  • CDK-related kinases are closely related to the occurrence and development of tumors.
  • Inhibitors or degraders targeting CDK9, CDK7 or CDK12-related kinase targets can regulate transcription CDKs, thereby regulating RNA polymerase II-mediated transcription initiation and extension, and effectively inhibiting the proliferation of tumor cells.
  • the purpose of the present invention is to provide a class of compounds that can be used to treat and/or prevent or improve such diseases and/or conditions by designing and synthesizing new inhibitors or degraders targeting CDK. Therefore, the development of inhibitors and degraders targeting CDK has important scientific significance and research value.
  • One object of the present invention is to provide a compound as represented by the general formula (I) and its tautomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts, pharmaceutical compositions containing the same, and uses thereof.
  • Another object of the present invention is to provide a method for preparing the compound represented by the general formula (I), an important intermediate for preparing the compound and a method for preparing the compound.
  • 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.
  • X is CH or N
  • Y is selected from -NH-, -O- or absent
  • R 1 is selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the following group: hydroxyl, C 1 -C 3 alkyl, propynyl, -C 1 -C 3 alkylhydroxyl, C 1 -C 3 alkylcarbonyl, halogen, 3-8 membered heterocyclyl, amino, (C 1 -C 3 alkyl) 1-2amino , methylsulfonyl;
  • substitution means that one or more H on the group is independently substituted by a substituent selected from the following group: deuterium, halogen, cyano, nitro, hydroxyl, amino, C 1 -C 3 alkyl, halogen-substituted C 1 -C 3 alkyl;
  • R 2 is selected from hydrogen, deuterium, halogen and unsubstituted or halogenated C 1 -C 3 alkyl;
  • R 3 is selected from deuterium, halogen, cyano, hydroxyl, nitro, unsubstituted or halogenated C 1 -C 3 alkyl;
  • n 1 or 2;
  • n 0, 1, 2, 3 or 4;
  • Z is selected from NH, N, O or absent
  • Z is selected from NH or N, each independently selected from hydrogen, -C(O)R 4 , C 1 -C 3 alkyl substituted with R 5 , wherein R 4 is selected from C 1 -C 6 alkyl substituted with R 6 , 3-6 membered heterocycloalkyl substituted with R 6 , and C 3 -C 6 cycloalkyl substituted with R 6 , wherein each R 6 is independently selected from hydrogen, hydroxy, C 1 -C 3 alkyl-C(O)-, halogen, and carboxyl; R 5 is selected from hydrogen, hydroxy, halogen, and carboxyl;
  • the premise is that when Z does not exist, and Not simultaneously selected from the following substituents: is phenyl, pyridyl, thienyl, furyl, thiazolyl, pyrrolyl and pyrimidinyl, It is an unsubstituted C 1 -C 6 alkyl group or an unsubstituted C 3 -C 6 cycloalkyl group.
  • each Independently selected from substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 3-6 membered heterocyclyl, wherein the substitution means that one or more H on the group is substituted by a substituent independently selected from the following group: deuterium, oxo ( O), halogen, cyano, nitro, hydroxyl, amino, carboxyl, formylamino, C 1 -C 3 alkyl, halogen-substituted C 1 -C 3 alkyl.
  • the compound of general formula (I) has a structure shown in formula (I-1)-(I-4):
  • (I-2) Can be the same or different
  • X is CH or N
  • Y is selected from -NH-, -O- or absent
  • R 1 is selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the following group: hydroxyl, C 1 -C 3 alkyl, propynyl, -C 1 -C 3 alkylhydroxyl, C 1 -C 3 alkylcarbonyl, halogen, 3-8 membered heterocyclyl, amino, (C 1 -C 3 alkyl) 1-2amino , methylsulfonyl;
  • R 2 , R 3 , m and As defined in the present invention.
  • the compound of general formula (I) has a structure shown in formula (I-5)-(I-8):
  • (I-6) and (I-8) Can be the same or different,
  • Y is selected from -NH-, -O- or absent
  • R 1 is selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, wherein the substitution means that one or more H on the group is independently substituted by a substituent selected from the following group: hydroxyl, C 1 -C 3 alkyl, propynyl, -C 1 -C 3 alkylhydroxyl, C 1 -C 3 alkylcarbonyl, halogen, 3-8 membered heterocyclyl, amino, (C 1 -C 3 alkyl) 1-2amino , methylsulfonyl;
  • substitution means that one or more H on the group is independently substituted by a substituent selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, amino, C 1 -C 3 alkyl, halogen-substituted C 1 -C 3 alkyl;
  • R 2 , R 3 and m are as defined in the present invention.
  • the compound of general formula (I) has a structure shown in formula (I-9)-(I-10):
  • Y is selected from -NH-, -O- or absent
  • R 1 is selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, wherein the aforementioned substitution refers to substitution by one or more of the following substituents: hydroxyl, C 1 -C 3 alkyl, propynyl, hydroxyC 1 -C 3 alkyl, C 1 -C 3 alkylcarbonyl, halogen, heterocyclyl, amino, alkylamino, methylsulfonyl;
  • substitution means that one or more H on the group is independently substituted by a substituent selected from the group consisting of deuterium, halogen, hydroxyl, C 1 -C 3 alkyl, halogen-substituted C 1 -C 3 alkyl;
  • substitution means that one or more H on the group is independently selected from the following group: deuterium, oxo ( O), halogen, cyano, nitro, hydroxyl, amino, carboxyl, formylamino, C 1 -C 3 alkyl, halogen-substituted C 1 -C 3 alkyl;
  • R 2 , R 3 and m are as defined in the present invention.
  • the compound of general formula (I) has a structure shown by formula (I-11)-(I-12):
  • Y is selected from -NH-, -O- or absent
  • substitution means that one or more H on the group is independently substituted by a substituent selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, amino, C 1 -C 3 alkyl, halogen-substituted C 1 -C 3 alkyl;
  • substitution means that one or more H on the group is independently selected from the following group: deuterium, oxo ( O), halogen, cyano, nitro, hydroxyl, amino, carboxyl, formylamino, C 1 -C 3 alkyl, halogen-substituted C 1 -C 3 alkyl,
  • R 1 , R 2 , R 3 and m are as defined in the present invention.
  • the compound of general formula (I) has a structure shown in formula (I-13)-(I-41):
  • X is CH or N; R1 and Y are as defined in the present invention.
  • the compound of the general formula (I) is characterized in that R 1 -Y is selected from:
  • the compound is selected from the following group:
  • the second aspect of the present invention provides a pharmaceutical composition, which comprises the compound as described in the first aspect of the present invention and one or more of its tautomers, stereoisomers, isotope compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, and pharmaceutically acceptable excipients.
  • the third aspect of the present invention provides the use of the compound as described in the first aspect of the present invention and its tautomers, stereoisomers, isotope compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof or the pharmaceutical composition as described in the second aspect of the present invention in the preparation of a drug for preventing and/or treating diseases or symptoms associated with abnormal activity of CDK or Cyclin K.
  • the CDK is selected from: CDK2, CDK9, CDK12, or Cyclin K, or a combination thereof.
  • the disease associated with abnormal activity of CDK or Cyclin K is cancer, pain, Central nervous system or immune system disorders.
  • the disease associated with abnormal activity of CDK or Cyclin K is a solid tumor or a blood tumor.
  • the disease is selected from the group consisting of myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, myelofibrosis, Burkitt's lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, ciliary body and chronic melanoma, iris melanoma, recurrent interocular melanoma, T-cell lymphoma, erythroid lymphoma, monocytic and monocytic leukemia, myeloid leukemia, blood disease, central nervous system lymphoma, meningioma, spinal cord tumor, non-small cell lung cancer, ovarian cancer
  • 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.
  • the CDK is selected from: CDK2, CDK9, CDK12, or a combination thereof.
  • the present invention also provides a method for preventing and/or treating diseases or symptoms associated with abnormal activity of CDK or Cyclin K, comprising the steps of administering to a subject in need thereof a compound as described in the first aspect of the present invention and its tautomers, stereoisomers, isotope compounds, pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof, or a pharmaceutical composition as described in the second aspect of the present invention.
  • the subject is a human or non-human mammal, such as a rat or a mouse.
  • the present invention also encompasses any novel intermediates disclosed herein.
  • Step 1-1 Compound 1A reacts with Boc anhydride to obtain compound 1B;
  • Step 1-2 Compound 1B is subjected to hydrogenation reaction with Raney nickel to obtain compound 1C;
  • Step 1-3 Compound 1C and compound 1D are subjected to phosphorus oxychloride and N,N-dimethylbenzylamine to obtain a halogenated product, which is then subjected to nucleophilic substitution under alkaline conditions to obtain compound 1E;
  • Step 1-4 Compound 1E and compound 1F react under the conditions of sodium hydrogen and anhydrous N,N-dimethylformamide to obtain compound 1H;
  • Step 1-5 Compound 1E and compound 1G react under 1-methyl-2-pyrrolidone to obtain compound 1J;
  • Step 1-6 Compound 1H is reacted in the presence of dioxane hydrochloride to obtain compound 1I.
  • Step 1-7 Compound 1J is reacted in the presence of dioxane hydrochloride to obtain compound 1K.
  • R 1 is the same as defined in the first aspect of the present invention.
  • Step 2-1 Compound 2A reacts with compound 2B in the presence of HATU and DIPEA to obtain compound 2C;
  • Step 2-2 Compound 2C is reacted in the presence of dioxane hydrochloride to obtain compound 2D;
  • Step 2-3 Compound 2D and compound 1D are reacted in the presence of phosphorus oxychloride and N,N-dimethylbenzylamine to obtain a halogenated product, which is then subjected to nucleophilic substitution under alkaline conditions to obtain compound 2E;
  • Step 2-4 Compound 2E and compound 2F react under the conditions of sodium hydrogen and anhydrous N,N-dimethylformamide to obtain compound 2I;
  • Step 2-5 Compound 2E and compound 2G react under 1-methyl-2-pyrrolidone to obtain compound 2J;
  • Step 2-6 Compound 2E and compound 2H react in 1-methyl-2-pyrrolidone to obtain compound 2K.
  • R 3 is selected from -CH 3 , -CH 2 CH 3 ,
  • R 1 is the same as defined in the first aspect of the present invention.
  • Step 3-1 Compound 3A and compound 1D are reacted in the presence of phosphorus oxychloride and N,N-dimethylbenzylamine to obtain a halogenated product, which is then subjected to nucleophilic substitution under alkaline conditions to obtain compound 3C;
  • Step 3-2 Compound 3B and compound 1D are reacted in the presence of phosphorus oxychloride and N,N-dimethylbenzylamine to obtain a halogenated product, which is then subjected to nucleophilic substitution under alkaline conditions to obtain compound 3D;
  • Step 3-3 Compound 3C and compound 3E react under 1-methyl-2-pyrrolidone to obtain compound 3F;
  • Step 3-4 Compound 3D and compound 3E react under 1-methyl-2-pyrrolidone to obtain compound 3G;
  • Step 3-5 Compound 3F is reacted in the presence of dioxane hydrochloride to obtain compound 3H;
  • Step 3-6 Compound 3G is reacted in the presence of dioxane hydrochloride to obtain compound 3I;
  • R 1 is the same as defined in the first aspect of the present invention.
  • Step 4-1 Compound 4A and compound 1C react under the conditions of N,N-diisopropylethylamine and ethanol to obtain compound 4B;
  • Step 4-2 Compound 4A and compound 2D react under the conditions of N,N-diisopropylethylamine and ethanol to obtain compound 4C;
  • Step 4-3 Compound 4B reacts with Boc anhydride to obtain compound 4D;
  • Step 4-4 Compound 4C reacts with Boc anhydride to obtain compound 4E;
  • Step 4-5 Compound 4D and compound 4F react under 1-methyl-2-pyrrolidone to obtain compound 4G;
  • Step 4-6 Compound 4E and compound 4F react under 1-methyl-2-pyrrolidone to obtain compound 4H;
  • Step 4-7 Compound 4G is reacted in the presence of dioxane hydrochloride to obtain compound 4I;
  • Step 4-8 Compound 4H is reacted in the presence of dioxane hydrochloride to obtain compound 4J;
  • R 1 is the same as defined in the first aspect of the present invention.
  • Figure 1 shows the results of a protein blotting experiment showing the activity of some compounds of the present invention in degrading Cyclin K.
  • 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.
  • substituents 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- .
  • the term “comprising” or “including (comprising)” may be open, semi-closed and closed. In other words, the term also includes “consisting essentially of” or “consisting of”.
  • the compounds shown in general formula (I) may contain one or more asymmetric or chiral centers and therefore may exist in different stereoisomeric forms.
  • the compounds of the present invention include all stereoisomeric forms, including but not limited to diastereomers, enantiomers and atropisomers and mixtures thereof (such as racemates), which are all included within the scope of the present invention.
  • 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.
  • 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.
  • substitution may refer to a group being substituted by one or more groups selected from the following: hydrogen, halogen, cyano, nitro, hydroxy, carboxyl, 4-10 membered heterocyclyl, C1-C6 alkyl, C1 - C6 alkoxy, halogen-substituted C1 - C6 alkyl, halogen-substituted C1 - C6 alkoxy, C2 - C6 alkenyl, C3-C8 heterocyclyloxy, C3-C8 cycloalkyloxy, hydroxy-substituted C1 - C6 alkoxy, and C1 - C6 alkoxy substituted by C1 - C6 alkoxy.
  • R substituents 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.
  • substituted applies only to sites that can be substituted by substituents and does not include substitutions that are not achievable based on existing chemical knowledge.
  • the compounds represented by the general formula (I) may also exist in different tautomeric forms, all of which are included within the scope of the present invention.
  • 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.
  • stereoisomer includes enantiomers, diastereomers, or mixtures thereof, such as racemates.
  • enantiomer refers to stereoisomers that are mirror images of each other and are not superimposable.
  • Stereomers refer to stereoisomers that have two or more chiral neutrals and are not mirror images.
  • Racemate refers to two stereoisomers that are mirror images of each other, with opposite optical rotations that cancel each other out.
  • “Pharmaceutically acceptable salts” refer to salts formed by drug molecules and corresponding organic acids, inorganic acids or organic bases, inorganic bases, such as hydrochloric acid, formic acid, trifluoroacetic acid, succinic acid, methanesulfonate, etc.
  • Prodrug refers to a class of compounds that are inactive or have low activity in vitro, but release active drugs through enzymatic or non-enzymatic conversion in vivo to exert their pharmacological effects.
  • Hydrophilate refers to a compound containing water.
  • the present invention also includes isotopically labeled compounds, which are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number from the original atoms.
  • isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, such as 2H , 3H , 13C , 11C , 14C , 15N , 18O , 17O , 31P , 32P , 35S , 18F and 36Cl , respectively.
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention.
  • Certain isotopically labeled compounds of the present invention such as radioactive isotopes of 3H and 14C , are also included, which are useful in tissue distribution experiments of drugs and substrates.
  • Tritium, i.e. 3H and carbon-14, i.e. 14C are relatively easy to prepare and detect. It is the first choice among isotopes.
  • heavier isotope substitutions such as deuterium, i.e.
  • 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.
  • the isotope compound is a deuterated compound, and more preferably, one or more H on carbon in the isotope compound is replaced by deuterium.
  • plurality refers to two or more, such as 2, 3, 4, 5 or 6.
  • halogen includes fluorine, chlorine, bromine or iodine.
  • 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.
  • C 1 -C 6 alkyl refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms in the chain, such as an alkyl group containing 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl group used herein or as part of another group has 1 to 6 carbon atoms (i.e., C1-C6 alkyl), or 1 to 3 carbon atoms (i.e., C1-3 alkyl), including but not limited to Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.
  • C 1 -C 6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.
  • C 1 -C 6 alkoxycarbonyl includes, but is not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent.
  • C 3 -C 8 cycloalkyl refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring.
  • Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentenyl, and cyclohexyl.
  • Polycyclic cycloalkyl groups include spirocyclic, condensed, and bridged cycloalkyl groups.
  • the 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 spiro
  • 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.
  • 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,
  • 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.
  • 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.
  • alkenyl refers to an alkenyl group which may be of 2 to 10 carbons, such as ethenyl, propenyl, butenyl, styryl, phenylpropenyl.
  • alkynyl refers to an alkynyl group which may be 2-10 carbons, such as ethynyl, propynyl, butynyl, phenylethynyl, phenylpropenyl.
  • 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.
  • prevent refers to the reduction of the risk of acquiring or developing a disease or disorder.
  • 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.
  • 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, cit
  • solvents are generally selected based on solvents that are considered safe and effective for administration to mammals by those skilled in the art.
  • 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.
  • 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.
  • a mammal e.g., a human
  • 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.
  • 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.
  • 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.
  • Solid dosage forms for oral administration may include capsules, tablets, powders, Powder or granular preparation.
  • the compound or pharmaceutical composition of the present invention is mixed with at least one inert excipient, diluent or carrier.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • 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.
  • an inert diluent commonly used in the art, such as water or other solvents
  • 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.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature but liquid at body temperature and melt in the rectum or vagina to release the active compound.
  • the compounds or pharmaceutical compositions of the present invention may be administered in other topical dosage forms, including creams, powders, sprays and inhalants.
  • the drug may be mixed under sterile conditions with a pharmaceutically acceptable excipient, diluent or carrier and any desired preservative, buffer or propellant.
  • Ophthalmic formulations, ophthalmic ointments, powders and solutions are also intended to be included within the scope of the present invention.
  • Another aspect of the present invention provides the use of the compound represented by general formula (I) and its tautomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or the above-mentioned pharmaceutical compositions in the preparation of drugs for preventing and/or treating diseases or symptoms associated with abnormal activity of CDK.
  • the diseases associated with abnormal CDK activity include solid tumors such as breast cancer, colon cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer, and blood tumors such as acute lymphocytic leukemia, acute lymphocytic leukemia, cellular lymphoma, cellular lymphoma, myeloma, acute and chronic myeloid leukemia, and promyelocytic leukemia.
  • solid tumors such as breast cancer, colon cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer
  • blood tumors such as acute lymphocytic leukemia, acute lymphocytic leukemia, cellular lymphoma, cellular lymphoma, myeloma, acute and chronic myeloid leukemia, and promyelocytic leukemia.
  • Another aspect of the present invention also provides the use of the compound represented by general formula (I) and its tautomers, enantiomers, diastereomers, racemates, pharmaceutically acceptable salts or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating diseases such as tumors, central nervous system diseases and immune diseases.
  • 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 TNF ⁇ -related diseases or functional disorders.
  • 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 TNF ⁇ -related diseases or functional disorders.
  • 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,
  • 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.
  • 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.
  • the compounds of the present invention are used as CDK kinase inhibitors, preferably having good selectivity and kinase activity for inhibiting CDK9.
  • the compounds of the present invention have excellent pharmacokinetic properties.
  • 1 H NMR spectrum testing instruments are 400MHz Bruker and 500MHz Bruker nuclear magnetic resonance instruments, and chemical shifts are expressed in ⁇ (ppm); mass spectra are measured by MS mass spectrometry UPLC-MS (ESI); wherein the UPLC model is Waters HPLC H-CLASS, and the MS (ESI) model is Waters SQ Detector 2; anhydrous tetrahydrofuran is prepared by benzophenone/metal sodium reflux drying and deoxygenation, and anhydrous toluene and anhydrous dichloromethane are prepared by calcium chloride reflux drying; petroleum ether, ethyl acetate, dichloromethane and other solvents used for column chromatography mobile phases are purchased from Sinopharm Chemical Reagent Co., Ltd.; The thin layer chromatography silica gel plate (HSGF254) used in the test was from Sinopharm Chemical Reagent Co., Ltd.; the 200-300 mesh silica gel from Sinopharm Chemical Reagent Co.
  • the raw materials in the present invention can be obtained from commercial sources, such as the main reagents purchased from Sinopharm Chemical Reagent Co., Ltd., or prepared by methods inhibited in the art, or prepared according to the method described in the present invention.
  • EtOH ethanol
  • DCM dichloromethane
  • ACN acetonitrile
  • TFA trifluoroacetic acid
  • TEA triethylamine
  • 1,4-dioxane 1,4-dioxane
  • NaH sodium hydride
  • H 2 O water
  • HATU 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DMF N,N-dimethylformamide
  • THF tetrahydrofuran
  • DIPEA N,N-diisopropylethylamine
  • AcOH acetic acid
  • Raney Ni Raney nickel
  • TBSCl tert-butyldimethylchlorosilane
  • imidazole imidazole
  • NMP N-methylpyrrolidone
  • EA ethyl acetate
  • DMAP 4-dimethylaminopyridine
  • C50 was prepared by replacing 1-methyl-4-piperidinol with (S)-3-hydroxypiperidine.
  • N-ethyl-4-cyanoaniline 500 mg, 3.42 mmol, 1.0 equiv
  • dichloromethane 10 mL
  • di-tert-butyl dicarbonate 786 uL, 3.42 mmol, 1.0 equiv
  • the solvent was dried and column chromatography was performed to obtain compound 5.1 (158 mg) with a yield of 19%.
  • Compound 10.1 was prepared with 4-(N-Boc-aminomethyl)aniline and propionic acid as raw materials and with reference to the synthetic route of compound 3.1, with a yield of 95%.
  • Compound 13.1 was prepared with 4-(N-Boc-aminomethyl)aniline and 1-fluorocyclopropylcarboxylic acid as raw materials and with reference to the synthetic route of compound 3.1, with a yield of 98%.
  • 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%.
  • 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%.
  • Compound 16.3 was prepared using compound 16.1 and compound 16.2 as raw materials and referring to the synthetic route of compound 1.4 with a yield of 58%.
  • Compound 18.1 was prepared using 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine and compound 13.2 as raw materials and referring to the synthetic route of compound 11.1 with a yield of 70%.
  • Compound 19.1 was prepared using compound 16.1 and compound 3.2 as raw materials and referring to the synthetic route of compound 16.3, with a yield of 55%.
  • Compound 19.2 was prepared using compound 19.1 as raw material and referring to the synthetic route of compound 16.4 with a yield of 88%.
  • Compound 20.1 was prepared using compound 16.1 and compound 10.2 as raw materials and referring to the synthetic route of compound 16.3 with a yield of 60%.
  • Compound 20.2 was prepared using compound 20.1 as raw material and referring to the synthetic route of compound 16.4 with a yield of 83%.
  • Compound 21.1 was prepared using compound 16.1 and compound 13.2 as raw materials and referring to the synthetic route of compound 16.3 with a yield of 47%.
  • Compound 21.2 was prepared using compound 21.1 as raw material and referring to the synthetic route of compound 16.4 with a yield of 76%.
  • Compound C64 can be synthesized according to the above synthetic route.
  • Compound C65 can be synthesized according to the above synthetic route.
  • Compound C66 can be synthesized according to the above synthetic route.
  • Compound C67 can be synthesized according to the above synthetic route.
  • Compound C68 can be synthesized according to the above synthetic route.
  • Compound C69 can be synthesized according to the above synthetic route.
  • Compound C70 can be synthesized according to the above synthetic route.
  • Compound C71 can be synthesized according to the above synthetic route.
  • Compound C72 can be synthesized according to the above synthetic route.
  • Compound C73 can be synthesized according to the above synthetic route.
  • Compound C74 can be synthesized according to the above synthetic route.
  • Compound C75 can be synthesized according to the above synthetic route.
  • Compound C76 can be synthesized according to the above synthetic route.
  • Compound C77 can be synthesized according to the above synthetic route.
  • Compound C78 can be synthesized according to the above synthetic route.
  • Compound C79 can be synthesized according to the above synthetic route.
  • Compound C80 can be synthesized according to the above synthetic route.
  • Compound C81 can be synthesized according to the above synthetic route.
  • Compound C82 can be synthesized according to the above synthetic route.
  • Compound C83 can be synthesized according to the above synthetic route.
  • Compound C84 can be synthesized according to the above synthetic route.
  • Compound C85 can be synthesized according to the above synthetic route.
  • Compound C86 can be synthesized according to the above synthetic route.
  • Compound C87 can be synthesized according to the above synthetic route.
  • Compound C88 can be synthesized according to the above synthetic route.
  • Compound C89 can be synthesized according to the above synthetic route.
  • Compound C90 can be synthesized according to the above synthetic route.
  • Compound C91 can be synthesized according to the above synthetic route.
  • Compound C92 can be synthesized according to the above synthetic route.
  • Compound C93 can be synthesized according to the above synthetic route.
  • Compound C94 can be synthesized according to the above synthetic route.
  • Compound C95 can be synthesized according to the above synthetic route.
  • Compound C96 can be synthesized according to the above synthetic route.
  • Compound C97 can be synthesized according to the above synthetic route.
  • Compound C98 can be synthesized according to the above synthetic route.
  • Compound C99 can be synthesized according to the above synthetic route.
  • Compound C100 can be synthesized according to the above synthetic route.
  • Compound C101 can be synthesized according to the above synthetic route.
  • Compound C102 can be synthesized according to the above synthetic route.
  • Compound C103 can be synthesized according to the above synthetic route.
  • Compound C104 can be synthesized according to the above synthetic route.
  • Compound C105 can be synthesized according to the above synthetic route.
  • Compound C106 can be synthesized according to the above synthetic route.
  • Compound C107 can be synthesized according to the above synthetic route.
  • Compound C108 can be synthesized according to the above synthetic route.
  • Compound C109 can be synthesized according to the above synthetic route.
  • Compound C110 can be synthesized according to the above synthetic route.
  • Compound C111 can be synthesized according to the above synthetic route.
  • Compound C112 can be synthesized according to the above synthetic route.
  • Compound C113 can be synthesized according to the above synthetic route.
  • Compound C114 can be synthesized according to the above synthetic route.
  • Compound C115 can be synthesized according to the above synthetic route.
  • Compound C116 can be synthesized according to the above synthetic route.
  • Compound C117 can be synthesized according to the above synthetic route.
  • Compound C118 can be synthesized according to the above synthetic route.
  • Compound C119 can be synthesized according to the above synthetic route.
  • Compound C120 can be synthesized according to the above synthetic route.
  • Compound C121 can be synthesized according to the above synthetic route.
  • Compound C122 can be synthesized according to the above synthetic route.
  • Example 22 Proliferation and growth inhibition activity of the compound on triple-negative breast cancer cells
  • the human triple-negative breast cancer cells MDA-MB-231, MDA-MB-468 and BT549 used in the present invention were purchased from the Shanghai Cell Bank, and the MDA-MB-231 and MDA-MB-468 cells were cultured in a 37°C, CO2- free incubator in Leibovitzs (L-15) medium supplemented with 10% fetal bovine serum (FBS) and penicillin-streptomycin (PS) antibiotics. 468 cells and BT549 cells were cultured in RPMI 1640 medium supplemented with 10% FBS, 1% penicillin-streptomycin (PS) antibiotics and recombinant human insulin solution (Insulin) at 37°C in an incubator containing 5% CO 2 .
  • Leibovitzs L-15
  • FBS fetal bovine serum
  • PS penicillin-streptomycin
  • A represents cell activity IC 50 ⁇ 1 ⁇ M
  • B represents cell activity 1 ⁇ M ⁇ IC 50 ⁇ 3 ⁇ M
  • C represents cell activity IC 50 >3 ⁇ M.
  • the compound of the present invention Based on the above compound cell growth inhibition activity test method, in triple-negative breast cancer cell lines MDA-MB-231, MDA-MB-468 and BT549, compared with the positive compound Control compound, the compound of the present invention has a good inhibitory activity on cell growth inhibition. Therefore, the compound of the present invention can be used as a new inhibitor of related targets in triple-negative breast cancer cells.
  • Example 23 In vitro kinase inhibitory activity of compounds against CDK
  • the LANCE Ultra KinaSelect Ser/Thr detection kit of Perkin Elmer was used to determine the kinase activity of CDK9.
  • the reaction of this method was carried out in a 384-well plate, and the total reaction volume was 10 ⁇ L.
  • CDK9 protein (final concentration of 1 ng/ ⁇ L), 4EBP-1 peptide substrate (final concentration of 50 nM) and ATP (final concentration of 2.5 ⁇ M) were reacted in a buffer solution: 50 mM HEPES-KOH (pH 7.5), 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA for 1 h, and the corresponding Eu-labeled anti-phosphorylation antibody Eu-anti-P-4E-BP1 (final concentration of 2 nM) was added and incubated for 30 min, and then the phosphorylation was detected, and the laser ratio at 620 nM and 665 nM wavelengths was detected by the fluorescence detector Envision (PerkinElmer, USA).
  • the compounds of the present invention 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.
  • the LANCE Ultra KinaSelect Ser/Thr detection kit of Perkin Elmer was used to determine the CDK2 kinase activity.
  • the reaction of this method was in a 384-well plate, and the total reaction volume was 10 ⁇ L.
  • CDK2 protein final concentration of 1ng/ ⁇ L
  • 4EBP-1 peptide substrate final concentration of 50nM
  • ATP final concentration of 2.5 ⁇ M
  • a buffer solution 50mM HEPES-KOH (pH 7.5)
  • 10mM MgCl 2 10mM MgCl 2 , 2mM DTT, 1mM EGTA for 1h
  • the corresponding Eu-labeled anti-phosphorylation antibody Eu-anti-P-4E-BP1 final concentration of 2nM
  • was added and incubated for 30min and then the phosphorylation was detected, and the laser ratio at 620nM and 665nM wavelengths was detected by the fluorescence detector Envision (PerkinElmer, USA).
  • A indicates cell activity IC 50 ⁇ 100nM
  • B indicates cell activity 100nM ⁇ IC 50 ⁇ 1000nM
  • C indicates cell activity 1 ⁇ M ⁇ IC 50 ⁇ 20 ⁇ M
  • D indicates cell activity IC 50 >20 ⁇ M.
  • the compounds of the present invention Based on the in vitro kinase inhibitory activity of the above compounds on CDK2, most of the compounds of the present invention have certain inhibitory activity on the in vitro kinase of CDK2, while some compounds have much higher in vitro kinase activity on CDK9, so these compounds have good CDK9/CDK2 selectivity.
  • the compounds of the present invention can be used as novel selective inhibitors of CDK9 or CDK2 targets, or they can be used as inhibitors of dual targets.
  • the LANCE Ultra KinaSelect Ser/Thr detection kit of Perkin Elmer was used to determine the kinase activity of CDK12.
  • the reaction of this method was carried out in a 384-well plate, and the total reaction volume was 10 ⁇ L.
  • CDK12 protein final concentration of 1 ng/ ⁇ L
  • 4EBP-1 peptide substrate final concentration of 50 nM
  • ATP final concentration of 2.5 ⁇ M
  • a buffer solution 50 mM HEPES-KOH (pH 7.5)
  • 10 mM MgCl 2 10 mM MgCl 2 , 2 mM DTT, 1 mM EGTA for 1 h
  • the corresponding Eu-labeled anti-phosphorylation antibody Eu-anti-P-4E-BP1 final concentration of 2 nM
  • the compounds of the present invention can be used as new inhibitors of CDK12 targets.
  • mice Twenty-four male ICR mice (6-8 weeks old, 18-22 g, Beijing Weitong Lihua Experimental Animal Science Technology Co., Ltd., China) were randomly divided into 8 groups, 3 mice in each group.
  • the mice were administered a single oral gavage (20 mg/kg) and intravenous injection (5 mg/kg) with a single dose of compounds C27, C44, C58 and C59 dissolved in DMSO/solutol HS-15/normal saline (5, 5 and 90%).
  • the oral gavage group fasted for 10-14 hours before administration, but was not allowed to drink water. They were allowed to eat freely 4 hours after administration, and then blood (50 ⁇ L) was collected from the eye sockets before administration and at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration.
  • the intravenous group did not fast before administration, and then blood was collected from the eye sockets before administration and at 0.083, 0.5, 1, 2, 4, 8, and 24 hours after administration. Blood (50 ⁇ L) was collected. The sample was centrifuged at 12000 rpm for 5 min to obtain plasma, which was stored at -20°C before analysis. LC-MS/MS technology was used for analysis to evaluate the pharmacokinetics of compounds C27, C44, C58 and C59 in plasma.
  • the compounds (C27, C44, C58 and C59) of the present invention have good absorption, bioavailability greater than 40%, and good pharmacokinetic properties. Since the compounds are inhibitors of a completely new structure, they have great potential in the development of new drugs and can be used as new CDK9 inhibitors.
  • Example 25 An experiment in which compounds act on CDK to cause degradation of its interacting proteins.
  • CDK12 inhibitors have the problem of poor restriction.
  • the compounds in the present invention can achieve the functions of other proteins in the RNA polymerase II complex or the function of the pre-mRNA splicing complex by inducing the hydrolysis of CDK12/Cyclin K protein. Therefore, the compounds in the present invention can weaken the function of CDK/Cyclin K, while preserving the selectivity for other CDKs, achieving effective treatment of diseases, and reducing undesirable side effects, providing clinical effectiveness. Therefore, the compounds of the present invention can achieve the function of weakening CDK12/Cyclin K, and can therefore be used in drugs for treating or preventing abnormal CDK12 activity or regulating diseases or symptoms related to CDK activity.
  • the protein was transferred to a PVDF membrane, blocked with 5% skim milk and incubated with the primary antibody (Cyclin K), washed with 5% skim milk and incubated with the secondary antibody (rabbit antibody), and washed and exposed after incubation.
  • the inventors of the present invention obtained the following important information by analyzing the complex crystal structure of CDK9 and the complex crystal structure of other CDKs (PDB ID: IQMZ, 3BLR, 1UA2, 3BLH):
  • the hydrogen bonds between the ligand and the hinge residues Asp104 and Cys106 in the CDK9 protein are crucial for the activity of the ligand.
  • 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.
  • the inventors 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.
  • CDK9 CDK2, 4, 6, 7, 9
  • triple-negative breast cancer cell lines including MDA-MB-231 and BT549
  • the present invention unexpectedly found that the substituents in the compound of formula (I) and The selection of different CDKs has different effects. By changing and The structure of can also achieve the activity of targeting CDK12.
  • the compounds in the present invention are also unexpectedly found to have the activity of targeting CDK12 and regulate the degradation of CyclinK protein.
  • the development of compounds that selectively weaken the function of CDK12/Cyclin K can be used to treat cancer and other diseases.
  • CDK12 inhibitors have the problem of poor restriction.
  • the compounds in the present invention can achieve the function of other proteins in the RNA polymerase II complex or the function of the pre-mRNA splicing complex by inducing the hydrolysis of CDK12/Cyclin K protein.
  • 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.

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Abstract

通式(I)所示的吡唑并[1,5-a][1,3,5]三嗪和吡唑并[1,5-a]嘧啶衍生物和/或其药学上可接受的盐、其药物组合物以及这些衍生物作为药物活性剂，用于预防和/或治疗CDKs异常活性相关的疾病的药物中的用途，所述化合物对实体肿瘤和血液肿瘤均具有较好的抑制细胞増殖的效果。

Description

吡唑并三嗪及吡唑并嘧啶衍生物、其制备方法、药物组合物及其用途 技术领域
本发明涉及药物化学领域，具体地，涉及及一类如通式(I)所示的化合物、其制备方法、药物组合物及其在制备靶向细胞周期依赖性激酶(CDKs)的降解剂在预防和/或治疗与细胞周期依赖性激酶的异常活性相关的疾病或者症状，以及治疗与选择性转录CDKs有关的疾病或病症的药物中的用途。本发明还提供了包含本发明化合物的可药用组合物和使用所述组合物治疗与选择性转录CDKs有关的疾病或病症的方法。
背景技术
细胞周期依赖性激酶(CDK)是肿瘤治疗重要靶点，细胞周期依赖性激酶(cyclin dependent kinase，CDK)是一类丝氨酸/苏氨酸激酶，多是一种由细胞周期催化激酶亚基和调节亚基组成的异二聚体复合物，通过与细胞周期蛋白结合而激活，从而调节细胞周期和转录过程，CDK活性失调会直接或间接引起细胞增殖失控、DNA突变增加、染色体缺失和染色体变化等，导致肿瘤的发生和发展。CDK家族蛋白参与细胞有丝分裂和转录过程，在细胞增殖中发挥重要作用，由于肿瘤细胞增殖异常活跃，在肿瘤细胞中常常观察到CDK的异常活化，从而促进肿瘤细胞的生长。一直以来，CDK家族都被认为是肿瘤治疗中的重要靶点，但由于不同的CDK蛋白之间的ATP结合口袋位置的氨基酸序列高度保守，很难找到在CDK家族之间具有高选择性的小分子抑制剂。目前上市的靶向CDK家族的药物有辉瑞的帕布昔利布(Palbociclib)、诺华的瑞博西尼(Ribociclib)、礼来的Abemaciclib、恒瑞的Dalpiciclib和G1 Therapeutics的Trilaciclib，除Trilaciclib用于降低小细胞肺癌患者化疗后的骨髓抑制频率，其余药物适应症均为激素受体阳性(HR+)、人表皮生长因子受体2阴性(HER2-)的复发性或转移性乳腺癌，针对CDK家族其他靶点的药物大多处于临床或者临床前研究阶段。
在CDK家族中，CDK7和CDK9最近逐渐引起学术界和各大制药公司广泛的关注。CDK7具有影响细胞周期和调控转录过程的双重功能。CDK7是CDK激活酶复合物(cyclinactivating kinase complex，CAK)的催化亚基，CDK激活酶复合物由CDK7、cyclin H和MAT1组成，CAK可以通过苏氨酸磷酸化激活与细胞周期相关的CDK蛋白，包括CDK1、CDK2、CDK4、CDK6,从而影响细胞周期进展。在转录调节方面，CDK7作为基础转录因子TFIIH复合物的组成部分，可以通过丝氨酸磷酸化RNA聚合酶Π的C端结构域激活RNA聚合酶Π，从而调节RNA聚合酶Π介导的转录起始和延伸。
CDK9/Cyclin T1(或T2)是正转录延伸因子b(P-TEFb)复合物亚基的一部分，通过磷酸化RNA聚合酶的羧基末端结构域(CTD)，激活RNA聚合酶II启动基因转录延伸的调节。CDK9处于与肿瘤密切相关的抗凋亡蛋白Bcl-2、Mcl-1、XIAP等细胞周期调节蛋白和有丝分裂调节激酶等关键分子的上游，通过调节CDK9可以直接或间接的对其进行调节，比如在慢性淋巴细胞白血病(CLL)中，可通过抑制CDK9的活性达到下调Bcl- 2家族的关键蛋白而达到治疗作用。CDK9则不会对细胞周期的调控产生影响，CDK9对转录过程的这种特异性调控，使它成为CDK家族中最具潜力的抗肿瘤靶点之一。此外，有文献报道CDK7/cyclin H和CDK9/cyclin T复合物也显示能够抑制HIV和HSV病毒的RNA的复制，因此在抗病毒领域也会有一定的应用前景。
CDK7和CDK9是治疗肿瘤的重要的靶点，目前已有多个CDK7和CDK9抑制剂进入了临床研究。然而，由于CDKs的结构高度保守，大部分是非选择性抑制剂。代表性的小分子抑制剂有Flavopiridol,Roscovitine,SNS-032,R547,TG-02,AT-7519等，但是高选择性靶向CDK7或CDK9，或者靶向CDK7和CDK9的双靶点的小分子抑制剂研究比较少，通过小分子抑制剂作用于CDK7和CDK9阻滞细胞周期诱导细胞凋亡和调控转录成为抗肿瘤的重要方法。由于已知的CDK9抑制剂大多存在非选择性或意外毒性等缺点，可能会带来不可预见的副作用。
细胞周期依赖性激酶(CDK)12，CDK13是疾病治疗重要靶点，CDK12是磷酸化RNA聚合酶II的C末端结构域(CTD)的CDK丝氨酸/苏氨酸激酶家族子集的成员。CDK12/CyclinK复合的CDK12通过RNA聚合酶II复合物CTD的Ser的磷酸化来调节转录、共转录和转录后过程。CDK13与CDK12密切相关的激酶，与CyclinK形成复合物并调节一组不同基因的转录。CDK12扩增和高表达水平表明CDK12的肿瘤促进作用至少部分地是基于可变剪接的mRNA、增加的DNA修复能力和增加应激耐受性。这些信息表明CDK12是开发治疗癌症和其他疾病药物的潜在靶点。
CDK相关激酶与肿瘤的发生发展密切相关，靶向CDK9或CDK7或CDK12相关激酶靶点的抑制剂或降解剂能够调控转录CDKs，从而调节RNA聚合酶Π介导的转录起始和延伸，有效抑制肿瘤细胞的增殖。本发明的目的是通过设计合成新的靶向CDK的抑制剂或降解剂，提供一类可以用于治疗和/或预防或改善该类疾病和/或病症的化合物。因此，靶向CDK的抑制剂及降解剂的开发具有重要的科学意义和研究价值。
发明内容
本发明的一个目的是提供如通式(I)所示的化合物以及其互变异构体、对映体、非对映体、消旋体、可药用的盐，包含其的药物组合物，及其用途。
本发明的另一个目的是提供如通式(I)所示的化合物的制备方法、制备该类化合物的重要中间体及制备方法。
本发明第一方面，提供了一种通式(I)所示的化合物以及其互变异构体、立体异构体、同位素化合物、可药用的盐、酯、前药或其水合物，

其中，X为CH或N；
Y选自-NH-、-O-或不存在；
R1选自取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代的3-8元杂环基，其中所述取代是指基团上的一个或多个H独立地被选自下组的取代基所取代：羟基、C1-C3烷基、丙炔基、-C1-C3烷基羟基、C1-C3烷基羰基、卤素、3-8元杂环基、氨基、(C1-C3烷基)1-2氨基、甲磺酰基；
选自氢、卤素、氰基、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代3-6元杂环基、取代或未取代的5-6元杂芳基，其中所述取代是指基团上的一个或多个H独立地选自下组的取代基所取代：氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基、卤素取代的C1-C3烷基；
R2选自氢、氘、卤素和未取代或卤代的C1-C3烷基；
R3选自氘、卤素、氰基、羟基、硝基、未取代或卤代的C1-C3烷基；
n为1或2；
m为0、1、2、3或4；
Z选自NH、N、O或不存在；
当Z选自NH或N时，各独立地选自氢、-C(O)R4、R5取代的C1-C3烷基，其中R4选自R6取代的C1-C6烷基、R6取代的3-6元杂环烷基和R6取代的C3-C6环烷基，其中各R6独立地选自氢、羟基、C1-C3烷基-C(O)-、卤素和羧基；R5选自氢、羟基、卤素和羧基；
当Z选自O或Z不存在时，各独立地选自取代或未取代的6-10元芳基、取代或未取代的5-6元杂芳基、取代或未取代3-8元杂环基，其中所述取代是指基团上的一个或多个H独立地选自下组的取代基所取代：氘、氧代(＝O)、卤素、氰基、硝基、羟基、氨基、羧基、甲酰基氨基、C1-C3烷基、卤素取代的C1-C3烷基；
前提是当Z不存在时，和不同时为选自下列取代基的组合：为苯基、吡啶基，噻吩基，呋喃基、噻唑基、吡咯基和嘧啶基、为未取代的C1-C6烷基或未取代的C3-C6环烷基。
在另一优选例中，当Z选自O或Z不存在时，各独立地选自取代或未取代的6-10元芳基、取代或未取代的5-6元杂芳基、取代或未取代3-6元杂环基，其中所述取代是指基团上的一个或多个H独立地选自下组的取代基所取代：氘、氧代(＝O)、卤素、氰基、硝基、羟基、氨基、羧基、甲酰基氨基、C1-C3烷基、卤素取代的C1-C3烷基。
在另一优选例中，所述通式(I)的化合物具有式(I-1)-(I-4)所示的结构：
其中，(I-2)中可以相同或不同，
X为CH或N；
Y选自-NH-、-O-或不存在；
R1选自取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代的3-8元杂环基，其中所述取代是指基团上的一个或多个H独立地被选自下组的取代基所取代：羟基、C1-C3烷基、丙炔基、-C1-C3烷基羟基、C1-C3烷基羰基、卤素、3-8元杂环基、氨基、(C1-C3烷基)1-2氨基、甲磺酰基；
R2、R3、m、和如本发明所定义。
在另一优选例中，通式(I)的化合物具有式(I-5)-(I-8)所示的结构：
其中，(I-6)和(I-8)中可以相同或不同，
Y选自-NH-、-O-或不存在；
R1选自取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代的3-8元杂环基，其中所述取代是指基团上的一个或多个H独立地被选自下组的取代基所取代：羟基、C1-C3烷基、丙炔基、-C1-C3烷基羟基、C1-C3烷基羰基、卤素、3-8元杂环基、氨基、(C1-C3烷基)1-2氨基、甲磺酰基；
选自氢、卤素、氰基、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代3-6元杂环基、取代或未取代的5-6元杂芳基，其中所述取代是指基团上的一个或多个H独立地被选自下组的取代基所取代：氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基、卤素取代的C1-C3烷基；
各独立地选自氢、-C(O)R4、R5取代的C1-C3烷基，其中R4选自R6取代的C1-C6烷基、R6取代的3-6元杂环烷基和R6取代的C3-C6环烷基，其中各R6独立地选自氢、羟基、C1-C3烷基羰基、卤素和羧基，R5选自氢、羟基、卤素和羧基；
R2、R3、m如本发明所定义。
在另一优选例中，所述通式(I)的化合物具有式(I-9)-(I-10)所示的结构：
其中，Y选自-NH-、-O-或不存在；
R1选自取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代的3-8元杂环基，其中前述取代是指被以下一种或多种取代基所取代：羟基、C1-C3烷基、丙炔基、羟C1-C3烷基、C1-C3烷基羰基、卤素、杂环基、氨基、烷基氨基、甲磺酰基；
选自氢、卤素、氰基、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代3-6元杂环基、取代或未取代的5-6元杂芳基，其中所述取代是指基团上的一个或多个H独立地被选自下组的取代基所取代：氘、卤素、羟基、C1-C3烷基、卤素取代的C1-C3烷基；
选自取代或未取代的6-10元芳基、取代或未取代的5-6元杂芳基、取代或未取代3-6元杂环基，其中所述取代是指基团上的一个或多个H独立地被选自下组的：氘、氧代(＝O)、卤素、氰基、硝基、羟基、氨基、羧基、甲酰基氨基、C1-C3烷基、卤素取代的C1-C3烷基；
R2、R3、m如本发明所定义。
在另一优选例中，所述通式(I)的化合物具有式(I-11)-(I-12)所示的结构：
其中，Y选自-NH-、-O-或不存在；
选自氢、卤素、氰基、取代的C1-C6烷基、取代的C3-C6环烷基、取代或未取代3-6元杂环基、取代或未取代的5-6元杂芳基，其中所述取代是指基团上的一个或多个H独立地被选自下组的取代基所取代：氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基、卤素取代的C1-C3烷基；
选自取代或未取代的6-10元芳基、取代或未取代的5-6元杂芳基、取代或未取代3-6元杂环基，其中所述取代是指基团上的一个或多个H独立地被选自下组的：氘、氧代(＝O)、卤素、氰基、硝基、羟基、氨基、羧基、甲酰基氨基、C1-C3烷基、卤素取代的C1-C3烷基，
R1、R2、R3、m如本发明所定义。
在另一优选例中，所述通式(I)的化合物具有式(I-13)-(I-41)所示的结构：
其中，X为CH或N；R1和Y的如本发明所定义。
在另一优选例中，所述通式(I)的化合物，其特征在于，R1-Y选自：
在另一优选例中，所述化合物选自下组：











在另一优选例中，n、m、X、Y、Z、R1、R2、R3、和任选独立地为C1-C149中任一对应的基团。
本发明第二方面，提供了一种药物组合物，所述的药物组合物包含如本发明第一方面所述的化合物以及其互变异构体、立体异构体、同位素化合物、可药用的盐、酯、前药或其水合物的一种或多种，以及药学上可接受的辅料。
本发明第三方面，提供了如本发明第一方面所述的化合物以及其互变异构体、立体异构体、同位素化合物、可药用的盐、酯、前药或其水合物或如如本发明第二方面所述的药物组合物在制备用于预防和/或治疗与CDK或与Cyclin K异常活性相关的疾病或者症状的药物中的用途。
在另一优选例中，所述CDK选自：CDK2、CDK9、CDK12，或Cyclin K，或其组合。
在另一优选例中，所述与CDK或与Cyclin K异常活性相关的疾病为癌症、疼痛、 中枢神经系统疾病或免疫系统疾病。
在另一优选例中，所述的与CDK或与Cyclin K异常活性相关的疾病为实体瘤、血液瘤，优选地，所述的疾病选自：骨髓增生异常综合征、多发性骨髓瘤、套细胞淋巴瘤、非霍奇金淋巴瘤、慢性淋巴细胞白血病、慢性粒单核细胞白血病、骨髓纤维化、伯基特淋巴瘤、霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、睫状体和慢性黑色素瘤、虹膜黑色素瘤、复发性两眼间黑色素瘤、T细胞淋巴瘤、红系淋巴瘤、成单核细胞和单核细胞白血病、髓性白血病、中枢神经系统淋巴瘤、脑膜瘤、脊髓肿瘤、非小细胞肺癌、卵巢癌、皮肤癌、肾细胞癌、星状细胞瘤、淀粉样变性、I型复杂性局部疼痛综合征、恶性黑色素瘤、神经根病、成胶质细胞瘤、胶质肉瘤、恶性胶质瘤、难治性浆细胞瘤、眼外延伸黑色素瘤、乳头状和滤泡状甲状腺癌、乳腺癌、前列腺癌、结直肠癌、卵巢癌、子宫内膜癌、宫颈癌、肝细胞癌、胃癌、食道癌、膀胱癌、小细胞肺癌、非小细胞肺癌、尤文肉瘤、胶质母细胞瘤、或原发性巨球蛋白血症。
此外，本发明还提供了如本发明第一方面所述的化合物以及其互变异构体、立体异构体、同位素化合物、可药用的盐、酯、前药或其水合物在制备CDK或Cyclin K抑制剂中的用途。
在另一优选例中，所述CDK选自：CDK2、CDK9、CDK12，或其组合。
本发明还提供了预防和/或治疗与CDK或Cyclin K异常活性相关的疾病或者症状的方法，包括步骤，对有需要的对象施用如本发明第一方面所述的化合物以及其互变异构体、立体异构体、同位素化合物、可药用的盐、酯、前药或其水合物或如如本发明第二方面所述的药物组合物。
在另一优选例中，所述对象为人或非人哺乳动物，如大鼠、小鼠。
本发明也包含这里公布的任何一种新的中间体。
本发明另一方面，提供了一种制备如本发明第一方面所述的化合物的方法，所述方法选自如下方法之一：
合成方法一：
步骤1-1：化合物1A和Boc酸酐反应得到化合物1B；
步骤1-2：化合物1B与雷尼镍氢化反应得到化合物1C；
步骤1-3：化合物1C和化合物1D在三氯氧磷和N,N-二甲基苯甲胺的条件下得到卤代物，在碱条件下亲核取代得到化合物1E；
步骤1-4：化合物1E和化合物1F在钠氢和无水N,N-二甲基甲酰胺条件下反应得到化合物1H；
步骤1-5：化合物1E和化合物1G在1-甲基-2-吡咯烷酮条件下反应得到化合物1J；
步骤1-6：化合物1H在盐酸二氧六环的条件下反应得到化合物1I。
步骤1-7：化合物1J在盐酸二氧六环的条件下反应得到化合物1K。
R1与本发明第一方面的定义相同；
合成方法二：
步骤2-1：化合物2A与化合物2B在HATU和DIPEA存在的条件下反应得到化合物2C；
步骤2-2：化合物2C在盐酸二氧六环的条件下反应得到化合物2D；
步骤2-3：化合物2D和化合物1D在三氯氧磷和N,N-二甲基苯甲胺的条件下得到卤代物，在碱条件下亲核取代得到化合物2E；
步骤2-4：化合物2E和化合物2F在钠氢和无水N,N-二甲基甲酰胺条件下反应得到化合物2I；
步骤2-5：化合物2E和化合物2G在1-甲基-2-吡咯烷酮条件下反应得到化合物2J；
步骤2-6：化合物2E和化合物2H在1-甲基-2-吡咯烷酮条件下反应得到化合物2K。
R3选自-CH3、-CH2CH3、
R1与本发明第一方面的定义相同；
合成方法三：
步骤3-1：化合物3A和化合物1D在三氯氧磷和N,N-二甲基苯甲胺的条件下得到卤代物，在碱条件下亲核取代得到化合物3C；
步骤3-2：化合物3B和化合物1D在三氯氧磷和N,N-二甲基苯甲胺的条件下得到卤代物，在碱条件下亲核取代得到化合物3D；
步骤3-3：化合物3C和化合物3E在1-甲基-2-吡咯烷酮条件下反应得到化合物3F；
步骤3-4：化合物3D和化合物3E在1-甲基-2-吡咯烷酮条件下反应得到化合物3G；
步骤3-5：化合物3F在盐酸二氧六环的条件下反应得到化合物3H；
步骤3-6：化合物3G在盐酸二氧六环的条件下反应得到化合物3I；
R1与本发明第一方面的定义相同；
合成方法四：
步骤4-1：化合物4A和化合物1C在N,N-二异丙基乙胺和乙醇的条件下反应得到化合物4B；
步骤4-2：化合物4A和化合物2D在N,N-二异丙基乙胺和乙醇的条件下反应得到化合物4C；
步骤4-3：化合物4B和Boc酸酐反应得到化合物4D；
步骤4-4：化合物4C和Boc酸酐反应得到化合物4E；
步骤4-5：化合物4D和化合物4F在1-甲基-2-吡咯烷酮条件下反应得到化合物4G；
步骤4-6：化合物4E和化合物4F在1-甲基-2-吡咯烷酮条件下反应得到化合物4H；
步骤4-7：化合物4G在盐酸二氧六环的条件下反应得到化合物4I；
步骤4-8：化合物4H在盐酸二氧六环的条件下反应得到化合物4J；
R1与本发明第一方面的定义相同。
应理解在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。上述说明，并不意味着以任何形式限制本发明的方面。
附图说明
图1为显示本发明部分化合物降解Cyclin K活性的蛋白印迹实验结果。
具体实施方式
本发明人经过广泛而深入的研究，通过大量筛选和测试，提供了一类结构新颖、抗肿瘤活性优异的CDK抑制剂化合物。
术语
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH2O-等同于-OCH2-。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
通式(I)所示的化合物可以含有一个或多个不对称或手性中心，因此可以以不同立体异构体形式存在。本发明化合物包括所有立体异构体形式，包括但不限于非对映异构体、对映异构体和阻转异构体以及它们的混合物(如外消旋体)，均包括在本发明的范围内。
术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中有相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个任意取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取代基，例如杂环烷基，可以与另一个环相连，例如环烷基，从而形成螺二环系，例如，两个环共用一个碳原子。如未特别说明，取代可以指基团被选自以下一个或多个基团所取代：氢、卤素、氰基、硝基、羟基、羧基、4-10元杂环基、C1-C6烷基、C1-C6烷氧基、卤素取代C1-C6的烷基、卤素取代C1-C6的烷氧基、C2-C6烯基、C3-C8杂环基氧基、C3-C8环烷基氧基、羟基取代的C1-C6烷氧基、和C1-C6烷氧基取代的C1-C6烷氧基。
本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。本发明中相关结构上的取代，包括取代和未取代，如“可选地”被某种 取代基取代，是指包括被某种取代基取代或者未取代的含义。
本发明中提到的当取代基数>1时，R取代基可以为相同或不同的取代基，指当某一种结构中取代基数为多个时，R的取代基组合可以为选自多种不同类型的取代基。
术语“取代”只适用于能够被取代基所取代的位点，不包括在现有的化学知识上不能实现的取代。
通式(I)所示的化合物还可以以不同互变异构体形式存在，所有这些形式均包括在本发明范围内。
术语“互变异构体”是指经由低能垒相互转化的具有不同能量的构造异构体，反应一般导致伴随单键和相邻双键转变的氢原子或质子的形式移动。
术语“立体异构体”包括对映体、非对映体，或它们的混合物，如消旋体。术语“对映体”是指互为镜像而不可重叠的立体异构体。
“非对映体”是指具有两个或者两个以上的手性中性，并且不成镜像的立体异构体。
“消旋体”是指两个互为镜像的立体异构体，旋光性相反，互相抵消了旋光性。
“可药用的盐”是指药物分子与对应的有机酸、无机酸或者有机碱、无机碱形成相应的盐的，例如盐酸、甲酸、三氟乙酸、琥珀酸、甲磺酸盐等。
“前药”是指在体外无活性或者活性较小，在体内经过酶或者非酶的转化释放出活性药物而发挥药效的一类化合物。
“水合物”是指含有水的化合物。
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢，碳，氮，氧，磷，硫，氟和氯同位素，分别如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如3H和14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即3H和碳-14，即14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。优选地同位素化合物为氘代化合物，更优选地，所述同位素化合物中有一个或多个碳上的H被氘取代。
术语“多个”指2个或以上，如2、3、4、5或6个。
术语“卤素”包括氟、氯、溴或碘。
术语“烃基”是指只含有碳原子和氢原子的取代基，非限制性地包括甲基、乙基、异丙基、丙基、环己基、苯基等。
术语“C1-C6烷基”是指链上具有1至6个碳原子的直链或支链饱和烃基，如包含1、2、3、4、5或6个碳原子的烷基，本文中使用的烷基或其作为其他基团的一部分具有1至6个碳原子(即，C1-C6烷基)、或者1至3个碳原子(即，C1-3烷基)，非限制性地包括 甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基等。
术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。
术语“C1-C6烷氧基羰基”非限制性地包括甲氧基羰基、乙氧基羰基、丙氧基羰基、异丙氧基羰基、丁氧基羰基、异丁氧基羰基、仲丁氧基羰基、叔丁氧基羰基、戊氧基羰基和已氧基羰基等。
术语“环烷基”是指饱和或部分不饱和单环或者多环环状烃取代基。如“C3-C8环烷基”是指在环上具有3至8个碳原子的环状烷基，单环环烷基非限制性包括环丙基、环丁基、环戊烯基、环己基。多环环烷基包括螺环、稠环和桥环的环烷基。
术语“杂环基”是指含有一个或多个饱和和/或部分饱和单环或者多环环状取代基，其中一个或多个环原子选自氮、氧、硫、氧代(＝O)或S(O)m(其中m是0至2的整数)的杂原子，其余环原子为碳；杂环基可以包括3-8元杂环基,优选地为5-6元杂环基，例如，环氧丙烷、四氢呋喃基、吡咯烷基、四氢吡喃基、哌啶基、哌嗪基、吗啉基、硫代吗啉基；杂环基可以稠合与芳基、杂芳基、或环烷基环上，与母体结构连接在一起的环为杂环基。杂环基包括螺环、稠环和桥环的杂环基。
术语“芳基”是指具有共轭的p电子体系的6-14元全碳单环或稠合多环基团，优选为6至10元环，优选为6至10元，更优选苯基和萘基，最优选苯基。所述芳基环可以稠合与杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环。
术语“杂芳基”是指具有1至4(如2、3)个杂原子作为环原子，其余的环原子为碳的5-14元芳基，其中杂原子包括氧、硫和氮。优选为5-10元。杂芳基优选为5元或6元，如噻吩基、吡啶基、吡咯基等。所述杂芳基环可以稠合与芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，
术语“螺杂环基”是指单环之间共用一个原子(称为螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧，硫或者S(O)m(其中m是0至2的整数)的杂原子，其余环原子为碳。螺杂环可以稠合与6-10元芳基或5-10元杂芳基环上，其中与母体结构连接在一起的环为螺杂环。
术语“卤素取代烷基”是指由单个或者多个卤素取代的直链、支链或者环状烷基，非限制性地包括2-溴乙基、2-溴丙基等。
术语“烯基”是指可以为2-10个碳的烯基，如乙烯基、丙烯基、丁烯基、苯乙烯基、苯丙烯基。
术语“炔基”是指可以为2-10个碳的炔基，如乙炔基、丙炔基、丁炔基、苯乙炔基、苯丙烯基。
术语“羟基取代烷基”是指由单个或者多个羟基取代的直链、支链或者环状烷基，非限制性地包括(S)-1-羟基异丁-2-基、(R)-1-羟基异丁-2-基等。
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
本发明也包含这里公布的任何一种新的中间体。
术语“预防”是指获得或发生疾病或障碍的风险降低。
术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的 一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，⑶改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或⑷减缓病症或者病症的一种或多种生物学表现发展。
本发明提供了一种结构如式(I)的化合物或结晶水合物及溶剂合物，在制备用于预防和/或治疗与CDK的异常活性相关的疾病或者症状的药物中的用途。
本发明化合物中含有碱性基团时可以制备成药学上可接受的盐，包括无机酸盐和有机酸盐。适合形成盐的酸包括(但并不限于)：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸、苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸等。
本发明的一个方面是提供了一种药物组合物，其包括治疗有效量的通式(I)所示的化合物，及其立体异构体、其可药用盐、前药、溶剂化物、水合物和晶型中的一种或多种，以及至少一种赋形剂、稀释剂或载剂。
典型的配方是通过混合本发明的通式(I)所示的化合物及载体、稀释剂或赋形剂制备而成。适宜的载体、稀释剂或赋形剂是本领域技术人员所熟知的，包括诸如碳水化合物、蜡、水溶性及/或可膨胀性聚合物、亲水性或疏水性物质、明胶、油、溶剂、水等物质。
所用的特定载体、稀释剂或赋形剂，将根据本发明的化合物的使用方式和目的而定。一般以本领域技术人员认为可安全有效地给药至哺乳类动物的溶剂为基础而选择溶剂。一般而言，安全的溶剂是无毒性含水溶剂诸如制药用水，以及其他可溶于水或与水混溶的无毒性溶剂。适宜的含水溶剂包括水、乙醇、丙二醇、聚乙二醇(如PEG400、PEG300)等中的一种或多种。该配方也可包括一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂，使式(I)表示的化合物以可被接受的形式制造或使用。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂，该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
本发明如式(I)的化合物与至少一种其它药物组合使用时，两种药物或多种药物可以分开使用也可以组合使用，优选以药学组合物的形式给药。本发明的如式(I)的化合物或药物组合物能以任一已知的口服、静脉注射、直肠给药、阴道给药、透皮吸收、其它局部或全身给药形式，分开或一起给药至受试者。
这些药物组合物亦可含有一种或多种缓冲剂、安定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、增甜剂、香料剂、调味剂或其它已知的添加剂，使该药物组合物以可被接受的形式制造或使用。
本发明药物优选口服给药途径。用于口服给药的固态剂型可包括胶囊、片剂、粉 末或颗粒制剂。在固态剂型中，本发明的化合物或药物组合物与至少一种惰性赋形剂、稀释剂或载剂混合。适宜的赋形剂、稀释剂或载剂包括诸如柠檬酸钠或磷酸二钙的物质，或淀粉、乳糖、蔗糖、甘露糖醇、硅酸等；粘合剂如羧甲基纤维素、褐藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖、阿拉伯胶等；湿润剂如甘油等；崩解剂如琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、特定的络合硅酸盐、碳酸钠等；溶液阻滞剂如石蜡等；吸收促进剂如季铵化合物等；吸附剂如高岭土、膨润土等；润滑剂如滑石、硬脂酸钙、硬脂酸镁、固态聚乙二醇、月桂基硫酸钠等。在胶囊与片剂的情况下，该剂型亦可包括缓冲剂。类似类型的固态组合物亦可作为软式与硬式填充明胶胶囊中的填料，其使用乳糖以及高分子量聚乙二醇等作为赋形剂。
用于口服给药的液态剂型包括药学上可接受的乳化液、溶液、悬浮液、糖浆液与酏剂。除了本发明的化合物或其组合物之外，该液态剂型可含有本领域中常用的惰性稀释剂，诸如水或其他溶剂；增溶剂及乳化剂诸如乙醇、异丙基醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄基酯、丙二醇、1,3-丁二醇、二甲基甲酰胺；油类(如棉籽油、落花生油、玉米胚芽油、橄榄油、蓖麻油、芝麻油等)；甘油；四氢糠基醇；聚乙二醇与脱水山梨糖醇的脂肪酸酯；或这些物质中的几种的混合物等。
除了这些惰性稀释剂之外，该组合物也可包括赋形剂，诸如润湿剂、乳化剂、悬浮剂、增甜剂、调味剂与香料剂中的一种或多种。
就悬浮液而言，除了本发明的化合物或组合之外，可进一步含有载剂诸如悬浮剂，如乙氧基化异硬脂醇、聚氧乙烯山梨醣醇、脱水山梨醣醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂及黄耆胶，或这些物质中几种的混合物等。
用于直肠或阴道投药之组合物优选栓剂，可通过将本发明的化合物或组合与适宜的非刺激性赋形剂或载剂混合而制备，赋形剂或载剂诸如可可豆脂、聚乙二醇或栓剂蜡，其在一般室温为固态而在体温为液态，可在直肠或阴道中熔化而释出活性化合物。
本发明化合物或药物组合物可采用其它局部给药剂型给药，包括膏、粉末、喷剂及吸入剂。该药物可在无菌条件下与药学上可接受的赋形剂、稀释剂或载剂以及所需要的任一防腐剂、缓冲剂或推进剂混合。眼用配方、眼用油膏、粉末与溶液，亦意欲涵盖于本发明的范围内。
本发明的又一个方面提供了通式(I)所示的化合物以及其互变异构体、对映体、非对映体、消旋体、可药用的盐或上述的药物组合物在制备用于预防和/或治疗与CDK的异常活性相关的疾病或者症状的药物中的用途。
所述的与CDK异常活性相关的疾病包括乳腺癌、结肠癌、前列腺癌、小细胞肺癌、非小细胞肺癌等实体肿瘤，以及急性淋巴细胞白血病、急性淋巴球白血病、细胞淋巴瘤、细胞淋巴瘤、骨髓瘤、急性和慢性髓细胞性白血病、早幼粒细胞性白血病等血液肿瘤。
本发明又一个方面还提供了通式(I)所示的化合物以及其互变异构体、对映体、非对映体、消旋体、可药用的盐或上述的药物组合物在制备用于治疗肿瘤、中枢系统疾病和免疫性疾病等疾病的药物的用途。
在一优选实施例中，所述的疾病包括，但不限于：癌症、与血管生成相关的疾病或功能紊乱、疼痛(包括但不限于复杂性局部疼痛综合症)、黄斑退化及相关功能紊乱、皮肤疾病、肺部功能紊乱、免疫缺陷型疾病、中枢神经系统的损伤及功能紊乱、TNFα相关的疾病或功能紊乱。
在另一优选实施例中，所述的癌症包括(但不限于)：所述的疾病为实体瘤、血液瘤，优选地，所述的疾病选自：骨髓增生异常综合征、多发性骨髓瘤、套细胞淋巴瘤、非霍奇金淋巴瘤、慢性淋巴细胞白血病、慢性粒单核细胞白血病、骨髓纤维化、伯基特淋巴瘤、霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、睫状体和慢性黑色素瘤、虹膜黑色素瘤、复发性两眼间黑色素瘤、T细胞淋巴瘤、红系淋巴瘤、成单核细胞和单核细胞白血病、髓性白血病、中枢神经系统淋巴瘤、脑膜瘤、脊髓肿瘤、非小细胞肺癌、卵巢癌、皮肤癌、肾细胞癌、星状细胞瘤、淀粉样变性、I型复杂性局部疼痛综合征、恶性黑色素瘤、神经根病、成胶质细胞瘤、胶质肉瘤、恶性胶质瘤、难治性浆细胞瘤、眼外延伸黑色素瘤、乳头状和滤泡状甲状腺癌、乳腺癌、前列腺癌、结直肠癌、卵巢癌、子宫内膜癌、宫颈癌、肝细胞癌、胃癌、食道癌、膀胱癌、小细胞肺癌、非小细胞肺癌、尤文肉瘤、胶质母细胞瘤、胰腺癌或原发性巨球蛋白血症。
本发明所提供的化合物同样对血液瘤和骨髓瘤有效，如能用于治疗多发性骨髓瘤和急慢性白血病。本发明所提供的化合物能用于预防或治疗原发肿瘤和转移性肿瘤。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。
本发明主要优点：
1、本发明中的化合物具有优异的癌细胞抑制活性，尤其是对三阴性乳腺癌细胞细胞的抑制活性，优于临床在研药物，可用于多种恶性肿瘤的治疗。
2、本发明的化合物用作CDK激酶抑制剂，优选地对CDK9的抑制具有很好的选择性和激酶活性。
3、本发明的化合物除了具有CDK激酶的抑制活性外，还意外发现部分化合物可以作为Cyclin K的降解剂，在肿瘤细胞中具有很好的降解效果。
4、本发明的化合物具有优异的药代动力学性质。
具体实施方法
下面结合具体实施例，进一步阐述本发明，但这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
所有实施例中，1H NMR谱测试仪器为400MHz Bruker和500MHz Bruker核磁共振仪，化学位移以δ(ppm)表示；质谱由MS质谱UPLC-MS(ESI)测定；其中UPLC型号是Waters HPLC H-CLASS，MS(ESI)的型号是Waters SQ Detector 2；无水四氢呋喃由二苯甲酮/金属钠回流干燥除氧制得，无水甲苯和无水二氯甲烷由氯化钙回流干燥制得；石油醚、乙酸乙酯、二氯甲烷等用于柱层析流动相的溶剂均购置于国药集团化学试剂有限公司；反 应检测中使用的薄层层析硅胶板(HSGF254)来自国药集团化学试剂有限公司；化合物分离选用国药集团化学试剂有限公司的200-300目硅胶。本发明中原料可以从商业途径获得，如主要试剂购买于国药集团化学试剂有限公司，或者通过本领域抑制的方法制备，或者根据本发明中所述方法制备。
EtOH：乙醇；DCM：二氯甲烷；ACN：乙腈；TFA：三氟乙酸；TEA：三乙胺；1,4-dioxane：1，4-二氧六环；NaH：氢化钠；H2O：水；HATU：2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯；DMF：N,N-二甲基甲酰胺；THF：四氢呋喃；DIPEA：N,N-二异丙基乙胺；AcOH：醋酸；Raney Ni：雷尼镍；TBSCl：叔丁基二甲基氯硅烷；imidazole：咪唑；NMP：N-甲基吡咯烷酮；EA：乙酸乙酯；DMAP：4-二甲氨基吡啶；(Boc)2O：二碳酸二叔丁酯；NaCl：氯化钠；Na2SO4：硫酸钠；POCl3：三氯氧磷；PhNMe2：N,N-二甲基苯胺；DMSO：二甲亚砜；N2：氮气；toluene：甲苯；Pd2(dba)3：三(二亚苄基丙酮)二钯；rac-BINAP：1,1’-联萘-2,2’-双二苯膦；Cs2CO3：碳酸铯；NaOH：氢氧化钠。
一、制备实施例
[Control compound]N-苄基-8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-a][1,3,5]三嗪-4-胺
参考化合物1.6的合成路线，将化合物1.2换成苯甲胺，制备得化合物Control compound。
实施例1
[C1]N-(4-氨基苄基)-8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-a][1,3,5]三嗪-4-胺
将对氰基苯胺(10g,84.65mmol,1.0equiv)和4-二甲氨基吡啶(2.07g,16.93mmol,0.2equiv)溶于二氯甲烷，冷却至0℃，加入二碳酸二叔丁酯(19.45mL,84.65mmol,1.0equiv)，升至室温反应4h。反应完全，加入二氯甲烷稀释反应液，用饱和氯化钠 水溶液洗涤3次，合并有机层，加入无水硫酸钠干燥，经过滤旋干后，柱层析得白色固体1.1(14.31g)，收率77％。1H 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)。
化合物1.1(14.31g,65.56mmol,1.0equiv)溶于氨甲醇，加入两管雷尼镍，抽换氮气3次，抽换氢气3次，在室温下反应4h后，反应完成，加入甲醇稀释反应液，经硅藻土过滤，旋干得产物1.2(14.28g)，收率98％。1H 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)。
化合物1.3(200mg,0.78mmol,1.0equiv)溶于4mL三氯氧磷，加入N,N-二甲基苯甲胺(297μL,2.34mmol,3.0equiv)，在100℃下反应2小时。反应结束后，冷却至室温，减压除去溶剂，残留物溶于4mL乙腈。化合物1.2(209mg,0.94mmol,1.2equiv)溶于6mL乙腈，加入上一步乙腈溶液和N,N-二甲基苯甲胺(258μL,1.56mmol,2.0equiv)，升温至50℃反应12h。反应结束后，冷却至室温，用150mL乙酸乙酯萃取3次，用饱和NaCl水溶液洗涤3次，无水硫酸钠干燥。过滤，除去乙酸乙酯，经柱层析得到化合物1.4(280mg)，收率78％。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.30(s,1H),8.28–8.24(m,1H),7.39(d,J＝8.4Hz,2H),7.31(d,J＝8.6Hz,2H),4.66(d,2H),3.27(s,3H),3.18–3.15(m,1H),1.45(s,9H),1.30(d,J＝7.0Hz,6H)。
1-甲基-4-哌啶醇(248mg,2.15mmol,5.0equiv)溶于2mL无水N,N-二甲基甲酰胺中，0℃下加入60％(w/w)钠氢(86mg,2.15mmol,5.0equiv)，加入化合物1.4(200mg,0.43mmol,1.0equiv)的2mL无水N,N-二甲基甲酰胺溶液，加热至50℃，反应3h。反应结束后，冷却至室温，加水淬灭反应，加入乙酸乙酯稀释，用饱和氯化钠水溶液洗涤，合并有机相，无水硫酸钠干燥。过滤，旋干，柱层析得化合物1.6(132mg)，收率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)。
化合物1.6(132mg,0.27mmol,1.0equiv)溶于4mL二氯甲烷，加入2mL三氟乙酸，室温下搅拌1h，旋干，经HPLC纯化得化合物C1(107mg)，收率99％。1H 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＝12.8,4.1Hz,1H),1.80–1.74(m,1H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C21H29N7O[M+H]+:396.24，实测值为396.33。
实施例2
[C38](S)-2-((4-((4-氨基苄基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-2-基)氨基)丁-1-醇
化合物1.4(30mg,0.065mmol,1.0equiv)溶于2mL 1-甲基-2-吡咯烷酮中，加入(S)-(+)-2-氨基-1-丁醇(25μL,0.26mmol,4.0equiv)，升温至120℃，反应5h。反应结束后，冷却至室温，加入60mL乙酸乙酯萃取，用饱和氯化钠水溶液洗涤，合并有机相，加入无水硫酸钠干燥。过滤，旋干，柱层析得到化合物2.2(22mg)，收率71％。1H 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)。
化合物2.2(22mg,0.047mmol,1.0equiv)溶于2mL二氯甲烷，加入1mL三氟乙酸，室温下搅拌1h，旋干，经HPLC纯化得化合物C38(19mg)，收率99％。1H NMR(400MHz,Methanol-d4)δ7.89(s,1H),7.54(d,J＝8.5Hz,2H),7.30(d,J＝8.5Hz,2H),4.85–4.78(m,2H),4.16–4.07(m,1H),3.63(d,J＝5.2Hz,2H),3.06–2.97(m,1H),1.72(ddd,J＝13.5,7.5,5.8Hz,1H),1.59(dt,J＝14.4,7.4Hz,1H),1.29(d,J＝7.0Hz,6H),0.94(t,J＝7.4Hz,3H).UPLC-MS(ESI)理论值为C19H27N7O[M+H]+:370.23，实测值为370.32。
实施例3
[C2]N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
4-(N-Boc-氨基甲基)苯胺(3g,13.50mmol,1.0equiv)溶于无水DMF中，加入乙酸(927μL,16.20mmol,1.2equiv)、DIPEA(23.5mL,135.0mmol,10.0equiv)，室温反应1h，加入乙酸乙酯稀释，用饱和氯化钠水溶液洗涤，合并有机相，无水硫酸钠干燥。过滤，旋干，柱层析得白色固体3.1(3.25g)，收率91％。1H 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)。
化合物3.1(3.25g,12.29mmol,1.0equiv)溶于20mL二氯甲烷，加入10mL三氟乙酸，室温下搅拌1h，旋干，经HPLC纯化得化合物3.2(1.92g)，收率95％。1H NMR(400MHz,DMSO-d6)δ10.05(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)。
以化合物3.2为原料，参照化合物1.6的合成，制备得化合物C2，收率62％。1HNMR(500MHz,Methanol-d4)δ7.84(s,1H),7.51(d,J＝8.5Hz,2H),7.34(d,J＝8.6Hz,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＝9.3,3.8Hz,2H),1.29(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C23H31N7O2[M+H]+:438.25，实测值为438.34。
[C41]N-(4-(((8-异丙基-2-(哌啶-4-基氨基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物3.3为原料，参照化合物C38的合成路线，将(S)-(+)-2-氨基-1-丁醇换成1-叔丁氧羰基-4-氨基哌啶，制备得C41，收率37％。1H NMR(500MHz,Methanol-d4)δ7.87(s,1H),7.52(d,J＝8.5Hz,2H),7.36(d,J＝8.6Hz,2H),4.76(s,2H),4.18(t,J＝4.4Hz,1H),3.43(dt,J＝13.3,3.7Hz,2H),3.19–3.10(m,2H),3.09–3.01(m,1H),2.11(s,5H),1.82–1.71(m,2H),1.28(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C22H30N8O[M+H]+:423.25，实测值为423.40。
[C42]N-(4-(((8-异丙基-2-(哌啶-3-基氨基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物3.3为原料，参照化合物C38的合成路线，将(S)-(+)-2-氨基-1-丁醇换成1-叔丁氧羰基-3-氨基哌啶，制备得C42，收率35％。1H NMR(500MHz,Methanol-d4)δ7.89(s,1H),7.52(d,J＝8.5Hz,2H),7.37(d,J＝8.3Hz,2H),4.79(s,2H),4.30–4.25(m,1H),3.41–3.33(m,1H),3.30–3.26(m,1H),3.11–3.05(m,1H),3.03–2.93(m,2H),2.11(s,3H),2.10–2.01(m,2H),1.83(dtd,J＝14.1,7.1,3.5Hz,1H),1.77–1.70(m,1H),1.28(d,J＝7.0Hz,6H).UPLC-MS(ESI)理论值为C22H30N8O[M+H]+:423.25，实测值为423.40。
[C43](R)-N-(4-(((2-(2-(羟甲基)吡咯烷-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物3.3为原料，参照化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成D-脯氨醇，制备得C43，收率25％。1H NMR(500MHz,Methanol-d4)δ7.88(s,1H),7.53(d,J＝8.6Hz,2H),7.38(d,J＝8.1Hz,2H),4.76(s,2H),4.27–4.18(m,1H),4.11–4.01(m,1H),3.94–3.86(m,1H),3.72(dt,J＝11.8,3.8Hz,2H),3.02–2.88(m,1H),2.30–2.23(m,1H),2.11(s,3H),2.00(dq,J＝13.7,7.0Hz,2H),1.90–1.79(m,1H),1.29(d,J＝6.8Hz,6H).UPLC-MS(ESI)理论值为C22H29N7O2[M+H]+:424.24，实测值为424.36。
[C44](S)-N-(4-(((2-(2-(羟甲基)吡咯烷-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物3.3为原料，参照化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成L-脯氨醇，制备得C44，收率29％。1H NMR(500MHz,Methanol-d4)δ7.88(s,1H),7.54(d,J＝8.6Hz,2H),7.39(d,J＝8.2Hz,2H),4.77(s,2H),4.26–4.18(m,1H),4.07(dt,J＝13.2,7.0Hz,1H),3.91(d,J＝11.3Hz,1H),3.72(dt,J＝12.3,6.5Hz,2H),2.95(q,J＝6.9Hz,1H),2.28(dd,J＝13.3,7.3Hz,1H),2.11(s,3H),2.00(dq,J＝13.5,7.3,6.7Hz,2H),1.90–1.80(m,1H),1.29(d,J＝6.6Hz,6H).UPLC-MS(ESI)理论值为C22H29N7O2[M+H]+:424.24，实测值为424.39。
[C45](R)-N-(4-(((2-(3-羟基哌啶-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物3.3为原料，参照化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成(R)-3-哌啶醇，制备得C45，收率36％。1H NMR(500MHz,Methanol-d4)δ7.88(s,1H),7.53(d,J＝8.5Hz,2H),7.38(d,J＝8.6Hz,2H),4.74(d,J＝3.6Hz,2H),4.21–4.08(m,1H),3.97–3.91(m,1H),3.83(td,J＝7.4,6.7,3.0Hz,1H),3.71(dd,J＝15.9,7.0Hz,1H),3.59(dd,J＝13.3,7.1Hz,1H),3.19–3.14(m,1H),2.11(s,3H),2.02–1.98(m,1H),1.96–1.90(m,1H),1.70–1.59(m,2H),1.28(dd,J＝6.9,3.5Hz,6H).UPLC-MS(ESI)理论值为C22H29N7O2[M+H]+:424.24，实测值为424.46。
[C46](S)-N-(4-(((2-(3-羟基哌啶-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物3.3为原料，参照化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成(S)-3-哌啶醇，制备得C46，收率38％。1H NMR(500MHz,Methanol-d4)δ7.89(s,1H),7.55(d,J＝8.5Hz,2H),7.40(d,J＝8.6Hz,2H),4.76(d,J＝3.4Hz,2H),4.20(dd,J＝11.9,5.2Hz,1H),4.01–3.96(m,1H),3.83(dt,J＝7.4,3.8Hz,1H),3.69(dd,J＝15.5,7.5Hz,1H),3.58(dd,J＝13.2,7.3Hz,1H),3.18(p,J＝6.8Hz,1H),2.13(s,3H),2.05–1.99(m,1H),1.94(ddd,J＝13.5,7.0,3.7Hz,1H),1.71–1.61(m,2H),1.30(dd,J＝6.9,3.3Hz,6H).UPLC-MS(ESI)理论值为C22H29N7O2[M+H]+:424.24，实测值为424.39。
[C47](S)-N-(4-(((2-((1-羟基丁-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基甲基)苯基)乙酰胺
以化合物3.3为原料，参照化合物2.2的合成路线，制备得C47，收率66％。1H NMR(500MHz,Methanol-d4)δ7.88(s,1H),7.54(d,J＝8.6Hz,2H),7.37(d,J＝8.6Hz,2H),4.76(d,J＝16.7Hz,2H),4.16–4.09(m,1H),3.65(d,J＝4.9Hz,2H),3.03–2.95(m,1H),2.11(s,3H),1.75–1.69(m,1H),1.60(dd,J＝14.3,7.3Hz,1H),1.29(d,J＝6.9Hz,6H),0.95(d,J＝7.5Hz,3H).UPLC-MS(ESI)理论值为C21H29N7O2[M+H]+:412.24，实测值为412.89。
[C48](R)-N-(4-(((2-((1-羟基丁-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基甲基)苯基)乙酰胺
以化合物3.3为原料，参照化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成(R)-(-)-2-氨基-1-丁醇，制备得C48，收率64％。1H NMR(500MHz,Methanol-d4)δ7.88(s,1H),7.54(d,J＝8.6Hz,2H),7.37(d,J＝8.5Hz,2H),4.76(d,J＝16.9Hz,2H),4.16–4.11(m,1H),3.68–3.64(m,2H),3.01–2.96(m,1H),2.11(s,3H),1.75–1.69(m,1H),1.63–1.59(m,1H),1.30(d,J＝6.9Hz,6H),0.96(t,J＝6.8Hz,3H).UPLC-MS(ESI)理论值为C21H29N7O2[M+H]+:412.24，实测值为412.44。
[C49](S)-N-(4-(((8-异丙基-2-(哌啶-3-基氧基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物3.3为原料，参照化合物1.6的合成路线，将1-甲基-4-哌啶醇换成(R)-3-羟基哌啶，制备得C49。
[C50](R)-N-(4-(((8-异丙基-2-(哌啶-3-基氧基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物3.3为原料，参照化合物1.6的合成路线线，将1-甲基-4-哌啶醇换成(S)-3-羟基哌啶，制备得C50。
[C51]N-(4-(((8-异丙基-2-(氧杂环丁烷-3-基氨基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物3.3为原料，参照化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成换成3-氧杂环丁胺，制备得C51，收率29％。1H NMR(500MHz,
Methanol-d4)δ7.86(s,1H),7.54(d,J＝8.6Hz,2H),7.36(d,J＝8.6Hz,2H),5.12–5.07(m,1H),4.91–4.90(m,1H),4.75(d,J＝4.2Hz,2H),4.67–4.63(m,2H),3.81–3.65(m,1H),3.04(p,J＝6.9Hz,1H),2.11(s,3H),1.29(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C20H25N7O2[M+H]+:396.21，实测值为396.74。
[C52]N-(4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物3.3为原料，参照化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成4-氨基四氢吡喃，制备得C52，收率64％。1H NMR(500MHz,Methanol-d4)δ7.89(s,1H),7.53(d,J＝8.2Hz,2H),7.36(d,J＝8.2Hz,2H),4.75(s,2H),4.15–4.09(m,1H),3.96(d,J＝11.1Hz,2H),3.51(t,J＝11.4Hz,2H),3.06–2.95(m,1H),2.11(s,3H),1.89–1.82(m,2H),1.64–1.57(m,2H),1.29(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C22H29N7O2[M+H]+:424.24，实测值为424.81。
[C53]N-(4-(((2-((1,3-二羟基丙-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基甲 基)苯基)乙酰胺
以化合物3.3为原料，参照化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成2-氨基-1,3-丙二醇，制备得C53，收率54％。1H NMR(500MHz,Methanol-d4)δ7.87(s,1H),7.53(d,J＝8.5Hz,2H),7.39(d,J＝8.2Hz,2H),4.77(s,2H),4.31–4.21(m,1H),3.78–3.73(m,4H),3.01–2.95(m,1H),2.11(s,3H),1.29(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C20H27N7O3[M+H]+:414.22，实测值为414.78。
[C54]N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氨基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物3.3为原料，参照化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成4-氨基-1-甲基哌啶，制备得C54，收率53％。1H NMR(500MHz,Methanol-d4)δ7.89(s,1H),7.52(d,J＝8.6Hz,2H),7.36(d,J＝8.4Hz,2H),4.77(s,2H),4.17–4.08(m,1H),3.58–3.53(m,2H),3.16–3.10(m,2H),3.06(q,J＝7.0Hz,1H),2.91(s,3H),2.12(s,3H),2.08–1.96(m,1H),1.81–1.70(m,2H),1.28(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C23H32N8O[M+H]+:437.27，实测值为437.41。
[C128](R)-N-(4-(((2-(3-羟基吡咯烷-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物3.3为原料，参照化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成(R)-3-吡咯烷醇，制备得C128，收率62％。1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),9.38(s,1H),7.87(s,1H),7.57–7.46(m,2H),7.33(d,J＝8.4Hz,2H),4.56(d,J＝6.2Hz,2H),4.38(s,1H),3.65–3.40(m,4H),3.06(q,J＝6.8Hz,1H),2.01(s,3H),1.94(d,J＝37.6Hz,2H),1.21(dd,J＝6.9,1.9Hz,6H).UPLC-MS(ESI)理论值为C21H27N7O2[M+H]+:410.49，实测值为410.47。
[C129](S)-N-(4-(((2-(3-羟基吡咯烷-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物3.3为原料，参照化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成(S)-3-吡咯烷醇，制备得C129，收率56％。1H NMR(600MHz,DMSO-d6)δ9.93(s,1H),9.53(s,1H),7.91(s,1H),7.51(d,J＝8.2Hz,2H),7.33(d,J＝8.1Hz,2H),4.57(d,J＝6.2Hz,2H),4.39(d,J＝21.8Hz,1H),3.79–3.40(m,4H),3.11(dd,J＝13.7,7.0Hz,1H),2.01(s,3H),1.90(s,2H),1.21(dd,J＝7.0,3.2Hz,6H).UPLC-MS(ESI)理论值为C21H27N7O2[M+H]+:410.49，实测值为410.47。
[C130](S)-N-(4-(((2-(2-(2-羟乙基)哌啶-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物3.3为原料，参照化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成(S)-2-(2-哌啶基)乙醇，制备得C130，收率47％。1H NMR(500MHz,DMSO-d6)δ9.91(s,1H),9.22(s,1H),7.82(s,1H),7.51(d,J＝8.3Hz,2H),7.32(d,J＝8.2Hz,2H),4.93(s,1H),4.55(d,J＝6.3Hz,3H),3.38(dq,J＝15.1,7.6,6.4Hz,2H),2.94(dd,J＝16.4,10.0Hz,2H),2.01(s,3H),1.93(s,1H),1.62(dt,J＝41.9,11.9Hz,6H),1.33(dd,J＝15.5,9.6Hz,1H),1.21(d,J＝6.8Hz,6H).UPLC-MS(ESI)理论值为C24H33N7O2[M+H]+:452.58，实测值为452.52。
实施例4
[C3]7-羟基-N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)庚酰胺
参照化合物3.3的合成路线，将乙酸换成7-羟基庚酸，制备得化合物4.3，收率65％。
以化合物4.3和化合物1.5为原料，参照化合物1.6的合成路线，制备得化合物C3，收率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)理论值为C28H41N7O3[M+H]+:524.33，实测值为524.85。
[C4](S)-7-羟基-N-(4-(((2-((1-羟基丁-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)庚酰胺
以化合物4.3为原料，参照化合物2.2的合成路线，制备得C4。
[C5](R)-7-羟基-N-(4-(((2-((1-羟基丁-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)庚酰胺
以化合物4.3为原料，参照化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成(R)-(-)-2-氨基-1-丁醇制备得C5。
[C6](R)-7-羟基-N-(4-(((8-异丙基-2-(哌啶-3-基氧基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)庚酰胺
以化合物4.3为原料，参照化合物1.6的合成路线，将1-甲基-4-哌啶醇换成(S)-3-羟基哌啶，制备得C6。
[C7](S)-7-羟基-N-(4-(((8-异丙基-2-(哌啶-3-基氧基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)庚酰胺
以化合物4.3为原料，参照化合物1.6的合成路线，将1-甲基-4-哌啶醇换成(R)-3-羟基哌啶，制备得C7。
实施例5
[C8](S)-2-((4-(4-(乙基氨基)苄基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-2-基)氨基)丁-1-醇
N-乙基-4-氰基苯胺(500mg,3.42mmol,1.0equiv)溶于二氯甲烷(10mL)中，降温至0℃，加入二碳酸二叔丁酯(786uL,3.42mmol,1.0equiv)，室温下反应5h，监测反应完全。旋干溶剂，柱层析得化合物5.1(158mg)，收率19％。1H NMR(500MHz,DMSO-d6)δ7.29(d,J＝8.3Hz,2H),7.12(d,J＝8.3Hz,2H),3.69(t,2H),3.56(q,J＝7.0Hz,2H),1.36(s,9H),1.02(t,J＝7.0Hz,3H)。
以化合物5.1为原料，参考化合物1.2的合成路线，得化合物5.2，收率87％。1H NMR(500MHz,DMSO-d6)δ7.29(d,J＝8.3Hz,2H),7.12(d,J＝8.3Hz,2H),3.69(t,2H),3.56(q,J＝7.0Hz,2H),1.36(s,9H),1.02(t,J＝7.0Hz,3H)。
以化合物1.3和化合物5.2为原料，参考化合物1.4的合成路线，得化合物5.3，收率22％。1H 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＝6.2Hz,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)。
以化合物5.3和化合物2.1为原料，参考化合物C38的合成路线，制备得化合物C8， 收率89％。1H NMR(500MHz,Methanol-d4)δ7.67(s,1H),7.19(d,J＝8.5Hz,2H),6.64(d,J＝8.3Hz,2H),4.60(d,J＝10.7Hz,2H),4.09–3.90(m,1H),3.65(d,J＝5.4Hz,2H),3.10(q,J＝7.1Hz,2H),2.99(p,J＝6.9Hz,1H),1.75–1.68(m,1H),1.58(dt,J＝14.5,7.4Hz,1H),1.27(d,J＝6.9Hz,6H),1.21(t,J＝7.1Hz,3H),0.99(t,J＝7.3Hz,3H).UPLC-MS(ESI)理论值为C21H31N7O[M+H]+:398.26，实测值为398.38。
实施例6
[C9](S)-2-羟基-N-(4-(((2-((1-羟基丁-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
化合物对氨基苯氰(1g,8.46mmol,1.0equiv)和乙醇酸(634mg,8.46mmol,1.0equiv)混合后，升温至130℃，加热搅拌4h，然后将混合物冷却至室温，静置1h，加入乙醚，析出固体，经过滤后，柱层析得化合物6.1(542mg)，收率36.4％。1H NMR(400MHz,DMSO-d6)δ10.13(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)。
化合物6.1(542mg,3.08mmol,1.0equiv)溶于二氯甲烷(2mL)中，降温至0℃，加入叔丁基二甲基氯硅烷(558mg,3.70mmol,1.2equiv)和咪唑(315mg,4.62mmol,1.5equiv)，室温搅拌12h，监测反应完全，加入150mL二氯甲烷萃取3次，水洗3次，合并有机相，加入无水硫酸钠干燥，过滤旋干，柱层析得化合物6.2(411mg)，收率46％。1H 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)。
化合物6.2(411mg,1.0mmol,1.0equiv)溶于氨甲醇(10mL)，加入两管雷尼镍，抽换氮气3次，再抽换氢气3次，室温下搅拌反应4h，监测反应完全后，经硅藻土过滤，旋干过滤液体，得化合物6.3(152mg)，收率52％。1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),7.52(d,J＝8.1Hz,2H),7.26(d,J＝8.1Hz,2H),4.19(s,2H),3.66(s,2H),0.91(s,9H),0.12(s,6H)。
以化合物1.3和化合物6.3为原料，参考化合物1.4的合成路线，制备得化合物6.4，收率26％。1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),9.45(s,1H),8.27(s,1H),7.56(d,J＝8.1Hz,2H),7.38(d,J＝8.1Hz,2H),4.70(d,J＝5.8Hz,2H),4.18(s,2H),3.32(d,J＝2.8Hz,3H),3.14(p,J＝6.9Hz,1H),1.31(d,J＝6.5Hz,6H),0.90(s,9H),0.10(s,6H)。
以化合物6.4和化合物2.1为原料，参考化合物C38的合成路线，制备得化合物C9，收率49％。1H NMR(500MHz,Methanol-d4)δ7.88(s,1H),7.61(d,J＝8.3Hz,2H),7.40(d,J＝8.6Hz,2H),4.77(d,J＝16.7Hz,2H),4.14(m,1H),4.10(s,2H),3.65(d,J＝4.8Hz,2H),3.04–2.92(m,1H),1.73(ddd,J＝13.8,7.6,6.1Hz,1H),1.61(dt,J＝14.4,7.4Hz,1H),1.30(d,J＝6.9Hz,6H),1.00–0.89(t,3H).UPLC-MS(ESI)理论值为C21H29N7O3[M+H]+:428.23，实测值为428.38。
实施例7
[C10](S)-2-((4-(4-(((2-羟乙基)氨基)苄基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-2-基)氨基)丁-1-醇
对氨基苯氰(2g,16.93mmol,1.0equiv)和2-碘乙醇(2.91g,16.93mmol,1.0equiv)倒入圆底烧瓶中，N2抽换3次，在N2保护下，升温至90℃，搅拌反应6h，反应液用100mL乙酸乙酯萃取，加入2M的氢氧化钠溶液，再用饱和氯化钠溶液洗涤，合并有机相，加入无水硫酸钠干燥，过滤旋干，柱层析得化合物7.1(1.038g)，收率38％。
化合物7.1(300mg,1.23mmol,1.0equiv)溶解在4mL二氯甲烷中，加入叔丁基二甲基氯硅烷(185mg,1.23mmol,1.0equiv)、三乙胺(359μL,2.58mmol,2.1equiv)和4-二甲氨基吡啶(15mg,0.123mmol,0.1equiv)，室温下搅拌反应12h，监测反应完全，加水稀释，用450mL二氯甲烷萃取3次，用饱和氯化钠溶液洗涤3次，合并有机相，加入无水硫酸钠干燥，过滤旋干，柱层析地化合物7.2(208mg)，收率为61％。1H NMR(400MHz,DMSO-d6)δ7.42(d,J＝8.3Hz,2H),6.66(d,J＝8.5Hz,3H),3.70(t,J＝5.2Hz,2H),3.22(q,J＝6.3Hz,2H),0.84(s,9H),0.01(s,6H)。
以化合物7.2为原料，参考化合物1.1的合成路线，制备得化合物7.3，收率80％。1H NMR(400MHz,CDCl3)δ7.58(d,J＝6.3Hz,2H),7.48(d,J＝7.0Hz,2H),3.78(dt,J＝13.0,3.8Hz,4H),1.47(s,9H),0.85(s,9H),0.02(s,6H)。
以化合物7.3为原料，参考化合物1.2的合成路线，制备得化合物7.4，收率99％。1H NMR(400MHz,CDCl3)δ7.58(d,J＝6.3Hz,2H),7.48(d,J＝7.0Hz,2H),4.72(q,J＝6.3Hz,2H),3.78(dt,J＝13.0,3.8Hz,4H),1.47(s,9H),0.85(s,9H),0.02(s,6H)。
以化合物7.4和化合物1.3为原料，参考化合物1.4的合成路线，制备得化合物7.5，收率26％。1H 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)。
以化合物7.5和化合物2.1为原料，参考化合物C38的合成路线，制备得化合物C10，收率38％。1H NMR(500MHz,Methanol-d4)δ7.67(s,1H),7.18(d,J＝8.1Hz,2H),6.64(d,J＝8.6Hz,2H),4.60(d,J＝10.3Hz,2H),4.15–3.94(m,1H),3.70(t,J＝5.8Hz,2H),3.65(d,J＝5.1Hz,2H),3.21(t,J＝5.7Hz,2H),2.99(p,J＝7.0Hz,1H),1.75–1.69(m,1H),1.58(dt,J＝14.1,7.3Hz,1H),1.27(d,J＝6.8Hz,6H),0.99(t,J＝7.4Hz,3H).UPLC-MS(ESI)理论值为C21H31N7O2[M+H]+:414.25，实测值为414.36。
实施例8
[C11]N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)四氢-2H-吡喃-4-甲酰胺
以4-(N-Boc-氨基甲基)苯胺和四氢吡喃-4-甲酸为原料，参考化合物3.1的合成路线，得化合物8.1，收率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)。
以化合物8.1为原料，参考化合物3.2的合成路线，得化合物8.2，收率99％。1H 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＝5.8Hz,2H),3.90(d,J＝11.6Hz,2H),3.35(td,J＝11.2,3.5Hz,2H),2.58(dt,J＝10.2,5.3Hz,1H),1.72–1.62(m,4H)。
以化合物8.2和化合物1.3为原料，参考化合物1.4的合成路线，得化合物8.3，收率56％。1H 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)。
以化合物8.3和化合物1.5为原料，参考化合物1.6的合成路线，得化合物C11，收率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)理论值为C27H37N7O3[M+H]+:508.30，实测值为508.92。
[C12]N-(4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)四氢-2H吡喃-4-甲酰胺
以化合物8.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成4-氨基四氢吡喃，制备得化合物C12，收率27％。1H NMR(500MHz,DMSO-d6)δ9.85(s,1H),8.60(t,1H),7.69(s,1H),7.52(d,J＝8.1Hz,2H),7.28(d,J＝8.1Hz,2H),6.87(d,J＝22.1Hz,1H),4.53(s,2H),3.91–3.88(m,2H),3.85–3.82(m,2H),3.36(d,J＝10.0Hz,2H),3.32(d,J＝7.5Hz,2H),2.93–2.85(m,1H),2.56(dt,J＝10.5,5.3Hz,1H),2.53(d,J＝5.3Hz,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＝8.4Hz,6H).UPLC-MS(ESI)理论值为C26H35N7O3[M+H]+:494.28，实测值为494.89。
[C13]N-(4-(((2-((1,3-二羟基丙-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)四氢-2H-吡喃-4-甲酰胺
以化合物8.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成2-氨基-1,3-丙二醇，制备得化合物C13，收率17％。1H NMR(500MHz,Methanol-d4)δ7.89(s,1H),7.55(d,J＝8.6Hz,2H),7.40(d,J＝8.2Hz,2H),4.78(s,2H),4.31–4.23(m,1H),4.02–3.98(m,2H),3.79–3.71(m,4H),3.48(td,J＝11.8,2.3Hz,2H),3.03–2.93(m,1H),2.62(td,J＝7.5,3.8Hz,1H),1.88–1.79(m,2H),1.76–1.72(m,2H),1.30(d,J＝7.0Hz,6H).UPLC-MS(ESI)理论值为C24H33N7O4[M+H]+:484.26，实测值为484.41。
[C14](S)-N-(4-(((2-((1-羟基丁-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)四氢-2H-吡喃-4-甲酰胺
以化合物8.3为原料，参考化合物2.2的合成路线，制备得化合物C14，收率38％。1H NMR(500MHz,Methanol-d4)δ7.88(s,1H),7.56(d,J＝8.5Hz,2H),7.38(d,J＝8.6Hz,2H),4.77(d,J＝18.0Hz,2H),4.14(t,J＝6.9Hz,1H),4.00(ddd,J＝11.5,4.5,2.0Hz,2H),3.66(d,J＝4.9Hz,2H),3.50–3.45(m,2H),3.04–2.96(m,1H),2.62(tt,J＝11.5,4.0Hz,1H),1.87–1.80(m,2H),1.77–1.73(m,2H),1.73–1.68(m,1H),1.61(dt,J＝14.4,7.5Hz,1H),1.29(d,J＝7.0Hz,6H),0.96(t,J＝7.4Hz,3H).UPLC-MS(ESI)理论值为C25H35N7O3[M+H]+:482.28，实测值为482.87。
[C15](R)-N-(4-(((2-((1-羟基丁-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)四氢-2H-吡喃-4-甲酰胺
以化合物8.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成(R)-(-)-2-氨基-1-丁醇，制备得化合物C15，收率25％。1H NMR(500MHz,Methanol-d4)δ7.88(s,1H),7.56(d,J＝8.6Hz,2H),7.38(d,J＝8.5Hz,2H),4.76(d,J＝17.6Hz,2H),4.17–4.10(m,1H),4.01–3.97(m,2H),3.65(d,J＝4.9Hz,2H),3.47(td,J＝11.8,2.4Hz,2H),3.04–2.95(m,1H),2.62(td,J＝7.5,3.8Hz,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)理论 值为C25H35N7O3[M+H]+:482.28，实测值为482.45。
[C16]N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氨基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)四氢-2H-吡喃-4-甲酰胺
以化合物8.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成4-氨基-1-甲基哌啶，制备得化合物C16，收率9％。1H NMR(500MHz,Methanol-d4)δ7.89(s,1H),7.54(d,J＝8.6Hz,2H),7.37(d,J＝8.6Hz,2H),4.77(s,2H),4.13(tt,J＝11.7,4.1Hz,1H),4.02–3.98(m,2H),3.59–3.53(m,2H),3.50–3.46(m,2H),3.17–3.11(m,2H),3.09–3.03(m,1H),2.91(s,3H),2.62(td,J＝7.5,3.8Hz,1H),2.19–2.11(m,2H),1.88–1.82(m,2H),1.79–1.72(m,4H),1.28(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C27H38N8O2[M+H]+:507.31，实测值为507.46。
[C17](S)-N-(4-(((2-(3-羟基哌啶-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)四氢-2H-吡喃-4-甲酰胺
以化合物8.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成(S)-3-哌啶醇，制备得化合物C17，收率19％。1H NMR(500MHz,Methanol-d4)δ7.91(s,1H),7.55(d,J＝8.5Hz,2H),7.39(d,J＝8.6Hz,2H),4.75(d,J＝4.4Hz,2H),4.18–4.04(m,1H),4.02–3.98(m,2H),3.87(ddd,J＝13.7,7.1,3.5Hz,2H),3.83–3.72(m,1H),3.66(dd,J＝13.3,7.0Hz,1H),3.48(td,J＝11.7,2.3Hz,2H),3.21–3.16(m,1H),2.61(ddt,J＝11.5,8.0,4.0Hz,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＝6.9,3.9Hz,6H).UPLC-MS(ESI)理论值为C26H35N7O3[M+H]+:494.28，实测值为494.44。
[C18](R)-N-(4-(((2-(3-羟基哌啶-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)四氢-2H-吡喃-4-甲酰胺
以化合物8.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成(R)-3-哌啶醇，制备得化合物C18，收率68％。1H NMR(500MHz,Methanol-d4)δ7.91(s,1H),7.55(d,J＝8.7Hz,2H),7.39(d,J＝8.7Hz,2H),4.75(d,J＝4.3Hz,2H),4.11(dd,J＝17.7,11.2Hz,1H),4.01–3.98(m,2H),3.92–3.83(m,2H),3.77(dd,J＝15.0,11.0Hz,1H),3.65(dd,J＝13.3,7.0Hz,1H),3.50–3.45(m,2H),3.21–3.15(m,1H),2.62(tt,J＝11.6,4.1Hz,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＝6.9,3.9Hz,6H).UPLC-MS(ESI)理论值为C26H35N7O3[M+H]+:494.28，实测值为494.47。
[C19](S)-N-(4-(((2-(2-(羟甲基)吡咯烷-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)四氢-2H-吡喃-4-甲酰胺
以化合物8.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成L-脯氨醇，制备得化合物C19，收率77％。1H NMR(500MHz,Methanol-d4)δ7.88(s,1H),7.55(d,J＝8.6Hz,2H),7.39(d,J＝8.0Hz,2H),4.77(s,2H),4.27–4.16(m,1H),4.11–4.03(m,1H),4.02–3.98(m,2H),3.91(d,J＝11.3Hz,1H),3.72(dt,J＝12.4,6.5Hz,2H),3.50–3.45(m,2H),3.03–2.88(m,1H),2.62 (ddd,J＝11.6,7.5,4.1Hz,1H),2.31–2.24(m,1H),1.99(dt,J＝13.5,7.0Hz,2H),1.87–1.79(m,3H),1.76–1.72(m,2H),1.29(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C26H35N7O3[M+H]+:494.28，实测值为494.45.。
[C20](R)-N-(4-(((2-(2-(羟甲基)吡咯烷-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)四氢-2H-吡喃-4-甲酰胺
以化合物8.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成D-脯氨醇，制备得化合物C20，收率37％。1H NMR(500MHz,Methanol-d4)δ7.66(s,1H),7.52(d,J＝8.5Hz,2H),7.36(d,J＝8.5Hz,2H),4.69–4.68(s,2H),4.21(d,J＝5.9Hz,1H),4.01(dd,J＝4.5,2.0Hz,1H),3.99–3.98(m,1H),3.73(t,J＝8.4Hz,2H),3.60(dq,J＝11.4,5.9,5.4Hz,2H),3.50–3.46(m,2H),2.98(dd,J＝8.8,3.3Hz,1H),2.61(p,J＝3.5Hz,1H),1.99(m,2H),1.88–1.80(m,4H),1.76–1.73(m,2H),1.27–1.26(dd,6H).UPLC-MS(ESI)理论值为C26H35N7O3[M+H]+:494.28，实测值为494.38。
实施例9
[C21]1-乙酰基-N-(4-(((2-((1,3-二羟基丙-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)哌啶-4-甲酰胺
以4-(N-Boc-氨基甲基)苯胺和1-乙酰基-4-哌啶甲酸为原料，参考化合物3.1的合成路线，制备得化合物9.1，收率69％。1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),7.51(d,J＝8.3Hz,2H),7.33(t,J＝6.1Hz,1H),7.14(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)。
以化合物9.1为原料，参考化合物3.2的合成路线，制备得化合物9.2，收率99％。1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.10(s,2H),7.62(d,J＝8.5Hz,2H),7.36(d,J＝8.6Hz,2H),4.40(d,J＝12.7Hz,1H),3.96(q,J＝5.8Hz,2H),3.86(d,J＝13.6Hz,1H),3.06(td,J＝13.6,13.0,2.7Hz,1H),2.57(td,J＝11.6,5.5Hz,2H),2.00(s,3H),1.80(t,J＝12.6Hz,2H),1.58(td,J＝12.4,4.2Hz,1H),1.42(qd,J＝12.5,4.3Hz,1H)。
以化合物9.2和化合物1.3为原料，参考化合物1.4的合成路线，制备得化合物9.3，收率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)。
以化合物9.3和化合物9.4为原料，参考化合物2.2的合成路线，制备得化合物C21，收率43％。1H NMR(500MHz,Methanol-d4)δ7.89(s,1H),7.55(d,J＝7.2Hz,2H),7.40(d,J＝8.2Hz,2H),4.78(s,2H),4.58–4.54(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＝12.9,2.9Hz,1H),2.62(ddt,J＝11.5,7.7,3.9Hz,1H),2.12(s,3H),1.89(t,J＝15.2Hz,2H),1.74(qd,J＝12.4,4.3Hz,1H),1.67–1.58(m,1H),1.30(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C26H36N8O4[M+H]+:525.29，实测值为525.88。
[C22]1-乙酰基-N-(4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)哌啶-4-甲酰胺
以化合物9.3为原料，参考化合物C21的合成路线，将2-氨基-1,3-丙二醇换成4-氨基四氢吡喃，制备得化合物C22，收率37％。1H NMR(500MHz,Methanol-d4)δ7.90(s,1H),7.55(d,J＝8.6Hz,2H),7.37(d,J＝8.5Hz,2H),4.75(s,2H),4.58–4.53(m,1H),4.16–4.09(m,1H),4.02–3.98(m,1H),3.95(d,J＝11.7Hz,2H),3.53–3.48(m,2H),3.21–3.15(m,1H),3.07–2.97(m,1H),2.75–2.69(m,1H),2.63(ddd,J＝11.5,7.7,3.9Hz,1H),2.11(s,3H),1.93–1.88(m,2H),1.87–1.82(m,2H),1.78–1.72(m,1H),1.66–1.59(m,3H),1.29(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C28H38N8O3[M+H]+:535.31，实测值为535.43.。
[C23](R)-1-乙酰基-N-(4-(((2-((1-羟基丁-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)哌啶-4-甲酰胺
以化合物9.3为原料，参考化合物C21的合成路线，将2-氨基-1,3-丙二醇换成(R)-(-)-2-氨基-1-丁醇，制备得化合物C23，收率33％。1H NMR(500MHz,Methanol-d4)δ7.89(s,1H),7.56(d,J＝8.4Hz,2H),7.38(d,J＝8.6Hz,2H),4.77(d,J＝18.5Hz,2H),4.58–4.54(m,1H),4.17–4.11(m,1H),4.02–3.97(m,1H),3.66(d,J＝4.8Hz,2H),3.21–3.15(m,1H),2.99(m,J＝6.9Hz,1H),2.72(td,J＝12.9,3.0Hz,1H),2.63(ddt,J＝11.5,7.7,3.8Hz,1H),2.11(s,3H),1.92–1.86(m,2H),1.77–1.70(m,2H),1.63(td,J＝13.4,12.9,8.2Hz,2H),1.29(d,J＝6.9Hz,6H),0.96(t,J＝7.5Hz,3H).UPLC-MS(ESI)理论值为C27H38N8O3[M+H]+:523.31，实测值为523.89。
[C24](S)-1-乙酰基-N-(4-(((2-((1-羟基丁-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)哌啶-4-甲酰胺
以化合物9.3为原料，参考化合物C21的合成路线，将2-氨基-1,3-丙二醇换成(S)-(+)-2-氨基-1-丁醇，制备得化合物C24，收率31％。1H NMR(500
MHz,Methanol-d4)δ7.89(s,1H),7.56(d,J＝8.6Hz,2H),7.38(d,J＝8.6Hz,2H),4.77(d,J＝18.2Hz,2H),4.58–4.53(m,1H),4.18–4.10(m,1H),4.02–3.98(m,1H),3.66(d,J＝4.9Hz,2H),3.21–3.16(m,1H),3.00(m,J＝6.9Hz,1H),2.75–2.69(m,1H),2.63(ddt,J＝11.5,7.7,3.9Hz,1H),2.11(s,3H),1.93–1.86(m,2H),1.78–1.70(m,2H),1.62(dt,J＝13.3,6.3Hz,2H),1.29(d,J＝6.9Hz,6H),0.96(t,J＝7.4Hz, 3H).UPLC-MS(ESI)理论值为C27H38N8O3[M+H]+:523.31，实测值为523.89。
[C25](R)-1-乙酰基-N-(4-(((2-(2-(羟甲基)吡咯烷-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)哌啶-4-甲酰胺
以化合物9.3为原料，参考化合物C21的合成路线，将2-氨基-1,3-丙二醇换成D-脯氨醇，制备得化合物C25，收率51％。1H NMR(500MHz,Methanol-d4)δ7.90(s,1H),7.57(d,J＝8.5Hz,2H),7.41(d,J＝8.0Hz,2H),4.79(s,2H),4.60–4.56(m,1H),4.28–4.21(m,1H),4.08(q,J＝6.8,6.2Hz,1H),4.02(d,J＝13.8Hz,1H),3.93(d,J＝11.2Hz,1H),3.74(dd,J＝11.5,5.7Hz,2H),3.20(ddd,J＝7.5,3.1,1.5Hz,1H),3.02–2.92(m,1H),2.76–2.71(m,1H),2.65(td,J＝7.7,3.8Hz,1H),2.34–2.27(m,1H),2.13(s,3H),2.07–1.97(m,2H),1.93–1.87(m,3H),1.76(dd,J＝12.5,4.1Hz,1H),1.65(dd,J＝12.3,4.2Hz,1H),1.31(d,J＝7.1Hz,6H).UPLC-MS(ESI)理论值为C28H38N8O3[M+H]+:535.31，实测值为535.43。
实施例10
[C26]N-(4-(((2-((1,3-二羟基丙-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以4-(N-Boc-氨基甲基)苯胺和丙酸为原料，参考化合物3.1的合成路线，制备得化合物10.1，收率95％。1H 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)。
以化合物10.1为原料，参考化合物3.2的合成路线，制备得化合物10.2，收率99％。1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.18–8.07(m,3H),7.62(d,J＝8.6Hz,2H),7.36(d,J＝8.6Hz,2H),3.96(q,J＝5.8Hz,2H),2.32(q,J＝7.5Hz,2H),1.07(t,J＝7.5Hz,3H)。
以化合物10.2和化合物1.3为原料，参考化合物1.4的合成路线，制备得化合物10.3，收率61％。1H 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)。
以化合物10.3和化合物9.4为原料，参考化合物2.2的合成路线，制备得化合物C26，收率62％。1H NMR(500MHz,Methanol-d4)δ7.67(s,1H),7.51(d,J＝8.5Hz,2H),7.34(d,J＝8.2Hz,2H),4.69(s,2H),4.14–4.06(m,1H),3.73(q,J＝5.4Hz,4H),3.02–2.96(m,1H),2.37(q,J＝7.6Hz,2H),1.27(d,J＝6.9Hz,6H),1.19(t,J＝7.6Hz,3H).UPLC-MS (ESI)理论值为C21H29N7O3[M+H]+:428.23，实测值为428.41.。
[C27]N-(4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物10.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成4-氨基四氢吡喃，制备得化合物C27，收率42％。1H NMR(500MHz,Methanol-d4)δ7.68(s,1H),7.52(d,J＝8.5Hz,2H),7.34(d,J＝8.6Hz,2H),4.68(s,2H),4.04–3.98(m,1H),3.94(t,J＝11.8Hz,2H),3.51(t,J＝12.0Hz,2H),3.03–2.97(m,1H),2.37(q,J＝7.6Hz,2H),1.98–1.86(m,2H),1.57–1.50(m,2H),1.27(d,J＝7.0Hz,6H),1.19(t,J＝7.6Hz,3H).UPLC-MS(ESI)理论值为C23H31N7O2[M+H]+:438.25，实测值为438.86。
[C28]N-(4-(((8-异丙基-2-(氧杂环丁烷-3-基氨基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物10.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成3-氧杂环丁胺，制备得化合物C28，收率15％。1H NMR(500MHz,Methanol-d4)δ7.84(s,1H),7.55(d,J＝8.5Hz,2H),7.35(d,J＝8.6Hz,2H),5.13–5.04(m,1H),4.74(d,J＝6.8Hz,2H),4.65(q,J＝6.7Hz,2H),3.82–3.63(m,1H),3.03(td,J＝14.6,14.1,7.2Hz,1H),2.37(q,J＝7.6Hz,2H),1.29(d,J＝7.0Hz,6H),1.19(t,J＝7.6Hz,3H).UPLC-MS(ESI)理论值为C21H27N7O2[M+H]+:410.22，实测值为410.76。
[C29](S)-N-(4-(((2-((1-羟基丁-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物10.3为原料，参考化合物2.2的合成路线，制备得化合物C29，收率50％。1H NMR(500MHz,Methanol-d4)δ7.70(s,1H),7.52(d,J＝8.5Hz,2H),7.35(d,J＝8.2Hz,2H),4.70(d,J＝12.8Hz,2H),4.04–3.90(m,1H),3.63(d,J＝5.0Hz,2H),2.99(p,J＝6.9Hz,1H),2.37(q,J＝7.6Hz,2H),1.71(ddd,J＝13.4,7.6,5.8Hz,1H),1.56(dt,J＝14.3,7.4Hz,1H),1.27(d,J＝6.9Hz,6H),1.19(t,J＝7.6Hz,3H),0.97(t,J＝7.4Hz,3H).UPLC-MS(ESI)理论值为C22H31N7O2[M+H]+:426.25，实测值为426.45。
[C30](R)-N-(4-(((2-((1-羟基丁-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物10.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成(R)-(-)-2-氨基-1-丁醇，制备得化合物C30，收率64％。1H NMR(500MHz,Methanol-d4)δ7.78(s,1H),7.53(d,J＝8.5Hz,2H),7.36(d,J＝8.4Hz,2H),4.72(d,J＝14.8Hz,2H),4.14–3.92(m,1H),3.64(d,J＝5.0Hz,2H),3.00(p,J＝6.9Hz,1H),2.37(q,J＝7.6Hz,2H),1.71(ddd,J＝13.5,7.6,5.9Hz,1H),1.58(dq,J＝14.3,7.4Hz,1H),1.28(d,J＝6.9Hz,6H),1.19(t,J＝7.6Hz,3H),0.97(t,3H).UPLC-MS(ESI)理论值为C22H31N7O2[M+H]+:426.25，实测值为426.77。
[C31](R)-N-(4-(((8-异丙基-2-(哌啶-3-基氧基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物10.3为原料，参考化合物1.6的合成路线，将1-甲基-4-哌啶醇换成(S)-3-羟基哌啶，制备得化合物C31，收率55％。1H NMR(500MHz,Methanol-d4)δ7.87(s,1H),7.52(d,J＝8.6Hz,2H),7.33(d,J＝8.6Hz,2H),4.73(d,J＝2.9Hz,2H),3.48(dd,J＝13.3,3.9Hz,1H),3.37–3.32(m,2H),3.29(d,J＝3.8Hz,1H),3.19–3.09(m,1H),3.08–3.03(m,1H),2.37(t,J＝7.6Hz,2H),2.11(dt,J＝14.5,4.9Hz,2H),1.98–1.91(m,1H),1.84–1.78(m,1H),1.31(dd,J＝6.9,1.9Hz,6H),1.19(t,J＝7.6Hz,3H).UPLC-MS(ESI)理论值为C23H31N7O2[M+H]+:438.25，实测值为438.41。
[C32](S)-N-(4-(((8-异丙基-2-(哌啶-3-基氧基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物10.3为原料，参考化合物1.6的合成路线，将1-甲基-4-哌啶醇换成(R)-3-羟基哌啶，制备得化合物C32，收率59％。1H NMR(500MHz,Methanol-d4)δ7.88(s,1H),7.53(d,J＝8.5Hz,2H),7.34(d,J＝8.6Hz,2H),4.74(d,J＝2.9Hz,2H),3.49(dd,J＝13.3,3.9Hz,1H),3.36(dd,J＝13.4,2.5Hz,2H),3.31–3.28(m,1H),3.16–3.11(m,1H),3.09–3.05(m,1H),2.38(q,J＝7.6Hz,2H),2.14–2.08(m,2H),1.95(td,J＝12.3,4.2Hz,1H),1.83(dt,J＝14.2,3.7Hz,1H),1.32(dd,J＝6.9,2.0Hz,6H),1.20(t,J＝7.6Hz,3H).UPLC-MS(ESI)理论值为C23H31N7O2[M+H]+:438.25，实测值为438.41。
[C33](S)-N-(4-(((8-异丙基-2-(哌啶-3-基氧基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物10.3为原料，参考化合物C38的合成路线，将(S)-(+)-2-氨基-1-丁醇换成1-叔丁氧羰基-4-氨基哌啶，制备得化合物C33，收率37％。1HNMR(500MHz,Methanol-d4)δ7.90(s,1H),7.54(d,J＝8.5Hz,2H),7.36(d,J＝8.5Hz,2H),4.77(s,2H),4.21(dq,J＝10.5,6.0,4.9Hz,1H),3.46–3.41(m,2H),3.14(dd,J＝12.0,3.1Hz,2H),3.10–3.06(m,1H),2.38(q,J＝7.6Hz,2H),2.10(d,J＝13.8Hz,2H),1.77(td,J＝10.8,7.7Hz,2H),1.28(d,J＝6.9Hz,6H),1.19(t,J＝7.6Hz,3H).UPLC-MS(ESI)理论值为C23H32N8O[M+H]+:437.27，实测值为437.45。
[C34]N-(4-(((8-异丙基-2-(哌啶-3-基氨基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物10.3为原料，参考化合物C38的合成路线，将(S)-(+)-2-氨基-1-丁醇换成N-叔丁氧羰基-3-氨基哌啶，制备得化合物C34，收率85％。1HNMR(500MHz,Methanol-d4)δ7.88(s,1H),7.53(d,J＝8.5Hz,2H),7.37(d,J＝8.5Hz,2H),4.79(s,2H),4.30–4.25(m,1H),3.41–3.32(m,2H),3.11–3.06(m,1H),3.03–2.93(m,2H),2.38(q,J＝7.6Hz,2H),2.11–2.04(m,2H),1.84(dt,J＝10.9,3.7Hz,1H),1.77–1.71(m,1H),1.28(d,J＝6.9Hz,6H),1.19(t,J＝7.6Hz,3H).UPLC-MS(ESI)理论值为C23H32N8O[M+H]+:437.27，实测值为437.44。
[C35]N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氨基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物10.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成4-氨基-1-甲基哌啶，制备得化合物C35，收率19％。1H NMR(500MHz,Methanol-d4)δ7.91(s,1H),7.54(d,J＝8.6Hz,2H),7.37(d,J＝8.6Hz,2H),4.77(d,J＝4.1Hz,2H),4.14(tt,J＝11.8,4.2Hz,1H),3.56(d,J＝12.5Hz,2H),3.16–3.11(m,2H),3.07(q,J＝6.8Hz,1H),2.91(s,3H),2.38(q,J＝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)理论值为C24H34N8O[M+H]+:451.29，实测值为451.43。
[C36]N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物10.3为原料，参考化合物1.6的合成路线，制备得化合物C36，收率62％。1H NMR(500MHz,Methanol-d4)δ7.84(s,1H),7.52(d,J＝8.5Hz,2H),7.34(d,J＝8.6Hz,2H),5.19–5.12(m,1H),4.72(s,2H),3.10(dd,J＝13.4,7.4Hz,2H),3.05(q,J＝7.0Hz,1H),2.96–2.79(m,2H),2.63(s,3H),2.37(q,J＝7.6Hz,2H),2.11(d,J＝13.2Hz,2H),2.00(s,2H),1.29(d,J＝6.9Hz,6H),1.19(t,J＝7.6Hz,3H).UPLC-MS(ESI)理论值为C24H33N7O2[M+H]+:452.27，实测值为452.81。
[C63]N-(4-(((8-异丙基-2-((1-(丙-2-炔-1-基)哌啶-4-基)氧基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物10.3为原料，参考化合物1.6的合成路线，将1-甲基-4-哌啶醇换成，将1-甲基-4-哌啶醇换成1-(丙-2-炔-1-基)哌啶-4-醇，制备得化合物C63。
[C131](R)-N-(4-(((2-(3-羟基吡咯烷-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物10.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成(R)-3-吡咯烷醇，制备得C131，收率45％。1H NMR(500MHz,DMSO-d6)δ9.84(s,1H),9.40(s,1H),7.87(s,1H),7.58–7.49(m,2H),7.33(d,J＝8.3Hz,2H),4.57(d,J＝6.3Hz,2H),4.38(s,1H),3.54(d,J＝58.8Hz,4H),3.16–2.99(m,1H),2.29(q,J＝7.5Hz,2H),1.94(d,J＝53.6Hz,2H),1.21(dd,J＝6.9,2.2Hz,6H),1.06(t,J＝7.6Hz,3H).UPLC-MS(ESI)理论值为C22H29N7O2[M+H]+:424.52，实测值为 424.49。
[C132](S)-N-(4-(((2-(3-羟基吡咯烷-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物10.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成(S)-3-吡咯烷醇，制备得C132，收率59％。1H NMR(500MHz,DMSO-d6)δ9.84(s,1H),9.44(s,1H),7.89(s,1H),7.57–7.49(m,2H),7.33(d,J＝8.3Hz,2H),4.57(d,J＝6.3Hz,2H),4.38(s,1H),3.55(d,J＝62.9Hz,4H),3.09(dt,J＝14.1,7.2Hz,1H),2.29(q,J＝7.6Hz,2H),2.00(dd,J＝12.9,5.4Hz,1H),1.90(s,1H),1.21(dd,J＝6.9,2.5Hz,6H),1.06(t,J＝7.6Hz,3H).UPLC-MS(ESI)理论值为C22H29N7O2[M+H]+:424.52，实测值为424.49。
[C133](R)-N-(4-(((2-(2-(羟基甲基)吡咯烷-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物10.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成(R)-2-吡咯烷甲醇，制备得C133，收率53％。1H NMR(500MHz,DMSO-d6)δ9.84(s,1H),9.47(s,1H),7.89(s,1H),7.58–7.49(m,2H),7.37–7.27(m,2H),4.57(dd,J＝6.5,3.3Hz,2H),4.19(s,1H),3.75–3.39(m,4H),3.03(d,J＝74.9Hz,1H),2.29(q,J＝7.5Hz,2H),1.96(d,J＝58.2Hz,4H),1.21(dd,J＝7.1,3.4Hz,6H),1.06(t,J＝7.5Hz,3H).UPLC-MS(ESI)理论值为C23H31N7O2[M+H]+:438.55，实测值为438.51。
[C134](S)-N-(4-(((2-(2-(羟基甲基)吡咯烷-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物10.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成(S)-2-吡咯烷甲醇，制备得C134，收率40％。1H NMR(600MHz,DMSO-d6)δ9.85(s,1H),9.41(s,1H),7.87(d,J＝15.4Hz,1H),7.53(d,J＝8.2Hz,2H),7.33(d,J＝8.2Hz,2H),4.57(s,2H),4.18(s,1H),3.70–3.38(m,4H),3.01(d,J＝84.4Hz,1H),2.29(q,J＝7.6Hz,2H),2.06–1.82(m,4H),1.21(d,J＝6.6Hz,6H),1.06(t,J＝7.5Hz,3H).UPLC-MS(ESI)理论值为C23H31N7O2[M+H]+:438.55，实测值为438.50。
[C135](S)-N-(4-(((2-(2-(2-羟乙基)哌啶-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物10.3为原料，参考化合物2.2的合成路线，将(S)-(+)-2-氨基-1-丁醇换成(S)-2-(2-哌啶基)乙醇，制备得C135，收率28％。1H NMR(500MHz,DMSO-d6)δ9.83(s,1H),9.13(s,1H),7.80(s,1H),7.57–7.47(m,2H),7.36–7.29(m,2H),4.91(s,1H),4.55(d,J＝6.3Hz,3H),3.39(tt,J＝12.4,6.6Hz,2H),2.92(dd,J＝17.3,9.4Hz,2H),2.29(q,J＝7.5Hz,2H),1.96–1.87(m,1H),1.61(dt,J＝41.5,12.4Hz,6H),1.39–1.28(m,1H),1.21(dd,J＝7.0,0.9Hz,6H),1.06(t,J＝7.5Hz,3H).UPLC-MS(ESI)理论值为 C25H35N7O2[M+H]+:466.60，实测值为466.47。
实施例11
[C37](S)-2-((7-((4-氨基苄基)氨基)-3-异丙基吡唑并[1,5-a]嘧啶-5-基)氨基)丁-1-醇
将化合物5,7-二氯-3-异丙基吡唑并[1,5-a]嘧啶(369mg,1.61mmol,1.0equiv)、化合物1.2(317mg,1.93mmol,1.2equiv)和N,N-二异丙基乙胺(532μL,3.22mmol,2.0equiv)溶于15mL乙醇中。反应液在90℃下，回流12h，反应结束后，将混合物冷却至室温，减压除去溶剂。剩余固体用二氯甲烷中溶解，用饱和氯化钠水溶液洗涤多次，用无水硫酸钠干燥。过滤后去除溶剂，经柱层析纯化得到化合物11.1(524mg)，收率82％。1H 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)。
以化合物11.1为原料，参考化合物1.1的合成路线，制备得化合物11.2，收率94％。1H NMR(500MHz,DMSO-d6)δ8.22(s,1H),7.32(d,J＝8.4Hz,2H),7.13(s,1H),7.07(d,J＝8.4Hz,2H),5.03(s,2H),3.14–3.10(m,1H),1.30(s,18H),1.28(d,J＝3.5Hz,6H)。
以化合物11.2和化合物2.1为原料，参照化合物C38的合成路线，制备得化合物C37，收率68％。1H NMR(500MHz,Methanol-d4)δ7.89(s,1H),7.52(d,J＝8.5Hz,2H),7.31(d,J＝8.5Hz,2H),5.40(s,1H),4.74–4.69(s,2H),3.78–3.64(m,2H),3.59(dd,J＝11.0,6.2Hz,1H),3.06(p,J＝7.0Hz,1H),1.71–1.66(m,1H),1.60–1.54(m,1H),1.31(dd,J＝6.9,2.9Hz,6H),0.97(t,J＝7.4Hz,3H).UPLC-MS(ESI)理论值为C20H28N6O[M+H]+:369.49，实测值为369.35。
实施例12
[C39](S)-N-(4-(((5-((1-羟基丁-2-基)氨基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)乙酰胺
以5,7-二氯-3-异丙基吡唑并[1,5-a]嘧啶和化合物3.2为原料，参考化合物11.1的合成路 线，制备得化合物12.1，收率91％。1H 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)。
以化合物12.1为原料，参考化合物1.1的合成路线，制备得化合物12.2，收率97％。1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.38(d,J＝8.2Hz,2H),7.10(d,J＝8.2Hz,2H),6.02(s,1H),5.76(s,2H),3.08(p,J＝6.8Hz,1H),2.45(s,3H),1.31(s,9H),1.27(d,J＝7.0Hz,6H)。
化合物12.3(114mg，0.56mmol，2.0equiv)溶于15mL甲苯，加入化合物12.2(128mg，0.28mmol，1.0equiv)、Pd2(dba)3(13mg，0.014mmol，5mol％equiv)、rac BINAP(26mg，0.042mmol，15mol％equiv)和Cs2CO3(137mg，0.42mmol，1.5equiv)，并用氮气抽换气3次。升温至100℃，加热搅拌12h。反应完成后，将混合物冷却至室温，减压除去甲苯，柱层析纯化残留物，得化合物12.4(87mg)，收率50％。1H 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,9H),1.32(s,6H),1.25(dd,J＝6.9,3.2Hz,6H),1.17(t,J＝7.2Hz,3H),0.81(s,9H)。
以化合物12.4为原料，参考化合物C1的合成路线，制备得到化合物C39，收率99％。1H NMR(500MHz,Methanol-d4)δ7.88(s,1H),7.56(d,J＝8.6Hz,2H),7.35(d,J＝8.4Hz,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＝13.7,7.6,6.0Hz,1H),1.60–1.49(m,1H),1.31(dd,J＝6.9,3.6Hz,6H),0.96(t,J＝7.3Hz,3H).UPLC-MS(ESI)理论值为C22H30N6O2[M+H]+:411.24，实测值为411.85。
[C40]N-(4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)乙酰胺
以化合物12.2为原料，参考化合物C39的合成路线，将化合物12.3换成4-氨基四氢呋喃，制备得化合物C40，收率45％。1H NMR(500MHz,Methanol-d4)δ7.90(s,1H),7.56(d,J＝8.6Hz,2H),7.36(d,J＝8.3Hz,2H),5.27(s,1H),4.68(d,2H),3.94(dd,J＝9.5,6.0Hz,2H),3.84–3.74(m,1H),3.51(td,J＝11.7,2.1Hz,2H),3.12–3.06(m,1H),2.11(s,3H),1.82(d,J＝13.0Hz,2H),1.54(qd,J＝11.6,4.3Hz,2H),1.30(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C23H30N6O2[M+H]+:423.24，实测值为423.85。
实施例13
[C55](S)-1-氟-N-(4-(((2-(3-羟基吡咯烷-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)环丙烷-1-甲酰胺
以化合物4-(N-Boc-氨基甲基)苯胺和1-氟环丙基甲酸为原料，参考化合物3.1的合成路线，制备得化合物13.1，收率98％。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,2H),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)。
以化合物13.1为原料，参考化合物3.2的合成路线，制备得化合物13.2，收率99％。1H NMR(500MHz,DMSO-d6)δ10.33(s,1H),8.17(s,3H),7.74(d,J＝8.6Hz,2H),7.40(d,J＝8.6Hz,2H),3.99(q,J＝5.8Hz,2H),1.45–1.37(m,2H),1.31(td,J＝9.4,8.9,5.7Hz,2H)。
以化合物13.2和化合物1.3为原料，参考化合物1.4的合成路线，制备得化合物13.3，收率76％。1H 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),3.32(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)。
以化合物13.3为原料，参考化合物2.2的合成路线，制备得化合物C55，收率32％。1H NMR(500MHz,Methanol-d4)δ7.92(s,1H),7.61(d,J＝8.6Hz,2H),7.42(d,J＝8.6Hz,2H),4.77(s,2H),4.63–4.52(m,1H),3.93(dd,J＝26.2,16.8Hz,1H),3.79(dd,J＝22.7,11.2Hz,3H),3.25–3.19(m,1H),2.11(d,J＝46.3Hz,2H),1.40(dd,J＝3.9,2.1Hz,1H),1.39–1.37(m,1H),1.37(d,2H),1.28(dd,J＝6.9,4.5Hz,6H).UPLC-MS(ESI)理论值为C23H28FN7O2[M+H]+:454.23，实测值为454.32。
[C56](R)-1-氟-N-(4-(((2-(3-羟基吡咯烷-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)环丙烷-1-甲酰胺
以化合物13.3为原料，参考C55的合成路线，将(S)-3-吡咯烷醇换成(R)-3-吡咯烷醇，制备得化合物C56，收率47％。1H NMR(500MHz,Methanol-d4)δ1H NMR(500MHz,Methanol-d4)δ7.69(s,1H),7.57(d,J＝8.6Hz,2H),7.41(d,J＝8.7Hz,2H),4.70(s,2H),4.48(dd,J＝4.9,2.6Hz,1H),3.74(t,J＝10.0Hz,1H),3.70–3.59(m,3H),3.07(p,J＝6.9Hz,1H),2.10(dp,J＝13.4,4.5Hz,1H),1.99(q,J＝10.2,8.9Hz,1H),1.39(dq,J＝7.7,2.8,2.2Hz,2H),1.36–1.35(m,2H),1.27(dd,J＝7.0,3.7Hz,6H).UPLC-MS(ESI)理论值为C23H28FN7O2[M+H]+:454.23，实测值为454.32。
[C57]1-氟-N-(4-(((8-异丙基-2-(氧杂环丁烷-3-基氨基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)环丙烷-1-甲酰胺
以化合物13.3为原料，参考化合物C55的合成路线，将(S)-3-吡咯烷醇换成3-氧杂环丁胺，制备得化合物C57，收率24％。1H NMR(500MHz,Methanol-d4)δ7.87(s,1H),7.61(d,J＝6.9Hz,2H),7.40(d,J＝8.0Hz,2H),5.12–5.08(m,1H),4.77(d,J＝4.1Hz,2H),4.66(td,J＝6.5,3.3Hz,2H),4.48–4.30(m,1H),3.82–3.65(m,1H),3.08–3.01(m,1H),1.40(d,2H),1.37(d,2H),1.29(d,J＝7.0Hz,6H).UPLC-MS(ESI)理论值为C22H26FN7O2[M+H]+:440.21，实测值为440.76。
[C58]1-氟-N-(4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)环丙烷-1-甲酰胺
以化合物13.3为原料，参考化合物C55的合成路线，将(S)-3-吡咯烷醇换成4-氨基四氢吡喃，收率59％。1H NMR(500MHz,Methanol-d4)δ7.89(s,1H),7.61(d,J＝8.1Hz,2H),7.40(d,J＝7.1Hz,2H),4.77(d,2H),4.12(dt,J＝11.6,5.3Hz,1H),3.96(d,J＝12.1Hz,2H),3.51(t,J＝11.6Hz,2H),3.05–2.97(m,1H),1.89–1.81(m,2H),1.65–1.58(m,2H),1.41–1.36(m,4H),1.29(d,J＝7.0Hz,6H).UPLC-MS(ESI)理论值为C24H30FN7O2[M+H]+:468.24，实测值为468.37。
[C59](S)-1-氟-N-(4-(((2-((1-羟基丁-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)环丙烷-1-甲酰胺
以化合物13.3为原料，参考化合物C55的合成路线，将(S)-3-吡咯烷醇换成(S)-(+)-2-氨基-1-丁醇，制备得化合物C59，收率68％。1H NMR(500MHz,Methanol-d4)δ7.68(s,1H),7.58(d,J＝8.6Hz,2H),7.39(d,J＝8.5Hz,2H),4.71(d,J＝11.9Hz,2H),4.03–3.91(m,1H),3.66–3.57(m,2H),3.00(p,J＝6.9Hz,1H),1.70(ddd,J＝13.6,7.7,5.9Hz,1H),1.59–1.50(m,1H),1.40–1.37(m,2H),1.37–1.35(m,2H),1.27(d,J＝7.0Hz,6H),0.97(t,J＝7.5Hz,3H).UPLC-MS(ESI)理论值为C23H30FN7O2[M+H]+:456.24，实测值为456.38。
[C60](R)-1-氟-N-(4-(((2-((1-羟基丁-2-基)氨基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)环丙烷-1-甲酰胺
以化合物13.3为原料，参考化合物C55的合成路线，将(S)-3-吡咯烷醇换成(R)-(-)-2-氨基-1-丁醇，制备得化合物C60，收率56％。1H NMR(500MHz,Methanol-d4)δ7.67(s,1H),7.58(d,J＝8.5Hz,2H),7.39(d,J＝8.3Hz,2H),4.71(d,J＝11.9Hz,2H),4.02–3.91(m,1H),3.66–3.56(m,2H),3.03–2.96(m,1H),1.70(ddd,J＝13.6,7.7,5.9Hz,1H),1.60–1.48(m,1H),1.40–1.37(m,2H),1.37–1.35(m,2H),1.27(d,J＝7.0Hz,6H),0.98(t,3H).UPLC-MS(ESI)理论值为C23H30FN7O2[M+H]+:456.24，实测值为456.38。
[C61](R)-1-氟-N-(4-(((2-(2-(羟甲基)吡咯烷-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)环丙烷-1-甲酰胺
以化合物13.3为原料，参考化合物C55的合成路线，将(S)-3-吡咯烷醇换成D-脯氨醇，制备得化合物C61，收率44％。1H NMR(500MHz,Methanol-d4)δ7.88(s,1H),7.61(d,J＝8.6Hz,2H),7.42(d,J＝8.1Hz,2H),4.78(d,2H),4.23(dd,J＝10.2,4.6Hz,1H),4.10–4.03(m,1H),3.91(d,J＝11.3Hz,1H),3.74–3.69(m,2H),3.00–2.91(m,1H),2.31–2.24(m,1H),1.98(ddd,J＝26.8,12.7,5.7Hz,2H),1.85(dq,J＝12.1,6.9,6.3Hz,1H),1.41(t,J＝3.0Hz,1H),1.38(t,J＝2.0Hz,1H),1.37(d,2H),1.29(d,J＝6.3Hz,6H).UPLC-MS(ESI)理论值为C24H30FN7O2[M+H]+:468.24，实测值为found 468.40。
[C62](S)-1-氟-N-(4-(((2-(2-(羟甲基)吡咯烷-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)环丙烷-1-甲酰胺
以化合物13.3为原料，参考化合物C55的合成路线，将(S)-3-吡咯烷醇换成L-脯氨醇，制备得化合物C62，收率35％。1H NMR(500MHz,Methanol-d4)δ7.89(s,1H),7.60(d,J＝8.3Hz,2H),7.42(d,J＝8.1Hz,2H),4.78(d,2H),4.29–4.15(m,1H),4.07(dd,J＝16.1,9.2Hz,1H),3.91(d,J＝11.2Hz,1H),3.72(dt,J＝12.4,6.3Hz,2H),3.06–2.84(m,1H),2.31–2.24(m,1H),2.07–1.94(m,2H),1.93–1.79(m,1H),1.41–1.38(m,2H),1.38–1.36(m,2H),1.29(d,J＝6.5Hz,6H).UPLC-MS(ESI)理论值为C24H30FN7O2[M+H]+:468.24，实测值为468.34。
[C136](S)-1-氟-N-(4-(((2-(2-(2-羟基乙基)哌啶-1-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)环丙烷-1-甲酰胺
以化合物13.3为原料，参考化合物C55的合成路线，将(S)-3-吡咯烷醇换成(S)-2-(2-哌啶基)乙醇，制备得C136，收率38％。1H NMR(500MHz,DMSO-d6)δ10.19(d,J＝2.3Hz,1H),9.14(s,1H),7.79(s,1H),7.66–7.60(m,2H),7.40–7.31(m,2H),4.91(s,1H),4.57(d,J＝6.3Hz,3H),3.38(tt,J＝12.9,6.6Hz,2H),3.01–2.84(m,2H),1.91(s,1H),1.74–1.50(m,6H),1.43–1.25(m,5H),1.21(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C26H34FN7O2[M+H]+:496.60，实测值为496.53。
实施例14
[C106]8-异丙基-N4-(4-(4-甲基-1H-咪唑-1-基)苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
以化合物14.1和化合物1.3为原料，参考化合物1.4的合成路线，制备得化合物14.2，收率63％。
以化合物14.2和化合物14.3为原料，参考化合物C55的合成路线，制备得C106，收率35％。1H NMR(600MHz,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＝65.2Hz,1H),4.64(s,2H),3.93–3.78(m,3H),3.35(tt,J＝12.5,6.6Hz,2H),2.90(s,1H),2.24–2.20(m,3H),1.74(d,J＝127.2Hz,2H),1.52–1.38(m,2H),1.24–1.20(m,6H).UPLC-MS(ESI)理论值为C24H30N8O[M+H]+:447.56，实测值为447.39。
[C108]5-(4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)-1-甲基吡啶-2(1H)-酮
以化合物1.3和化合物14.3为原料，参考化合物C106的合成路线，将(4-(4-甲基-1H-咪唑-1-基)苯基)甲胺换成5-(4-(氨基甲基)苯基)吡啶-2(1H)-酮，制备得化合物C108，收率48％。1H NMR(500MHz,DMSO-d6)δ8.08(d,J＝2.7Hz,1H),7.78(dd,J＝9.5,2.7Hz,2H),7.55–7.48(m,2H),7.41(d,J＝8.0Hz,2H),6.46(d,J＝9.4Hz,1H),4.62(d,J＝6.2Hz,2H),3.96–3.88(m,1H),3.84(d,J＝11.3Hz,2H),3.49(s,3H),3.36(td,J＝11.6,2.1Hz,2H),2.97–2.84(m,1H),1.76(d,J＝73.7Hz,2H),1.46(s,2H),1.22(d,J＝6.4Hz,6H).UPLC-MS(ESI)理论值为C26H31N7O2[M+H]+:474.58，实测值为474.38。
[C122]8-异丙基-N4-(4-(哒嗪-3-基)苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
以化合物1.3和化合物14.3为原料，参考化合物C106的合成路线，将(4-(4-甲基-1H-咪唑-1-基)苯基)甲胺换成(4-(哒嗪-3-基)苯基)甲胺，制备得化合物C122，收率40％。1H NMR(500MHz,DMSO-d6)δ9.19(dd,J＝4.9,1.6Hz,1H),8.19(dd,J＝8.7,1.6Hz,1H),8.15–8.08(m,2H),7.76(dd,J＝8.7,4.9Hz,1H),7.54(d,J＝7.9Hz,2H),7.11(d,J＝201.7Hz,1H),4.70(d,J＝6.3Hz,2H),3.85(d,J＝33.2Hz,3H),3.35(t,J＝11.7Hz,2H),2.92(t,J＝7.1Hz,1H),1.74(d,J＝100.3Hz,2H),1.42(d,J＝37.7Hz,2H),1.22(t,J＝5.1Hz,6H).UPLC-MS(ESI)理论值为C24H28N8O[M+H]+:445.54，实测值为445.35。
[C107]1-(4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)吡啶-2(1H)-酮
以化合物1.3和化合物14.3为原料，参考化合物C106的合成路线，将(4-(4-甲基-1H-咪唑-1-基)苯基)甲胺换成1-(4-(氨基甲基)苯基)吡啶-2(1H)-酮，制备得化合物C107，收率52％。1H NMR(800MHz,DMSO-d6)δ7.73(s,1H),7.60(d,J＝8.3Hz,1H),7.48(ddd,J＝14.3,7.0,3.7Hz,3H),7.35–7.32(m,2H),6.46(dt,J＝9.3,0.9Hz,1H),6.29(td,J＝6.7,1.4Hz,1H),4.66(d,J＝16.8Hz,2H),3.93–3.86(m,1H),3.84(d,J＝10.9Hz,2H),3.35(s,2H),2.91(s,1H),1.95–1.52(m,2H),1.45(d,J＝45.6Hz,2H),1.23(dd,J＝12.1,6.1Hz,6H).UPLC-MS(ESI)理论值为C25H29N7O2[M+H]+:460.55，实测值为460.36。
[C114]8-异丙基-N4-(4-(1-甲基-1H-吡唑-4-基)苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
以化合物1.3和化合物14.3为原料，参考化合物C106的合成路线，将(4-(4-甲基-1H-咪唑-1-基)苯基)甲胺换成(4-(1-甲基-1H-吡唑-4-基)苯基)甲胺，制备得化合物C114，收率37％。1H NMR(500MHz,DMSO-d6)δ8.78(d,J＝153.1Hz,1H),8.08(d,J＝0.7Hz,1H),7.81(d,J＝0.8Hz,1H),7.71(s,1H),7.49(d,J＝7.8Hz,2H),7.34(d,J＝8.0Hz,2H),6.86(s,1H),4.58(s,2H),3.84(s,6H),3.34(d,J＝11.2Hz,2H),2.91(d,J＝12.5Hz,1H),1.93–1.58(m,2H),1.46(s,2H),1.22(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C24H30N8O[M+H]+:447.56，实测值为447.38。
[C115]8-异丙基-N4-(4-(恶唑-5-基)苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
以化合物1.3和化合物14.3为原料，参考化合物C106的合成路线，将(4-(4-甲基-1H-咪唑-1-基)苯基)甲胺换成(4-(恶唑-5-基)苯基)甲胺，制备得化合物C115，收率48％。1H NMR(500MHz,DMSO-d6)δ9.03(s,1H),8.41(s,1H),7.72(s,1H),7.68(d,J＝8.0Hz,2H),7.64(s,1H),7.46(d,J＝8.1Hz,2H),6.92(d,J＝52.1Hz,1H),4.63(s,2H),3.83(s,3H),3.34(s,2H),2.90(s,1H),1.92–1.56(m,2H),1.45(s,2H),1.22(d,J＝7.5Hz,6H).
UPLC-MS(ESI)理论值为C23H27N7O2[M+H]+:434.52，实测值为434.25。
[C87]8-异丙基-N4-(4-苯氧基苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
以化合物1.3和化合物14.3为原料，参考化合物C106的合成路线，将(4-(4-甲基-1H-咪唑-1-基)苯基)甲胺换成(4-苯氧基苯基)甲胺，制备得化合物C87，收率44％。1H NMR(500MHz,DMSO-d6)δ9.99(s,1H),8.21(d,J＝244.0Hz,2H),7.41(d,J＝8.1Hz,2H),7.39–7.34(m,2H),7.12(t,J＝7.4Hz,1H),6.96(dd,J＝8.8,6.8Hz,4H),4.63(d,J＝6.1Hz,2H),3.99(s,1H),3.83(d,J＝11.3Hz,2H),3.37(td,J＝11.6,2.2Hz,2H),2.97(p,J＝6.9Hz,1H),1.91–1.66(m,2H),1.51(dt,J＝12.3,6.2Hz,2H),1.21(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C26H30N6O2[M+H]+:459.57，实测值为459.40。
[C93]N4-(4-(4-氯苯氧基)苄基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
以化合物1.3和化合物14.3为原料，参考化合物C106的合成路线，将(4-(4-甲基-1H-咪唑-1-基)苯基)甲胺换成(4-(4-氯苯氧基)苯基)甲胺，制备得化合物C93，收率55％。1H NMR(500MHz,DMSO-d6)δ9.99(s,1H),8.22(d,J＝257.5Hz,2H),7.47–7.37(m,4H),7.04–6.92(m,4H),4.63(d,J＝6.2Hz,2H),3.99(s,1H),3.92–3.74(m,2H),3.37(td,J＝11.6,2.2Hz,2H),2.97(p,J＝6.9Hz,1H),1.77(t,J＝27.6Hz,2H),1.49(qd,J＝11.4,4.3Hz,2H),1.21(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C26H29ClN6O2[M+H]+:494.01，实测值为493.33。
[C120]8-异丙基-N4-(4-(1-甲基-1H-咪唑-2-基)苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
以化合物1.3和化合物14.3为原料，参考化合物C106的合成路线，将(4-(4-甲基-1H-咪唑-1-基)苯基)甲胺换成(4-(1-甲基-1H-咪唑-2-基)苯基)甲胺，制备得化合物C120，收率47％。1H NMR(500MHz,DMSO-d6)δ9.99(s,1H),8.81(d,J＝107.7Hz,1H),7.97(s,1H),7.84(d,J＝1.9Hz,1H),7.80(d,J＝2.0Hz,1H),7.79–7.74(m,2H),7.66(d,J＝7.9Hz,2H),4.77(d,J＝6.3Hz,2H),3.94(s,1H),3.84(s,5H),3.44–3.28(m,2H),2.97(q,J＝6.9Hz,1H),1.93–1.64(m,2H),1.45(d,J＝12.9Hz,2H),1.21(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C24H30N8O[M+H]+:447.56，实测值为447.39。
[C102]1-(4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)吡咯烷-2-酮
以化合物1.3和化合物14.3为原料，参考化合物C106的合成路线，将(4-(4-甲基-1H-咪唑-1-基)苯基)甲胺换成1-(4-(氨基甲基)苯基)吡咯烷-2-酮，制备得化合物C102，收率39％。1H NMR(500MHz,DMSO-d6)δ10.25–9.81(m,1H),8.71(d,J＝113.4Hz,1H),7.86(d,J＝101.7Hz,1H),7.58(d,J＝8.4Hz,2H),7.38(d,J＝8.2Hz,2H),4.62(d,J＝6.1Hz,2H),4.03–3.96(m,1H),3.87–3.82(m,2H),3.79(t,J＝7.0Hz,2H),3.38(t,J＝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)理论值为C24H31N7O2[M+H]+:450.56，实测值为450.50。
实施例15
[C123]4'-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)-[1,1'-联苯]-3-羧酸
以化合物15.1和化合物1.3为原料，参考化合物1.4的合成路线，制备得化合物15.2，收率51％。
以化合物15.2和化合物14.3为原料，参考化合物C55的合成路线，制备得15.3，收率40％。
将化合物15.3溶于二氯甲烷中，加入三氟乙酸，室温反应6h，减压浓缩后残渣用少量水和乙腈分别洗涤，得化合物C123，收率95％。1H NMR(800MHz,DMSO-d6)δ10.05(s,1H),8.16(d,J＝1.9Hz,1H),7.98(s,1H),7.92(d,J＝7.7Hz,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＝6.2Hz,2H),3.99(s,1H),3.89–3.75(m,2H),3.38(t,J＝11.6Hz,2H),2.98(p,J＝6.9Hz,1H),1.90–1.67(m,2H),1.47(d,J＝12.5Hz,2H),1.21(d,J＝7.3Hz,6H).UPLC-MS(ESI)理论值为C27H30N6O3[M+H]+:487.58，实测值为487.34。
实施例16
[C111]8-溴-N2-(四氢-2H-吡喃-4-基)-N4-(4-(噻吩-2-基)苄基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
以化合物16.1和化合物16.2为原料，参考化合物1.4的合成路线，制备得化合物16.3，收率58％。
将化合物16.3(72mg,0.167mmol,1.0equiv.)溶于二氯甲烷中，冰浴下分批加入间氯过氧苯甲酸(108mg,80％,0.500mmol,3.0equiv.)，转移至室温反应5h，反应完毕后减压浓缩，柱层析纯化，得化合物16.4(65mg)，收率84％。
以化合物16.4和化合物14.3为原料，参考化合物C55的合成路线，制备得C111，收率38％。1H 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＝5.1,3.6Hz,1H),4.70–4.54(m,2H),4.04–3.76(m,3H),3.35 (dt,J＝23.9,11.6Hz,2H),1.71(dd,J＝101.3,12.5Hz,2H),1.56–1.33(m,2H).UPLC-MS(ESI)理论值为C21H21BrN6OS[M+H]+:486.40，实测值为485.17,487.16。
[C110]8-溴-N4-(4-(吡啶-2-基)苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
以化合物16.1和化合物14.3为原料，参考化合物C111的合成路线，将(4-(噻吩-2-基)苯基)甲胺换成(4-(吡啶-2-基)苯基)甲胺，制备得化合物C110，收率42％。1H NMR(500MHz,DMSO-d6)δ9.16(d,J＝182.7Hz,1H),8.70(dt,J＝5.0,1.4Hz,1H),8.07–8.00(m,4H),7.97(s,1H),7.51(d,J＝8.1Hz,2H),7.48(d,J＝4.4Hz,1H),4.69(d,J＝13.7Hz,2H),4.06–3.72(m,3H),3.43–3.26(m,2H),1.88–1.57(m,2H),1.57–1.30(m,2H).UPLC-MS(ESI)理论值为C22H22BrN7O[M+H]+:481.37，实测值为480.21,482.20。
[C124]1-(4-(((8-溴-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)吡啶-2(1H)-酮
以化合物16.1和化合物14.3为原料，参考化合物C111的合成路线，将(4-(噻吩-2-基)苯基)甲胺换成1-(4-(氨基甲基)苯基)吡啶-2(1H)-酮，制备得化合物C124，收率37％。1H NMR(500MHz,DMSO-d6)δ9.24(d,J＝227.3Hz,1H),7.97(d,J＝8.6Hz,1H),7.72–7.41(m,5H),7.36–7.33(m,2H),6.46(dt,J＝9.3,0.9Hz,1H),6.29(td,J＝6.7,1.4Hz,1H),4.77–4.61(m,2H),3.93(d,J＝24.4Hz,1H),3.83(d,J＝11.3Hz,2H),3.36(t,J＝11.3Hz,2H),1.74(d,J＝64.7Hz,2H),1.46(d,J＝32.5Hz,2H).UPLC-MS(ESI)理论值为C22H22BrN7O2[M+H]+:497.37，实测值为496.26,498.24。
[C125]8-溴-N4-(4-(4-甲基-1H-咪唑-1-基)苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
以化合物16.1和化合物14.3为原料，参考化合物C111的合成路线，将(4-(噻吩-2-基)苯基)甲胺换成(4-(4-甲基-1H-咪唑-1-基)苯基)甲胺，制备得化合物C125，收率25％。1H NMR(500MHz,DMSO-d6)δ9.51(s,1H),9.13(d,J＝130.4Hz,1H),7.96(s,2H),7.70(d,J＝8.2Hz,2H),7.61(d,J＝8.2Hz,2H),7.49–7.22(m,1H),4.68(s,2H),4.00(d,J＝7.2Hz,3H),3.36(dt,J＝20.5,11.2Hz,2H),2.34(s,3H),1.81(d,J＝12.7Hz,1H),1.61(d,J＝12.6Hz,1H),1.49(d,J＝13.0Hz,1H),1.38(d,J＝12.0Hz,1H).UPLC-MS(ESI)理论值为C21H23BrN8O[M+H]+:484.37，实测值为483.24,485.21。
实施例17
[C127]N-(4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)丙酰胺
以5,7-二氯-3-异丙基吡唑并[1,5-a]嘧啶和化合物10.2为原料，参考化合物11.1的合成路线，制备得化合物17.1，收率78％。
以化合物17.1为原料，参考化合物11.2的合成路线，制备得化合物17.2，收率85％。
以化合物17.2和化合物14.3为原料，参考化合物11.3的合成路线，制备得化合物17.3，收率51％。
以化合物17.3为原料，参考化合物C37的合成路线，制备得化合物C127，收率93％。1H NMR(500MHz,DMSO-d6)δ9.87(s,1H),9.37(s,1H),8.20(s,1H),7.99(s,1H),7.59–7.52(m,2H),7.33(d,J＝8.3Hz,2H),5.37(s,1H),4.58(d,J＝6.2Hz,2H),3.88–3.84(m,3H),3.41(td,J＝11.6,2.1Hz,2H),3.09(s,1H),2.29(q,J＝7.6Hz,2H),1.80–1.69(m,2H),1.50–1.37(m,2H),1.21(d,J＝6.9Hz,6H),1.06(t,J＝7.5Hz,3H).UPLC-MS(ESI)理论值为C24H32N6O2[M+H]+:437.56，实测值为437.50。
实施例18
[C126]1-氟-N-(4-(((3-异丙基-5-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)环丙烷-1-甲酰胺
以5,7-二氯-3-异丙基吡唑并[1,5-a]嘧啶和化合物13.2为原料，参考化合物11.1的合成路线，制备得化合物18.1，收率70％。
以化合物18.1为原料，参考化合物11.2的合成路线，制备得化合物18.2，收率82％。
以化合物18.2和化合物14.3为原料，参考化合物11.3的合成路线，制备得化合物18.3，收率42％。
以化合物18.3为原料，参考化合物C37的合成路线，制备得化合物C126，收率90％。1H NMR(500MHz,DMSO-d6)δ10.24(d,J＝2.2Hz,1H),9.31(s,1H),8.11(s,1H),7.97(s,1H),7.69–7.62(m,2H),7.37(d,J＝8.3Hz,2H),5.37(s,1H),4.60(d,J＝6.2Hz,2H),3.93–3.81(m,3H),3.44–3.38(m,2H),3.08(p,J＝7.2Hz,1H),1.84–1.70(m,2H),1.42(dddd,J＝ 23.0,18.1,9.5,4.6Hz,4H),1.32–1.25(m,2H),1.21(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C25H31FN6O2[M+H]+:467.56，实测值为467.74。
实施例19
[C137](R)-N-(4-(((8-溴-2-(2-(羟基甲基)吡咯烷-1-基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物16.1和化合物3.2为原料，参考化合物16.3的合成路线，制备得化合物19.1，收率55％。
以化合物19.1为原料，参考化合物16.4的合成路线，制备得化合物19.2，收率88％。
以化合物19.2和(R)-2-吡咯烷甲醇为原料，参考化合物C111的合成路线，制备得化合物C137，收率45％。1H NMR(500MHz,DMSO-d6)δ9.90(s,1H),9.19–8.96(m,1H),7.94(d,J＝4.4Hz,1H),7.55–7.46(m,2H),7.32(d,J＝8.1Hz,2H),4.55(t,J＝5.2Hz,2H),4.12(d,J＝9.5Hz,1H),3.63(dd,J＝10.4,3.9Hz,1H),3.60–3.29(m,3H),2.01(s,3H),1.99–1.74(m,4H).UPLC-MS(ESI)理论值为C19H22BrN7O2[M+H]+:461.34，实测值为460.33,462.33。
[C138](S)-N-(4-(((8-溴-2-(2-(羟基甲基)吡咯烷-1-基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物19.2和(S)-2-吡咯烷甲醇为原料，参考化合物C137的合成路线，制备得化合物C138，收率49％。1H NMR(500MHz,DMSO-d6)δ9.90(s,1H),9.16–9.00(m,1H),7.94(d,J＝4.1Hz,1H),7.51(d,J＝8.4Hz,2H),7.32(d,J＝8.0Hz,2H),4.55(d,J＝5.6Hz,2H),4.12(d,J＝6.3Hz,1H),3.63(dd,J＝10.4,3.9Hz,1H),3.60–3.29(m,3H),2.01(s,3H),2.00–1.78(m,4H).UPLC-MS(ESI)理论值为C19H22BrN7O2[M+H]+:461.34，实测值为460.34,462.34。
[C139](S)-N-(4-(((8-溴-2-(2-(2-羟乙基)哌啶-1-基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺
以化合物19.2和(S)-2-(2-哌啶基)乙醇为原料，参考化合物C137的合成路线，制备得化合物C139，收率39％。1H NMR(500MHz,DMSO-d6)δ9.91(s,1H),9.01(s,1H),7.93(s,1H),7.50(d,J＝8.5Hz,2H),7.31(d,J＝8.2Hz,2H),4.99(s,1H),4.70–4.59(m,1H),4.53(d,J＝6.2Hz,2H),3.35(t,J＝6.6Hz,2H),2.87(t,J＝12.1Hz,1H),2.01(s,3H),1.88(s,1H),1.74–1.58(m,4H),1.58–1.44(m,2H),1.35–1.25(m,1H).UPLC-MS(ESI)理论值为C21H26BrN7O2[M+H]+:489.39，实测值为488.37,490.36。
实施例20
[C140](R)-N-(4-(((8-溴-2-(3-羟基吡咯烷-1-基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物16.1和化合物10.2为原料，参考化合物16.3的合成路线，制备得化合物20.1，收率60％。
以化合物20.1为原料，参考化合物16.4的合成路线，制备得化合物20.2，收率83％。
以化合物20.2和(R)-3-吡咯烷醇为原料，参考化合物C111的合成路线，制备得化合物C140，收率49％。1H NMR(600MHz,DMSO-d6)δ9.84(s,1H),9.05(d,J＝6.6Hz,1H),7.94(s,1H),7.52(d,J＝8.2Hz,2H),7.35–7.29(m,2H),4.54(d,J＝6.3Hz,2H),4.36–4.31(m,1H),3.69–3.41(m,4H),2.29(q,J＝7.5Hz,2H),2.01–1.92(m,1H),1.88–1.83(m,1H),1.06(t,J＝7.5Hz,3H).UPLC-MS(ESI)理论值为C19H22BrN7O2[M+H]+:461.34，实测值为460.37,462.35。
[C141](S)-N-(4-(((8-溴-2-(3-羟基吡咯烷-1-基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物20.2和(S)-3-吡咯烷醇为原料，参考化合物C140的合成路线，制备得化合物C141，收率53％。1H NMR(600MHz,DMSO-d6)δ9.84(s,1H),9.09(d,J＝6.7Hz,1H),7.94(s,1H),7.53(d,J＝8.3Hz,2H),7.32(d,J＝8.1Hz,2H),4.55(d,J＝6.3Hz,2H),4.34(dt,J＝6.1,2.8Hz,1H),3.69–3.41(m,4H),2.29(q,J＝7.5Hz,2H),1.97(q,J＝3.9Hz,1H),1.86(dt,J＝8.9,4.3Hz,1H),1.06(t,J＝7.6Hz,3H).UPLC-MS(ESI)理论值为C19H22BrN7O2[M+H]+:461.34，实测值为460.37,462.36。
[C142](R)-N-(4-(((8-溴-2-(2-(羟基甲基)吡咯烷-1-基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物20.2和(R)-2-吡咯烷甲醇为原料，参考化合物C140的合成路线，制备得化合物C142，收率55％。1H NMR(500MHz,DMSO-d6)δ9.82(s,1H),9.14–9.00(m,1H),7.94(d,J＝4.1Hz,1H),7.52(d,J＝8.4Hz,2H),7.32(d,J＝8.1Hz,2H),4.54(t,J＝5.7Hz,2H),4.11(s,1H),3.63(dd,J＝10.5,3.8Hz,1H),3.60–3.30(m,3H),2.29(q,J＝7.5Hz,2H),1.92(ddd,J＝56.2,32.2,10.3Hz,4H),1.06(t,J＝7.6Hz,3H).UPLC-MS(ESI)理论值为C20H24BrN7O2[M+H]+:475.36，实测值为474.35,476.35。
[C143](S)-N-(4-(((8-溴-2-(2-(羟基甲基)吡咯烷-1-基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物20.2和(S)-2-吡咯烷甲醇为原料，参考化合物C140的合成路线，制备得化合物C143，收率40％。1H NMR(500MHz,DMSO-d6)δ9.82(s,1H),9.16–9.00(m,1H),7.94(d,J＝4.6Hz,1H),7.52(d,J＝8.3Hz,2H),7.32(d,J＝8.0Hz,2H),4.55(t,J＝5.7Hz,2H),4.16–4.06(m,1H),3.63(dd,J＝10.4,3.9Hz,1H),3.61–3.30(m,3H),2.29(q,J＝7.5Hz,2H),1.92(ddd,J＝55.6,35.0,8.7Hz,4H),1.06(t,J＝7.5Hz,3H).UPLC-MS(ESI)理论值为C20H24BrN7O2[M+H]+:475.36，实测值为474.35,476.34。
[C144](S)-N-(4-(((8-溴-2-(2-(2-羟乙基)哌啶-1-基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
以化合物20.2和(S)-2-(2-哌啶基)乙醇为原料，参考化合物C140的合成路线，制备得化合物C144，收率37％。1H NMR(600MHz,DMSO-d6)δ9.83(s,1H),9.03(s,1H),7.94(s,1H),7.52(d,J＝8.2Hz,2H),7.31(d,J＝8.1Hz,2H),4.97(s,1H),4.57–4.50(m,3H),3.36(d,J＝6.6Hz,2H),2.87(t,J＝13.4Hz,1H),2.29(q,J＝7.5Hz,2H),1.87(s,1H),1.74–1.45(m,6H),1.36–1.25(m,1H),1.05(t,J＝7.5Hz,3H).UPLC-MS(ESI)理论值为C22H28BrN7O2[M+H]+:503.42，实测值为502.38,504.37。
实施例21
[C145](R)-N-(4-(((8-溴-2-(3-羟基吡咯烷-1-基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)-1-氟环丙烷-1-甲酰胺
以化合物16.1和化合物13.2为原料，参考化合物16.3的合成路线，制备得化合物21.1，收率47％。
以化合物21.1为原料，参考化合物16.4的合成路线，制备得化合物21.2，收率76％。
以化合物21.2和(R)-3-吡咯烷醇为原料，参考化合物C111的合成路线，制备得化合物C145，收率31％。1H NMR(500MHz,DMSO-d6)δ10.24–10.15(m,1H),9.08(d,J＝5.5Hz,1H),7.94(s,1H),7.68–7.60(m,2H),7.35(d,J＝8.1Hz,2H),4.57(d,J＝6.3Hz,2H),4.38–4.31(m,1H),3.69–3.42(m,4H),1.96(qd,J＝8.7,4.4Hz,1H),1.85(dq,J＝12.7,3.5Hz,1H),1.43–1.34(m,2H),1.33–1.25(m,2H).UPLC-MS(ESI)理论值为C20H21BrFN7O2[M+H]+:491.34，实测值为490.32,492.32。
[C146](S)-N-(4-(((8-溴-2-(3-羟基吡咯烷-1-基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)-1-氟环丙烷-1-甲酰胺
以化合物21.2和(S)-3-吡咯烷醇为原料，参考化合物C145的合成路线，制备得化合物C146，收率50％。1H NMR(500MHz,DMSO-d6)δ10.19(s,1H),9.03(d,J＝6.2Hz,1H),7.93(s,1H),7.63(d,J＝8.4Hz,2H),7.39–7.30(m,2H),4.57(d,J＝6.3Hz,2H),4.33(s,1H),3.61–3.42(m,4H),1.96(dtd,J＝13.2,8.7,4.3Hz,1H),1.84(dd,J＝14.3,6.1Hz,1H),1.43–1.25(m,4H).UPLC-MS(ESI)理论值为C20H21BrFN7O2[M+H]+:491.34，实测值为490.33,492.32。
[C147](R)-N-(4-(((8-溴-2-(2-(羟基甲基)吡咯烷-1-基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)-1-氟环丙烷-1-甲酰胺
以化合物21.2和(R)-2-吡咯烷甲醇为原料，参考化合物C145的合成路线，制备得化合物C147，收率39％。1H NMR(500MHz,DMSO-d6)δ10.19(d,J＝2.3Hz,1H),9.14–8.99(m,1H),7.94(d,J＝3.8Hz,1H),7.63(d,J＝8.4Hz,2H),7.35(d,J＝8.1Hz,2H),4.62–4.52(m,2H),4.11(s,1H),3.63(dd,J＝10.5,3.8Hz,1H),3.60–3.28(m,3H),1.92(td,J＝42.9,41.8,11.2Hz,4H),1.43–1.25(m,4H).UPLC-MS(ESI)理论值为C21H23BrFN7O2[M+H]+:505.36，实测值为504.31,506.30。
[C148](S)-N-(4-(((8-溴-2-(2-(羟基甲基)吡咯烷-1-基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)-1-氟环丙烷-1-甲酰胺
以化合物21.2和(S)-2-吡咯烷甲醇为原料，参考化合物C145的合成路线，制备得化合物C148，收率42％。1H NMR(500MHz,DMSO-d6)δ10.19(d,J＝2.2Hz,1H),9.19–9.01(m,1H),7.94(d,J＝3.8Hz,1H),7.62(d,J＝8.4Hz,2H),7.35(d,J＝8.1Hz,2H),4.57(t,J＝5.3Hz,2H),4.10(d,J＝7.6Hz,1H),3.62(dd,J＝10.4,3.9Hz,1H),3.59–3.29(m,3H),1.91(tdd,J＝36.5,17.5,8.5Hz,4H),1.43–1.24(m,4H).UPLC-MS(ESI)理论值为C21H23BrFN7O2[M+H]+:505.36，实测值为504.31,506.30。
[C149](S)-N-(4-(((8-溴-2-(2-(2-羟基乙基)哌啶-1-基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)-1-氟环丙烷-1-甲酰胺
以化合物21.2和(S)-2-(2-哌啶基)乙醇为原料，参考化合物C145的合成路线，制备得化合物C149，收率40％。1H NMR(500MHz,DMSO-d6)δ10.19(d,J＝2.2Hz,1H),9.05(s,1H),7.94(s,1H),7.66–7.60(m,2H),7.35(d,J＝8.2Hz,2H),5.00(s,1H),4.60(dd,J＝40.8,9.4Hz,3H),3.35(t,J＝6.6Hz,2H),2.87(td,J＝13.6,12.7,4.3Hz,1H),1.87(s,1H),1.75–1.45(m,6H),1.43–1.25(m,5H).UPLC-MS(ESI)理论值为C23H27BrFN7O2[M+H]+:533.42，实测值为532.36,534.34。
[C64]N-(4-(((8-环丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C64。
[C65]N-(4-(((8-异丙基-2-吗啉基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C65。
[C66]N-(4-(((8-环丙基-2-吗啉基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C66。
[C67]N-(4-(((8-溴-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C67。
[C68]N-(4-(((8-(1-甲基-1H-吡唑-4-基)-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C68。
[C69]N-(4-(((2-((四氢-2H-吡喃-4-基)氨基)-8-(三氟甲基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C69。
[C70]N-(4-(((8-氰基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C70。
[C71]N-(4-(((8-环丁基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C71。
[C72]N-(4-(((2-((四氢-2H-吡喃-4-基)氨基)-8-(2,2,2-三氟乙基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C72。
[C73]N-(4-(((8-(氧杂环丁烷-3-基)-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C73。
[C74]N-(4-(((8-(2,2-二氟环丙基)-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C74。
[C75]N-(4-(((8-(四氢-2H-吡喃-4-基)-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C75。
[C76]N-(4-(((8-(1-(二氟甲基)-1H-吡唑-4-基)-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C76。
[C77]N-(4-(((8-(哒嗪-4-基)-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C77。
[C78]N-(4-(((2-((四氢-2H-吡喃-4-基)氨基)-8-(噻唑-2-基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C78。
[C79]N-(4-(((2-((四氢-2H-吡喃-4-基)氨基)-8-(噻唑-4-基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C79。
[C80]N-(4-(((2-((四氢-2H-吡喃-4-基)氨基)-8-(噻唑-5-基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C80。
[C81]N-(2-氟-4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C81。
[C82]N-(2,3,5,6-四氟-4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C82。
[C83]N-(3,5-二氟-4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C83。
[C84]N-(2,6-二氟-4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C84。
[C85]N-(4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基-2,3,5,6-d4)丙酰胺
按上述合成路线可以合成化合物C85。
[C86]N-(4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)丙酰胺
按上述合成路线可以合成化合物C86。
[C87]8-异丙基-N4-(4-苯氧基苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C87。
[C88]N4-(4-(3-氟苯氧基)苄基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C88。
[C89]N4-(4-(4-氟苯氧基)苄基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C89。
[C90]N4-(4-(2-氟苯氧基)苄基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C90。
[C91]N4-(4-(3-氯-4-氟苯氧基)苄基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C91。
[C92]N4-(4-(3,4-二氟苯氧基)苄基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C92。
[C93]N4-(4-(4-氯苯氧基)苄基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C93。
[C94]N4-(4-(3,4-二氯苯氧基)苄基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C94。
[C95]8-异丙基-N2-(四氢-2H-吡喃-4-基)-N4-(4-((四氢呋喃-3-基)氧基)苄基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C95。
[C96]8-异丙基-N4-(4-(吡啶-4-基氧基)苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C96。
[C97]4-(4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)吗啉-3-酮
按上述合成路线可以合成化合物C97。
[C98]1-(4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)哌啶-2-酮
按上述合成路线可以合成化合物C98。
[C99]8-异丙基-N4-(4-(哌嗪-1-基)苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三 嗪-2,4-二胺
按上述合成路线可以合成化合物C99。
[C100]8-异丙基-N4-(4-吗啉苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C100。
[C101]8-异丙基-N4-(4-(4-甲基哌嗪-1-基)苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C101。
[C102]1-(4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)吡咯烷-2-酮
按上述合成路线可以合成化合物C102。
[C103]N4-(4-(4,7-二氮杂螺[2.5]辛-7-基)苄基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C103。
[C104]4'-(((8-溴-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)-[1,1'-联苯]-3-羧酸
按上述合成路线可以合成化合物C104。
[C105]N4-(4-(2H-四唑-5-基)苄基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C105。
[C106]8-异丙基-N4-(4-(4-甲基-1H-咪唑-1-基)苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C106。
[C107]1-(4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)吡啶-2(1H)-酮
按上述合成路线可以合成化合物C107。
[C108]5-(4-(((8-异丙基-2-((四氢-2H-吡喃-4-基)氨基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)-1-甲基吡啶-2(1H)-酮
按上述合成路线可以合成化合物C108。
[C109]8-溴-N2-(四氢-2H-吡喃-4-基)-N4-(4-(噻吩-3-基)苄基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C109。
[C110]8-溴-N4-(4-(吡啶-2-基)苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C110。
[C111]8-溴-N2-(四氢-2H-吡喃-4-基)-N4-(4-(噻吩-2-基)苄基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C111。
[C112]N4-(4-(1H-吡唑-4-基)苄基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C112。
[C113]N4-(4-(1H-咪唑-1-基)苄基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C113。
[C114]8-异丙基-N4-(4-(1-甲基-1H-吡唑-4-基)苄基)-N2-(四氢-2H-吡唑-4基)吡唑[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C114。
[C115]8-异丙基-N4-(4-(恶唑-5-基)苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C115。
[C116]8-异丙基-N4-(4-(异恶唑-4-基)苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C116。
[C117]8-异丙基-N2-(四氢-2H-吡喃-4-基)-N4-(4-(噻唑-5-基)苄基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C117。
[C118]N4-(4-(1H-咪唑-2-基)苄基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C118。
[C119]N4-(4-(1H-咪唑-4-基)苄基)-8-异丙基-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C119。
[C120]8-异丙基-N4-(4-(1-甲基-1H-咪唑-2-基)苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C120。
[C121]8-异丙基-N4-(4-(哒嗪-4-基)苄基)-N2-(四氢-2H-吡喃-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C121。
[C122]8-异丙基-N4-(4-(哒嗪-3-基)苄基)-N2-(四氢-2H-吡嗪-4-基)吡唑并[1,5-a][1,3,5]三嗪-2,4-二胺
按上述合成路线可以合成化合物C122。
实施例22：化合物对三阴性乳腺癌细胞的增殖生长抑制活性
1、实验方法
本发明中使用的人类三阴性乳腺癌细胞MDA-MB-231、MDA-MB-468及BT549都购买于上海细胞库，其中使用加有10％胎牛血清(FBS)及青霉素-链霉素(PS)抗生素的Leibovitzs(L-15)培养基，在37℃、不含CO2的培养箱中培养MDA-MB-231和MDA-MB- 468细胞，使用加有10％ FBS、1％青霉素-链霉素(PS)抗生素和重组人胰岛素溶液(Insulin)的RPMI 1640培养基，在37℃，含5％ CO2培养箱中培养BT549细胞。
在细胞活性测试实验中，根据细胞生长情况将合适浓度的90μL细胞悬液加入到96孔细胞培养板中，将每种需要测试的化合物用对应的培养基进行梯度稀释，取10μL稀释后的化合物加入到90μL的细胞液中，然后在37℃、5％ CO2条件中培养4天，细胞增殖通过WST-8进行分析，WST-8可以被细胞中的乳酸脱氢酶还原为黄色的甲瓒产物，取10μL的WST-8试剂(DOJINDO)加入到细胞中，在37℃下反应1小时以上，用DMSO处理的细胞作为阳性对照，酶标仪读取OD450nm，并用GraphPad Prism6软件处理数据。活性结果：A表述细胞活性IC50<1μM，B表述细胞活性1μM<IC50<3μM，C表述细胞活性IC50>3μM。
2、实验结果



基于以上化合物细胞生长抑制活性测试方法，在三阴性乳腺癌细胞株MDA-MB-231、MDA-MB-468及BT549中，与阳性化合物Control compound相比，本发明的化合物的对细胞生长抑制具有很好的抑制活性。因此，本发明的化合物可以作为三阴性乳腺癌细胞中相关靶点的新型抑制剂。
实施例23：化合物对CDK的体外激酶抑制活性
1、实验方法
在体外激酶活性测试实验中，使用Perkin Elmer公司的LANCE Ultra KinaSelect Ser/Thr检测试剂盒来测定CDK9激酶活性。该方法的反应是在384孔板中，反应的总体积是10μL。CDK9蛋白(终浓度为1ng/μL)、4EBP-1多肽底物(终浓度为50nM)和ATP(终浓度为2.5μM)在缓冲液：50mM HEPES-KOH(pH 7.5)，10mM MgCl2，2mM DTT，1mM EGTA中反应1h，加入相应Eu标记的抗磷酸化抗体Eu-anti-P-4E-BP1(终浓度为2nM)孵育30min，然后检测磷酸化情况，通过荧光检测仪Envision(PerkinElmer,USA)检测620nM和665nM波长处的激光比值。活性结果：A表示细胞活性IC50<100nM，B表示细胞活性100nM<IC50<1000nM，C表示细胞活性1μM<IC50<20μM,D表示细胞活性IC50>20μM。
2、实验结果
化合物对CDK9的体外激酶抑制活性


基于以上化合物对CDK9的体外激酶抑制活性，本发明的大部分化合物的对CDK9的体外激酶具有很好的抑制活性。因此，本发明的化合物可以作为CDK9靶点的新型抑制剂。
采用类似的上述激酶测试方法，相关激酶如CDK2、CDK4、CDK6、CDK7、CDK12、CDK13的体外激酶抑制活性进行测试。
2、实验方法
在体外激酶活性测试实验中，使用Perkin Elmer公司的LANCE Ultra KinaSelect Ser/Thr检测试剂盒来测定CDK2激酶活性。该方法的反应是在384孔板中，反应的总体积是10μL。CDK2蛋白(终浓度为1ng/μL)、4EBP-1多肽底物(终浓度为50nM)和ATP(终浓度为2.5μM)在缓冲液：50mM HEPES-KOH(pH 7.5)，10mM MgCl2，2mM DTT，1mM EGTA中反应1h，加入相应Eu标记的抗磷酸化抗体Eu-anti-P-4E-BP1(终浓度为2nM)孵育30min，然后检测磷酸化情况，通过荧光检测仪Envision(PerkinElmer,USA)检测620nM和665nM波长处的激光比值。活性结果：
A表示细胞活性IC50<100nM，B表示细胞活性100nM<IC50<1000nM，C表示细胞活性1μM<IC50<20μM,D表示细胞活性IC50>20μM。
化合物对CDK2的体外激酶抑制活性

基于以上化合物对CDK2的体外激酶抑制活性，本发明的大部分化合物的对CDK2的体外激酶具有一定的抑制活性，而部分化合物在CDK9的体外激酶活性要高很多，因此这部分化合物具有很好的CDK9/CDK2的选择性。因此，本发明的化合物可以根据化合 物对CDK靶点的活性和选择性特点，分别作为CDK9或者CDK2靶点的新型选择性抑制剂，或者本发明化合物亦可以作为其双靶点的抑制剂。
3、实验方法
在体外激酶活性测试实验中，使用Perkin Elmer公司的LANCE Ultra KinaSelect Ser/Thr检测试剂盒来测定CDK12激酶活性。该方法的反应是在384孔板中，反应的总体积是10μL。CDK12蛋白(终浓度为1ng/μL)、4EBP-1多肽底物(终浓度为50nM)和ATP(终浓度为2.5μM)在缓冲液：50mM HEPES-KOH(pH 7.5)，10mM MgCl2，2mM DTT，1mM EGTA中反应1h，加入相应Eu标记的抗磷酸化抗体Eu-anti-P-4E-BP1(终浓度为2nM)孵育30min，然后检测磷酸化情况，通过荧光检测仪Envision(PerinElmer,USA)检测620nM和665nM波长处的激光比值。活性结果：体外激酶抑制率(10μM)A表述激酶抑制率>40％，B表述激酶抑制率10％<IC50<40％，C表述激酶抑制率1％<IC50<10％,D表述激酶抑制率IC50<1％。
化合物对CDK12的体外激酶抑制活性
基于以上化合物对CDK12的体外激酶抑制活性，本发明的大部分化合物的对CDK12的体外激酶具有很好的抑制活性。因此，本发明的化合物可以作为CDK12靶点的新型抑制剂。
实施例24：化合物的药物代谢动力学表征
1、实验方法
将24只雄性ICR小鼠(6～8周龄，18～22g，北京维通利华实验动物科技术有限公司，中国)随机分成8组，每组3只。小鼠通过单次灌胃(20mg/kg)和静脉注射(5mg/kg)给药，单剂量化合物C27、C44、C58和C59溶于DMSO/solutol HS-15/生理盐水(5、5和90％)。灌胃组给药前禁食10-14小时，不禁水，给药4h后可自由饮食，然后在给药前及给药后0.25、0.5、1、2、4、8、24h分别从眼窝采集血液(50μL)。静脉组给药前不禁食，然后在给药前及给药后0.083、0.5、1、2、4、8、24h分别从眼窝 采集血液(50μL)。样品以12000rpm离心5min得到血浆，分析前将血浆置于-20℃下储存。采用LC-MS/MS技术进行分析，评价化合物C27、C44、C58和C59在血浆中的药代动力学。
2、实验结果
本发明中的化合物(C27、C44、C58和C59)的吸收好，生物利用度均大于40％，药物代谢动力学性质较好。由于该类化合物是一种全新结构的抑制剂，在新药研发方面具有很好的潜力，可以作为新型的CDK9抑制剂。
实施例25：化合物作用于CDK后，导致其相互作用蛋白的降解实验。
本发明中，我们还意外发现部分化合作用于CDK之后，可以导致其相互作用蛋白，如CyclinK蛋白的降解。因此，开发选择性削弱CDK12/Cyclin K功能的化合物可以用于治疗癌症及其他疾病的作用。CDK12的抑制剂存在限制性不好的问题，本发明中的化合物可以通过诱导CDK12/Cyclin K蛋白的水解，实现对RNA聚合酶II复合物中其他蛋白质的功能，或者前mRNA剪接复合物的功能，因此本发明中的化合可以削弱对CDK/Cyclin K的功能，而保存对其他CDK的选择性，实现疾病的有效治疗，而降低不希望存在的副作用，提供其中临床中的有效性。因此，本发明的化合物可以实现对削弱CDK12/Cyclin K的功能，因此可以用于治疗或预防CDK12活性异常或调节CDK活性相关的疾病或者症状的药物中的用途。
1、实验方法
将MDA-MB-231细胞接种于6孔板中，加入相应化合物或DMSO空白对照，孵育相应时间后用裂解液(RIPA:PI＝6:1，RIPA+PI:PMSF＝200:1)冰上裂解10min，4℃下15000g离心30min，取蛋白上清液，用BCA试剂进行蛋白定量和归一化。将蛋白质进行8％SDS-PAGE凝胶电泳后将蛋白质转移至PVDF膜上，使用5％脱脂牛奶封闭并孵育一抗(Cyclin K)，洗膜后用5％脱脂牛奶封闭并孵育二抗(兔抗)，孵育完毕后洗膜并曝光。
实验结果如图1所示，结果表明在浓度为50nM的化合物处理MDA-MB-231细胞2小时后，与阳性化合物Cyclin K降解剂CR8相比,本发明绝大多数化合物对Cyclin K的都具有更显著降解效果。因此本专利化合物可以通过降解Cyclin K，用于三阴性乳腺癌或其他与cyclin K活性异常导致的相关疾病治疗。
讨论
本发明的发明人通过分析CDK9的复合物晶体结构及其他CDKs的复合物晶体结构(PDB ID：IQMZ，3BLR，1UA2，3BLH)，得到下述重要信息：CDK9蛋白中配体与铰链残基Asp104以及Cys106之间的氢键对配体的活性至关重要。例如，临床试验中的CDK9抑制剂的核心支架与铰链区的残基形成氢键，这大大有助于其CDK9的效力。激活环(T环)是一个苏氨酸残基的位置，其磷酸化对酶的活性至关重要，在CDK9中是Thr186。此外，CDK9的残基Asp149、Lys151和Thr191形成催化环，直接参与磷酸转移反应。值得注意的是，CDK9结合位点中一些不太保守的区域，包括疏水区、溶剂暴露区，可能为设计选择性的CDK9抑制剂提供机会。通过对结构的分析，我们在CDK9与其他小分子抑制剂的对接结果中也获得重要的信息(PDB ID：3LQ5)：吡唑啉[1,5-a][1,3,5]三嗪的4-氨基和N6分别与铰链区相互作用，与Cys106残基的酰胺氮和羰基部分形成氢键，这种相互作用导致了其对CDK9激酶活性的抑制作用。此外，苯环指向溶剂区，异丙基位于由Ala46和Val79组成的疏水区域。因此这些特点将主要作为我们设计CDK9的小分子抑制剂的出发点。基于晶体结构的分子对接，发明人主要设计合成靶向转录调控的CDK9小分子抑制剂，在CDK激酶家族(包括CDK2、4、6、7、9)以及三阴性乳腺癌细胞系(包括MDA-MB-231和BT549)中进行活性测试并筛选；测试结果表明，该类分子具有非常高的三阴性乳腺癌细胞抗增殖活性，对CDK9有非常高的激酶抑制活性，对其他CDK亚型有非常高的选择性。同时，通过相关的测试方法发现，该类分子大部分化合物透膜吸收好，为高渗透性化合物，且药代动数据良好。从机制初步研究发现，化合物促进细胞凋亡，抑制癌细胞增殖，进而实现基于CDK9靶点的有效的疾病治疗。
本发明中意外地发现，通式(I)化合物中取代基和对不同的CDK的选择具有不同的影响，通过改变和的结构，还可以实现靶向CDK12的活性。本发明中的化合物还意外发现具有靶向CDK12的活性，并调节CyclinK蛋白的降解。开发选择性削弱CDK12/Cyclin K功能的化合物可以用于治疗癌症及其他疾病的作用。CDK12的抑制剂存在限制性不好的问题，本发明中的化合物可以通过诱导CDK12/Cyclin K蛋白的水解，实现对RNA聚合酶II复合物中其他蛋白质的功能，或者前mRNA剪接复合物的功能，因此本发明中的化合可以削弱对CDK/Cyclin K的功能，而保存对其他CDK的选择性，实现疾病的有效治疗，而降低不希望存在的副作用，提供其中临床中的有效性。因此，本发明的化合物可以实现对削弱CDK12/Cyclin K的功能，因此可以用于治疗或预防CDK12活性异常或调节CDK活性相关的疾病或者症状的药物中的用途。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (13)

  1. 一种通式(I)所示的化合物，以及其互变异构体、立体异构体、同位素化合物、可药用的盐、酯、前药或其水合物，
    其中，X为CH或N；
    Y选自-NH-、-O-或不存在；
    R1选自取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代的3-8元杂环基，其中所述取代是指基团上的一个或多个H独立地被选自下组的取代基所取代：羟基、C1-C3烷基、丙炔基、C1-C3烷基羟基、C1-C3烷基羰基、卤素、3-8元杂环基、氨基、(C1-C3烷基)1-2氨基、甲磺酰基；
    选自氢、卤素、氰基、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代3-6元杂环基、取代或未取代的5-6元杂芳基，其中所述取代是指基团上的一个或多个H独立地选自下组的取代基所取代：氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基、卤素取代的C1-C3烷基；
    R2选自氢、氘、卤素和未取代或卤代的C1-C3烷基；
    R3选自氘、卤素、氰基、羟基、硝基、未取代或卤代的C1-C3烷基；
    n为1或2；
    m为0、1、2、3或4；
    Z选自NH、N、O或不存在；
    当Z选自NH或N时，各独立地选自氢、-C(O)R4、R5取代的C1-C3烷基，其中R4选自R6取代的C1-C6烷基、R6取代的3-6元杂环烷基和R6取代的C3-C6环烷基，其中各R6独立地选自氢、羟基、C1-C3烷基-C(O)-、卤素和羧基；R5选自氢、羟基、卤素和羧基；
    当Z选自O或Z不存在时，各独立地选自取代或未取代的6-10元芳基、取代或未取代的5-6元杂芳基、取代或未取代3-8元杂环基，其中所述取代是指基团上的一个或多个H独立地选自下组的取代基所取代：氘、氧代(＝O)、卤素、氰基、硝基、羟基、氨基、羧基、甲酰基氨基、C1-C3烷基、卤素取代的C1-C3烷基；
    前提是当Z不存在时，不同时为选自下列取代基的组合：为苯基、吡啶基，噻吩基，呋喃基、噻唑基、吡咯基和嘧啶基、为未取代的C1-C6烷基或未取代的C3-C6环烷基。
  2. 如权利要求1所述的化合物，以及其互变异构体、立体异构体、同位素化合物、可药用的盐、酯、前药或其水合物，其中所述化合物具有式(I-1)-(I-4)所示的结构：
    其中，(I-2)中可以相同或不同，
    X为CH或N；
    Y选自-NH-、-O-或不存在；
    R1选自取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代的3-8元杂环基，其中所述取代是指基团上的一个或多个H独立地被选自下组的取代基所取代：羟基、C1-C3烷基、丙炔基、-C1-C3烷基羟基、C1-C3烷基羰基、卤素、3-8元杂环基、氨基、(C1-C3烷基)1-2氨基、甲磺酰基；
    R2、R3、m、与权利要求1定义相同。
  3. 如权利要求1所述的化合物，以及其互变异构体、立体异构体、同位素化合物、可药用的盐、酯、前药或其水合物，，其中所述化合物具有式(I-5)-(I-8)所示的结构：
    其中，(I-6)和(I-8)中可以相同或不同，
    Y选自-NH-、-O-或不存在；
    R1选自取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代的3-8元杂环基，其中所述取代是指基团上的一个或多个H独立地被选自下组的取代基所取代：羟基、C1-C3烷基、丙炔基、-C1-C3烷基羟基、C1-C3烷基羰基、卤素、3-8元杂环基、氨基、(C1-C3烷基)1-2氨基、甲磺酰基；
    选自氢、卤素、氰基、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代3-6元杂环基、取代或未取代的5-6元杂芳基，其中所述取代是指基团上的一个或多个H独立地被选自下组的取代基所取代：氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基、卤素取代的C1-C3烷基；
    各独立地选自氢、-C(O)R4、R5取代的C1-C3烷基，其中R4选自R6取代的C1-C6烷基、 R6取代的3-6元杂环烷基和R6取代的C3-C6环烷基，其中各R6独立地选自氢、羟基、C1-C3烷基羰基、卤素和羧基，R5选自氢、羟基、卤素和羧基；
    R2、R3、m与权利要求1定义相同。
  4. 如权利要求1所述的化合物，以及其互变异构体、立体异构体、同位素化合物、可药用的盐、酯、前药或其水合物，其中所述化合物具有式(I-9)-(I-10)所示的结构：
    其中，Y选自-NH-、-O-或不存在；
    R1选自取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代的3-8元杂环基，其中前述取代是指被以下一种或多种取代基所取代：羟基、C1-C3烷基、丙炔基、羟C1-C3烷基、C1-C3烷基羰基、卤素、杂环基、氨基、烷基氨基、甲磺酰基；
    选自氢、卤素、氰基、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代3-6元杂环基、取代或未取代的5-6元杂芳基，其中所述取代是指基团上的一个或多个H独立地被选自下组的取代基所取代：氘、卤素、羟基、C1-C3烷基、卤素取代的C1-C3烷基；
    选自取代或未取代的6-10元芳基、取代或未取代的5-6元杂芳基、取代或未取代3-6元杂环基，其中所述取代是指基团上的一个或多个H独立地被选自下组的：氘、氧代(＝O)、卤素、氰基、硝基、羟基、氨基、羧基、甲酰基氨基、C1-C3烷基、卤素取代的C1-C3烷基；
    R2、R3、m与权利要求1定义相同。
  5. 如权利要求1所述的化合物，以及其互变异构体、立体异构体、同位素化合物、可药用的盐、酯、前药或其水合物，其中所述化合物具有式(I-11)-(I-12)所示的结构：
    其中，Y选自-NH-、-O-或不存在；
    选自氢、卤素、氰基、取代的C1-C6烷基、取代的C3-C6环烷基、取代或未取代3-6元杂环基、取代或未取代的5-6元杂芳基，其中所述取代是指基团上的一个或多个H独立 地被选自下组的取代基所取代：氘、卤素、氰基、硝基、羟基、氨基、C1-C3烷基、卤素取代的C1-C3烷基；
    选自取代或未取代的6-10元芳基、取代或未取代的5-6元杂芳基、取代或未取代3-6元杂环基，其中所述取代是指基团上的一个或多个H独立地被选自下组的：氘、氧代(＝O)、卤素、氰基、硝基、羟基、氨基、羧基、甲酰基氨基、C1-C3烷基、卤素取代的C1-C3烷基，
    R1、R2、R3、m与权利要求1定义相同。
  6. 如权利要求1所述的化合物，以及其互变异构体、立体异构体、同位素化合物、可药用的盐、酯、前药或其水合物，其中所述化合物具有式(I-13)-(I-41)所示的结构：

    其中，X为CH或N；R1和Y的定义与权利要求1中相同。
  7. 如权利要求1所述的化合物，以及其互变异构体、立体异构体、同位素化合物、可药用的盐、酯、前药或其水合物，其中R1-Y选自：

  8. 一种如权利要求1所述的化合物，以及其互变异构体、立体异构体、同位素化合物、可药用的盐、酯、前药或其水合物，其中所述的化合物选自下组：











  9. 一种制备权利要求1-8中任一项所述化合物的方法，所述方法选自如下方法之一：
    合成方法一：
    步骤1-1：化合物1A和Boc酸酐反应得到化合物1B；
    步骤1-2：化合物1B与雷尼镍氢化反应得到化合物1C；
    步骤1-3：化合物1C和化合物1D在三氯氧磷和N,N-二甲基苯甲胺的条件下得到卤代物，在碱条件下亲核取代得到化合物1E；
    步骤1-4：化合物1E和化合物1F在钠氢和无水N,N-二甲基甲酰胺条件下反应得到 化合物1H；
    步骤1-5：化合物1E和化合物1G在1-甲基-2-吡咯烷酮条件下反应得到化合物1J；
    步骤1-6：化合物1H在盐酸二氧六环的条件下反应得到化合物1I；
    步骤1-7：化合物1J在盐酸二氧六环的条件下反应得到化合物1K；
    R1与权利要求1的定义相同；
    合成方法二：
    步骤2-1：化合物2A与化合物2B在HATU和DIPEA存在的条件下反应得到化合物2C；
    步骤2-2：化合物2C在盐酸二氧六环的条件下反应得到化合物2D；
    步骤2-3：化合物2D和化合物1D在三氯氧磷和N,N-二甲基苯甲胺的条件下得到卤代物，在碱条件下亲核取代得到化合物2E；
    步骤2-4：化合物2E和化合物2F在钠氢和无水N,N-二甲基甲酰胺条件下反应得到化合物2I；
    步骤2-5：化合物2E和化合物2G在1-甲基-2-吡咯烷酮条件下反应得到化合物2J；
    步骤2-6：化合物2E和化合物2H在1-甲基-2-吡咯烷酮条件下反应得到化合物2K；
    R3选自-CH3、-CH2CH3、
    R1与权利要求1的定义相同；
    合成方法三：
    步骤3-1：化合物3A和化合物1D在三氯氧磷和N,N-二甲基苯甲胺的条件下得到卤代物，在碱条件下亲核取代得到化合物3C；
    步骤3-2：化合物3B和化合物1D在三氯氧磷和N,N-二甲基苯甲胺的条件下得到卤代物，在碱条件下亲核取代得到化合物3D；
    步骤3-3：化合物3C和化合物3E在1-甲基-2-吡咯烷酮条件下反应得到化合物3F；
    步骤3-4：化合物3D和化合物3E在1-甲基-2-吡咯烷酮条件下反应得到化合物3G；
    步骤3-5：化合物3F在盐酸二氧六环的条件下反应得到化合物3H；
    步骤3-6：化合物3G在盐酸二氧六环的条件下反应得到化合物3I；
    R1与权利要求3的定义相同；
    合成方法四：
    步骤4-1：化合物4A和化合物1C在N,N-二异丙基乙胺和乙醇的条件下反应得到化合物4B；
    步骤4-2：化合物4A和化合物2D在N,N-二异丙基乙胺和乙醇的条件下反应得到化合物4C；
    步骤4-3：化合物4B和Boc酸酐反应得到化合物4D；
    步骤4-4：化合物4C和Boc酸酐反应得到化合物4E；
    步骤4-5：化合物4D和化合物4F在1-甲基-2-吡咯烷酮条件下反应得到化合物4G；
    步骤4-6：化合物4E和化合物4F在1-甲基-2-吡咯烷酮条件下反应得到化合物4H；
    步骤4-7：化合物4G在盐酸二氧六环的条件下反应得到化合物4I；
    步骤4-8：化合物4H在盐酸二氧六环的条件下反应得到化合物4J；
    R1与权利要求1的定义相同。
  10. 一种药物组合物，所述的药物组合物包含如权利要求1-8中任一项所述的化合物，以及其互变异构体、立体异构体、同位素化合物、可药用的盐、酯、前药或其水合物的一种或多种，以及药学上可接受的辅料。
  11. 如权利要求1-8中任一项所述的化合物，以及其互变异构体、立体异构体、同位素化合物、可药用的盐、酯、前药或其水合物或如权利要求10所述的药物组合物在制备用于预防和/或治疗与CDK或与Cyclin K异常活性相关的疾病或者症状的药物中的用途。
  12. 如权利要求11所述的用途，其特征在于，所述与CDK或与Cyclin K异常活性相关的疾病为癌症、疼痛、中枢神经系统疾病或免疫系统疾病。
  13. 如权利要求11所述的用途，其特征在于所述的与CDK或与Cyclin K异常活性相关的疾病为实体瘤、血液瘤，优选地，所述的疾病选自：骨髓增生异常综合征、多发性骨髓瘤、套细胞淋巴瘤、非霍奇金淋巴瘤、慢性淋巴细胞白血病、慢性粒单核细胞白血病、骨髓纤维化、伯基特淋巴瘤、霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、睫状体和慢性黑色素瘤、虹膜黑色素瘤、复发性两眼间黑色素瘤、T细胞淋巴瘤、红系淋巴瘤、成单核细胞和单核细胞白血病、髓性白血病、中枢神经系统淋巴瘤、脑膜瘤、脊髓肿瘤、非小细胞肺癌、卵巢癌、皮肤癌、肾细胞癌、星状细胞瘤、淀粉样变性、I型复杂性局部疼痛综合征、恶性黑色素瘤、神经根病、成胶质细胞瘤、胶质肉瘤、恶性胶质瘤、难治性浆细胞瘤、眼外延伸黑色素瘤、乳头状和滤泡状甲状腺癌、乳腺癌、前列腺癌、结直肠癌、卵巢癌、子宫内膜癌、宫颈癌、肝细胞癌、胃癌、食道癌、膀胱癌、小细胞肺癌、非小细胞肺癌、尤文肉瘤、胶质母细胞瘤、胰腺癌或原发性巨球蛋白血症。
PCT/CN2024/122446 2023-09-28 2024-09-29 吡唑并三嗪及吡唑并嘧啶衍生物、其制备方法、药物组合物及其用途 Pending WO2025067540A1 (zh)

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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07278150A (ja) * 1993-12-21 1995-10-24 Shionogi & Co Ltd ピラゾロ［１，５−ａピリミジン誘導体
US5571813A (en) * 1993-06-10 1996-11-05 Beiersdorf-Lilly Gmbh Fused pyrimidine compounds and their use as pharmaceuticals
CN1735614A (zh) * 2002-09-04 2006-02-15 先灵公司 作为细胞周期蛋白依赖性激酶抑制剂的吡唑并嘧啶
CN1946725A (zh) * 2004-02-11 2007-04-11 先灵公司 用作细胞周期蛋白依赖激酶抑制剂的新型吡唑并嘧啶
WO2008130570A1 (en) * 2007-04-20 2008-10-30 Schering Corporation Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors
WO2008130569A1 (en) * 2007-04-20 2008-10-30 Schering Corporation Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors
CN101321756A (zh) * 2005-10-06 2008-12-10 先灵公司 用作细胞周期蛋白依赖性激酶抑制剂的新的吡唑并嘧啶化合物
US20120184557A1 (en) * 2009-03-11 2012-07-19 Centre National De La Recherche Scientifique Pyrazolo[1,5-a]-1,3,5-triazine derivatives, preparation thereof, and therapeutic use thereof
CN107530329A (zh) * 2015-03-09 2018-01-02 奥瑞基尼探索技术有限公司 用作CDK抑制剂的吡唑并[1,5‑a][1,3,5]三嗪和吡唑并[1,5‑a]嘧啶衍生物
CN110835345A (zh) * 2018-08-17 2020-02-25 中国科学院上海药物研究所 一类细胞周期依赖性激酶的降解剂、其制备方法、药物组合物及其用途
WO2022263604A1 (en) * 2021-06-16 2022-12-22 Carrick Therapeutics Limited Substituted pyrazolo[1,5-a]pyrimidine-7-amine compounds as cdk inhibitors and their therapeutic use

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5571813A (en) * 1993-06-10 1996-11-05 Beiersdorf-Lilly Gmbh Fused pyrimidine compounds and their use as pharmaceuticals
JPH07278150A (ja) * 1993-12-21 1995-10-24 Shionogi & Co Ltd ピラゾロ［１，５−ａピリミジン誘導体
CN1735614A (zh) * 2002-09-04 2006-02-15 先灵公司 作为细胞周期蛋白依赖性激酶抑制剂的吡唑并嘧啶
CN1946725A (zh) * 2004-02-11 2007-04-11 先灵公司 用作细胞周期蛋白依赖激酶抑制剂的新型吡唑并嘧啶
CN101321756A (zh) * 2005-10-06 2008-12-10 先灵公司 用作细胞周期蛋白依赖性激酶抑制剂的新的吡唑并嘧啶化合物
WO2008130570A1 (en) * 2007-04-20 2008-10-30 Schering Corporation Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors
WO2008130569A1 (en) * 2007-04-20 2008-10-30 Schering Corporation Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors
US20120184557A1 (en) * 2009-03-11 2012-07-19 Centre National De La Recherche Scientifique Pyrazolo[1,5-a]-1,3,5-triazine derivatives, preparation thereof, and therapeutic use thereof
CN107530329A (zh) * 2015-03-09 2018-01-02 奥瑞基尼探索技术有限公司 用作CDK抑制剂的吡唑并[1,5‑a][1,3,5]三嗪和吡唑并[1,5‑a]嘧啶衍生物
CN110835345A (zh) * 2018-08-17 2020-02-25 中国科学院上海药物研究所 一类细胞周期依赖性激酶的降解剂、其制备方法、药物组合物及其用途
WO2022263604A1 (en) * 2021-06-16 2022-12-22 Carrick Therapeutics Limited Substituted pyrazolo[1,5-a]pyrimidine-7-amine compounds as cdk inhibitors and their therapeutic use

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY 7 March 2012 (2012-03-07), XP093297962, Database accession no. 1360261-22-8 *
SHIOTA T, ET AL.: "SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP OF A NEW SERIES OF POTENT ANGIOTENSIN II RECEPTOR ANTAGONISTS: PYRAZOLOÄ1,5-AÜPYRIMIDINE DERIVATIVES", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, JP, vol. 47, no. 07, 1 January 1999 (1999-01-01), JP , pages 928 - 938, XP001156827, ISSN: 0009-2363 *
WEI DAN, WANG HANLIN, ZENG QINGHE, WANG WENJING, HAO BINGBING, FENG XULE, WANG PEIPEI, SONG NING, KAN WEIJUAN, HUANG GUIFANG, ZHOU: "Discovery of Potent and Selective CDK9 Degraders for Targeting Transcription Regulation in Triple-Negative Breast Cancer", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 64, no. 19, 14 October 2021 (2021-10-14), US , pages 14822 - 14847, XP055952451, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.1c01350 *

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