WO2020035049A1 - 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 - Google Patents

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 Download PDF

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WO2020035049A1
WO2020035049A1 PCT/CN2019/100969 CN2019100969W WO2020035049A1 WO 2020035049 A1 WO2020035049 A1 WO 2020035049A1 CN 2019100969 W CN2019100969 W CN 2019100969W WO 2020035049 A1 WO2020035049 A1 WO 2020035049A1
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compound
amino
group
methyl
esi
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French (fr)
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陈小华
李佳
冯序乐
周宇波
田洪涛
张凯祥
王培培
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中国科学院上海药物研究所
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    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
    • 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
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    • A61P35/02—Antineoplastic agents specific for leukemia
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention belongs to the field of pharmacology, and specifically relates to a class of compounds represented by the general formula (I), a preparation method thereof, a pharmaceutical composition, and a degradation agent for preparing targeted cell cycle dependent kinases (CDKs) in preventing and / or Or the use of a medicament for treating a disease or symptom associated with abnormal activity of a cell cycle-dependent kinase, and for treating a disease or disorder associated with selective transcription of CDKs.
  • the invention also provides a pharmaceutically acceptable composition comprising a compound of the invention and a method of using the composition to treat a disease or condition associated with selective transcription of CDKs.
  • CDK cell cycle dependent kinase
  • Cyclin dependent kinases are a class of serine / threonine kinases, mostly heterodimeric complexes composed of cell cycle catalytic kinase subunits and regulatory subunits. Protein binding and activation, thereby regulating the cell cycle and transcription process, CDK activity imbalance can directly or indirectly cause uncontrolled cell proliferation, increased DNA mutations, chromosome deletions and chromosomal changes, etc., leading to the occurrence and development of tumors. CDK family proteins are involved in the process of cell mitosis and transcription, and play an important role in cell proliferation. Due to the abnormal 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 as an important target in tumor treatment. However, due to the highly conserved amino acid sequence of the ATP-binding pocket positions between different CDK proteins, it is difficult to find small, highly selective CDK families. Molecular inhibitors.
  • the drugs currently targeting the CDK family include Pfizer's Palbociclib (2015), Novartis' Ribociclib (2017) and Lilly's Abemaciclib (2017). Inhibitors targeting CDK4 / 6 are used to treat breast cancer. Drugs targeting other targets in the CDK family are mostly in clinical or preclinical research.
  • 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).
  • the CDK activating enzyme complex consists of CDK7, cyclin H, and MAT1.
  • CAK can activate CDK related to the cell cycle through threonine phosphorylation Proteins, including CDK1, CDK2, CDK4, and CDK6, affect the cell cycle progression.
  • CDK7 as a component of the basic transcription factor TFIIH complex, can activate RNA polymerase II through serine phosphorylation of the C-terminal domain of RNA polymerase II, thereby regulating RNA polymerase II-mediated transcription initiation and extend.
  • CDK9 / CyclinT1 (or T2) is part of the positive transcription elongation factor b (P-TEFb) complex subunit. It activates RNA polymerase II to initiate regulation of gene transcriptional extension by phosphorylating the carboxyl terminal domain (CTD) of RNA polymerase .
  • CDK9 is upstream of key molecules such as cell cycle regulatory proteins such as anti-apoptotic proteins Bcl-2, Mcl-1, and XIAP and mitogen-regulated kinases, which are closely related to tumors.
  • CDK9 By regulating CDK9, it can be directly or indirectly regulated, such as: In chronic lymphocytic leukemia (CLL), the therapeutic effect can be achieved by inhibiting the activity of CDK9 to down-regulate key proteins of the Bcl-2 family. CDK9 does not affect the regulation of the cell cycle. This specific regulation of the transcription process by CDK9 makes it one of the most promising antitumor targets in the CDK family.
  • CDK7 / cyclin H and CDK9 / cyclin T complexes have also been shown to be able to inhibit the replication of RNA of HIV and HSV viruses, and therefore have certain application prospects in the field of antivirals.
  • Targeted protein degradation technology is a new drug development technology that has received widespread attention in recent years.
  • This technology uses the ubiquitin-proteasome-mediated protein degradation pathway in the body to artificially control the degradation of target proteins.
  • a bifunctional molecule By designing a bifunctional molecule, one end of this bifunctional molecule can recognize the target protein and the other end can recognize E3 ubiquitin ligase, and the middle is connected by a linker (Linker) to form a targeted induction protein degradation complex (Proteolysis targeting chimeras, PROTACs).
  • Linker Linker
  • Protein degradation agents targeting CDK7 and CDK9 Protein degradation agents targeting CDK7 and CDK9:
  • CDK7 and CDK9 are important targets for the treatment of tumors.
  • CDK7 and CDK9 inhibitors have entered clinical research, most of which are non-selective inhibitors (J. Med. Chem. 2016, 59, 8667-8684. Bioorganic & Medical Chemistry Letters 2015, 25, 3420-3435).
  • Representative small molecule inhibitors include Flavopidolol, Roscovitine, SNS-032, R547, TG-02, AT-7519, etc .; but highly selective small molecule inhibition against CDK7 or CDK9, or dual target of CDK7 and CDK9 Agent studies are relatively few (US2007179161A1, US2015111873A1, WO2016193939A1, WO2016142855A2).
  • WO2017185023A1 is a targeted degradation agent for CDK9.
  • One representative CDK9 degradation agent is THAL-SNS-032.
  • CDK-related kinases are closely related to the occurrence and development of tumors. Therefore, degradation agents that target CDK9 or CDK7-related kinase targets can degrade target proteins, thereby regulating RNA polymerase II-mediated transcription initiation and extension, effectively inhibiting tumor cells. Proliferation; at the same time, it can solve the problem of drug resistance of small molecule inhibitors of this type of target. It is therefore an object of the present invention to provide a class of compounds that can be used to treat and / or prevent or ameliorate such diseases and / or disorders by designing and synthesizing new protein degradation agents that target CDK9 or CDK7.
  • CDK9 has greater conformational flexibility than other CDKs. For example, when a small molecule inhibitor is combined with CDK9 / cyclinT, it can down-regulate the position of the glycine (Gly) loop in the CDK structure to adapt to the binding of the ligand; meanwhile, this feature of the structure of the CDK9 protein allows its binding region to accommodate a larger area Ligand structure.
  • CDK9 and other small molecule inhibitors (PDB ID: 3LQ5): the substituents on C-6 on the purine ring extended the CDK9 ATP binding pocket Partially exposed to the solvent; At the same time, if this position is a substituent with a larger steric substitution, it can also maintain good binding ability with CDK9. Therefore, these characteristics will mainly serve as the starting point for our design of CDK9 small molecule degradation agents.
  • the inventors Based on CDK9 small molecule inhibitors, the inventors mainly designed and synthesized a class of small molecule degradation agents that specifically targeted CDK9.
  • one end of the molecule can recognize the target protein, and the other end can recognize E3 ubiquitin ligase, which is connected by a linker in the middle.
  • E3 ubiquitin ligase which is connected by a linker in the middle.
  • the degradants can be very efficient Degraded CDK9 target. After the molecule acts on the organism, it can artificially control the degradation of the target protein CDK9 through the ubiquitin-proteasome-mediated protein degradation pathway in the organism, thereby achieving effective disease treatment based on the CDK9 target.
  • An object of the present invention is to provide a compound represented by the general formula (I), a tautomer, an enantiomer, a diastereomer, a racemate, a metabolic precursor, a pharmaceutically acceptable salt, an ester, a pro Medicine or its hydrate.
  • Another object of the present invention is to provide important intermediates and preparation methods of such compounds.
  • Another object of the present invention is to provide the use of such compounds in the preparation of a medicament for the prevention and treatment of diseases associated with abnormal activity of CDK.
  • Diseases associated with abnormal activity of CDK include breast cancer, colon cancer, prostate cancer, small cells Solid tumors such as lung cancer, non-small cell lung cancer, and blood such as acute lymphocytic leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, myeloma, acute and chronic myeloid leukemia, promyelocytic leukemia, and other blood Tumor.
  • the present invention provides a compound represented by the following general formula (I), its tautomer, enantiomer, diastereomer, racemate, metabolic precursor, pharmaceutically acceptable salt, ester, prodrug or its Hydrate:
  • R a1 is hydrogen, fluorine or methyl
  • R a2 is hydrogen or methyl
  • R c1 is hydrogen or fluorine
  • R a3 , R a4 , and R a5 are each independently hydrogen, halogen, cyano, nitro, hydroxy, amino, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-6 alkoxy , Substituted or unsubstituted amino, substituted or unsubstituted C 2-6 alkylcarbonyl, wherein the substitution refers to substitution with one or more of the following substituents: halogen, hydroxyl, C 1-6 alkoxy, Cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 3-10 cycloalkyl, containing 1-3 selected from N, O and S Atomic 3-6 membered heterocyclic group;
  • L is selected from - (CH 2) m1 - ( OCH 2 CH 2) m2 -, - (CH 2 OCH 2) m3 -, - (CH 2) m4 -W1- (CH 2) m5 -, - (CH 2) m4 -W2- (CH 2 CH 2 O ) m6 - (CH 2) m7 -, wherein, W1, W2 are each independently selected from -O -, - CH 2 -, five yuan heteroaromatic ring, six membered heteroaryl ring, C 3-10 alkyl ring or 3-6 membered heteroalkyl ring;
  • n1 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • n2 0, 1, 2, 3, 4, 5 or 6;
  • n3 0, 1, 2, 3, 4 or 5;
  • n4 0, 1, 2, 3, 4 or 5;
  • n5 0, 1, 2, 3, 4, 5 or 6;
  • n 0, 1, 2, 3 or 4;
  • m7 is 0, 1, 2, 3, 4, 5, 6, or 7;
  • R 4 is selected from a hydrogen atom, halogen, C 1-6 alkoxy, cyano, amino, nitro, C 1-6 alkyl, C 3-10 cycloalkyl, 5-8 membered heterocyclyl, C 6 -10aryl , 5-6 membered heteroaryl, -NHC (O) R 5 , -NHC (O) OR 6 , -NR 7 R 8 , wherein the alkyl or alkoxy group is optionally further Or more selected from halogen, hydroxy, C 1 -C 6 alkoxy, cyano, nitro substituents;
  • R 5 , R 6 , R 7 and R 8 are each independently selected from a hydrogen atom, a C 1-6 alkyl group, a C 3-10 cycloalkyl group, a 5-8 membered heterocyclic group, a C 6-10 aryl group or 5 -8-membered heteroaryl, wherein said alkyl, cycloalkyl, aryl or heteroaryl is optionally further selected from one or more of halogen, hydroxy, C 1 -C 6 alkoxy, cyano, Substituted with a nitro substituent;
  • n 0,1,2,3,4;
  • R 1 is hydrogen, deuterium or CH 3 ;
  • X 1 -X 7 are each independently C or N, preferably, the structure consisting of the five-membered ring and six-membered ring where X 1 -X 7 is located and R 2 , R 3 and E is selected from:
  • R 2 is hydrogen or a substituted or unsubstituted C 1-8 hydrocarbon group, wherein the substitution refers to being substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxyl, and amino;
  • E is selected from --O--, --CO--NH--, --NH--CO--, --O--CH 2- , --CO--NH--CH 2- , --NR 6- , --NR 6 --CH 2- , --CH 2 -NR 6- , -S-, -CH (OH)-or -CH 2- ; preferably E is selected from -O- or -NH-;
  • R 3 is selected from a substituted or unsubstituted C 1-6 alkyl group, a substituted or unsubstituted C 1-6 alkoxy group, a substituted or unsubstituted amino group, a substituted or unsubstituted C 2-6 alkylcarbonyl group, wherein The said substitution means being substituted by one or more of the following substituents: halogen, hydroxyl, C 1-6 alkoxy, cyano, nitro, C 1-6 alkyl, halo C 1-6 alkyl, HydroxyC 1-6 alkyl, C 3-10 cycloalkyl, 3-8 membered heterocyclic group containing 1-3 selected from N, O and S atoms.
  • the compound of general formula (I) is selected from the following general formula:
  • the compound of general formula (I) is selected from the following general formula:
  • R 3 -E- is selected from the following groups:
  • R 1 is hydrogen, deuterium or CH 3 ;
  • R 2 is hydrogen or a substituted or unsubstituted C 1 -C 3 alkyl, wherein the substitution refers to substitution with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxyl, and amino ;
  • R 4 is selected from the group consisting of a hydrogen atom, halogen, cyano, amino, nitro, -NHC (O) CH 3 , 3-6 membered cycloalkyl, C 1-4 alkoxy, C 1-4 alkyl, The alkyl or alkoxy group is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, and nitro;
  • n 0, 1, 2;
  • the compound of general formula (I) is selected from the following general formula:
  • R 3 -E- is selected from the following groups:
  • R 1 is hydrogen, deuterium or CH 3 ;
  • R 2 is hydrogen or a substituted or unsubstituted C 1-3 alkyl group, wherein the substitution refers to being substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, hydroxyl, and amino;
  • R 4 is a hydrogen atom, halogen, cyano, amino, nitro, -NHC (O) CH 3 , 3-6 membered cycloalkyl;
  • n 0, 1, 2;
  • L is selected from - (CH 2) m1 - ( OCH 2 CH 2) m2 -, - (CH 2 OCH 2) m3 -, - (CH 2) m4 -W1- (CH 2) m5 -, - (CH 2) m4 -W2- (CH 2 CH 2 O ) m6 - (CH 2) m7 -;
  • W1 and W2 are each independently preferably selected from -O-, -CH 2- ,
  • the compound represented by the general formula (I) is selected from the following general formula:
  • the compound represented by the general formula (I) is selected from the following general formula:
  • R 1 , R 2 , R 3 , E, R 4 , n The definitions of X, L, Y, R c1 , R a2 , R a3 and R a4 are the same as in the above definitions.
  • the compound represented by the general formula (I) is selected from the following general formula:
  • the compound of general formula (I) is selected from the following compounds:
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydrocarbyl refers to a substituent containing only carbon and hydrogen atoms, and includes, without limitation, methyl, ethyl, isopropyl, propyl, cyclohexyl, phenyl, and the like.
  • C 1 -C 8 alkyl refers to a straight or branched chain saturated hydrocarbon group having 1 to 8 carbon atoms in the chain and includes, without limitation, methyl, ethyl, propyl, isopropyl, butyl , Isobutyl, sec-butyl, tert-butyl, etc.
  • cycloalkyl refers to a saturated cyclic alkyl group composed of carbon atoms, and includes, without limitation, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • haloalkyl refers to a linear, branched, or cyclic alkyl group substituted with a single or multiple halogens, and includes without limitation 2-bromoethyl, 2-bromopropyl, and the like.
  • hydroxyalkyl refers to a straight-chain, branched-chain or cyclic alkyl group substituted with a single or multiple hydroxyl groups, including without limitation (S) -1-hydroxyisobut-2-yl, (R)- 1-hydroxyisobut-2-yl and the like.
  • C 5 -C 8 cycloalkyl refers to a saturated mono- or poly-cyclic ring system containing 5 to 8 carbon atoms, including without limitation cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl .
  • C 6 -C 10 aryl group refers to an aromatic ring group containing 6 to 10 ring atoms but no hetero atoms in the ring atoms, such as phenyl and naphthyl.
  • arylene refers to a divalent aromatic monocyclic or divalent aromatic fused bicyclic hydrocarbon group, and representative examples include, but are not limited to, phenylene, naphthylene, and the like.
  • 5- to 10-membered heterocyclyl refers to a heterocycle containing one or more saturated and / or partially saturated rings, which includes 5 to 10 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, or sulfur. Atom, the remaining ring atoms are carbon; for example, propylene oxide, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl.
  • heteroaryl refers to a monovalent aromatic ring group containing 5-12 ring atoms and containing 1-4 heteroatoms as ring members in the ring atoms. Heteroatoms may be selected from nitrogen, oxygen or sulfur.
  • the heteroaryl group may be a monocyclic heteroaryl group having 5-7 ring atoms, or a bicyclic heteroaryl group having 7-12 ring atoms. In the bicyclic heteroaryl group, as long as one ring is a heteroaryl ring, the other may be an aromatic ring or a non-aromatic ring, a heteroatom-containing or a heteroatom-free.
  • heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, pyridyl, pyrimidinyl, furyl, thienyl, thiazolyl, thiadiazolyl, tetrazolyl, triazole , Isoxazolyl, indolyl, methylpyridinylthiazolyl, benzo [d] oxazole, benzo [d] imidazole, and the like.
  • the 5- to 12-membered heteroaryl is selected from pyridyl, pyrimidinyl, oxazolyl, thienyl, indolyl, 1,3-dioxoisoindolyl, 1-oxoisoindole , Imidazolyl, pyrazolyl, isoxazolyl, benzimidazolyl and furyl.
  • aryl heterocycloalkyl refers to a cycloalkyl group that is aryl or heteroaryl and contains oxygen, nitrogen, or sulfur, and includes, but is not limited to, 1,3-benzodioxo, 2,3-dihydro Benzofuran, indolin, etc.
  • heteroarylene refers to a divalent aromatic ring group containing 5-12 ring atoms and containing 1-4 heteroatoms as ring members in the ring atom. Heteroatoms may be selected from nitrogen, oxygen or sulfur.
  • the heteroarylene may be a monocyclic heteroarylene having 5-7 ring atoms, or a bicyclic heteroarylene having 7-12 ring atoms.
  • triazolyl pyrrolidyl, pyrimidyl, imidazolyl, oxazolyl, pyridyl, pyrimidyl, furanyl, thienyl, thiazolyl, thiadiazole , Tetrazolyl, isoxazolyl, indole, methylenepyridinylthiazolyl, benzo [d] oxazole, benzo [d] imidazole, and the like.
  • tautomer refers to a structural isomer that is easily interconverted by a chemical reaction that is an isomer, which reaction generally results in the shift of the form of a hydrogen atom or a proton that accompanies the conversion of a single bond and an adjacent double bond.
  • enantiomer refers to stereoisomers that are mirror images of each other and cannot overlap, such as compound C045 and its enantiomers.
  • Diastereomers refer to stereoisomers that have two or more chiral neutrality and are not mirror images, such as compound C045 and its diastereomers.
  • Racemate refers to two stereoisomers that are mirror images of each other and have opposite optical rotations, which cancel out the optical rotations of each other, for example, compound C001, compound C002, compound C003, and the like.
  • Metal precursors refer to a class of compounds that are inactive or have low activity in vitro, and release active drugs in vivo through transformation of metabolic pathways in the body.
  • “Pharmaceutically acceptable salt” means that the drug molecule forms the corresponding salt with the corresponding organic acid, inorganic acid, or organic base, or inorganic base, such as the hydrochloric acid, formic acid, trifluoroacetic acid, succinic acid, and mesylate of compound C001 Wait.
  • Prodrugs refer to a class of compounds that are inactive or have low activity in vitro, and release active drugs in the body through enzymatic or non-enzymatic conversion to exert their effects.
  • Hydrophilate means a compound containing water.
  • the invention also includes any of the new intermediates disclosed herein.
  • a method for preparing a degradation agent represented by the general formula (I) is provided.
  • the method is selected from one of the following methods: Synthesis method 1:
  • R 2 , R 3 , E, X 1 , X 2 and X 7 are the same as above;
  • n 1 is an integer from 0 to 12, and n 2 is an integer from 0 to 6;
  • Step a Compound 1A is obtained by a condensation reaction between compound 1A and linking chain 1B;
  • Step b Compound 1C and 1D are reacted under the conditions of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (PPh 3 ) to obtain 1E.
  • DIAD diisopropyl azodicarboxylate
  • Ph 3 triphenylphosphine
  • R 2 , R 3 , E, X 1 , X 2 and X 7 are the same as above;
  • U is -O- or -CH 2- ;
  • n 3 is an integer of 0-9, n 4 is an integer of 0-5;
  • Step c Compound 2A is reacted with linker 2B under the conditions of cuprous iodide and bistriphenylphosphine palladium dichloride to obtain compound 2C;
  • Step d Compound 2C is reacted under hydrogen and palladium-carbon hydrogenation catalyst conditions to obtain compound 2D;
  • Step e Compound 2D and 1A are obtained by condensation reaction to obtain compound 2E.
  • R 2 , R 3 , E, X 1 , X 2 and X 7 are the same as above;
  • n 5 is an integer of 0-12, n 6 is an integer of 0-6;
  • Step f The compound 3B is obtained by a condensation reaction between the connecting chain 3A and the compound 1A;
  • Step g Compound 3B is obtained under deprotection conditions of hydrochloric acid or trifluoroacetic acid;
  • Step h Compound 3C and compound 3D are obtained by a condensation reaction to obtain compound 3E;
  • Step i Compound 3C is reacted with compound 3F under N, N-diisopropylethylamine conditions to obtain compound 3G.
  • R 2 , R 3 , E, X 1 , X 2 and X 7 are the same as above;
  • Z is methylene or carbonyl
  • n 7 is an integer of 0-12, n 8 is an integer of 0-6;
  • Step j Compound 4A and 4B are reacted under the conditions of DIAD and PPh 3 to obtain 4C;
  • Step k Compound 4C is reacted under tetrabutylammonium fluoride to obtain compound 4D.
  • Step 1 Compound 4E is reacted under hydrogen and palladium-carbon hydrogenation catalyst conditions to obtain compound 4F;
  • Step m Compound 1A is obtained by a condensation reaction between compound 1A and a linking chain 4F.
  • R 2 , R 3 , E, X 1 , X 2 and X 7 are the same as above;
  • n 9 is an integer of 0-10, n 10 is an integer of 0-6;
  • Step n Compound 5A is obtained by a condensation reaction between compound 5A and linking chain 5B;
  • Step o Compound 5C is deprotected under the conditions of lithium hydroxide to obtain compound 5D;
  • Step p Compound 5D is compounded with compound 1A to obtain compound 5E.
  • R 2 , R 3 , Ra 3 , Ra 4, E, X 1 , X 2 and X 7 are the same as above;
  • n 11 is an integer from 0 to 6
  • n 12 is an integer from 0 to 10
  • Step q Compound 6A and compound 6B are obtained through a condensation reaction to obtain compound 6C;
  • Step r Compound 6C is removed from the protective group under conditions of lithium hydroxide to obtain compound 6D;
  • Step s Compound 6D and compound 1A are obtained by a condensation reaction to obtain compound 6E.
  • R 2 , R 3 , E, X 1 , X 2 and X 7 are the same as above;
  • n 13 is an integer of 0-9, n 14 is an integer of 0-5;
  • Step u Compound 2A is reacted with linker 7A under the conditions of cuprous iodide and bistriphenylphosphine palladium dichloride to obtain compound 7B;
  • Step v Compound 7B is reacted under trifluoroacetic acid to obtain compound 7C;
  • Step w Compound 7C and compound 1A are condensed under the conditions of HATU and DIPEA to obtain compound 7D;
  • Step x Compound 2C is catalyzed by palladium-carbon under normal pressure hydrogen to obtain compound 7E.
  • R 2 , R 3 , E, X 1 , X 2 and X 7 are the same as above;
  • n 15 is an integer of 0-9, n 16 is an integer of 0-5;
  • Step y Compounds 8A and 8B are reacted under the conditions of bistriphenylphosphine palladium dichloride and cuprous iodide to obtain compound 8C;
  • Step z1 Compound 8C is hydrogenated under Raney nickel catalysis to obtain compound 8D;
  • Step z2 Compound 8D is reacted under the conditions of imidazole and TBSCl to obtain compound 8E;
  • Step z3 Compound 8E is prepared by nucleophilic substitution reaction with compounds 8E and 8F under basic conditions;
  • Step z4 Compound 8G is prepared by nucleophilic substitution reaction with R 3 EH under basic conditions;
  • Step z5 Compound 8H is reacted under the condition of tetrabutylammonium fluoride to obtain compound 8I;
  • Step z6 Compound 8I is reacted under the conditions of diisopropyl azodicarboxylate and triphenylphosphine to obtain compound 8J.
  • the present invention provides the use of a compound having a structure such as formula (I) or a crystalline hydrate and a solvate, for preparing a medicament for preventing and / or treating a disease or symptom associated with abnormal activity of CDK.
  • Suitable acids for salt formation include (but are not limited to): hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, and fuma Organic acids such as acids, 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.
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the general formula (I), and a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug, a solvate, and a hydrate.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by the general formula (I), and a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug, a solvate, and a hydrate.
  • a typical formulation is prepared by mixing the compound represented by the general formula (I) of the present invention and a carrier, a diluent or an excipient.
  • Suitable carriers, diluents or excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents , Water and other substances.
  • solvents are generally selected on the basis of solvents considered by those skilled in the art to be safe and effective for administration to mammals.
  • safe solvents are non-toxic aqueous solvents such as water, and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include one or more of water, ethanol, propylene glycol, polyethylene glycol (such as PEG400, PEG300), and the like.
  • the formulation may also include one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, sunscreens, glidants, processing aids, Colorants, sweeteners, flavoring agents, flavoring agents, or other known additives make the drug acceptable or acceptable.
  • the two drugs or multiple drugs may be used separately or in combination, preferably in the form of a pharmaceutical composition.
  • the compounds or pharmaceutical compositions of the invention of formula (I) can be administered separately or together in any of the known forms of oral, intravenous, rectal, vaginal, transdermal, and other topical or systemic administration. Medication to the subject.
  • compositions may also contain one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, sunscreen agents, glidants, processing aids Agents, colorants, sweeteners, flavoring agents, flavoring agents, or other known additives to make the pharmaceutical composition in an acceptable form or use.
  • Solid dosage forms for oral administration may include capsules, tablets, powders or granules.
  • the compound or pharmaceutical composition of the invention is mixed with at least one inert excipient, diluent or carrier.
  • Suitable excipients, diluents or carriers include substances such as sodium citrate or dicalcium phosphate, or starch, lactose, sucrose, mannitol, silicic acid, etc .; binders such as carboxymethyl cellulose, alginic acid Salt, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc .; wetting agents such as glycerol; disintegrants such as agar, calcium carbonate, potato or cassava starch, alginic acid, specific complex silicates, sodium carbonate, etc .; Solution blockers such as paraffin; absorption enhancers such as quaternary ammonium compounds; adsorbents such as kaolin, bentonite; etc.
  • substances such as sodium citrate or dicalcium phosphate, or starch, lactose, sucrose, mannitol, silicic acid, etc .
  • binders such as carboxymethyl cellulose, alginic acid
  • lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate Wait.
  • the dosage form may also include buffering agents.
  • Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using lactose and high molecular weight polyethylene glycols as excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage form may contain an inert diluent such as water or other solvents commonly used in the art; a solubilizer and an emulsifier such as ethanol, isopropyl alcohol, ethyl carbonate, acetic acid Ethyl ester, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide; oils (such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, etc. ); Glycerol; tetrahydrofurfuryl alcohol; fatty acid esters of polyethylene glycol and sorbitan; or a mixture of several of these substances, and the like.
  • an inert diluent such as water or other solvents commonly used in the art
  • composition may also include excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and flavoring agents.
  • excipients such as one or more of wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and flavoring agents.
  • a carrier such as a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline Cellulose, aluminum hydroxide, bentonite, agar and tragacanth, or a mixture of several of these.
  • a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline Cellulose, aluminum hydroxide, bentonite, agar and tragacanth, or a mixture of several of these.
  • the compounds or pharmaceutical compositions of the invention can be administered in other topical dosage forms, including creams, powders, sprays and inhalants.
  • the drug can be mixed under sterile conditions with pharmaceutically acceptable excipients, diluents or carriers, and any preservatives, buffers or propellants required.
  • Ophthalmic formulations, ointments, powders and solutions are also intended to be included within the scope of the present invention.
  • Another aspect of the present invention provides a compound represented by the general formula (I) and its tautomers, enantiomers, diastereomers, racemates, metabolic precursors, pharmaceutically acceptable salts, esters, Use of a prodrug or a hydrate thereof or the above-mentioned pharmaceutical composition for the manufacture of a medicament for the prevention and / or treatment of a disease or symptom associated with an abnormal activity of CDK.
  • the diseases related to abnormal CDK activity include breast cancer, colon cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer and other solid tumors, as well as acute lymphocytic leukemia, acute lymphocytic leukemia, B-cell lymphoma, and T cells. Lymphoma, myeloma, acute and chronic myeloid leukemia, promyelocytic leukemia and other blood tumors.
  • Another aspect of the present invention also provides a compound represented by the general formula (I), and a stereoisomer, a pharmaceutically acceptable salt, a prodrug, a solvate, a hydrate or a crystalline form thereof, or a pharmaceutical composition for preparing the same.
  • Use of medicine for treating diseases such as tumor, central system disease and immune disease.
  • the diseases include, but are not limited to: cancer, angiogenesis-related diseases or functional disorders, pain (including but not limited to complex local pain syndrome), macular degeneration and related functional disorders, Skin diseases, lung dysfunction, immunodeficiency diseases, central nervous system damage and dysfunction, TNF ⁇ -related diseases or dysfunction.
  • the cancer includes (but is not limited to): skin cancer (such as melanoma), lymphatic cancer, breast cancer, cervical cancer, uterine cancer, digestive tract cancer, lung cancer, ovarian cancer, prostate Cancer, colon cancer, rectal cancer, oral cancer, brain tumor, head and neck cancer, throat cancer, testicular cancer, kidney cancer, pancreatic cancer, spleen cancer, liver cancer, bladder cancer, laryngeal cancer, and AIDS-related cancer.
  • the compounds provided by the present invention are also effective for hematomas and myeloma, for example, they can be used to treat multiple myeloma and acute and chronic leukemia.
  • the compounds provided by the present invention can be used for preventing or treating primary tumors and metastatic tumors.
  • Figure 1 shows the degradation effects of compounds C022 and C025 on CDK detected by Western Blot
  • EtOH ethanol; DCM: dichloromethane; TFA: trifluoroacetic acid; MeOH: methanol; NaOH: sodium hydroxide; HCl: hydrogen chloride; TEA: triethylamine; 1,4-dioxane: 1,4-dioxane ; NaH: sodium hydride; H 2 O: water; HATU: 2- (7-benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate; DMF: N, N-dimethylformamide; THF: tetrahydrofuran; DIPEA: N, N-diisopropylethylamine; AcOH: acetic acid; K 2 CO 3 : potassium carbonate; Cs 2 CO 3 : cesium carbonate; Pd (dppf) Cl 2 : [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride; LiOH:
  • 6-chlorohexyne (1 g, 8.58 mmol), potassium phthalimide (2.54 g, 13.72 mmol, 1.6 equiv) were dissolved in 10 mL of DMF, and after reacting at 70 ° C for 18 hours, water and ethyl acetate were added to the reaction solution. Extraction, combined ethyl acetate layers, washed with saturated NaCl, dried over anhydrous Na 2 SO 4 , and column chromatography, to obtain the product 1.2 (1.82 g), yield 85%.
  • N-methyl-4-piperidinol (980 mg, 8.14 mmol, 3 equiv) was dissolved in 10 mL of anhydrous DMF, and NaH (60% dispersed in liquid paraffin, 326 mg, 8.14 mmol, 3 equiv) was added dropwise at 0 ° C.
  • a solution of compound 2.6 (1.25 g, 2.7 mmol) in DMF was reacted at 60 ° C. After 3 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layers were combined, washed with saturated NaCl, and dried over anhydrous Na 2 SO 4.
  • Column chromatography gave the product 2.7 (900 mg) with a yield of 67%.
  • Esters (2.76 mL, 12 mmol, 1.2 equiv), react at room temperature for 12 hours, remove 1,4-dioxane under reduced pressure, add 20 mL of water, wash with diethyl ether, adjust the pH of the aqueous layer to 3 with 1N aqueous HCl solution, and extract with ethyl acetate Three times, the ethyl acetate layers were combined, washed with saturated NaCl, dried over anhydrous Na 2 SO 4 , filtered, and the solvent was removed under reduced pressure to give the product 2.9 (2.5 g) in a yield of 99%.
  • 6-heptynic acid 250mg, 1.98mmol
  • cesium carbonate 322mg, 0.99mmol, 0.5equiv
  • benzyl bromide 259 ⁇ L, 2.18mmol, 1.1 equiv
  • 12 hours at room temperature the reaction mixture was added ethyl acetate, washed with water several times, washed with saturated NaCl, dried over anhydrous Na 2 SO 4, by column chromatography to give the product 9.1 (400mg), 94% yield.
  • Azelaic acid (2g, 10.63mmol) was dissolved in 20mL of anhydrous tetrahydrofuran, DBU (1.59mL, 10.63mmol, 1equiv) was added, and benzyl bromide (1.26mL, 10.63mmol, 1equiv) was added dropwise at 0 ° C, and the reaction was performed at room temperature for 12 hours After that, the solvent was removed under reduced pressure, water was added thereto, and the mixture was extracted with ethyl acetate.
  • Example 20 Proliferation-inhibitory activity of compounds on triple-negative breast cancer cells
  • the human triple-negative breast cancer cells MDA-MB-468 and BT549 used in the present invention were purchased from Shanghai Cell Bank. L-15 medium supplemented with 10% fetal bovine serum (FBS) and 1% double antibody was used. MDA-MB-468 cells were cultured in an incubator at 37 ° C without CO 2 , and BT549 was cultured in DMEM / HIGH GLUCOSE medium supplemented with 20% FBS and 1% double antibody, at 37 ° C, 5% CO 2 Medium growth.
  • FBS fetal bovine serum
  • the cells treated with DMSO were used as a positive control, the OD450nm was read by a microplate reader, and the data was processed with GraphPad Prism6 software.
  • NT indicates that it is not a test.
  • the compound in triple negative breast cancer cell lines MDA-MB-468 and BT549, the compound has a good inhibitory activity on cell growth inhibition. Therefore, the compounds of the present invention can be used as novel degradation agents for related targets in triple-negative breast cancer cells.
  • Example 21 Inhibitory activity of compounds on the proliferation and growth of blood tumor cells and other solid tumor cells
  • the experimental method is the same as the above cell test method, and the relevant cell viability test results are as follows:
  • the compounds of the present invention are in hematological tumor cell lines, such as diffuse large B-cell lymphoma cell line (OCI-LY-10), multiple myeloma cell line (MM.1S), human acute Lymphocytic leukemia T lymphocyte strains (CCRF-CEM) all have high activity, and the cell growth inhibitory activity IC 50 ⁇ 200 nM.
  • the compounds of the invention also have good activity in human prostate cancer cell line (PC-3) and human colon cancer cell line (HCT116), respectively, and can be used as novel CDK-targeting degradation agents for prevention and treatment of CDK.
  • Diseases associated with abnormal activity such as solid tumors and hematological tumors.
  • CDK1 (Absin, abs132093)
  • CDK2 (Absin, abs100510)
  • CDK4 CST, 12790
  • CDK5 (Absin, abs100524)
  • CDK9 CST, 2316
  • Actin (Absin, abs132001)
  • Tubulin (Absin, abs131993a).
  • the compound of the present invention mainly has a very high selectivity for CDK9 and has a good degradation effect, but has no obvious degradation effect on other proteins of the CDK family. Therefore, the compounds of the present invention can be used as novel CDK9-degrading agents in triple-negative breast cancer cells.

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Abstract

公开了通式(I)所示的靶向细胞周期依赖性激酶(CDKs)降解剂的化合物和/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增殖的效果，说明具有潜在的治疗相关癌症和自身免疫性疾病的潜力。

Description

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 技术领域
本发明属于药物学领域，具体涉及一类如通式(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)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2015年上市的辉瑞的帕布昔利布(Palbociclib)和2017年上市的诺华的瑞博西尼(Ribociclib)以及礼来的Abemaciclib，这三个药物都是靶向CDK4/6的抑制剂，用于治疗乳腺癌，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(cyclin-activating 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Ⅱ的C端结构域激活RNA聚合酶Ⅱ，从而调节RNA聚合酶Ⅱ介导的转录起始和延伸。
CDK9/CyclinT1(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。
靶向蛋白降解技术：
靶向蛋白降解技术是近几年受到广泛关注的一种药物研发的新技术，这种技术利用生物体内泛素—蛋白酶体介导的蛋白降解途径，可以人为控制靶蛋白的降解。通过设计一种双功能分子，这种双功能分子的一端可以识别靶蛋白，另外一端可以识别E3泛素连接酶，中间通过一段连接链(Linker)连接，形成一种靶向诱导蛋白降解联合体(Proteolysis targeting chimeras，PROTACs)。当这种双功能分子进入细胞后，两端可以分别识别靶蛋白和E3泛素连接酶，将两个蛋白拉近，使E2泛素结合酶上的泛素转移至靶蛋白上，将靶蛋白泛素化，然后通过泛素—蛋白酶体途径使靶蛋白降解。经过近几年的快速发展，靶向蛋白降解技术已经从一个化学生物学概念转变为药物研发的一种新技术，利用这种PROTAC分子靶向降解与疾病相关的靶点，可以克服传统小分子抑制剂存在的缺点，有望重新定义小分子药物。CN103265635A，CN107257800A等文献介绍了这种技术在降解靶点蛋白上的作用。
靶向CDK7和CDK9的蛋白降解剂：
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，其中多为非选择性抑制剂(J.Med.Chem.2016,59,8667-8684.Bioorganic&Medicinal Chemistry Letters2015，25，3420–3435)。代表性的小分子抑制剂有Flavopiridol,Roscovitine,SNS-032,R547,TG-02,AT-7519等；但是高选择性针对CDK7或CDK9，或者针对于CDK7和CDK9的双靶点的小分子抑制剂研究比较少(US2007179161A1，US2015111873A1，WO2016193939A1，WO2016142855A2)。尽管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，但最新研究表明，小分子抑制剂作用于CDKs靶点出现耐药性，仅通过小分子抑制剂进行治疗不能成为有效的抗肿瘤方法。Nathanael Grag等以SNS-032为靶蛋白配体，开发了通式为
Figure PCTCN2019100969-appb-000001
WO2017185023A1的靶向降解CDK9的降解剂,其中代表性的一个CDK9降解剂为THAL-SNS-032。
CDK相关激酶与肿瘤的发生发展密切相关，因此靶向CDK9或CDK7相关激酶靶点的降解剂能够降解靶点蛋白，从而调节RNA聚合酶Ⅱ介导的转录起始和延伸，有效抑制肿瘤细胞的增殖；同时能解决该类靶点的小分子抑制剂的耐药性问题。因此本发明的一个目的是通过设计合成新的靶向CDK9或CDK7的蛋白降解剂，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。
发明内容
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：1QMZ,3BLR，1UA2，3BLH)下述重要信息：CDK9相比其他CDKs拥有更大的构象柔性，比如小分子抑制剂与CDK9/cyclinT结合时，可以下调CDK结构中富含甘氨酸(Gly)环的位置，以适应配体的结合；同时CDK9蛋白质结构的这种特点使得其结合区域可以容纳更大的配体结构。通过对结构的分析，我们在CDK9与其他小分子抑制剂的复合物结构中也获得重要的信息(PDB ID：3LQ5)：嘌呤环上C-6上的取代基则伸出CDK9的ATP结合口袋，部分暴露于溶剂中；同时如果该位置是一个较大位阻取代的取代基，也能够保持与CDK9具有好的结合能力。因此这些特点将主要作为我们设计CDK9的小分子降解剂的出发点。基于CDK9的小分子抑制剂，发明人主要设计及合成了一类特异性靶向CDK9的小分子降解剂。通过设计一种双功能分子，该分子的一端可以识别靶蛋白，另外一端可以识别E3泛素连接酶，中间通过一段连接链(Linker)连接。我们合成一系列本申请所述的CDK9降解剂，并测试了化合物的活性；测试结果表明，降解剂具有非常高的细胞的生长抑制活性，同时通过相关的测试方法发现，降解剂可以非常高效地降解CDK9靶点。该分子作用于生物体后，通过生物体内泛素—蛋白酶体介导的蛋白降解途径，可以人为控制靶蛋白CDK9的降解，进而实现基于CDK9靶点的有效的疾病治疗。
本发明的一个目的是提供通式(I)所示的化合物、其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物。
本发明的另一个目的是提供该类化合物的重要中间体及制备方法。
本发明的另一个目的是提供该类化合物在制备预防和治疗与CDK的异常活性相关的疾病的药物中的用途，与CDK的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、B细胞淋巴瘤、T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。
本发明提供如下通式(I)所示的化合物、其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物：
Figure PCTCN2019100969-appb-000002
其中，
Figure PCTCN2019100969-appb-000003
选自以下基团：
Figure PCTCN2019100969-appb-000004
所述G 1、G 2、G 3各自独立地任选自–C(R b1)＝或–N＝；其中R b1选自氢、卤素、或者C 1-4烃基；
Z为–CH 2–或–C(＝O)–；
R a1为氢、氟或甲基；
R a2为氢或甲基；
R c1为氢或氟；
R a3、R a4、R a5各自独立地为氢、卤素、氰基、硝基、羟基、氨基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基、取代或未取代的氨基、取代或未取代的C 2-6烷羰基，其中所述取代是指被如下一种或多种取代基所取代：卤素、羟基、C 1-6烷氧基、氰基、硝基、C 1-6烷基、卤代C 1-6烷基、羟C 1-6烷基、C 3-10环烷基、含有1-3个选自N、O和S原子的3-6元杂环基；
X为–O–、–NH–、–CH 2–、–NH–CO–、–CO–NH–、–CO–、–CH＝CH–、-C≡C-、–CO–NH–S(O) 2–、–NH–CO–NH–、–NH–CO–O–、–OCONH–、–SO 2–、––SO 2NH–、–NHSO 2–、
Figure PCTCN2019100969-appb-000005
或者X不存在；
L选自–(CH 2) m1–(OCH 2CH 2) m2–、–(CH 2OCH 2) m3–、–(CH 2) m4–W1-(CH 2) m5–、–(CH 2) m4–W2-(CH 2CH 2O) m6–(CH 2) m7–，其中，W1、W2各自独立选自-O-、-CH 2-、五元杂芳环、六元杂芳环、C 3-10烷基环或3-6元杂烷基环；
m1为0，1，2，3，4，5，6，7，8，9，10，11或12；
m2为0，1，2，3，4，5或6；
m3为0，1，2，3，4或5；
m4为0，1，2，3，4或5；
m5为0，1，2，3，4，5或6；
m6为0，1，2，3或4；
m7为0，1，2，3，4，5，6或7；
Y为–CH 2–、–CH＝CH–、-C≡C-、–O–、–NR 2a–、–CO–NR 2b–、–NR 2c–CO–CH 2O–、–NR 2d–CO–CH 2NR 2e–或者Y不存在，其中–CO–NR 2b–、–NR 2c–CO–CH 2O–、–NR 2d–CO–CH 2NR 2e–与L连接的形式分别为–L–CO–NR 2b–、–L–NR 2c–CO–CH 2O–、–L–NR 2d–CO–CH 2NR 2e–；其中所述R 2a、R 2b、R 2c、R 2d、R 2e各自独立地任选自氢或者C 1-C 4烃基；
Figure PCTCN2019100969-appb-000006
选自C 6-12芳基、5-8元环烷基、含有1-3个选自N、O和S的杂原子的5-8元杂环基或5-8元杂芳基、5-8元环烷基并C 6-12芳基、含有1-3个选自N、O和S的杂原子的5-8元杂环基或5-8元杂芳基并C 6-12芳基；
R 4选自氢原子、卤素、C 1-6烷氧基、氰基、氨基、硝基、C 1-6烷基、C 3-10环烷基、5-8元杂环基、C 6-10芳基、5-6元杂芳基、-NHC(O)R 5、-NHC(O)OR 6、-NR 7R 8、其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、C 1-C 6烷氧基、氰基、硝基取代基所取代；
R 5、R 6、R 7和R 8各自独立地选自氢原子、C 1-6烷基、C 3-10环烷基、5-8元杂环基、C 6-10芳基或5-8元杂芳基，其中所述的烷基、环烷基、芳基或杂芳基任选进一步被一个或多个选自卤素、羟基、C 1-C 6烷氧基、氰基、硝基取代基所取代；
n为0，1，2，3，4；
R 1为氢、氘或者CH 3；
其中X 1-X 7各自独立地为C或者N，优选地，X 1-X 7所在的五元环并六元环与R 2、R 3和E所组成的结构选自：
Figure PCTCN2019100969-appb-000007
R 2为氢或者取代或未取代的C 1-8烃基，其中所述取代是指被选自如下的一种或多种取代基所取代：卤素、氰基、硝基、羟基和氨基；
E选自–O–、–CO–NH–、–NH–CO–、–O–CH 2–、–CO–NH–CH 2–、–NR 6–、–NR 6–CH 2–、–CH 2–NR 6–、–S–、–CH(OH)–或–CH 2–；优选地E选自–O–或–NH–；
R 3选自取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基、取代或未取代的氨基、取代或未取代的C 2-6烷羰基，其中所述取代是指被如下一种或多种取代基所取代：卤素、羟基、C 1-6烷氧基、氰基、硝基、C 1-6烷基、卤代C 1-6烷基、羟C 1-6烷基、C 3-10环烷基、含有1-3个选自N、O和S原子的3-8元杂环基。
优选地，通式(I)的化合物选自如下通式：
Figure PCTCN2019100969-appb-000008
其中，R 1、R 2、R 3、E、R 4、n、
Figure PCTCN2019100969-appb-000009
X、L、Y和
Figure PCTCN2019100969-appb-000010
的定义与上述定义中相同。
更优选地，通式(I)的化合物选自如下通式：
Figure PCTCN2019100969-appb-000011
其中R 3-E-所代表的基团选自以下基团：
Figure PCTCN2019100969-appb-000012
R 1为氢、氘或者CH 3；
R 2为氢或者取代或未取代的C 1-C 3烷基，其中所述取代是指被选自如下的一种或多种取代基所取代：卤素、氰基、硝基、羟基和氨基；
R 4选自氢原子、卤素、氰基、氨基、硝基、-NHC(O)CH 3、3-6元环烷基、C 1-4烷氧基、C 1-4烷基、其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、硝基的取代基所取代；
n为0，1，2；
Figure PCTCN2019100969-appb-000013
选自苯基或萘环基、5-6元环烷基、含有1-3个选自N、O和S的杂原子的5-6元杂环基或5-6元杂芳基、5-6元环烷基并苯基、含有1-3个选自N、O和S的杂原子的5-8元杂环基或5-6元杂芳基并苯基；
X、L、Y和
Figure PCTCN2019100969-appb-000014
的定义与上述定义中相同。
进一步优选地，通式(I)的化合物选自如下通式：
Figure PCTCN2019100969-appb-000015
其中R 3-E-所代表的基团选自以下基团：
Figure PCTCN2019100969-appb-000016
R 1为氢、氘或者CH 3；
R 2为氢或者取代或未取代的C 1-3烷基，其中所述取代是指被选自如下的一种或多种取代基所取代：卤素、氰基、硝基、羟基和氨基；
R 4为氢原子、卤素、氰基、氨基、硝基、-NHC(O)CH 3、3-6元环烷基；
n为0，1，2；
Figure PCTCN2019100969-appb-000017
选自以下基团：
Figure PCTCN2019100969-appb-000018
Figure PCTCN2019100969-appb-000019
L选自–(CH 2) m1–(OCH 2CH 2) m2–、–(CH 2OCH 2) m3–、–(CH 2) m4–W1-(CH 2) m5–、–(CH 2) m4–W2-(CH 2CH 2O) m6–(CH 2) m7–；
其中W1、W2各自独立优选自-O-、-CH 2-、
Figure PCTCN2019100969-appb-000020
X、Y、
Figure PCTCN2019100969-appb-000021
m1、m2、m3、m4、m5、m6、m7的定义与上述定义中相同。
在一优选实施方式中，其中通式(I)所示的化合物选自如下通式：
Figure PCTCN2019100969-appb-000022
其中，R 1、R 2、R 3、E、X、L、Y和
Figure PCTCN2019100969-appb-000023
的定义与上述定义中相同。
在一优选实施方式中，其中通式(I)所示的化合物选自如下通式：
Figure PCTCN2019100969-appb-000024
其中，R 1、R 2、R 3、E、R 4、n、
Figure PCTCN2019100969-appb-000025
X、L、Y、R c1、R a2、R a3和R a4的定义与上述定义中相同。
在一优选实施方式中，其中通式(I)所示的化合物选自如下通式：
Figure PCTCN2019100969-appb-000026
其中，R 1、R 2、R 3、E、R 4、n、
Figure PCTCN2019100969-appb-000027
X、L、Y和
Figure PCTCN2019100969-appb-000028
的定义与上述定义中相同。
更优选地，通式(I)的化合物选自下列化合物：
Figure PCTCN2019100969-appb-000029
Figure PCTCN2019100969-appb-000030
Figure PCTCN2019100969-appb-000031
Figure PCTCN2019100969-appb-000032
Figure PCTCN2019100969-appb-000033
Figure PCTCN2019100969-appb-000034
Figure PCTCN2019100969-appb-000035
Figure PCTCN2019100969-appb-000036
Figure PCTCN2019100969-appb-000037
Figure PCTCN2019100969-appb-000038
Figure PCTCN2019100969-appb-000039
Figure PCTCN2019100969-appb-000040
其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物。
术语“卤素”是指氟、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“C 1-C 8烷基”是指链上具有1至8个碳原子的直链或支链饱和烃基，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“环烷基”是指由碳原子组成的饱和环状烷基，非限制性地包括环丁基、环戊基、环己基等。
术语“卤代烷基”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“羟烷基”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。
术语“C 5-C 8环烷基”是指含5至8个碳原子的饱和单-或多-环系，非限制性地包括环丙基，环丁基，环戊基，或环己基。
术语“C 6-C 10芳基”是指包含6-10个环原子但环原子中不含杂原子的芳香族环基，如苯基、萘基。
术语“亚芳基”是指二价的芳香族单环或二价芳香族稠合双环烃基，代表性的实例包括但不限于亚苯基、亚萘基等。
术语“5-10元杂环基”是指含有一个或多个饱和和/或部分饱和环，其包括5至10个环原子，其中一个或多个环原子选自氮、氧或硫的杂原子，其余环原子为碳；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。
术语“5-12元杂芳基”是指包含5-12个环原子且在环原子中含有1-4个杂原子作为环成员的单价芳香环基团。杂原子可以选自氮、氧或硫。杂芳基可以是具有5-7个环原子的单环杂芳基，或者具有7-12个环原子的双环杂芳基。所述双环杂芳基中只要一个环是杂芳环即可，另一个可以是芳香环或非芳香环的，含杂原子的或不含杂原子的。杂芳基的例子包括但不限于吡咯基、吡唑基、咪唑基、噁唑基、吡啶基、嘧啶基、呋喃基、噻吩基、噻唑基、噻二唑基、四唑基、三氮唑基、异噁唑基、吲哚基、甲基吡啶鎓基噻唑基、苯并[d]恶唑、苯并[d]咪唑等。优选地，所述5-12元杂芳基选自吡啶基，嘧啶基，噁唑基，噻吩基，吲哚基，1，3-二氧代异吲哚基，1-氧代异吲哚基，咪唑基，吡唑基，异噁唑基，苯并咪唑基和呋喃基。
术语“芳基并杂环烷基”是指芳基或者杂芳基并含有氧、氮或者硫的环烷基，非限制性包括1,3-苯并二噁茂、2，3-二氢苯并呋喃、吲哚啉等。
术语“5-12元亚杂芳基”是指含5-12个环原子且在环原子中含有1-4个杂原子作为环成员的二价芳香环基团。杂原子可以选自氮、氧或硫。亚杂芳基可以是具有5-7个环原子的单环亚杂芳基，或者具有7-12个环原子的双环亚杂芳基。例如，亚三氮唑基、亚吡咯基、亚吡唑基、亚咪唑基、亚噁唑基、亚吡啶基、亚嘧啶基、亚呋喃基、亚噻吩基、亚噻唑基、亚噻二唑基、亚四唑基、亚异噁唑基、亚吲哚基、亚甲基吡啶鎓基噻唑基、亚苯并[d]恶唑、亚苯并[d]咪唑等。
术语“互变异构体”是指容易通过互为异构体的化学反应互变的结构异构体，该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“对映体”是指互为镜像而不可重叠的立体异构体，例如化合物C045以及它的对映异构体。
“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，例如化合物C045以及它的非对映异构体。
“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，例如，化合物C001、化合物C002、化合物C003等。
“代谢前体”是指在体外无活性或者活性较小，在体内经过体内代谢途径的转化释放出活性药物而发挥药效的一类化合物。
“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，例如化合物C001的盐酸、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。
本发明也包含这里公布的任何一种新的中间体。
本发明有一个方面提供了通式(I)所示的降解剂的制备方法，所述方法选自如下方法之一：合成方法一：
靶向CDK靶点的配体(1A)的合成参考文献J.Med.Chem.2016,59,8667-8684；Bioorganic&Medicinal Chemistry Letters 2015，25，3420-3435；J.Med.Chem.2009，52,655-663；J.Med.Chem.2010,53,8508-8522；以及US2007179161A1，US2015111873A1，WO2016193939A1，WO2016142855A2。
Figure PCTCN2019100969-appb-000041
其中，R 2、R 3、E、X 1、X 2和X 7的定义与上述相同；
n 1为0～12的整数、n 2为0～6的整数；
步骤a:化合物1A与连接链1B通过缩合反应得到化合物1C；
步骤b:化合物1C与1D在偶氮二甲酸二异丙酯(DIAD)和三苯基膦(PPh 3)条件下反应得到1E。
合成方法二：
Figure PCTCN2019100969-appb-000042
其中，R 2、R 3、E、X 1、X 2和X 7的定义与上述相同；
U为-O-或-CH 2-；
n 3为0-9的整数，n 4为0-5的整数；
步骤c:化合物2A与连接链2B在碘化亚铜和双三苯基膦二氯化钯条件下反应得到化合物2C；
步骤d:化合物2C在氢气和钯碳加氢催化剂条件反应得到化合物2D；
步骤e:化合物2D和1A通过缩合反应得到化合物2E。
合成方法三：
Figure PCTCN2019100969-appb-000043
其中，R 2、R 3、E、X 1、X 2和X 7的定义与上述相同；
n 5为0-12的整数，n 6为0-6的整数；
步骤f:连接链3A与化合物1A通过缩合反应得到化合物3B；
步骤g:化合物3B在盐酸或三氟醋酸脱保护条件下得到化合物3C；
步骤h:化合物3C与化合物3D通过缩合反应得到化合物3E；
步骤i:化合物3C与化合物3F在N,N-二异丙基乙胺条件下反应得到化合物3G。
合成方法四：
Figure PCTCN2019100969-appb-000044
其中，R 2、R 3、E、X 1、X 2和X 7的定义与上述相同；
Z为亚甲基或羰基；
n 7为0-12的整数，n 8为0-6的整数；
步骤j:化合物4A与4B在DIAD和PPh 3条件下反应得到4C；
步骤k:化合物4C在四丁基氟化氨条件下反应得到化合物4D；
步骤l:化合物4E在氢气和钯碳加氢催化剂条件反应得到化合物4F；
步骤m:化合物1A与连接链4F通过缩合反应得到化合物4G。
合成方法五：
Figure PCTCN2019100969-appb-000045
其中，R 2、R 3、E、X 1、X 2和X 7的定义与上述相同；
n 9为0-10的整数，n 10为0-6的整数；
步骤n:化合物5A与连接链5B通过缩合反应得到化合物5C；
步骤o:化合物5C在氢氧化锂条件下脱除保护基得到化合物5D；
步骤p：化合物5D与化合物1A通过缩合反应得到化合物5E。
合成方法六：
Figure PCTCN2019100969-appb-000046
其中，R 2、R 3、Ra3、Ra4、E、X 1、X 2和X 7的定义与上述相同；
n 11为0-6的整数，n 12为0-10的整数；
步骤q:化合物6A与连接链6B通过缩合反应得到化合物6C；
步骤r:化合物6C在氢氧化锂条件下脱除保护基得到化合物6D；
步骤s：化合物6D与化合物1A通过缩合反应得到化合物6E。
合成方法七：
Figure PCTCN2019100969-appb-000047
其中，R 2、R 3、E、X 1、X 2和X 7的定义与上述相同；
n 13为0-9的整数，n 14为0-5的整数；
步骤u：化合物2A与连接链7A在碘化亚铜和双三苯基膦二氯化钯条件下反应得到化合物7B；
步骤v：化合物7B在三氟乙酸条件下反应得到化合物7C；
步骤w：化合物7C和化合物1A在HATU和DIPEA的条件下缩合得到化合物7D；
步骤x：化合物2C在钯碳催化常压氢气条件下得到化合物7E。
合成方法八：
Figure PCTCN2019100969-appb-000048
其中，R 2、R 3、E、X 1、X 2和X 7的定义与上述相同；
n 15为0-9的整数，n 16为0-5的整数；
8F合成参考文献J.Med.Chem.2016,59,8667-8684；Bioorganic&Medicinal Chemistry Letters 2015，25，3420-3435；J.Med.Chem.2009，52,655-663；J.Med.Chem.2010,53,8508-8522；以及US2007179161A1，US2015111873A1，WO2016193939A1，WO2016142855A2。
步骤y：化合物8A与8B在双三苯基膦二氯化钯与碘化亚铜的条件下反应得到化合物8C；
步骤z1：化合物8C在雷尼镍催化下氢化得到化合物8D；
步骤z2：化合物8D在咪唑和TBSCl的条件下反应得到化合物8E；
步骤z3：以化合物8E与8F在碱性条件下通过亲核取代反应，制备得到化合物8G；
步骤z4：化合物8G与R 3EH在碱性条件下通过亲核取代反应，制备得到化合物8H；
步骤z5：化合物8H在四丁基氟化铵的条件下反应得到化合物8I；
步骤z6：化合物8I在偶氮二甲酸二异丙酯和三苯基膦的条件下反应得到化合物8J。
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。
本发明的又一个方面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，使该药物以可被接受的形式制造或使用。
本发明所述的如式(I)的化合物与至少一种其它药物的组合使用时，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。
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、代谢前体、可药用的盐、酯、前药或其水合物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、B细胞淋巴瘤、T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，及其立体异构体、可药用盐、前药、溶剂化物、水合物或晶型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)：皮肤癌症(如黑色素瘤)、淋巴系统癌症、乳腺癌、宫颈癌、子宫癌、消化道癌症、肺癌、卵巢癌、前列腺癌、结肠癌、直肠癌、口腔癌、脑瘤、头颈部癌、咽喉癌、睾丸癌、肾癌、胰腺癌、脾癌、肝癌、膀胱癌，喉癌以及与艾滋病相关的癌症。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。
附图说明
图1为Western Blot检测化合物C022和C025对CDK的降解效果
具体实施方式
下面结合实施例对本发明作进一步阐述，但这些实施例绝不是对本发明的任何限制。
所有实施例中， 1H NMR由Bruker Avance III-300或Avance III-400型核磁共振仪记录，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。邻硝基苯磺酰氯、巯基乙酸、二甘醇胺等试剂购买于国药集团化学试剂有限公司。
EtOH：乙醇；DCM：二氯甲烷；TFA：三氟乙酸；MeOH：甲醇；NaOH：氢氧化钠；HCl：氯化氢；TEA：三乙胺；1,4-dioxane：1,4-二氧六环；NaH：氢化钠；H 2O：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；K 2CO 3：碳酸钾；Cs 2CO 3：碳酸铯；Pd(dppf)Cl 2：[1,1’-双(二苯基膦基)二茂铁]二氯化钯；LiOH：氢氧化锂；PPh 3：三苯基膦；DEAD：偶氮二甲酸二乙酯；DIAD：偶氮二甲酸二异丙酯；KOH：氢氧化钾；MsCl：甲基磺酰氯；NaN 3：叠氮化钠；Pd/C：钯碳加氢催化剂；Pd 2dba 3：三(二亚苄基丙酮)二钯；rac-BINAP：1,1'-联萘-2,2'-双二苯膦；Toluene：甲苯；t-BuONa：叔丁醇钠；(Boc) 2O：二碳酸二叔丁酯；CuI：碘化亚铜；Pd(PPh 3) 2Cl 2：双三苯基膦二氯化钯；EA：乙酸乙酯；DMAP：4-二甲氨基吡啶；NaHCO 3：碳酸氢钠；KI：碘化钾；HCOOH：甲酸；Fmoc-OSU：9-芴甲基-N-琥珀酰亚胺基碳酸酯；NH 4Cl：氯化铵；piperidine：哌啶；POCl 3：三氯氧磷；PhNMe 2：N,N-二甲基苯胺；MeCN：乙腈；Raney Ni：雷尼镍；BPO：过氧化苯甲酰；NBS：N-溴代丁二酰亚胺；Benzene：苯；p-TsCl：4-甲基苯磺酰氯；pyridine：吡啶；DMSO：二甲亚砜；NaBH 3CN：氰基硼氢化钠；TBSCl：叔丁基二甲基氯硅烷；imidazole：咪唑；CBZ-Cl：氯甲酸苄酯；m-CPBA：间氯过氧苯甲酸；DBU：1,8-二氮杂双环[5.4.0]十一碳-7-烯；BH 3.THF：硼烷四氢呋喃；NMP：N-甲基吡咯烷酮。
一、制备实施例
实施例1.
[C001]N-(6-(4-(((5-((6-正己胺基)氨基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)正己基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)乙酰胺的制备
Figure PCTCN2019100969-appb-000049
对溴苄胺(1g，5.37mmol)溶于二氯甲烷中，加入三乙胺(1.23mL，5.37mmol，1equiv)，0℃下滴加二碳酸二叔丁酯，室温反应12小时后，向反应液中加入二氯甲烷，饱和NaHCO 3洗涤，无水Na 2SO 4干燥，柱层析，得产物1.1(1.35g)，收率88％。 1H NMR(400MHz,CDCl 3)δ7.43(d,J＝7.5Hz,2H),7.15(d,J＝8.0Hz,2H),4.25(d,J＝5.6Hz,2H),1.45(s,9H)。
6-氯己炔(1g，8.58mmol)，酞酰亚胺钾(2.54g，13.72mmol，1.6equiv)溶于10mL DMF中，70℃下反应18小时后，向反应液中加水，乙酸乙酯萃取，合并乙酸乙酯层，饱和NaCl洗涤，无水Na 2SO 4干燥，柱层析，得产物1.2(1.82g)，收率85％。 1H NMR(400MHz,CDCl 3)δ7.83(dd,J＝5.4,3.1Hz,2H),7.70(dd,J＝5.4,3.1Hz,2H),3.70(t,J＝7.1Hz,2H),2.23(td,J＝7.0,2.6Hz,2H),1.93(t,J＝2.6Hz,1H),1.84-1.75(m,2H),1.61-1.51(m,2H)。
化合物1.1(286mg，1mmol)，化合物1.2(454mg，2mmol，2equiv)，碘化亚铜(38mg，0.2mmol，20mol％)，双三苯基磷二氯化钯(70mg，0.1mmol，10mol％)加入反应瓶中，N 2保护，加入2.5mL三乙胺和5mL DMF，N 2保护，80℃下反应12小时后，反应液滤过硅藻土，用 120mL乙酸乙酯洗涤，水洗数次，饱和NaCl洗涤，无水Na 2SO 4干燥，柱层析，得产物1.3(405mg)，收率89％。 1H NMR(400MHz,CDCl 3)δ7.84(dd,J＝5.4,3.1Hz,2H),7.71(dd,J＝5.4,3.0Hz,2H),7.33(d,J＝8.2Hz,2H),7.18(d,J＝8.1Hz,1H),4.28(d,J＝5.7Hz,1H),3.74(t,J＝7.1Hz,2H),2.46(t,J＝7.0Hz,2H),1.91-1.81(m,2H),1.69-1.60(m,2H),1.45(s,9H)。
化合物1.3(405mg，0.94mmol)溶于25mL乙酸乙酯和25mL甲醇中，加入钯碳(含量5％，81mg)，通入3atm氢气，室温反应6小时后，滤出钯碳，减压除去溶剂，得产物1.4。 1H NMR(400MHz,CDCl 3)δ7.83(dd,J＝5.4,3.1Hz,2H),7.70(dd,J＝5.3,3.1Hz,2H),7.17(d,J＝7.9Hz,2H),7.10(d,J＝8.0Hz,2H),4.26(d,J＝5.5Hz,2H),3.66(t,J＝7.3Hz,2H),2.56(t,J＝7.7Hz,2H),1.70-1.53(m,4H),1.45(s,9H),1.39-1.26(m,4H)。
化合物1.5(76mg，0.33mmol)(参照EP2634190A1)，化合物1.4(165mg，0.5mmol，1.5equiv)溶于10mL乙醇中，加入DIPEA(109μL，0.66mmol，2equiv)，回流12小时，减压除去溶剂，柱层析，得产物1.6(69mg)，收率39％。 1H NMR(400MHz,CDCl 3)δ7.83-7.78(m,3H),7.71-7.64(m,2H),7.34-7.18(m,2H),7.11(dd,J＝26.2,7.1Hz,2H),5.90(d,J＝1.0Hz,1H),4.49(d,J＝5.5Hz,2H),3.65(t,J＝7.3Hz,2H),3.29-3.19(m,1H),2.57(t,J＝7.5Hz,2H),1.69-1.51(m,4H),1.39-1.27(m,10H)。
化合物1.6(69mg，0.13mmol)溶于3mL THF中，室温下分别加入DMAP(3mg，0.026mmol，0.2equiv)和(Boc) 2O(46μL，0.2mmol，1.5equiv)，室温反应12小时，减压除去溶剂，柱层析，得产物1.7(78mg)，收率95％。
化合物1.7(78mg，0.124mmol)、Pd 2dba 3(6mg，0.0062mmol，5mol％)、rac-BINAP(12mg，0.0186mmol，15mol％)、Cs 2CO 3(60mg，0.186mmol，1.5equiv)溶于3mL无水甲苯中，N 2保护，室温反应15分钟后，化合物1.8(433mg，2mmol，2equiv)溶于2mL无水甲苯中，加入反应液中，再次抽换气，N 2保护，100℃下反应16小时后，向反应液中加入乙酸乙酯，分别用水和饱和NaCl洗涤，无水Na 2SO 4干燥，柱层析得产物1.9(40mg)，收率40％。
化合物1.9(40mg，0.0494mmol)溶于4mL乙醇中，加入水合肼(85％，57μL，0.988mmol，20equiv)，回流4小时后，滤出其中的固体，乙酸乙酯洗涤，减压除去溶剂，柱层析得产物1.10(22mg)，收率65％。 1H NMR(400MHz,CDCl 3)δ7.72(s,1H),7.14(d,J＝8.1Hz,2H),7.08(d,J＝8.1Hz,2H),5.66(s,1H),4.89(d,J＝5.7Hz,2H),3.31(dd,J＝12.7,6.7Hz,2H),3.11(dt,J＝13.7,6.9Hz,3H),2.67(t,J＝7.0Hz,2H),2.59-2.52(m,2H),1.63-1.51(m,4H),1.50-1.26(m,36H).UPLC-MS(ESI)理论值为C 38H 61N 7O 4[M+H] +:680.48，实测值为680.87。
化合物1.10(22mg，0.0324mmol)，化合物1.11(10.7mg，0.0324mmol，1equiv)(化合物1.11的制备参照Lohbeck J.,Miller A.K.Practical synthesis of a phthalimide-based Cereblon ligand to enable PROTAC development.Bioorganic&medicinal chemistry letters.2016；26(21):5260-5262.)，HATU(18mg，0.0486mmol，1.5equiv)溶于2mL DMF中，0℃下滴加DIPEA(16μL，0.0972mmol，3equiv)，室温反应12小时后，向反应液中加水，乙酸乙酯萃取，合并乙酸乙酯层，饱和NaCl洗涤数次，无水Na 2SO 4干燥，过滤，减压除去溶剂，柱层析，得产物1.12(30mg)，收率94％。
化合物1.12(30mg，0.0302mmol)溶于3mL二氯甲烷中，0℃下滴加800μL三氟乙酸，室温反应3小时，减压除去溶剂，HPLC纯化，制备得C001(21mg)，收率99％。 1H NMR(400MHz,DMSO-d 6)δ11.13(s,1H),7.95(t,J＝5.6Hz,1H),7.78(dd,J＝8.5,7.3Hz,1H),7.48(d,J＝7.2Hz,1H),7.37(d,J＝8.6Hz,1H),7.29(d,J＝8.0Hz,2H),7.15(d,J＝8.1Hz,2H),5.32(s,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.76(s,2H),4.56(s,2H),3.32-3.22(m,2H),3.17-3.00(m,3H),2.94-2.82(m,1H),2.80-2.71(m,2H),2.62-2.43(m,4H),2.05-1.95(m,1H),1.56-1.36(m,8H),1.34-1.15(m,14H).UPLC-MS(ESI)理论值为C 43H 55N 9O 6[M+H] +:794.43，实测值为794.81。
[C002]N-(6-(3-(((5-((6-氨基正己基)氨基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)正己基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧代)乙酰胺的制备
参照实施例1中的合成路线，将对溴苄胺替换成间溴苄胺，制备得C002。 1H NMR(400MHz,DMSO-d 6)δ11.13(s,1H),7.98(s,1H),7.78(dd,J＝8.4,7.4Hz,1H),7.48(d,J＝7.2Hz,1H),7.38(d,J＝8.5Hz,1H),7.28-7.17(m,3H),7.09(d,J＝7.2Hz,1H),5.39(s,1H),5.11(dd,J＝12.9,5.4Hz,1H),4.77(s,2H),4.63(s,2H),3.31-3.22(m,2H),3.18-3.01(m,3H),2.94-2.81(m,1H),2.79-2.71(m,2H),2.63-2.44(m,4H),2.06-1.98(m,1H),1.58-1.36(m,8H),1.35-1.13(m,14H).UPLC-MS(ESI)理论值为C 43H 55N 9O 6[M+H] +:794.43，实测值为794.92。
实施例2
[C012]7-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)乙酰胺基)-N-(4-(((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-基)氨基)甲基)苯基)庚酰胺的制备
Figure PCTCN2019100969-appb-000050
4-硝基苄胺盐酸盐溶于(590mg，3.13mmol)溶于15mL二氯甲烷中，0℃下加入DIPEA(1.03mL，6.26mmol，2equiv)，Fmoc-OSU(1.1g，3.28mmol，1.05equiv)溶于二氯甲烷，逐滴加入反应液中，室温反应4小时，向反应中加入100mL二氯甲烷，0.5N的HCl水溶液洗涤数次，饱和NaCl洗涤，无水Na 2SO 4干燥，过滤，减压除去溶剂，柱层析，得产物2.1(1.15g)，收率98％。 1H NMR(400MHz,CDCl 3)δ8.18(d,J＝8.5Hz,2H),7.78(d,J＝7.6Hz,2H),7.59(d,J＝7.4Hz,2H),7.46-7.29(m,6H),4.54(d,J＝6.4Hz,2H),4.45(d,J＝6.3Hz,2H),4.22(t,J＝6.4Hz,1H).
化合物2.1(600mg，1.6mmol)溶于THF/MeOH/H 2O(6mL、4mL、2mL)的混合溶剂中，加入锌粉(1.05g，16mmol，10equiv)和氯化铵(856mg，16mmol，10equiv)，50℃下反应4小时，反应完全，反应液滤过硅藻土，二氯甲烷洗涤，减压除去溶剂，用二氯甲烷重新溶解，水洗数次，无水Na 2SO 4干燥，过滤，减压除去溶剂得产物2.2(531mg)。 1H NMR(400MHz,DMSO-d 6)δ7.89(d,J＝7.4Hz,2H),7.69(d,J＝7.5Hz,2H),7.41(t,J＝7.2Hz,2H),7.32(t,J＝7.5Hz,2H),6.88(d,J＝8.3Hz,2H),6.49(d,J＝8.3Hz,2H),4.30(d,J＝7.1Hz,2H),4.21(t,J＝7.0Hz,1H),4.00(d,J＝6.0Hz,2H).
化合物2.2(950mg，2.76mmol)溶于20mL无水二氯甲烷中，加入三乙胺(714μL，5.52mmol，2equiv)、二碳酸二叔丁酯(1.3mL，5.52mmol，2equiv)，室温反应24小时，减压除去溶剂，柱层析，得产物2.3(620mg)，收率51％。 1H NMR(400MHz,CDCl 3)δ7.76(d,J＝7.5Hz,2H),7.59(d,J＝7.2Hz,2H),7.40(t,J＝7.4Hz,2H),7.35-7.27(m,4H),7.19(d,J＝8.2Hz,2H),4.45(d,J＝7.0Hz,2H),4.32(d,J＝5.8Hz,2H),4.23(t,J＝6.8Hz,1H),1.52(s,9H)。
化合物2.3(254mg，0.57mmol)溶于5mL二氯甲烷中，加入1mL哌啶，室温反应2小时，减压除去溶剂，柱层析，得产物2.4(125mg)，收率99％。 1H NMR(400MHz,CDCl 3)δ7.32(d,J＝8.2Hz,2H),7.22(d,J＝8.5Hz,2H),3.80(s,2H),1.51(s,9H)。
化合物2.5(297mg，1.16mmol)(参照EP2634190A1)，N,N-二甲基苯胺(440μL，3.47mmol，3equiv)溶于8mL三氯氧磷中，100℃下反应4小时后，减压除去三氯氧磷，用乙腈溶解残渣，减压除去乙腈，重复数次，除尽其中的三氯氧磷。化合物2.4(190mg，1.16mmol，1equiv)溶于10mL乙腈中，加入DIPEA(573μL，3.47mmol，3equiv)，将上一步得到的残渣溶于乙腈，加入反应液中，室温反应12小时后，减压除去乙腈，用乙酸乙酯溶解，饱和NaHCO 3洗涤，无水Na 2SO 4干燥，柱层析得产物2.6(330mg)，收率62％。
N-甲基-4-哌啶醇(980mg，8.14mmol，3equiv)溶于10mL无水DMF中，加入NaH(60％分散于液状石蜡中，326mg，8.14mmol，3equiv)，0℃下滴加化合物2.6(1.25g，2.7mmol)的DMF溶液，60℃下反应，3小时后，向反应液中加水，乙酸乙酯萃取，合并乙酸乙酯层，饱和NaCl洗涤，无水Na 2SO 4干燥，柱层析得产物2.7(900mg)，收率67％。 1H NMR(400MHz,CDCl 3)δ7.67(s,1H),7.31(d,J＝8.3Hz,2H),7.22(d,J＝8.5Hz,2H),5.10-5.00(m,1H),4.70(d,J＝5.8Hz,2H),3.11-3.02(m,1H),2.87-2.76(m,2H),2.38-2.25(m,5H),2.18-2.08(m,2H),1.99-1.90(m,2H),1.49(s,9H),1.28(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 26H 37N 7O 3[M+H] +:496.30，实测值为496.96。
以化合物2.7为原料，参照化合物C001的合成，制备得化合物2.8。
7-氨基庚酸(1.45g，10mmol)溶于1N的NaOH水溶液(15mL，1.5equiv)和1,4-二氧六环(15mL)的混合溶剂中，0℃下缓慢加入二碳酸二叔丁酯(2.76mL，12mmol，1.2equiv)，室温反应12小时，减压除去1,4-二氧六环，加入20mL水，乙醚洗涤，水层用1N HCl水溶液调pH至3，乙酸乙酯萃取三次，合并乙酸乙酯层，饱和NaCl洗涤，无水Na 2SO 4干燥，过滤，减压除去溶剂，得产物2.9(2.5g)，收率99％。 1H NMR(400MHz,DMSO-d 6)δ11.98(s,1H),2.88(dd,J＝13.0,6.7Hz,2H),2.18(t,J＝7.4Hz,2H),1.54-1.41(m,2H),1.42-1.29(m,11H),1.28-1.16(m,4H)。
以化合物2.8和化合物2.9为原料，参照化合物1.12的合成，制备得化合物2.10。 1H NMR(400MHz,CDCl 3)δ7.72(s,1H),7.54(d,J＝8.3Hz,2H),7.26(d,J＝8.3Hz,2H),5.18-5.09(m,1H),4.73(d,J＝5.8Hz,2H),3.14-3.02(m,3H),3.01-2.91(m,2H),2.72-2.56(m,2H),2.48(s,3H),2.34(t,J＝7.3Hz,2H),2.28-2.15(m,2H),2.09-1.97(m,2H),1.77-1.65(m,2H),1.51-1.40(m,11H),1.38-1.24(m,10H).UPLC-MS(ESI)理论值为C 33H 50N 8O 4[M+H] +:623.40，实测值为623.84。
以化合物2.10为原料，参照实施例1中的合成路线，制备得C012。 1H NMR(400MHz, DMSO-d 6)δ11.12(s,1H),7.95(d,J＝0.8Hz,1H),7.80(dd,J＝8.5,7.4Hz,1H),7.52(d,J＝8.3Hz,2H),7.49(d,J＝7.2Hz,1H),7.38(d,J＝8.5Hz,1H),7.26(d,J＝8.5Hz,2H),5.25-5.20(m,0.5H),5.12(dd,J＝12.9,5.3Hz,1H),5.07-4.98(m,0.5H),4.76(s,2H),4.59(dd,J＝9.6,6.4Hz,2H),3.49(d,J＝13.9Hz,1H),3.33(d,J＝11.3Hz,1H),3.22-3.07(m,4H),2.97(dd,J＝14.0,7.2Hz,1H),2.89(dd,J＝15.9,10.5Hz,1H),2.81(dd,J＝13.3,4.6Hz,3H),2.62-2.44(m,2H),2.31-2.22(m,3H),2.18(d,J＝14.5Hz,1H),2.10-1.94(m,2H),1.82-1.70(m,1H),1.64-1.49(m,2H),1.47-1.38(m,2H),1.33-1.17(m,10H).UPLC-MS(ESI)理论值为C 43H 52N 10O 8[M+H] +:837.40，实测值为837.91。
[C013]7-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧代)乙酰胺基)-N-(3-(((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-基)氨基)甲基)苯基)庚酰胺的制备
参照实施例2中的合成路线，将对硝基苄胺盐酸盐替换成间硝基苄胺盐酸盐，制备得C013。 1H NMR(400MHz,DMSO-d 6)δ11.12(s,1H),7.97(s,1H),7.80(dd,J＝8.4,7.4Hz,1H),7.56(d,J＝5.3Hz,1H),7.50-7.45(d,J＝7.3Hz,2H),7.38(d,J＝8.5Hz,1H),7.23(t,J＝7.9Hz,1H),7.00(d,J＝7.7Hz,1H),5.24-5.19(m,0.5H),5.12(dd,J＝12.9,5.4Hz,1H),5.06-4.97(m,0.5H),4.76(s,2H),4.62(dd,J＝10.4,6.4Hz,2H),3.48(d,J＝12.1Hz,1H),3.32(d,J＝11.3Hz,1H),3.20-3.07(m,4H),3.02-2.94(m,1H),2.93-2.84(m,1H),2.80(dd,J＝12.8,4.6Hz,3H),2.64-2.44(m,2H),2.30-2.21(m,3H),2.17(d,J＝15.1Hz,1H),2.07-1.94(m,2H),1.83-1.68(m,1H),1.60-1.49(m,2H),1.47-1.38(m,2H),1.32-1.20(m,10H).UPLC-MS(ESI)理论值为C 43H 52N 10O 8[M+H] +:837.40，实测值为837.87。
实施例3
[C014]N-(4-(二甲基氨基)-3-(((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-基)氨基)甲基)苯基)-7-(2-((2-(2,6-二氧代-3-基)-1,3-二氧代异吲哚-4-基)氧基)乙酰胺基)庚酰胺
Figure PCTCN2019100969-appb-000051
2-氟-5-硝基苯腈(2g，12.04mmol)、盐酸二甲胺(1.96g，24.08mmol，2equiv)、碳酸钾(5g，36.12mmol，3equiv)溶于DMF，室温反应12小时，向反应中加150mL乙酸乙酯，水洗数次，饱和NaCl洗涤，无水Na 2SO 4干燥，过滤，减压除去溶剂，得产物3.1(2.24g)，收率97％。 1H NMR(400MHz,CDCl 3)δ8.38(d,J＝2.8Hz,1H),8.15(dd,J＝9.6,2.8Hz,1H),6.78(d,J＝9.6Hz,1H),3.32(s,6H)。
化合物3.1(2.24g，11.72mmol)溶于EtOH(20mL)/H 2O(10mL)/THF(20mL)中，加入铁粉(3.27g，58.58mmol，5equiv)和NH 4Cl(3.13g，58.58mmol，5equiv)，回流3小时，将反应液滤过硅藻土，乙酸乙酯洗涤，滤液分别用水、饱和NaCl洗涤，无水Na2SO4干燥，过滤，减压除去溶剂，柱层析，得产物3.2(1.25g)，收率66％。
以化合物2.9和化合物3.2为原料，参照化合物1.12的合成，制备得化合物3.3。 1H NMR(400MHz,CDCl 3)δ7.71-7.63(m,2H),6.86(d,J＝9.0Hz,1H),3.14-3.06(m,2H),2.97(s,6H),2.31(t,J＝7.3Hz,2H),1.75-1.65(m,2H),1.55-1.28(m,15H)。
化合物3.3(514mg，1.32mmol)溶于氨乙醇中，加入催化量的雷尼镍，通入3atm的氢气，室温反应，6小时后，滤出雷尼镍，滤液减压除去溶剂，得产物3.4(446mg)，收率86％。UPLC-MS(ESI)理论值为C 21H 36N 4O 3[M+H] +:393.28，实测值为393.69。
以化合物3.4和化合物2.5为原料，参照实施例2中的合成路线，制备得C014。 1H NMR(400MHz,DMSO-d 6)δ11.12(s,1H),7.98(s,1H),7.80(dd,J＝8.4,7.4Hz,1H),7.65(t,J＝8.8Hz,1H),7.48(d,J＝7.2Hz,1H),7.38(d,J＝8.6Hz,1H),7.35-7.28(m,1H),7.27-7.16(m,1H),5.19-5.15(m,0.5H),5.11(dd,J＝12.9,5.4Hz,1H),5.06-4.97(s,0.5H),4.75(s,2H),4.75-4.69(m,2H),3.48(d,J＝ 12.6Hz,1H),3.32(d,J＝10.8Hz,1H),3.12(dd,J＝12.8,6.7Hz,3H),3.03-2.95(m,1H),2.94-2.84(m,1H),2.83-2.68(m,10H),2.63-2.44(m,2H),2.30(d,J＝14.9Hz,1H),2.23-2.12(m,3H),2.06-1.93(m,2H),1.77(d,J＝12.8Hz,1H),1.56-1.46(m,2H),1.46-1.36(m,2H),1.31-1.19(m,10H).UPLC-MS(ESI)理论值为C 45H 57N 11O 8[M+H] +:880.44，实测值为880.93。
实施例4
[C011]N-(6-(4-(二甲基氨基)-3-(((8-异丙基-2-((1-甲基-4-基)氧基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)正己基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)乙酰胺的制备
Figure PCTCN2019100969-appb-000052
以2-氟-5-溴苯腈为原料，参照化合物3.1的合成，制备得化合物4.1。 1H NMR(400MHz,CDCl 3)δ7.56(d,J＝2.5Hz,1H),7.44(dd,J＝9.1,2.5Hz,1H),6.74(d,J＝9.1Hz,1H),3.05(s,6H)。
以化合物4.1和化合物1.2为原料，参照化合物1.3的合成，制备得化合物4.2。 1H NMR(400MHz,CDCl 3)δ7.84(dd,J＝5.5,3.0Hz,2H),7.71(dd,J＝5.5,3.0Hz,2H),7.49(d,J＝2.0Hz,1H),7.37(dd,J＝8.8,2.1Hz,1H),6.75(d,J＝8.8Hz,1H),3.74(t,J＝7.1Hz,2H),3.07(s,6H),2.44(t,J＝7.0Hz,2H),1.90-1.81(m,2H),1.69–1.57(m,3H)。
以化合物4.2为原料，参照化合物1.10的合成，制备得化合物4.3。 1H NMR(400MHz,CDCl 3)δ7.50(d,J＝2.1Hz,1H),7.36(dd,J＝8.8,2.1Hz,1H),6.74(d,J＝8.8Hz,1H),3.06(s,6H),2.73(t,J＝6.7Hz,2H),2.38(t,J＝6.7Hz,2H),1.66-1.52(m,4H)。
化合物4.3(354mg，1.47mmol)溶于10mL二氯甲烷中，0℃下分别加入三乙胺(305μL，2.21mmol，1.5equiv)和(Boc) 2O(370μL，1.61mmol，1.1equiv)，室温反应12小时，减压除去溶剂，柱层析得产物4.4(437mg)，收率87％。 1H NMR(400MHz,CDCl 3)δ7.51(d,J＝2.1Hz,1H),7.37(dd,J＝8.8,2.1Hz,1H),6.75(d,J＝8.8Hz,1H),3.20-3.13(m,2H),3.08(s,6H),2.40(t,J＝6.5Hz,2H),1.65-1.57(m,4H),1.44(s,9H)。
以化合物4.4为原料，参照实施例3中的合成路线，制备得C011。 1H NMR(400MHz,DMSO-d 6)δ11.12(s,1H),7.96(d,J＝1.3Hz,1H),7.83-7.69(m,1H),7.46(d,J＝7.3Hz,1H),7.38 (d,J＝8.6Hz,1H),7.34-7.08(m,3H),5.22-5.16(m,0.5H),5.14-4.98(m,1.5H),4.83(s,2H),4.77(s,2H),3.41(d,J＝11.3Hz,1H),3.27(d,J＝14.1Hz,1H),3.19-2.81(m,12H),2.7-2.64(m,3H),2.61-2.45(m,2H),2.29-2.08(m,4H),2.06-1.92(m,3H),1.52-1.42(m,2H),1.40-1.32(m,2H),1.30-1.17(m,10H).UPLC-MS(ESI)理论值为C 44H 56N 10O 7[M+H] +:837.43，实测值为837.87。
[C010]N-(6-(3-(二甲基氨基)-4-(((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-基)氨基)甲基)苯基)正己基)-2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)乙酰胺的制备
参照实施例4中的合成路线，将2-氟-5-溴苯腈替换成2-氟-4-溴苯腈，制备得C010。 1H NMR(400MHz,DMSO-d 6)δ11.13(s,1H),7.98(d,J＝1.8Hz,1H),7.79(dd,J＝8.4,7.4Hz,1H),7.49(d,J＝7.2Hz,1H),7.37(d,J＝8.5Hz,1H),7.30-7.10(m,2H),7.05-6.90(m,1H),5.20-5.15(s,0.5H),5.11(dd,J＝12.9,5.4Hz,1H),5.07-4.99(m,0.5H),4.76(s,2H),4.71(t,J＝6.3Hz,2H),3.49(d,J＝11.6Hz,1H),3.33(d,J＝11.3Hz,1H),3.20-3.03(m,4H),2.97(ddd,J＝13.8,6.9,3.0Hz,1H),2.94-2.73(m,10H),2.63-2.44(m,4H),2.31(d,J＝12.9Hz,1H),2.17(d,J＝14.7Hz,1H),2.05-1.94(m,2H),1.78(d,J＝13.5Hz,1H),1.56-1.48(m,2H),1.46-1.38(m,2H),1.32-1.19(m,10H).UPLC-MS(ESI)理论值为C 44H 56N 10O 7[M+H] +:837.43，实测值为837.84。
[C015]N-(3-(二甲基氨基((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-基)氨基)甲基)苯基)-7-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)乙酰胺基)庚酰胺的制备
参照实施例3中的合成路线，将2-氟-5-硝基苯腈替换成2-氟-4-硝基苯腈，制备得C015。 1H NMR(400MHz,DMSO-d 6)δ11.13(s,1H),7.97(s,1H),7.83–7.77(m,1H),7.58(d,J＝10.2Hz,1H),7.49(d,J＝7.3Hz,1H),7.38(d,J＝8.5Hz,1H),7.23(t,J＝8.5Hz,1H),7.13(d,J＝8.5Hz,1H),5.20-5.15(m,0.5H),5.12(dd,J＝12.9,5.4Hz,1H),5.06-4.96(m,0.5H),4.76(s,2H),4.71-4.65(m,2H),3.49(d,J＝12.0Hz,1H),3.32(d,J＝11.3Hz,1H),3.20-3.05(m,4H),3.02-2.94(m,1H),2.94-2.83(m,1H),2.83-2.68(m,9H),2.64-2.42(m,2H),2.34-2.24(m,3H),2.18(d,J＝14.0Hz,1H),2.07-1.93(m,2H),1.82-1.70(m,1H),1.60-1.51(m,2H),1.48-1.38(m,2H),1.34-1.21(m,10H).UPLC-MS(ESI)理论值为C 45H 57N 11O 8[M+H] +:880.44，实测值为880.97。
实施例5
[C009]4-((6-(3-(二甲基氨基)-4-(((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-基)氨基)甲基)苯基)正己基)氨基)-2-(2,6-二氧代哌啶-3-基)异吲哚-1,3-二酮的制备
Figure PCTCN2019100969-appb-000053
参照实施例4中的合成路线，将2-氟-5-溴苯腈替换成2-氟-4-溴苯腈，制备得化合物5.1。
化合物5.1(80mg，0.126mmol)和化合物5.2(42mg，0.151mmol，1.2equiv)溶于5mL DMF中，加入DIPEA(104μL，0.63mmol，5equiv)，90℃下反应24小时，向反应液中加入水，乙酸乙酯萃取，合并乙酸乙酯层，饱和NaCl洗涤，无水Na 2SO 4干燥，柱层析后，HPLC进一步纯化，制备得C009。 1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),7.98(d,J＝1.6Hz,1H),7.61-7.44(m,1H),7.31-7.12(m,2H),7.07(d,J＝8.7Hz,1H),7.01(d,J＝7.0Hz,1H),6.98-6.91(m,1H),5.20-5.16(m,0.5H),5.08-4.98(m,1.5H),4.71(t,J＝6.2Hz,2H),3.49(d,J＝11.2Hz,1H),3.38-3.23(m,3H),3.21-3.03(m,2H),2.98(tdd,J＝9.4,6.5,2.5Hz,1H),2.94-2.75(m,10H),2.62-2.43(m,4H),2.31(d,J＝12.9Hz,1H),2.17(d,J＝14.5Hz,1H),2.06-1.93(m,2H),1.84-1.70(m,1H),1.61-1.50(m,2H),1.41-1.31(m,2H),1.30-1.18(m,10H).UPLC-MS(ESI)理论值为C 42H 54N 10O 5[M+H] +:779.43，实测值为779.81。
[C016]N-(3-(二甲基氨基)-4-(((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-基)氨基)甲基)苯基)-7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)庚酰胺的制备
参照实施例3和实施例5中的合成路线，制备得C016。 1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),7.97(s,1H),7.61-7.50(m,2H),7.25-7.18(m,1H),7.14-7.06(m,2H),7.01(d,J＝7.0Hz,1H),5.19-5.15(m,0.5H),5.08-4.96(m,1.5H),4.68(t,J＝5.9Hz,2H),3.49(d,J＝12.5Hz,1H),3.36-3.24(m,3H),3.20-3.05(m,2H),2.99(dtd,J＝9.7,6.7,2.6Hz,1H),2.92-2.76(m,4H),2.76-2.65(m,6H),2.62–2.45(m,2H),2.35-2.24(m,3H),2.18(d,J＝15.1Hz,1H),2.06-1.93(m,2H),1.84-1.70(m,1H),1.62-1.53(m,2H),1.35(s,2H),1.30-1.20(m,10H)。
实施例6
[C022]7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(4-(((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-基)氨基)甲基)苯基)庚酰胺的制备
Figure PCTCN2019100969-appb-000054
以化合物2.8和7-羟基庚酸为原料，参照化合物1.12的合成，制备得化合物6.1。 1H NMR(400MHz,CDCl 3)δ7.71(s,1H),7.52(d,J＝8.2Hz,2H),7.21(d,J＝8.2Hz,2H),5.17-5.08(m,1H),4.70(d,J＝5.3Hz,2H),3.59(t,J＝6.4Hz,2H),3.07(dt,J＝13.8,6.9Hz,1H),3.00-2.92(m,2H),2.70-2.56(m,2H),2.47(s,3H),2.35(t,J＝7.3Hz,2H),2.30-2.20(m,2H),2.08-2.96(m,2H), 1.76-1.64(m,2H),1.56-1.48(m,2H),1.40-1.32(m,4H),1.27(d,J＝5.6Hz,6H).UPLC-MS(ESI)理论值为C 28H 41N 7O 3[M+H] +:524.33，实测值为524.94。
化合物6.1(40mg，0.0764mmol)、化合物6.2(32mg，0.115mmol，1.5equiv)(化合物6.2的制备参照Lohbeck J.,Miller A.K.Practical synthesis of a phthalimide-based Cereblon ligand to enable PROTAC development.Bioorganic&medicinal chemistry letters.2016；26(21):5260-5262.)、三苯基膦(40mg，0.153mmol，2equiv)溶于4mL无水THF中，0℃下滴加DIAD(30μL，0.153mmol，2equiv)，室温反应3小时后，减压除去溶剂，柱层析后，HPLC进一步纯化制备得C022(35mg)，收率65％。 1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),7.96(d,J＝0.9Hz,1H),7.79(dd,J＝8.4,7.4Hz,1H),7.55-7.48(m,3H),7.43(d,J＝7.2Hz,1H),7.25(d,J＝8.5Hz,2H),5.25-5.21(m,0.5H),5.12-4.98(m,1.5H),4.59(dd,J＝10.1,6.5Hz,2H),4.23-4.17(m,2H),3.49(d,J＝12.7Hz,1H),3.33(d,J＝11.4Hz,1H),3.21-3.08(m,2H),2.97(dt,J＝14.3,7.2Hz,1H),2.92-2.77(m,4H),2.62-2.44(m,2H),2.33-2.23(m,3H),2.18(d,J＝15.1Hz,1H),2.07-1.96(m,2H),1.82-1.70(m,3H),1.64-1.55(m,2H),1.52–1.43(m,2H),1.41-1.32(m,2H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 41H 49N 9O 7[M+H] +:780.38，实测值为780.84。
[C017]7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氨基)-N-(4-(((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-基)氨基)甲基)苯基)庚酰胺的制备
参照实施例2和实施例5中的合成路线，制备得C017。 1H NMR(400MHz,DMSO-d 6)δ11.08(s,1H),7.95(s,1H),7.60-7.46(m,3H),7.25(d,J＝7.9Hz,2H),7.07(d,J＝8.4Hz,1H),7.00(d,J＝6.8Hz,1H),5.36-5.27(m,1H),5.26-5.17(m,0.5H),5.11-4.98(m,0.5H),4.60(s,2H),3.53-3.42(m,1H),3.36-3.23(m,3H),3.22-3.08(m,2H),3.02-2.94(m,1H),2.92-2.74(m,4H),2.62-2.42(m,2H),2.33-2.23(m,3H),2.18(d,J＝13.9Hz,1H),2.08-1.94(m,2H),1.85-1.71(m,1H),1.65-1.49(m,4H),1.40-1.13(m,10H).UPLC-MS(ESI)理论值为C 41H 49N 9O 7[M+H] +:779.39，实测值为779.32。
实施例7
[C005]4-((6-(3-(二甲基氨基)-4-(((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-基)氨基)甲基)苯基)正己基)氧基)-2-(2,6-二氧代哌啶-3-基)异吲哚-1,3-二酮的制备
Figure PCTCN2019100969-appb-000055
以化合物7.1(参照实施例4)为原料，参照实施例4中的合成路线，制备得化合物7.3。UPLC-MS(ESI)理论值为C 15H 26N 2O[M+H] +:251.20，实测值为251.75。
化合物7.3(190mg，0.759mmol)溶于10mL无水二氯甲烷中，0℃下分别加入TBSCl(137mg，0.911mmol，1.2equiv)和咪唑(77mg，1.139mmol，1.5equiv)，室温反应12小时，向反应中加入二氯甲烷，水洗数次，无水Na 2SO 4干燥，过滤，加压除去溶剂，柱层析，得产物7.4(197mmol)，收率71％。UPLC-MS(ESI)理论值为C 21H 40N 2OSi[M+H] +:365.29，实测值为365.94。
以化合物7.4为原料，参照实施例3中的合成路线，制备得化合物7.6。
化合物7.6(15mg，0.0235mmo)溶于1mL四氢呋喃中，加入TBAF(1M溶于THF的溶液，71μL，0.0705mmol，3equiv)，室温反应12小时后，减压除去溶剂，柱层析，得产物7.7(12mg)，收率98％。 1H NMR(400MHz,CDCl 3)δ7.69(s,1H),7.20(d,J＝7.7Hz,1H),6.99(s,1H),6.86(d,J＝6.7Hz,1H),5.12-5.04(m,1H),4.83(d,J＝5.4Hz,2H),3.62(t,J＝6.6Hz,2H),3.07(dt,J＝13.8,6.9Hz,1H),2.91-2.82(m,2H),2.73(s,6H),2.61-2.53(m,2H),2.42-2.33(m,5H),2.22-2.13(m,2H),2.04-1.91(m,2H),1.65-1.51(m,4H),1.42-1.32(m,4H),1.29(d,J＝7.0Hz,6H).UPLC-MS(ESI)理论值为C 29H 45N 7O 2[M+H] +:524.36，实测值为524.67。
以化合物7.7和化合物6.2为原料，参照化合物C022的合成，制备得C005。 1H NMR(400MHz,CDCl 3)δ7.82(s,1H),7.67(t,J＝7.8Hz,1H),7.46(d,J＝7.1Hz,1H),7.41(d,J＝7.7Hz,1H),7.20(d,J＝10.7Hz,3H),5.53-5.37(m,1H),5.01-4.88(m,3H),4.16(t,J＝5.7Hz,2H),3.46-3.22(m,3H),3.17(s,6H),3.05(dt,J＝13.7,7.0Hz,1H),2.93-2.80(m,4H),2.76(d,J＝15.6Hz,1H),2.67(t,J＝7.0Hz,2H),2.47-2.34(m,2H),2.31-2.20(m,2H),2.17-2.09(m,1H),1.93-1.81(m,2H),1.73-1.63(m,2H),1.62-1.52(m,2H),1.46-1.36(m,2H),1.33-1.21(m,8H).UPLC-MS(ESI)理论值 为C 42H 53N 9O 6[M+H] +:780.41，实测值为780.77。
实施例8
[C003]2-(2,6-二氧代哌啶-3-基)-4-((7-(4-(((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-基)氨基)甲基)苯基)正庚基)氧基)异吲哚-1,3-二酮的制备
Figure PCTCN2019100969-appb-000056
对溴苄胺(2g，10.75mmol)溶于20mL二氯甲烷中，加入三乙胺(2.24mL，16.13mmol，1.5equiv)，0℃下缓慢滴加氯甲酸苄酯，室温反应12小时，向反应中加入二氯甲烷，饱和NaHCO 3洗涤，无水Na 2SO 4干燥，柱层析，得产物8.1(3.1g)，收率90％。 1H NMR(400MHz,CDCl 3)δ7.44(d,J＝8.3Hz,2H),7.39-7.27(m,5H),7.15(d,J＝8.0Hz,2H),5.13(s,2H),4.32(d,J＝6.0Hz,2H)。
以化合物8.1为原料，参照实施例7中的合成路线，制备得化合物8.4。
化合物8.4(206mg，0.614mmol)、化合物8.5(164mg，0.675mmol，1.1equiv)(参照EP2634190A1)溶于10mL乙腈中，加入DIPEA(304μL，1.842mmol，3equiv)，60℃下反应16小时，减压除去溶剂，柱层析得产物8.6(305mg)，收率92％。
化合物8.6(305mg，0.56mmol)溶于10mL二氯甲烷中，分批加入m-CPBA(291mg，1.69mmol，3equiv)，室温反应4小时后，向反应中加入二氯甲烷稀释，用0.5N的NaOH水溶液洗涤数次，无水Na 2SO 4干燥，得产物8.7(270mg)，收率90％。 1H NMR(400MHz,CDCl 3)δ7.93(s,1H),7.30(d,J＝8.0Hz,2H),7.18(d,J＝8.0Hz,2H),4.87(d,J＝5.8Hz,2H),3.59(t,J＝6.6Hz,2H),3.36(s,3H),3.25(dt,J＝13.8,6.9Hz,1H),2.63-2.56(m,2H),1.63-1.55(m,2H),1.54-1.45(m,2H),1.37-1.27(m,12H),0.89(s,9H),0.04(s,6H)。
以化合物8.7为原料，参照实施例7中的合成路线，制备得C003。 1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),7.95(d,J＝1.1Hz,1H),7.82-7.75(m,1H),7.49(d,J＝8.6Hz,1H),7.43(d,J＝7.2Hz,1H),7.24(d,J＝7.0Hz,2H),7.13(d,J＝7.9Hz,2H),5.25-5.20(m,0.5H),5.11-5.01(m,1.5H),4.62(dd,J＝11.2,6.3Hz,2H),4.18(t,J＝6.2Hz,2H),3.49(d,J＝11.9Hz,1H),3.33(d,J＝11.4Hz,1H),3.23-3.08(m,2H),2.97(dt,J＝13.6,6.9Hz,1H),2.93-2.77(m,4H),2.58-2.45(m,4H),2.26(d,J＝11.8Hz,1H),2.17(d,J＝14.7Hz,1H),2.08-1.95(m,2H),1.83-1.69(m,3H), 1.59-1.48(m,2H),1.48-1.38(m,2H),1.37-1.21(m,10H).UPLC-MS(ESI)理论值为C 41H 50N 8O 6[M+H] +:751.39，实测值为751.68。
[C004]2-(2,6-二氧代哌啶-3-基)-4-(2-(2-(3-(4-(((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-基)氨基)甲基)苯基)丙氧基)乙氧基)乙氧基)异吲哚-1,3-二酮的制备
参照实施例8中的合成路线，制备得C004。 1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),7.96(d,J＝1.4Hz,1H),7.78(t,J＝7.7Hz,1H),7.52(d,J＝8.6Hz,1H),7.44(d,J＝7.2Hz,1H),7.23(d,J＝6.2Hz,2H),7.12(d,J＝8.0Hz,2H),5.24-5.19(s,0.5H),5.11-4.99(m,1.5H),4.61(dd,J＝11.3,6.3Hz,2H),4.36-4.31(m,2H),3.82-3.78(m,2H),3.66-3.61(m,2H),3.52-3.45(m,3H),3.34(dd,J＝15.8,9.4Hz,3H),3.21-3.08(m,2H),3.01-2.93(m,1H),2.92-2.77(m,4H),2.61-2.43(m,4H),2.26(d,J＝11.0Hz,1H),2.17(d,J＝14.3Hz,1H),2.04-1.94(m,2H),1.82-1.67(m,3H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 41H 50N 8O 8[M+H] +:783.38，实测值为784.12。
[C006]4-((6-(3-(二甲基氨基)-2-(((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-基)氨基)甲基)苯基)正己基)氧基)-2-(2,6-二氧代哌啶-3-基)异吲哚-1,3-二酮的制备
参照实施例7中的合成路线，将2-氟-4-溴苯腈替换成2-氟-6-溴苯腈，制备得C006。 1H NMR(400MHz,DMSO-d 6)δ11.10(s,1H),7.94(d,J＝3.5Hz,1H),7.80(t,J＝7.9Hz,1H),7.46(dd,J＝10.9,7.9Hz,2H),7.40-7.28(m,2H),7.23-7.08(m,1H),5.29-5.24(m,0.5H),5.14-5.02(m,1.5H),4.82(dd,J＝11.2,4.6Hz,2H),4.12(t,J＝6.2Hz,2H),3.52(d,J＝11.8Hz,1H),3.39(d,J＝11.6Hz,1H),3.16(dt,J＝22.3,10.5Hz,2H),3.05-2.76(m,11H),2.74-2.65(m,2H),2.63-2.43(m,2H),2.35(d,J＝13.5Hz,1H),2.23(d,J＝14.0Hz,1H),2.12-1.96(m,2H),1.84(td,J＝13.8,3.6Hz,1H),1.69-1.59(m,2H),1.54-1.44(m,2H),1.41–1.13(m,10H).UPLC-MS(ESI)理论值为C 42H 53N 9O 6[M+H] +:780.41，实测值为780.58。
[C007]4-((7-(3-(二甲基氨基)-4-(((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-基)氨基)甲基)苯基)正庚基)氧基)-2-(2,6-二氧代哌啶-3-基)异吲哚-1,3-二酮的制备
参照实施例7中的合成路线，将5-己炔-1-醇替换成6-庚炔-1-醇，制备得C007。 1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),7.97(s,1H),7.85-7.73(m,1H),7.50(d,J＝8.6Hz,1H),7.44(d,J＝7.2Hz,1H),7.19-7.05(m,2H),6.97-6.81(m,1H),5.20-5.15(s,0.5H),5.11-4.97(m,1.5H),4.71(t,J＝5.9Hz,2H),4.18(t,J＝6.3Hz,2H),3.48(d,J＝12.4Hz,1H),3.31(d,J＝11.8Hz,1H),3.20-3.03(m,2H),2.98(dtd,J＝10.0,6.7,3.4Hz,1H),2.93-2.64(m,10H),2.63-2.40(m,4H),2.30(d,J＝15.1Hz,1H),2.16(d,J＝15.7Hz,1H),2.05-1.93(m,2H),1.87-1.68(m,3H),1.60-1.50(m,2H),1.48-1.40(m,2H),1.39-1.18(m,10H).UPLC-MS(ESI)理论值为C 43H 55N 9O 6[M+H] +:794.43，实测值为794.55.
[C008]4-((7-(2-(二甲基氨基)-3-(((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-基)氨基)甲基)苯基)正庚基)氧基)-2-(2,6-二氧代哌啶-3-基)异吲哚-1,3-二酮的制备
参照实施例7中的合成路线，将2-氟-4-溴苯腈替换成2-氟-3-溴苯腈，5-己炔-1-醇替换成6-庚炔-1-醇，制备得C008。 1H NMR(400MHz,CDCl 3)δ7.86(s,1H),7.70-7.64(m,1H),7.44(d,J＝7.2Hz,1H),7.25-7.10(m,4H),5.55-5.49(m,1H),4.92(dd,J＝11.9,5.0Hz,1H),4.83(s,2H),4.19 (t,J＝6.0Hz,2H),3.52-3.23(m,3H),3.09(dd,J＝13.5,6.7Hz,1H),2.99(s,6H),2.92-2.73(m,5H),2.73–2.62(m,2H),2.51-2.34(m,2H),2.34-2.21(m,2H),2.16-1.98(m,1H),1.95-1.82(m,2H),1.73-1.41(m,8H),1.35-1.20(d,J＝6.7Hz,8H).UPLC-MS(ESI)理论值为C 43H 55N 9O 6[M+H] +:794.43，实测值为794.52。
[C030]2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)乙氧基)-N-(4-(((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-基)氨基)甲基)苯基)乙酰胺的制备
参照实施例6中的合成路线，将7-羟基庚酸替换成2-(2-(2-羟基乙氧基)乙酸，制备得C030。 1H NMR(400MHz,CDCl 3)δ7.87(s,1H),7.78-7.72(m,1H),7.52(d,J＝7.2Hz,1H),7.36(d,J＝8.2Hz,2H),7.31(d,J＝8.4Hz,1H),7.22(d,J＝8.3Hz,2H),5.45-5.39(m,1H),4.85-4.66(m,3H),4.46-4.40(m,2H),4.23(s,2H),4.11-4.02(m,2H),3.43(d,J＝10.9Hz,2H),3.27-3.13(m,2H),3.07(dt,J＝13.8,6.9Hz,1H),2.86-2.77(m,4H),2.74-2.63(m,2H),2.44-2.27(m,2H),2.24-2.11(m,2H),2.07-1.97(m,1H),1.29(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 38H 43N 9O 8[M+H] +:754.33，实测值为754.99。
[C031]2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)乙氧基)乙氧基)-N-(4-(((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-基)氨基)甲基)苯基)乙酰胺的制备
参照实施例6中的合成路线，将7-羟基庚酸替换成2-(2-(2-羟基乙氧基)乙氧基)乙酸，制备得C031。 1H NMR(400MHz,CDCl 3)δ7.93(s,1H),7.74-7.68(m,1H),7.55(d,J＝8.1Hz,2H),7.51(d,J＝7.3Hz,1H),7.27(d,J＝5.5Hz,1H),7.12(d,J＝7.9Hz,2H),5.48-5.42(m,1H),4.88-4.80(m,1H),4.72-4.56(m,2H),4.46-4.38(m,2H),4.09-3.98(m,4H),3.89-3.75(m,4H),3.51-3.38(m,2H),3.33-3.19(m,2H),3.13-3.04(m,1H),2.91-2.74(m,5H),2.72-2.61(m,1H),2.44-2.21(m,4H),2.15-1.98(m,1H),1.28(t,J＝5.7Hz,6H).UPLC-MS(ESI)理论值为C 40H 47N 9O 9[M+H] +:798.34，实测值为798.99。
[C032]2-(2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)乙氧基)乙氧基)乙氧基)-N-(4-(((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-基)氨基)甲基)苯基)乙酰胺的制备
参照实施例6中的合成路线，将7-羟基庚酸替换成2-(2-(2-羟基乙氧基)乙氧基)乙氧基)乙酸，制备得C032。 1H NMR(400MHz,CDCl 3)δ7.86(s,1H),7.70-7.64(m,1H),7.58(d,J＝8.5Hz,2H),7.46(d,J＝7.2Hz,1H),7.26-7.19(m,3H),5.42–5.37(m,1H),4.89-4.81(m,1H),4.68(dd,J＝11.9,6.0Hz,2H),4.31(t,J＝4.4Hz,2H),4.13-4.08(m,2H),3.97-3.91(m,2H),3.85(t,J＝4.3Hz,2H),3.79-3.69(m,6H),3.43(d,J＝10.4Hz,2H),3.26-3.14(m,2H),3.07(dt,J＝13.8,7.0Hz,1H),2.86-2.66(m,6H),2.44-2.33(m,2H),2.33-2.25(m,2H),2.11-1.98(m,1H),1.29(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 42H 51N 9O 10[M+H] +:842.38，实测值为842.94。
实施例9
[C041]7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)-N-(4-(((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-基)氨基)甲基)苯基)庚酰胺的制备
Figure PCTCN2019100969-appb-000057
6-庚炔酸(250mg，1.98mmol)溶于6mL DMF中，加入碳酸铯(322mg，0.99mmol，0.5equiv)，反应20分钟后，滴加溶于1mL DMF的苄溴(259μL，2.18mmol，1.1equiv)，室温反应12小时，向反应液中加入乙酸乙酯，水洗数次，饱和NaCl洗涤，无水Na 2SO 4干燥，柱层析，得产物9.1(400mg)，收率94％。 1H NMR(400MHz,CDCl 3)δ7.40-7.30(m,6H),5.12(s,2H),2.39(t,J＝7.5Hz,2H),2.21(td,J＝7.0,2.7Hz,2H),1.95(t,J＝2.7Hz,1H),1.82-1.73(m,2H),1.61-1.52(m,2H)。
以化合物9.1为原料，参照化合物1.3的合成，制备得化合物9.2。 1H NMR(400MHz,CDCl 3)δ7.80(d,J＝7.0Hz,1H),7.55(dd,J＝7.6,0.8Hz,1H),7.42(t,J＝7.6Hz,1H),7.38-7.29(m,5H),5.24(dd,J＝13.4,5.1Hz,1H),5.10(s,2H),4.50(d,J＝16.8Hz,1H),4.36(d,J＝16.8Hz,1H),2.94-2.76(m,2H),2.50-2.39(m,5H),2.22-2.14(m,1H),1.88-1.79(m,2H),1.69-1.60(m,2H)。
以化合物9.2为原料，参照化合物1.4，制备得化合物9.3。
以化合物9.3和化合物2.8为原料，参照化合物1.12的合成，制备得C041。 1H NMR(400MHz,DMSO-d 6)δ11.00(s,1H),7.96(d,J＝0.7Hz,1H),7.59-7.48(m,3H),7.46-7.40(m,2H),7.25(d,J＝8.5Hz,2H),5.25-5.21(m,0.5H),5.13(dd,J＝13.3,5.1Hz,1H),5.08-4.99(m,0.5H),4.59(dd,J＝10.0,6.4Hz,2H),4.45(d,J＝17.2Hz,1H),4.29(d,J＝17.2Hz,1H),3.48(d,J＝11.9Hz,1H),3.33(d,J＝11.4Hz,1H),3.21-3.07(m,2H),3.02-2.86(m,2H),2.81(dd,J＝12.9,4.6Hz,3H),2.67-2.59(m,2H),2.58-2.37(m,2H),2.31-2.23(m,3H),2.18(d,J＝14.7Hz,1H),2.07-1.95(m,2H),1.83-1.70(m,1H),1.65-1.51(m,4H),1.39-1.29(m,4H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 41H 51N 9O 5[M+H] +:750.40，实测值为751.08。
实施例10
[C027]9-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)-N-(4-(((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-基)氨基)甲基)苯基)壬酰胺的制备
Figure PCTCN2019100969-appb-000058
壬二酸(2g，10.63mmol)溶于20mL无水四氢呋喃中，加入DBU(1.59mL，10.63mmol，1equiv)，0℃下滴加苄溴(1.26mL，10.63mmol，1equiv)，室温反应12小时后，减压除去溶剂，向其中加水，乙酸乙酯萃取，合并乙酸乙酯层，饱和NaCl洗涤，无水Na 2SO 4干燥，柱层析得化合物10.1(1.45g)，收率49％。 1H NMR(400MHz,CDCl 3)δ7.40-7.29(m,5H),5.12(s,2H),2.38-2.31(m,4H),1.69-1.56(m,4H),1.38-1.28(m,6H)。
化合物10.1(1.45g，5.2mmol)溶于15mL无水四氢呋喃中，0℃下滴加硼烷(1M溶于THF的溶液，5.2mL，5.2mmol，1equiv)，室温反应12小时，向反应中滴加甲醇淬灭反应，减压除去溶剂，柱层析得化合物10.2(1.35g)，收率98％。
以化合物10.2和化合物10.3为原料，参照化合物C022的合成，制备得化合物10.4，收率98％。 1H NMR(400MHz,CDCl 3)δ7.42-7.37(m,2H),7.37-7.30(m,5H),7.00-6.97(m,1H),5.11(s,2H),4.91(dd,J＝8.8,6.2Hz,1H),4.43(d,J＝17.6Hz,1H),4.36(d,J＝17.5Hz,1H),4.03(td,J＝6.3,1.3Hz,2H),3.63(s,3H),2.50-2.29(m,5H),2.25-2.14(m,1H),1.83-1.74(m,2H),1.70-1.61(m,2H),1.49-1.40(m,2H),1.40-1.30(m,6H).UPLC-MS(ESI)理论值为C 30H 38N 2O 7[M+H] +:539.27，实测值为539.80。
化合物10.4(220mg，0.408mmol)溶于3mL四氢呋喃中，加入TBAF(1M溶于THF的溶液，816μL，0.816mmol，2equiv)，室温反应4小时，减压除去溶剂，柱层析得化合物10.5(200mg)，收率97％。 1H NMR(400MHz,DMSO-d 6)δ10.96(s,1H),7.47(t,J＝7.8Hz,1H),7.39-7.32(m,5H),7.30(d,J＝7.4Hz,1H),7.23(d,J＝8.1Hz,1H),5.13–5.06(m,3H),4.36(d,J＝17.5Hz,1H),4.21(d,J＝17.3Hz,1H),4.10(t,J＝6.4Hz,2H),2.96-2.84(m,1H),2.62-2.54(m,1H),2.49-2.38(m,1H),2.34(t,J＝7.4Hz,2H),2.02-1.93(m,1H),1.77-1.67(m,2H),1.58-1.49(m,2H),1.45-1.36(m,2H),1.33-1.21(m,6H)。
以化合物10.5为原料，参照化合物9.3的合成，制备得化合物10.6。UPLC-MS(ESI)理论 值为C 22H 28N 2O 6[M+H] +:417.19，实测值为417.54。
以化合物10.6和化合物2.8为原料，参照化合物1.12的合成路线，制备得化合物C027。 1H NMR(400MHz,DMSO-d 6)δ10.97(s,1H),7.96(d,J＝0.9Hz,1H),7.52(d,J＝8.5Hz,2H),7.46(t,J＝7.8Hz,1H),7.29(d,J＝7.3Hz,1H),7.25(d,J＝8.5Hz,2H),7.22(d,J＝8.1Hz,1H),5.25-5.20(m,0.5H),5.10(dd,J＝13.4,5.1Hz,1H),5.07-4.99(m,0.5H),4.59(dd,J＝9.9,6.3Hz,2H),4.36(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,2H),4.09(t,J＝6.4Hz,2H),3.49(d,J＝12.2Hz,1H),3.33(d,J＝11.9Hz,1H),3.22-3.08(m,2H),3.04-2.85(m,2H),2.81(dd,J＝13.2,4.7Hz,3H),2.61-2.39(m,2H),2.31-2.22(m,3H),2.18(d,J＝13.9Hz,1H),2.06-1.94(m,2H),1.82-1.67(m,3H),1.61-1.52(m,2H),1.47-1.37(m,2H),1.27(t,J＝10.8Hz,12H).UPLC-MS(ESI)理论值为C 43H 55N 9O 6[M+H] +:794.43，实测值为794.37。
实施例11
[C026]9-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(4-(((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-基)氨基)甲基)苯基)壬酰胺的制备
Figure PCTCN2019100969-appb-000059
根据以上合成路线，参照实施例10中的实验过程，制备得C026。 1H NMR(400MHz,DMSO-d 6)δ11.12(s,1H),7.96(d,J＝0.7Hz,1H),7.85-7.71(m,1H),7.54-7.48(m,3H),7.43(d,J＝7.2Hz,1H),7.25(d,J＝8.5Hz,2H),5.26-5.21(m,0.5H),5.11-4.98(m,1.5H),4.59(dd,J＝10.0,6.4Hz,2H),4.18(t,J＝6.3Hz,2H),3.48(d,J＝12.4Hz,1H),3.33(d,J＝10.9Hz,1H),3.23-3.08(m,2H),2.97(dt,J＝13.8,6.8Hz,1H),2.93-2.75(m,4H),2.63-2.42(m,2H),2.31-2.22(m,3H),2.18(d,J＝15.1Hz,1H),2.07-1.94(m,2H),1.82-1.69(m,3H),1.61-1.52(m,2H),1.50-1.39(m,2H),1.38-1.21(m,12H).UPLC-MS(ESI)理论值为C 43H 53N 9O 7[M+H] +:808.41，实测值为808.93。
[C018]5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(4-(((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-基)氨基)甲基)苯基)戊酰胺的制备
参照实施例11中的合成路线，将壬二酸替换成戊二酸，制备得C018。 1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),7.96(d,J＝0.8Hz,1H),7.83-7.77(m,1H),7.56-7.49(m,3H),7.44(d,J＝7.2Hz,1H),7.26(d,J＝8.5Hz,2H),5.25-5.20(m,0.5H),5.11-4.98(m,1.5H),4.59(dd,J＝9.8,6.5Hz,2H),4.26-4.20(m,2H),3.49(d,J＝12.1Hz,1H),3.33(d,J＝10.9Hz,1H),3.21-3.07(m,2H),2.97(dt,J＝13.8,6.8Hz,1H),2.92-2.76(m,4H),2.61-2.46(m,2H),2.38(t,J＝6.3Hz,2H),2.27(d, J＝11.6Hz,1H),2.18(d,J＝15.1Hz,1H),2.06-1.96(m,2H),1.84-1.72(m,J＝10.4Hz,5H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 39H 45N 9O 7[M+H] +:752.34，实测值为752.98。
[C019]5-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)-N-(4-(((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-基)氨基)甲基)苯基)戊酰胺的制备
参照实施例10中的合成路线，将壬二酸替换成戊二酸，制备得C019。 1H NMR(400MHz,DMSO-d 6)δ10.97(s,1H),7.96(d,J＝0.7Hz,1H),7.52(d,J＝8.5Hz,2H),7.46(t,J＝7.8Hz,1H),7.30(d,J＝7.5Hz,1H),7.28-7.20(m,3H),5.25-5.20(m,0.5H),5.10(dd,J＝13.3,5.1Hz,1H),5.07-4.99(m,0.5H),4.60(dd,J＝9.9,6.4Hz,2H),4.36(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,1H),4.14(t,J＝5.1Hz,2H),3.49(d,J＝12.6Hz,1H),3.33(d,J＝11.5Hz,1H),3.23-3.07(m,2H),2.98(dt,J＝13.4,6.7Hz,1H),2.95-2.84(m,1H),2.81(dd,J＝13.1,4.6Hz,3H),2.59–2.42(m,2H),2.41-2.32(m,2H),2.27(d,J＝13.7Hz,1H),2.18(d,J＝15.5Hz,1H),2.06-1.92(m,2H),1.82-1.69(m,5H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 39H 47N 9O 6[M+H] +:738.37，实测值为738.98。
[C020]6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(4-(((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-基)氨基)甲基)苯基)己酰胺的制备
参照实施例11中的合成路线，将壬二酸替换成己二酸，制备得C020。 1H NMR(400MHz,DMSO-d 6)δ11.12(s,1H),7.96(d,J＝0.8Hz,1H),7.84-7.75(m,1H),7.55-7.48(m,3H),7.43(d,J＝7.2Hz,1H),7.25(d,J＝8.6Hz,2H),5.25-4.97(m,2H),4.59(dd,J＝10.0,6.5Hz,2H),4.20(t,J＝6.3Hz,2H),3.49(d,J＝12.4Hz,1H),3.33(d,J＝11.0Hz,1H),3.25-3.07(m,2H),2.97(dt,J＝13.8,7.0Hz,1H),2.92-2.75(m,4H),2.61-2.42(m,2H),2.34-2.23(m,3H),2.18(d,J＝15.2Hz,1H),2.06-1.95(m,2H),1.82-1.72(m,3H),1.70-1.60(m,2H),1.53-1.42(m,2H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 40H 47N 9O 7[M+H] +:766.36，实测值为766.95。
[C021]6-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)-N-(4-(((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-基)氨基)甲基)苯基)己酰胺的制备
参照实施例10中的合成路线，将壬二酸替换成己二酸，制备得C021。 1H NMR(400MHz,DMSO-d 6)δ10.99(s,1H),7.96(d,J＝0.7Hz,1H),7.52(d,J＝8.5Hz,2H),7.46(t,J＝7.8Hz,1H),7.30(d,J＝7.4Hz,1H),7.27-7.20(m,3H),5.26-5.20(s,0.5H),5.10(dd,J＝13.3,5.0Hz,1H),5.07-4.99(m,0.5H),4.59(dd,J＝10.1,6.3Hz,2H),4.36(d,J＝17.4Hz,1H),4.20(d,J＝17.4Hz,1H),4.11(t,J＝6.3Hz,2H),3.51-3.45(m,1H),3.33(d,J＝10.7Hz,1H),3.21-3.08(m,2H),2.97(dt,J＝13.7,6.9Hz,1H),2.95-2.85(m,1H),2.81(dd,J＝13.3,4.7Hz,3H),2.60-2.36(m,2H),2.35-2.23(m,3H),2.18(d,J＝13.9Hz,1H),2.07-1.91(m,2H),1.82-1.70(m,3H),1.69-1.59(m,2H),1.51-1.40(m,2H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 40H 49N 9O 6[M+H] +:752.38，实测值为752.53。
[C023]7-((2-(2,6-二氧代哌啶-3-基)-1-氧代吲哚-4-基)氧基)-N-(4-(((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-基)氨基)甲基)苯基)庚酰胺的制备
参照实施例10中的合成路线，将壬二酸替换成庚二酸，制备得C023。 1H NMR(400MHz, DMSO-d 6)δ10.99(s,1H),7.96(s,1H),7.51(d,J＝8.4Hz,2H),7.45(t,J＝7.8Hz,1H),7.29(d,J＝7.4Hz,1H),7.27-7.19(m,3H),5.25-5.19(m,0.5H),5.10(dd,J＝13.3,5.0Hz,1H),5.06-4.98(m,0.5H),4.59(dd,J＝10.3,6.5Hz,2H),4.36(d,J＝17.4Hz,1H),4.20(d,J＝17.4Hz,1H),4.10(t,J＝6.2Hz,2H),3.51-3.45(m,1H),3.33(d,J＝10.5Hz,1H),3.23-3.07(m,2H),3.03-2.84(m,2H),2.81(dd,J＝13.4,4.7Hz,3H),2.62-2.38(m,2H),2.34-2.23(m,3H),2.18(d,J＝15.1Hz,1H),2.06-1.92(m,2H),1.82-1.68(m,3H),1.64-1.55(m,2H),1.50-1.40(m,2H),1.40-1.31(m,2H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 41H 51N 9O 6[M+H] +:766.40，实测值为766.91。
[C024]8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(4-(((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-基)氨基)甲基)苯基)辛酰胺的制备
参照实施例11中的合成路线，将壬二酸替换成辛二酸，制备得C024。 1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),7.96(s,1H),7.82–7.75(m,1H),7.54-7.47(m,3H),7.43(d,J＝7.2Hz,1H),7.25(d,J＝8.5Hz,2H),5.26-5.20(m,0.5H),5.11-4.99(m,1.5H),4.59(dd,J＝10.1,6.3Hz,2H),4.19(t,J＝6.3Hz,2H),3.48(d,J＝11.8Hz,1H),3.33(d,J＝11.3Hz,1H),3.22-3.08(m,2H),3.02-2.93(m,1H),2.93-2.76(m,4H),2.62-2.44(m,2H),2.34-2.22(m,3H),2.18(d,J＝14.3Hz,1H),2.06-1.95(m,2H),1.82-1.70(m,3H),1.63-1.53(m,2H),1.50-1.41(m,2H),1.41-1.29(m,4H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 42H 51N 9O 7[M+H] +:794.39，实测值为795.04。
[C025]8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)-N-(4-(((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-基)氨基)甲基)苯基)辛酰胺的制备
参照实施例10中的合成路线，将壬二酸替换成辛二酸，制备得C025。 1H NMR(400MHz,DMSO-d 6)δ10.99(s,1H),7.96(d,J＝0.9Hz,1H),7.52(d,J＝8.4Hz,2H),7.46(t,J＝7.8Hz,1H),7.29(d,J＝7.4Hz,1H),7.27-7.19(m,3H),5.25-5.18(s,0.5H),5.10(dd,J＝13.3,5.1Hz,1H),5.07-4.98(m,0.5H),4.59(dd,J＝10.2,6.5Hz,2H),4.36(d,J＝17.4Hz,1H),4.20(d,J＝17.4Hz,1H),4.09(t,J＝6.3Hz,2H),3.48(d,J＝12.1Hz,1H),3.33(d,J＝11.6Hz,1H),3.22-3.07(m,2H),3.02-2.92(m,1H),2.95-2.76(m,4H),2.59-2.41(m,2H),2.31-2.23(m,3H),2.18(d,J＝14.8Hz,1H),2.05-1.93(m,2H),1.81-1.68(m,3H),1.62–1.52(m,2H),1.47-1.38(m,2H),1.38-1.28(m,4H),1.25(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 42H 53N 9O 6[M+H] +:780.41，实测值为781.07。
[C028]10-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)基)-N-(4-(((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-基)氨基)甲基)苯基)癸酰胺的制备
参照实施例11中的合成路线，将壬二酸替换成癸二酸，制备得C028。 1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),7.95(s,1H),7.83-7.75(m,1H),7.54-7.47(m,3H),7.43(d,J＝7.2Hz,1H),7.25(d,J＝8.5Hz,2H),5.26-5.20(m,0.5H),5.11-4.99(m,1.5H),4.63–4.55(m,2H),4.18(t,J＝6.1Hz,2H),3.48(d,J＝12.4Hz,1H),3.33(d,J＝11.7Hz,1H),3.22-3.08(m,2H),3.01–2.93(m,1H),2.92-2.76(m,4H),2.63-2.44(m,2H),2.30-2.22(m,3H),2.18(d,J＝14.6Hz,1H),2.06-1.95(m,2H),1.83-1.69(m,3H),1.61-1.51(m,2H),1.49-1.40(m,2H),1.36-1.22(m,14H).UPLC-MS(ESI)理论值为C 44H 55N 9O 7[M+H] +:822.43，实测值为822.90。
[C029]10-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)-N-(4-(((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-基)氨基)甲基)苯基)癸酰胺的制备
参照实施例10中的合成路线，将壬二酸替换成癸二酸，制备得C029。 1H NMR(400MHz,DMSO-d 6)δ10.97(s,1H),7.95(s,1H),7.52(d,J＝8.4Hz,2H),7.46(t,J＝7.7Hz,1H),7.29(d,J＝7.5Hz,1H),7.25(d,J＝8.5Hz,2H),7.22(d,J＝8.2Hz,1H),5.26-5.20(m,0.5H),5.14-4.98(m,1.5H),4.64-4.53(m,2H),4.36(d,J＝17.5Hz,1H),4.21(d,J＝17.4Hz,1H),4.09(t,J＝6.4Hz,2H),3.49(d,J＝13.2Hz,1H),3.33(d,J＝12.9Hz,1H),3.23-3.07(m,2H),2.97(dt,J＝14.6,7.2Hz,1H),2.95-2.76(m,4H),2.61-2.41(m,2H),2.30-2.23(m,3H),2.18(d,J＝15.1Hz,1H),2.07-1.92(m,2H),1.85-1.67(m,3H),1.61-1.50(m,2H),1.46-1.37(m,2H),1.37-1.19(m,14H).UPLC-MS(ESI)理论值为C 44H 57N 9O 6[M+H] +:808.44，实测值为808.78。
[C033]8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(3-(((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-基)氨基)甲基)苯基)辛酰胺的制备
参照实施例2和实施例6中的合成路线，制备得C033。 1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),7.97(d,J＝0.9Hz,1H),7.84-7.77(m,1H),7.56(s,1H),7.52-7.45(m,2H),7.44(d,J＝7.2Hz,1H),7.23(t,J＝7.8Hz,1H),7.02-6.97(m,1H),5.24-5.19(m,0.5H),5.07(dd,J＝12.8,5.3Hz,1H),5.04-4.97(m,0.5H),4.62(dd,J＝10.1,6.2Hz,2H),4.19(t,J＝6.4Hz,2H),3.47(d,J＝13.0Hz,1H),3.32(d,J＝12.5Hz,1H),3.20-3.08(m,2H),2.98(ddd,J＝13.9,8.8,1.9Hz,1H),2.93-2.76(m,4H),2.62-2.44(m,2H),2.30-2.22(m,3H),2.17(d,J＝13.8Hz,1H),2.05-1.94(m,2H),1.81-1.69(m,3H),1.62-1.53(m,2H),1.45(s,2H),1.39-1.29(m,4H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 42H 51N 9O 7[M+H] +:794.39，实测值为794.96。
[C039]8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(4-(((8-异丙基-2-(((R)-哌啶-3-基)氧基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)辛酰胺的制备
参照实施例11中的合成路线，制备得C039。 1H NMR(400MHz,DMSO-d 6)δ11.09(s,1H),7.97(s,1H),7.82–7.76(m,1H),7.58–7.48(m,3H),7.43(d,J＝7.2Hz,1H),7.26(d,J＝8.4Hz,2H),5.26–5.20(m,1H),5.07(dd,J＝12.8,5.3Hz,1H),4.60(d,J＝6.0Hz,2H),4.19(t,J＝6.3Hz,2H),3.40–3.27(m,2H),3.11–2.94(m,3H),2.92–2.81(m,1H),2.62–2.43(m,2H),2.28(t,J＝7.3Hz,2H),2.05–1.97(m,1H),1.95–1.82(m,3H),1.80–1.64(m,3H),1.63–1.53(m,2H),1.50–1.29(m,6H),1.29–1.22(m,6H).UPLC-MS(ESI)理论值为C 40H 49N 9O 7[M+H] +:780.38，实测值为780.99。
[C040]8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(4-(((8-异丙基-2-(((S)-哌啶-3-基)氧基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)辛酰胺的制备
参照实施例11中的合成路线，制备得C040。 1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),7.97(s,1H),7.79(dd,J＝8.4,7.4Hz,1H),7.56–7.47(m,3H),7.43(d,J＝7.2Hz,1H),7.26(d,J＝8.5Hz,2H),5.27–5.20(m,1H),5.07(dd,J＝12.8,5.4Hz,1H),4.60(d,J＝6.2Hz,2H),4.19(t,J＝6.4Hz,2H),3.40–3.26(m,2H),3.12–2.94(m,3H),2.92–2.80(m,1H),2.62–2.44(m,2H),2.28(t,J＝7.4Hz,2H),2.07–1.96(m,1H),1.95–1.82(m,3H),1.79–1.64(m,3H),1.62–1.53(m,2H),1.51–1.29(m,6H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 40H 49N 9O 7[M+H] +: 780.38，实测值为781.14。
实施例12
[C045]N1-((R)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)甲酰胺基)吡咯烷-1-基)-3,3-二甲基-1-氧丁烷-2-基)-N8-(4-(((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-基)氨基)甲基)苯基)辛二酰胺的制备
Figure PCTCN2019100969-appb-000060
以化合物12.1(参照Buckley D.L.,Van Molle I.,Gareiss P.C.,et al.Targeting the von Hippel-Lindau E3ubiquitin ligase using small molecules to disrupt the VHL/HIF-1alpha interaction.Journal of the American Chemical Society.2012；134(10):4465-4468)和辛二酸单甲酯为原料，参照化合物1.12的合成，制备得化合物12.2。 1H NMR(400MHz,CDCl 3)δ8.67(s,1H),7.41-7.29(m,4H),6.21(d,J＝8.8Hz,1H),4.68(dd,J＝10.4,5.7Hz,1H),4.59-4.44(m,4H),4.33(dd,J＝15.0,5.3Hz,1H),4.07(d,J＝11.4Hz,1H),3.66-3.57(m,4H),2.53-2.42(m,4H),2.28(t,J＝7.5Hz,2H),2.20-2.08(m,3H),1.64-1.52(m,4H),1.34-1.22(m,4H),0.93(s,9H).UPLC-MS(ESI)理论值为C 31H 44N 4O 6S[M+H] +:601.30，实测值为601.78。
化合物12.2(40mg，0.0666mmol)溶于2mL甲醇中，加入2mL 1M氢氧化锂水溶液，室温反应2小时，用1N HCl调pH至3，二氯甲烷萃取，合并二氯层，无水Na 2SO 4干燥，过滤，减压除去溶剂，得粗品化合物12.3(40mg)。UPLC-MS(ESI)理论值为C 30H 42N 4O 6S[M+H] +:587.28，实测值为587.81。
以化合物12.3和化合物2.8为原料，参照化合物1.12的合成，制备得C045。 1H NMR(400MHz,DMSO-d 6)δ9.00(s,1H),7.95(s,1H),7.52(d,J＝8.1Hz,2H),7.44-7.35(m,4H),7.25(d,J＝8.3Hz,2H),5.26-5.19(m,0.5H),5.09-4.98(m,0.5H),4.64-4.56(m,2H),4.53(d,J＝9.4Hz,1H),4.46-4.38(m,2H),4.37-4.32(m,1H),4.21(dd,J＝15.8,5.3Hz,1H),3.69-3.55(m,2H),3.54-3.42(m,1H),3.38-3.26(m,1H),3.21-3.06(m,2H),2.97(dt,J＝13.5,6.8Hz,1H),2.81(d,J＝11.1Hz,3H),2.44(s,3H),2.32-2.21(m,3H),2.21-1.96(m,5H),1.89(ddd,J＝12.9,8.7,4.5Hz,1H),1.77(d,J＝ 13.0Hz,1H),1.60-1.40(m,4H),1.34-1.20(m,10H),0.92(s,9H).UPLC-MS(ESI)理论值为C 51H 69N 11O 6S[M+H] +:964.52，实测值为965.08。
实施例13
[C049]N1-(4-(N-(3-氰基-4-甲基-1H-吲哚-7-基)磺酰胺基)苄基)-N8-(4-(((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-基)氨基)甲基)苯基)辛二酰胺的制备
Figure PCTCN2019100969-appb-000061
参照实施例12中的合成路线，将化合物12.1替换成化合物13.1，制备得C049。 1H NMR(400MHz,DMSO-d 6)δ8.17(d,J＝3.2Hz,1H),7.95(s,1H),7.65(d,J＝8.4Hz,2H),7.52(d,J＝8.5Hz,2H),7.34(d,J＝8.4Hz,2H),7.25(d,J＝8.5Hz,2H),6.76(d,J＝8.3Hz,1H),6.57(d,J＝7.7Hz,1H),5.26-5.20(m,0.5H),5.07-4.98(m,0.5H),4.64-4.55(m,2H),4.28(d,J＝5.9Hz,2H),3.49(d,J＝12.7Hz,1H),3.33(d,J＝11.3Hz,1H),3.21-3.08(m,2H),2.97(dt,J＝13.9,6.9Hz,1H),2.81(dd,J＝13.1,4.7Hz,3H),2.55(s,3H),2.30-2.22(m,3H),2.21-2.09(m,3H),2.06-1.95(m,1H),1.81-1.71(m,1H),1.59-1.46(m,4H),1.32-1.20(m,10H).UPLC-MS(ESI)理论值为C 46H 55N 11O 5S[M+H] +:874.41，实测值为874.97。
[C046]N1-(4-(N-(3-氰基-4-甲基-1H-吲哚-7-基)磺酰胺基)苄基)-N10-(4-(((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-基)氨基)甲基)苯基)癸二酰胺的制备
参照实施例13中的合成路线，将辛二酸替换成癸二酸，制备得C046。 1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝3.1Hz,1H),7.95(d,J＝0.7Hz,1H),7.65(d,J＝8.4Hz,2H),7.52(d,J＝8.4Hz,2H),7.34(d,J＝8.4Hz,2H),7.26(d,J＝8.5Hz,2H),6.76(d,J＝8.4Hz,1H),6.59(d,J＝7.7Hz,1H),5.25–5.20(m,0.5H),5.07–5.00(m,0.5H),4.60(dd,J＝9.5,6.4Hz,2H),4.28(d,J＝5.9Hz,2H),3.52–3.45(m,1H),3.37–3.30(m,1H),3.22–3.08(m,2H),2.98(dt,J＝13.9,6.8Hz,1H),2.81(dd,J＝12.7,4.6Hz,3H),2.55(s,3H),2.31–2.22(m,3H),2.22–2.09(m,3H),2.07–1.95(m,1H),1.83–1.71(m,1H),1.60–1.45(m,4H),1.31–1.18(m,14H).UPLC-MS(ESI)理论值为C 48H 59N 11O 5S[M+H] +:902.44，实测值为902.65。
[C047]N-(4-(N-(3-氰基-4-甲基-1H-吲哚-7-基)磺酰胺基)苄基)-2-(2-(2-((4-(((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-基)氨基)甲基)苯基)氨基)-2-氧代乙氧基)乙氧基)乙酰胺的制备
参照实施例13中的合成路线，将辛二酸替换成3,6-二氧杂辛二酸，制备得C047。 1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝3.1Hz,1H),7.95(s,1H),7.64(d,J＝8.4Hz,2H),7.56(d,J＝8.5Hz,2H),7.36(d,J＝8.3Hz,2H),7.27(d,J＝8.5Hz,2H),6.75(d,J＝8.4Hz,1H),6.57(d,J＝7.7Hz,1H),5.25–5.19(m,0.5H),5.07–4.98(m,0.5H),4.64–4.56(m,2H),4.34(d,J＝6.2Hz, 2H),4.07(s,2H),4.00(s,2H),3.71–3.62(m,4H),3.51–3.44(m,1H),3.36–3.28(m,1H),3.21–3.08(m,2H),2.97(dt,J＝13.7,6.8Hz,1H),2.80(dd,J＝12.0,4.7Hz,3H),2.54(s,3H),2.30–2.23(m,1H),2.21–2.14(m,1H),2.06–1.95(m,1H),1.82–1.70(m,1H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 44H 51N 11O 7S[M+H] +:878.37，实测值为879.29。
[C048]N1-(4-(N-(3-氰基-4-甲基-1H-吲哚-7-基)磺酰胺基)苄基)-N6-(4-(((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-基)氨基)甲基)苯基)己二酰胺的制备
参照实施例13中的合成路线，将辛二酸替换成己二酸，制备得C048。 1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝3.1Hz,1H),7.95(s,1H),7.65(d,J＝8.3Hz,2H),7.53(d,J＝8.4Hz,2H),7.35(d,J＝8.3Hz,2H),7.26(d,J＝8.5Hz,2H),6.76(d,J＝8.0Hz,1H),6.58(d,J＝7.7Hz,1H),5.25–5.20(m,0.5H),5.07–4.99(m,0.5H),4.60(dd,J＝9.5,6.6Hz,2H),4.29(d,J＝5.8Hz,2H),3.52–3.44(m,1H),3.36–3.29(m,1H),3.21–3.08(m,2H),2.97(dt,J＝13.5,6.7Hz,1H),2.85–2.77(m,3H),2.55(s,3H),2.33–2.23(m,3H),2.22–2.12(m,3H),2.07–1.96(m,1H),1.83–1.71(m,1H),1.60–1.48(m,4H),1.25(d,J＝6.8Hz,6H).UPLC-MS(ESI)理论值为C 44H 51N 11O 5S[M+H] +:846.38，实测值为846.83。
实施例14
[C034]N-(3-(1H-咪唑-1-基)-4-(((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-基)氨基)甲基)苯基)-8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)辛酰胺的制备
Figure PCTCN2019100969-appb-000062
根据以上合成路线，参照实施例2和实施例11中的合成路线，制备得C034。 1H NMR(400MHz,DMSO-d 6)δ11.09(s,1H),9.39(d,J＝10.3Hz,1H),9.19(dd,J＝12.7,6.0Hz,1H),8.04(s,1H),7.98-7.91(m,2H),7.86(s,1H),7.83-7.77(m,1H),7.64-7.54(m,2H),7.50(d,J＝8.5Hz,1H),7.43(d,J＝7.2Hz,1H),5.19-5.14(m,0.5H),5.11-4.96(m,1.5H),4.46(d,J＝5.5Hz,2H),4.19(t,J＝6.3Hz,2H),3.51(d,J＝11.0Hz,1H),3.37(d,J＝12.7Hz,1H),3.24-3.04(m,2H),3.02-2.93(m,1H),2.92-2.76(m,4H),2.64-2.42(m,2H),2.37-2.27(m,3H),2.21(d,J＝14.2Hz,1H),2.11-1.94(m,2H),1.88-1.68(m,3H),1.64-1.53(m,2H),1.50-1.41(m,2H),1.40-1.15(m,10H).UPLC-MS(ESI)理论值为C 45H 53N 11O 7[M+H] +:860.41，实测值为860.52。
[C035]N-(2-(二甲基氨基)-3-(((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-基)氨基)甲基)苯基)-8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)辛酰胺的制备
参照实施例14中的合成路线，将2-氟-4-硝基苯腈替换成2-氟-3-硝基苯腈，咪唑替换成盐酸二甲胺，制备得C035。 1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),7.98(s,1H),7.83-7.77(m,1H),7.63-7.55(m,1H),7.51(d,J＝8.7Hz,1H),7.44(d,J＝7.2Hz,1H),7.03(t,J＝8.0Hz,1H),6.95-6.89(m,1H),5.18-5.14(m,0.5H),5.08(dd,J＝12.9,5.5Hz,1H),5.01-4.92(m,0.5H),4.74-4.67(m,2H),4.21(t,J＝6.3Hz,2H),3.54-3.47(m,1H),3.34-3.27(m,1H),3.15-3.04(m,2H),3.03-2.96(m,1H),2.93-2.73(m,10H),2.61-2.45(m,2H),2.44-2.35(m,2H),2.30-2.22(m,1H),2.21-2.13(m,1H),2.05-1.91(m,2H),1.82-1.69(m,3H),1.67-1.57(m,2H),1.51-1.43(m,2H),1.42-1.33(m,4H),1.31-1.19(m,6H).UPLC-MS(ESI)理论值为C 44H 56N 10O 7[M+H] +:837.43，实测值为837.58。
[C036]N-(3-(二甲基氨基)-4-(((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-基)氨基)甲基)苯基)-8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)辛酰胺的制备
参照实施例14中的合成路线，将咪唑替换成盐酸二甲胺，制备得C036。 1H NMR(400MHz,DMSO-d 6)δ11.10(s,1H),7.97(s,1H),7.83-7.77(m,1H),7.53-7.48(m,2H),7.43(d,J＝7.2Hz,1H),7.23-7.17(m,1H),7.12-7.05(m,1H),5.19-5.15(m,0.5H),5.07(dd,J＝13.1,5.5Hz,1H),5.04-4.96(m,0.5H),4.68(t,J＝5.8Hz,2H),4.19(t,J＝6.5Hz,2H),3.54-3.47(m,1H),3.35-3.27(m,1H),3.19-3.05(m,2H),3.03-2.94(m,1H),2.92–2.76(m,4H),2.67(s,6H),2.61-2.44(m,2H),2.34-2.23(m,3H),2.17(d,J＝14.7Hz,1H),2.05-1.93(m,2H),1.81-1.69(m,3H),1.62-1.53(m,2H),1.51-1.41(m,2H),1.41–1.30(m,4H),1.27(dd,J＝6.9,2.9Hz,6H).UPLC-MS(ESI)理论值为C 44H 56N 10O 7[M+H] +:837.43，实测值为837.72。
实施例15
[C042]5-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)-N-(4-(((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-基)氨基)甲基)苯基)戊酰胺的制备
Figure PCTCN2019100969-appb-000063
化合物15.1(786mg，4.5mmol)溶于10mL二氯甲烷和10mL 35％(w/w)的氢氧化钠水溶液中，加入四丁基氯化铵(1.25g，4.5mmol，1equiv)，0℃下滴加溴丙炔(800μL，9mmol，2equiv)，室温反应12小时，向反应中加入二氯甲烷，水洗数次，无水Na 2SO 4干燥，柱层析，得产物15.2(342mg)，收率36％。 1H NMR(400MHz,CDCl 3)δ4.11(d,J＝2.4Hz,2H),3.51(t,J＝6.2Hz,2H),2.40(t,J＝2.4Hz,1H),2.25–2.20(m,2H),1.68–1.57(m,4H),1.43(s,9H)。
以化合物15.2为原料，参照实施例9中的合成路线，制备得C042。 1H NMR(400MHz,DMSO-d 6)δ10.98(s,1H),7.95(s,1H),7.59–7.49(m,3H),7.44(d,J＝4.2Hz,2H),7.26(d,J＝8.4 Hz,2H),5.25–5.00(m,2H),4.60(dd,J＝9.4,6.5Hz,2H),4.45(d,J＝17.1Hz,1H),4.30(d,J＝17.1Hz,1H),3.53–3.45(m,1H),3.42–3.30(m,5H),3.22–3.08(m,2H),3.02–2.85(m,2H),2.81(dd,J＝12.3,4.5Hz,3H),2.68(t,J＝7.6Hz,2H),2.63–2.54(m,1H),2.47–2.36(m,1H),2.34–2.23(m,3H),2.22–2.14(m,1H),2.08–1.96(m,2H),1.88–1.72(m,3H),1.66–1.57(m,2H),1.56–1.47(m,2H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 42H 53N 9O 6[M+H] +:780.41，实测值为780.66。
实施例16
[C037]8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(4-(((2-(((R)-1-羟基丁基-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)辛酰胺的制备
Figure PCTCN2019100969-appb-000064
化合物2.6(110mg，0.239mmol)，化合物16.1(90μL，0.955mmol，4equiv)溶于3mL NMP中，120℃下反应12小时，向反应中加入乙酸乙酯，水洗数次，无水Na 2SO 4干燥，柱层析，得产物16.2(105mg)，收率94％。UPLC-MS(ESI)理论值为C 24H 35N 7O 3[M+H] +:470.28，实测值为470.96。
以化合物27.2为原料，参照实施例11中的合成路线，制备得C037。 1H NMR(400MHz,DMSO-d 6)δ11.09(s,1H),7.98(s,1H),7.83–7.75(m,1H),7.56–7.47(m,3H),7.43(d,J＝7.2Hz,1H),7.32(d,J＝7.5Hz,2H),5.07(dd,J＝12.9,5.4Hz,1H),4.67–4.51(m,2H),4.19(t,J＝6.3Hz,2H),4.01–3.90(m,1H),3.55–3.40(m,2H),3.00–2.80(m,2H),2.62–2.45(m,2H),2.28(t,J＝7.3Hz,2H),2.05–1.97(m,1H),1.82–1.70(m,2H),1.67–1.53(m,3H),1.52–1.41(m,3H),1.41–1.27(m,4H),1.22(d,J＝7.1Hz,6H),0.86(t,J＝7.3Hz,3H).UPLC-MS(ESI)理论值为C 40H 49N 9O 7[M+H] +:768.38，实测值为769.04。
[C038]8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(4-(((2-(((S)-1-羟基丁基-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)辛酰胺的制备
参照实施例16中的合成路线，将化合物27.1替换成S-(+)-2-氨基-1-丁醇，制备得C038。 1H NMR(400MHz,DMSO-d 6)δ11.09(s,1H),7.99(s,1H),7.83–7.75(m,1H),7.57–7.47(m,3H),7.43(d,J＝7.2Hz,1H),7.32(d,J＝7.3Hz,2H),5.07(dd,J＝12.9,5.3Hz,1H),4.69–4.51(m,2H),4.19(t,J＝6.3Hz,2H),4.01–3.92(m,1H),3.55–3.41(m,2H),3.00–2.81(m,2H),2.61–2.45(m,2H),2.28(t,J＝7.3Hz,2H),2.05–1.97(m,1H),1.80–1.70(m,2H),1.68–1.53(m,3H),1.52–1.41(m,3H),1.40–1.27(m,4H),1.22(d,J＝6.9Hz,6H),0.86(t,J＝7.3Hz,3H).UPLC-MS(ESI)理论值为C 40H 49N 9O 7[M+H] +:768.38，实测值为768.63。
[C043]N1-(2-(二甲基氨基)-3-(((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-基)氨基)甲基)苯基)-N8-((S)-1-((2S,4R)-4-羟基-2-((4-(4-甲基噻唑-5-基)苄基)甲酰胺基)吡咯烷-1-基)-3,3-二甲基-1-氧丁烷-2-基)辛二酰胺的制备
参照实施例12中的合成路线，制备得C043。UPLC-MS(ESI)理论值为C 53H 74N 12O 6S[M+H] +:1007.56，实测值为1007.80。
[C044](2S,4R)-1-((S)-2-(7-(2-(二甲基氨基)-3-(((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-基)氨基)甲基)苯基)庚酰胺)-3,3-二甲基丁酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺的制备
参照实施例4中的合成路线，制备得C044。UPLC-MS(ESI)理论值为C 52H 73N 11O 5S[M+H] +:964.55，实测值为964.71。
[C050]8-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)-N-(4-(((3-异丙基-5-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)辛酰胺的制备
参照化合物C025和实施例17的合成方法，制备得C050。UPLC-MS(ESI)理论值为C 43H 54N 8O 6[M+H] +:779.42,实测值为779.73.
[C051]8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(4-(((5-(((S)-1-羟基丁吡啶-2-基)氨基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)辛酰胺的制备
参照实施例10和实施例19中的合成方法，制备得C051。 1H NMR(400MHz,DMSO)δ11.10(s,1H),9.89(s,1H),7.96(s,1H),7.82–7.76(m,1H),7.55(d,J＝8.5Hz,2H),7.49(d,J＝8.5Hz,1H),7.43(d,J＝7.2Hz,1H),7.32(d,J＝8.2Hz,2H),5.45(s,1H),5.07(dd,J＝12.8,5.3Hz,1H),4.55(s,2H),4.33(d,J＝17.2Hz,1H),4.25(d,J＝17.2Hz,1H),4.18(t,J＝6.3Hz,2H),3.68–3.29(m,3H),3.11–2.95(m,1H),2.92–2.80(m,1H),2.62–2.43(m,2H),2.28(t,J＝7.3Hz,2H),2.06–1.96(m,1H),1.78–1.68(m,2H),1.66–1.52(m,3H),1.49–1.40(m,3H),1.39–1.26(m,4H),1.22(d,J＝6.9Hz,6H),0.85(t,J＝7.4Hz,3H).UPLC-MS(ESI)理论值为C 41H 52N 8O 6[M+H] +:753.40,实测值为753.78.
[C052]5-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-氧代异吲哚-4-基)氧基)乙氧基)-N-(4-(((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-基)氨基)甲基)苯基)戊酰胺的制备
参照化合物C024和C030的合成方法，制备得C052。UPLC-MS(ESI)理论值为C 41H 49N 9O 8[M+H] +:796.37,实测值为796.65
[C053]5-(2-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)乙氧基)-N-(4-(((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-基)氨基)甲基)苯基)戊酰胺的制备
参照化合物C024和C030的合成方法，制备得C053。UPLC-MS(ESI)理论值为C 41H 51N 9O 7[M+H] +:782.39,实测值为782.65
[C056]5-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-氧代异吲哚-4-基)氧基)乙氧基)-N-(4-(((2–((((3S,4S)-3-羟基哌啶-4-基)甲基)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)戊酰胺的制备
参照化合物C030和C038的合成方法，制备得C056。UPLC-MS(ESI)理论值为C 41H 50N 10O 8[M+H] +:811.38,实测值为811.72
[C058]8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(4-(((2-(((R)-1-羟基丁吡 啶-2-基)氨基)-9-异丙基-9H-嘌呤-6-基)氨基)甲基)苯基)辛酰胺的制备
参考文献Eur.J.Med.Chem.2013,61,61-72及实施例10，参照化合物C038的合成的合成方法，制备得C058。 1H NMR(500MHz,DMSO)δ11.09(s,1H),9.87(s,1H),8.33(s,1H),7.79(dd,J＝8.5,7.3Hz,1H),7.55(d,J＝8.2Hz,2H),7.50(d,J＝8.6Hz,1H),7.43(d,J＝7.2Hz,1H),7.29(d,J＝8.3Hz,2H),5.07(dd,J＝12.7,5.4Hz,1H),4.67–4.51(m,3H),4.19(t,J＝6.4Hz,2H),3.91–3.81(m,1H),3.56–3.43(m,2H),2.87(ddd,J＝16.9,13.9,5.4Hz,1H),2.61–2.55(m,1H),2.53–2.46(m,1H),2.29(t,J＝7.4Hz,2H),2.02(ddd,J＝10.4,5.3,3.1Hz,1H),1.79–1.71(m,2H),1.67–1.55(m,3H),1.54–1.42(m,9H),1.40–1.28(m,4H),0.93–0.83(m,3H).UPLC-MS(ESI)理论值为C 40H 49N 9O 7[M+H] +:768.38，实测值为768.66.
[C059]10-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)-N-(4-(((2-(((R)-1-羟基丁-2-基)氨基)-9-异丙基-9H-嘌呤-6-基)氨基)甲基)苯基)癸酰胺的制备
参考文献Eur.J.Med.Chem.2013,61,61-72及实施例10，参照化合物C038的合成方法，制备得C059。 1H NMR(500MHz,DMSO)δ10.97(s,1H),9.77(s,1H),7.77(s,1H),7.50–7.44(m,3H),7.29(d,J＝7.3Hz,1H),7.26(d,J＝8.5Hz,2H),7.21(d,J＝8.1Hz,1H),5.10(dd,J＝13.3,5.2Hz,1H),4.63–4.44(m,3H),4.36(d,J＝17.4Hz,1H),4.21(d,J＝17.4Hz,1H),4.09(t,J＝6.4Hz,2H),3.84–3.75(m,1H),3.49–3.44(m,1H),3.39–3.29(m,1H),2.95–2.84(m,1H),2.61–2.54(m,1H),2.49–2.39(m,1H),2.25(t,J＝7.4Hz,2H),2.02–1.94(m,2H),1.76–1.68(m,2H),1.64–1.52(m,3H),1.49–1.37(m,2H),1.34–1.20(m,14H),0.84(t,J＝7.4Hz,3H).UPLC-MS(ESI)理论值为C 42H 55N 9O 6[M+H] +:782.43,实测值为782.63.
[C066]7-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)-N-(4-(((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-基)氨基)甲基)苯基)庚酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C066。UPLC-MS(ESI)理论值为C 44H 57N 9O 6[M+H] +:808.44,实测值为808.67.
[C068]5-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)-N-(4-(((8-异丙基-2-(((R)-哌啶-3-基)氧基)吡唑[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)戊酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C068。UPLC-MS(ESI)理论值为C 41H 51N 9O 6[M+H] +:766.40,实测值为766.63.
[C069]5-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)-N-(4-(((8-异丙基-2-(((S)-哌啶-3-基)氧基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)戊酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C069。UPLC-MS(ESI)理论值为C 41H 51N 9O 6[M+H] +:766.40,实测值为766.65.
[C071]5-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)-N-(4-(((5-(((R)-1-羟丁基-2-基)氨基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)戊酰胺的制备
参照实施例19和化合物C042的合成方法，制备得C071。UPLC-MS(ESI)理论值为C 41H 52N 8O 6[M+H] +:753.40,实测值为753.75.
[C072]5-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)-N-(4-(((5-((((3S,4S)-3-羟基哌啶-4-基)甲基)氨基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)戊酰胺的制备
参照实施例19和化合物C042的合成方法，制备得C072。UPLC-MS(ESI)理论值为C 43H 55N 9O 6[M+H] +:794.43,实测值为794.68.
[C075]3-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基(乙氧基)-N-(3-氟-4-(((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-基)氨基)甲基)苯基)丙酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C075。UPLC-MS(ESI)理论值为C 42H 52F 1N 9O 7[M+H] +:814.40,实测值为814.67.
[C076]2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)乙氧基)-N-(4-(((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-基)氨基)甲基)苯基)乙酰胺的制备
参照化合物C042的合成方法，制备得C076。 1H NMR(400MHz,DMSO)δ10.99(s,1H),9.62(s,1H),7.96(d,J＝1.0Hz,1H),7.60–7.51(m,3H),7.44–7.38(m,2H),7.28(d,J＝8.5Hz,2H),5.26–5.20(m,0.5H),5.12(dd,J＝13.3,5.1Hz,1H),5.08–4.99(m,0.5H),4.61(dd,J＝9.8,6.4Hz,2H),4.44(d,J＝17.2Hz,1H),4.29(d,J＝17.1Hz,1H),4.08(s,2H),3.71–3.63(m,2H),3.59–3.53(m,2H),3.52–3.45(m,1H),3.43(t,J＝6.4Hz,2H),3.38–3.28(m,1H),3.22–3.08(m,2H),3.02–2.85(m,2H),2.81(dd,J＝12.3,4.6Hz,3H),2.68(t,J＝7.7Hz,2H),2.62–2.54(m,1H),2.44–2.31(m,1H),2.30–2.23(m,1H),2.22–2.13(m,1H),2.05–1.94(m,2H),1.89–1.70(m,3H),1.27(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 41H 51N 9O 7[M+H] +:782.39,实测值为782.63.
[C078]2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)乙氧基)-N-(4-(((8-乙基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C078。UPLC-MS(ESI)理论值为C 40H 49N 9O 7[M+H] +:768.38,实测值为768.72.
[C079]2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)乙氧基)-N-(4-(((8-甲基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C079。UPLC-MS(ESI)理论值为C 39H 47N 9O 7[M+H] +:754.36,实测值为754.67.
[C080]2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)乙氧基)-N-(4-(((2-((1-甲基哌啶-4-基)氧基)-8-丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C080。。UPLC-MS(ESI)理论值为C 41H 51N 9O 7[M+H] +:782.39,实测值为782.65.
[C082]2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)乙氧基)-N-(4-((S)-1-((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-基)氨基)乙基)苯基)乙酰基的制备
参照化合物C042和实施例15的合成方法，制备得C082。UPLC-MS(ESI)理论值为C 42H 53N 9O 7[M+H] +:796.41,实测值为796.67.
[C083]2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)乙氧基)-N-(6-(((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-基)氨基)甲基)吡啶-3-基)乙酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C083。UPLC-MS(ESI)理论值为C 40H 50N 10O 7[M+H] +:783.39,实测值为783.69.
[C084]2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)乙氧基)-N-(5-(((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-基)氨基)甲基)嘧啶-2-基)乙酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C084。UPLC-MS(ESI)理论值为C 39H 49N 11O 7[M+H] +:784.38,实测值为784.72.
[C085]2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)乙氧基)-N-(5-(((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-基)氨基)甲基)吡啶-2-基)乙酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C085。UPLC-MS(ESI)理论值为C 40H 50N 10O 7[M+H] +:783.39,实测值为783.75.
[C086]2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)乙氧基)-N-(8-(((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-基)氨基)甲基)喹啉-5-基)乙酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C086。UPLC-MS(ESI)理论值为C 44H 52N 10O 7[M+H] +:833.40,实测值为833.81.
[C087]2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)乙氧基)-N-(8-(((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-基)氨基)甲基)异喹啉-5-基)乙酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C087。UPLC-MS(ESI)理论值为C 44H 52N 10O 7[M+H] +:833.40,实测值为833.77.
[C088]2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)乙氧基)-N-(7-(((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-基)氨基)甲基)苯并[d][1,3]二氧-4-基)乙酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C088。UPLC-MS(ESI)理论值为C 42H 51N 9O 9[M+H] +:826.38,实测值为826.71.
[C089]2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)乙氧基)-N-(4-(((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-基)氨基)甲基)环己基)乙酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C089。UPLC-MS(ESI)理论值为C 41H 57N 9O 7[M+H] +:788.44,实测值为788.72.
[C090]N-(7-((2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)氧基)庚基)-4-(((8-异丙基-2-((1-甲基哌-4-基)氧基)吡唑并[1,5-α][1,3,5]三嗪-4-基)氨基)甲基苯甲酰胺的制备
参照实施例10中的合成路线，制备得C090。 1H NMR(400MHz,DMSO-d 6)δ9.25(s,1H),7.95(d,J＝0.9Hz,1H),7.83(d,J＝8.4Hz,2H),7.45(t,J＝7.8Hz,1H),7.31(d,J＝7.4Hz,1H),7.30-7.18(m,3H),5.25-5.15(s,0.5H),5.12(dd,J＝13.3,5.2Hz,1H),5.09-4.97(m,0.5H),4.56(dd,J＝10.2,6.5Hz,2H),4.35(d,J＝17.2Hz,1H),4.18(d,J＝17.4Hz,1H),4.07(t,J＝6.3Hz,2H),3.52(d,J＝12.1Hz,1H),3.35(d,J＝11.6Hz,1H),3.22-3.07(m,4H),3.09-2.98(m,1H),2.93-2.75(m,4H),2.32-2.21(m,3H),2.15(d,J＝14.8Hz,1H),2.04-1.92(m,2H),1.82-1.65(m,3H),1.65–1.50(m,2H),1.487-1.35(m,2H),1.35-1.22(m,4H),1.28(d,J＝6.8Hz,6H).UPLC-MS(ESI)理论值为C 42H 53N 9O 6[M+H] +:780.41，实测值为780.87。
[C091]N-(2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙氧基)乙氧基)乙基)-4-(((8- 异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-α][1,3,5]三嗪-4-基)氨基)甲基)苯甲酰胺的制备
参照化合物C042的合成方法，制备得C091。 1H NMR(400MHz,DMSO)δ10.99(s,1H),9.12(s,1H),7.95(d,J＝1.0Hz,1H),7.85–7.68(m,3H),7.42–7.37(m,2H),7.26(d,J＝8.5Hz,2H),5.26–4.99(m,2H),4.61(dd,J＝9.8,6.4Hz,2H),4.44(d,J＝17.1Hz,1H),4.29(d,J＝17.1Hz,1H),3.75–3.61(m,4H),3.59–3.43(m,4H),3.55–3.42(m,1H),3.40(t,J＝6.4Hz,2H),3.38–3.25(m,1H),3.20–3.05(m,2H),3.00–2.81(m,2H),2.78(dd,J＝12.3,4.6Hz,3H),2.65(t,J＝7.7Hz,2H),2.60–2.52(m,1H),2.45–2.30(m,1H),2.28–2.21(m,1H),2.19–2.11(m,1H),2.06–1.92(m,2H),1.87–1.70(m,3H),1.26(d,J＝6.8Hz,6H).UPLC-MS(ESI)理论值为C 42H 53N 9O 7[M+H] +:796.41,实测值为796.75.
[C093]N-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)正戊基)-4-(((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-基)氨基)甲基)苯甲酰胺的制备
参照化合物C042的合成方法，制备得C093。UPLC-MS(ESI)理论值为C 40H 49N 9O 5[M+H] +:736.39,实测值为736.73.
[C095]6-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)-N-(6-(4-(((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-基)氨基)甲基)苯基)吡啶-3-基)己酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C095。UPLC-MS(ESI)理论值为C 45H 52N 10O 5[M+H] +:813.41,实测值为813.65.
[C096]1-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代吲哚-4-基)正戊基)-3-(4-(((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-基)氨基)甲基)苯基)尿素的制备
参照化合物C041的合成方法，制备得C096。UPLC-MS(ESI)理论值为C 40H 50N 10O 5[M+H] +:751.40,实测值为751.69.
[C097](E)-2-(2-((3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)烯丙基)氧基)乙氧基)-N-(4-(((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-基)氨基)甲基)苯基)乙酰胺的制备
参照合成方法七中的路线，制备得C097。UPLC-MS(ESI)理论值为C 41H 49N 9O 7[M+H] +:780.38,实测值为780.72.
[C098]2-(2-(2-((3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙-2-炔-1-基)氧基)乙氧基)乙氧基基-N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-α][1,3,5]三嗪-4-基)氨基)甲基)苯基)乙酰胺的制备
参照合成方法七中的路线，制备得C098。UPLC-MS(ESI)理论值为C 43H 51N 9O 8[M+H] +:822.39,实测值为822.74.
[C099]2-(2-(2-((3-(2-(2,6-二氧代哌啶-3-基)-7-氟-1-氧代异吲哚-4-基)丙-2-炔-1-基)氧基乙氧基)乙氧基)乙氧基)-N-(4-(((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-基)氨基)甲基)苯基)乙酰胺的制备
参照合成方法七中的路线，制备得C099。UPLC-MS(ESI)理论值为C 43H 50F 1N 9O 8[M+H] +:840.38,实测值为840.79.
[C100]2-(2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-5-基)丙氧基)乙氧基)乙氧 基)-N-(4-(((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-基)氨基)甲基)苯基)乙酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C100。UPLC-MS(ESI)理论值为C 43H 55N 9O 8[M+H] +:826.42,实测值为826.73.
[C101]2-(2-(2-(3-(2-(2,6-二氧代哌啶-3-基)-3-氧代异吲哚-5-基)丙氧基)乙氧基)乙氧基)-N-(4-(((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-基)氨基)甲基)苯基)乙酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C101。UPLC-MS(ESI)理论值为C 43H 55N 9O 8[M+H] +:826.42,实测值为826.79.
[C102]5-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧-2,3-二氢-1H-吡咯并[3,4-c]吡啶-4-基)丙氧基)-N-(4-(((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-基)氨基)甲基)苯基)戊酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C102。UPLC-MS(ESI)理论值为C 41H 52N 10O 6[M+H] +:781.41,实测值为781.77.
[C103]5-(3-(2-(2,6-二氧代哌啶-3-基)-3-氧-2,3-二氢-1H-吡咯并[3,4-c]吡啶-7-基)丙氧基)-N-(4-(((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-基)氨基)甲基)苯基)戊酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C103。UPLC-MS(ESI)理论值为C 41H 52N 10O 6[M+H] +:781.41,实测值为781.77.
[C104]5-(3-(6-(2,6-二氧代哌啶-3-基)-7-氧-6,7-二氢-5H-吡咯并[3,4-b]吡啶-4-基)丙氧基)-N-(4-(((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-基)氨基)甲基)苯基)戊酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C104。UPLC-MS(ESI)理论值为C 41H 52N 10O 6[M+H] +:781.41,实测值为781.69.
[C105]5-(3-(2-(2,6-二氧代哌啶-3-基)-6-氟-1-氧代异吲哚-4-基)丙氧基)-N-(4-(((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-基)氨基)甲基)苯基)戊酰胺的制备
参照化合物C042和实施例15的合成方法，制备得C105。UPLC-MS(ESI)理论值为C 42H 52F 1N 9O 6[M+H] +:798.40,实测值为798.67.
[C106]8-((4-(N-(3-氰基-4-甲基-1H-吲哚-7-基)磺酰胺基)苯基)磺酰胺)-N-(4-(((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-基)氨基)甲基)苯基)辛酰胺的制备
参照实施例13中的合成路线及化合物C049的合成方法，制备得C106。 1H NMR(500MHz,DMSO)δ12.02(d,J＝2.8Hz,1H),10.17(s,1H),9.85(s,1H),9.51(d,J＝32.4Hz,1H),9.31(dt,J＝18.3,6.2Hz,1H),8.18(d,J＝3.1Hz,1H),7.96(s,1H),7.89(dd,J＝20.4,8.5Hz,4H),7.81(t,J＝5.8Hz,1H),7.53(d,J＝8.4Hz,2H),7.26(d,J＝8.5Hz,2H),6.77(d,J＝7.8Hz,1H),6.49(d,J＝7.7Hz,1H),5.33(t,J＝4.6Hz,1H),5.24(s,0.5H),5.09–5.00(m,0.5H),4.60(dd,J＝12.5,6.2Hz,2H),3.49(d,J＝12.3Hz,1H),3.34(d,J＝11.8Hz,1H),3.22–3.09(m,2H),2.98(dt,J＝13.8,6.9Hz,1H),2.82(dd,J＝16.5,4.4Hz,3H),2.72(dd,J＝13.0,6.7Hz,2H),2.56(d,J＝11.2Hz,3H), 2.32–2.15(m,4H),2.01(dd,J＝18.5,10.8Hz,1H),1.85-1.71(m,1H),1.53(dd,J＝14.2,7.1Hz,2H),1.37-1.13(m,13H).UPLC-MS(ESI)理论值为C 45H 55N 11O 6S 2[M+H] +:910.38,实测值为910.55.
[C107]10-((3-(N-(3-氰基-4-甲基-1H-吲哚-7-基)磺酰胺基)苯基)磺酰胺)-N-(4-(((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-基)氨基)甲基)苯基)癸酰胺的制备
参照实施例13中的合成路线及化合物C049的合成方法，制备得C107。 1H NMR(500MHz,DMSO)δ12.01(d,J＝2.9Hz,1H),10.18(s,1H),9.85(s,1H),9.60(d,J＝32.1Hz,1H),9.30(dt,J＝18.2,6.3Hz,1H),8.17(d,J＝3.1Hz,1H),7.95(d,J＝1.2Hz,1H),7.88(q,J＝8.6Hz,4H),7.80(t,J＝5.8Hz,1H),7.52(d,J＝8.3Hz,2H),7.25(d,J＝8.6Hz,2H),6.76(d,J＝8.1Hz,1H),6.49(d,J＝7.7Hz,1H),5.23(s,0.5H),5.05–5.02(m,0.5H),4.59(dd,J＝12.5,6.2Hz,2H),3.49(d,J＝12.3Hz,1H),3.33(d,J＝11.3Hz,1H),3.19–3.09(m,3H),3.04–2.93(m,1H),2.81(dd,J＝15.9,4.4Hz,3H),2.71(dd,J＝13.0,6.7Hz,2H),2.55(d,J＝10.0Hz,3H),2.30–2.14(m,4H),2.07–1.94(m,1H),1.83–1.71(m,1H),1.53(dd,J＝14.2,7.0Hz,2H),1.31–1.15(m,15H).UPLC-MS(ESI)理论值为C 47H 59N 11O 6S 2[M+H] +:938.41,实测值为938.75.
[C108]2-(2-(2-((4-(N-(3-氯-1H-吲哚-7-基)磺酰胺基)苄基)氨基)乙氧基)乙氧基)-N-(4-(((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-基)氨基)甲基)苯基)乙酰胺的制备
参照实施例13和化合物C047的合成方法，制备得C108。UPLC-MS(ESI)理论值为C 42H 51ClN 10O 6S[M+H] +:859.34,实测值为859.72.
[C109]N1-(4-(N-(5-氯喹喔啉-2-基)磺酰胺基)苄基)-N8-(4-(((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-基)氨基)甲基)苯基)辛二酰胺的制备
参照实施例13和化合物C049的合成方法，制备得C109。UPLC-MS(ESI)理论值为C 44H 52ClN 11O 5S[M+H] +:882.36,实测值为882.67.
[C110]N-(4-(((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-基)氨基)甲基)苯基)-8-((4-(N-(喹喔啉-2-基)磺酰胺基)苯基)磺酰胺)辛酰胺的制备
参照实施例13和化合物C049的合成方法，制备得C110。UPLC-MS(ESI)理论值为C 43H 53N 11O 6S 2[M+H] +:884.36,实测值为884.72.
[C111]2,4-二氯-N-((5-(((8-((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)氨基)-8-氧代辛基)氨基)甲基)噻吩-2-基)磺酰胺基)苯甲酰胺的制备
参照实施例13中的合成路线及化合物C049的合成方法，制备得C111。 1H NMR(400MHz,DMSO)δ9.83(s,1H),9.41(s,1H),9.35–9.25(m,1H),8.59(t,J＝5.9Hz,1H),7.95(s,1H),7.76–7.65(m,2H),7.55-7.48(m,3H),7.25(d,J＝8.5Hz,2H),7.05(d,J＝3.9Hz,1H),4.60(dd,J＝9.5,6.5Hz,2H),4.46(d,J＝5.9Hz,2H),3.49(d,J＝11.6Hz,1H),3.33(d,J＝11.9Hz,1H),3.23–3.09(m,2H),2.98(dt,J＝13.7,6.7Hz,1H),2.81(dd,J＝13.4,4.4Hz,3H),2.30–1.94(m,8H),1.77(m,1H),1.61–1.44(m,4H),1.29–1.22(m,12H).UPLC-MS(ESI)理论值为C 42H 51Cl 2N 9O 6S 2[M+H] +:912.28,实测值为912.49.
[C112]2,4-二氯-N-((5-(N-(8-((4-(((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-基)氨基)甲基)苯基)氨基)-8-氧代辛基)磺酰氨基)噻吩-2-基)磺酰基)苯甲酰胺的制备
参照实施例13中的合成路线及化合物C049的合成方法，制备得C112。UPLC-MS(ESI)理论值为C 40H 49Cl 2N 9O 7S 3[M+H] +:934.23,实测值为934.65.
[C116]3-(4-(5-(4-(4-(((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-基)氨基)甲基)苯基)哌嗪-1-基)正戊基)-1-氧代异吲哚-2-基)哌啶-2,6-二酮的制备
参照化合物C041的合成方法，制备得C116。UPLC-MS(ESI)理论值为C 43H 56N 10O 4[M+H] +:777.45,实测值为777.72.
[C117]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((8-异丙基-2-((1-甲基哌-4-基)氧基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例2和实施例17中的合成方法，制备得C117。 1H NMR(400MHz,DMSO)δ11.00(s,1H),7.93(s,1H),7.58–7.54(m,1H),7.48–7.44(m,2H),7.38(d,J＝8.5Hz,2H),7.20(d,J＝8.6Hz,2H),5.14(dd,J＝13.2,4.9Hz,1H),5.01(s,1H),4.57(d,J＝6.2Hz,2H),4.46(d,J＝17.3Hz,1H),4.30(d,J＝17.2Hz,1H),3.47–3.25(m,10H),3.04–2.86(m,4H),2.70–2.51(m,5H),2.47–2.24(m,6H),2.11–1.96(m,2H),1.88–1.74(m,1H),1.66–1.57(m,2H),1.54–1.44(m,2H),1.39–1.29(m,2H),1.28–1.24(m,6H).UPLC-MS(ESI)理论值为C 44H 57N 11O 5[M+H] +:820.45,实测值为820.78.
[C118]4-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丁基)-N-(4-(((8-异丙基-2-((1-甲基哌-4-基)氧基)吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例2和实施例17中的合成方法，制备得C118。 1H NMR(400MHz,DMSO)δ11.00(s,1H),7.94(s,1H),7.59–7.55(m,1H),7.48–7.44(m,2H),7.38(d,J＝8.6Hz,2H),7.20(d,J＝8.6Hz,2H),5.14(dd,J＝13.2,5.1Hz,1H),5.06(s,1H),4.57(d,J＝5.8Hz,2H),4.47(d,J＝17.3Hz,1H),4.31(d,J＝17.2Hz,1H),3.46–3.26(m,14H),3.01–2.86(m,2H),2.71–2.57(m,6H),2.44–2.26(m,3H),2.14–1.98(m,2H),1.94–1.82(m,1H),1.68–1.58(m,2H),1.55–1.45(m,2H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 43H 55N 11O 5[M+H] +:806.44,实测值为806.73.
[C120]N-(3,5-二氟-4-(((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-基)氨基)甲基)苯基)-3-(3-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)正丙基)氮杂环丁-1-基)丙酰胺的制备
参照化合物C041的合成方法，制备得C120。UPLC-MS(ESI)理论值为C 43H 52F 2N 10O 5[M+H] +:827.41,实测值为827.69.
[C121]N-(3-氰基-4-(((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-基)氨基)甲基)苯基)-5-(4-(2-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)乙基)-1H-吡唑-1-基)戊酰胺的制备
参照化合物C041的合成方法，制备得C121。UPLC-MS(ESI)理论值为C 45H 52N 12O 5[M+H] +:841.42,实测值为841.79.
[C122]N-(3-氯-4-(((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-基)氨基)甲基)苯基)-2-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)正戊基)哌嗪-1-基)乙酰胺的制备
参照化合物C041和实施例17的合成方法，制备得C122。UPLC-MS(ESI)理论值为 C 45H 58ClN 11O 5[M+H] +:868.43,实测值为868.82.
实施例17
[C123]N-(4-(((5-(环戊基氨基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)-4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)哌嗪-1-甲酰胺的制备
Figure PCTCN2019100969-appb-000065
化合物17.1(350mg,0.57mmol)，Cs 2CO 3(278mg,0.85mmol,1.5equiv),BINAP(53mg,0.09mmol,0.15equiv),Pd 2dba 3(26mg,0.03mmol,0.05equiv)加入干燥茄型瓶，注入8mL无水甲苯，抽换气，N 2保护，5分钟后，注入溶于2mL无水甲苯中的化合物17.2(193mg,2.27mmol,4.0equiv),再次抽换气，N 2保护，90℃下反应12小时后，向反应液中加入乙酸乙酯，分别用水和饱和NaCl洗涤，无水NaSO4干燥，过滤，柱层析得产物17.3(180mg),收率56％。
化合物17.3(180mg,0.32mmol)溶于6mL二氯甲烷，搅拌下缓慢滴加2mL三氟乙酸，室温反应2小时后，向反应液加入二氯甲烷，分别用饱和NaCHO 3和饱和NaCl洗涤，无水NaSO4干燥，过滤，旋干得产物17.4(115mg)，收率98％。 1H NMR(400MHz,CDCl 3)δ7.72(s,1H),7.25(d,J＝9.5Hz,2H),7.07(d,J＝8.3Hz,2H),5.64(s,1H),4.93(s,2H),4.67(d,J＝6.3Hz,1H),4.21–4.06(m,1H),3.15–3.02(m,1H),2.08–1.99(m,2H),1.94(s,2H),1.72–1.57(m,4H),1.40(d,J＝5.0Hz,18H),1.32(d,J＝6.9Hz,6H)。
化合物17.4(180mg,0.32mmol)溶于无水二氯甲烷，加入吡啶(58μL，0.71mmol,2.3equiv),冰浴下缓慢注入化合物17.5(83mg,0.41mmol,1.3equiv)，室温下反应，TLC板检测反应至原料消失，加入化合物17.6(120mg,0.64mmol,2.0equiv),三乙胺(133μL,0.96mmol,3.0equiv)，室温反应2小时后，分别用水和饱和NaCl洗涤，无水NaSO4干燥，过滤，柱层析得产物17.7(126mg),收率68％。
化合物17.7(126mg,0.22mmol)溶于6mL二氯甲烷，搅拌下缓慢滴加2mL三氟乙酸，室温反应2小时后，旋干得产物17.8(131mg)，收率100％。 1H NMR(400MHz,CDCl 3)δ7.64(s,1H),7.32(d,J＝8.5Hz,2H),7.25(d,J＝8.6Hz,2H),6.56(s,1H),6.40(t,J＝5.6Hz,1H),4.65(d,J＝6.1Hz,1H),4.43(d,J＝5.7Hz,2H),4.02-3.95(m,1H),3.48(s,8H),3.09(dt,J＝13.8,6.9Hz,1H),2.03–1.96(m,2H),1.81(s,2H),1.73–1.66(m,2H),1.65–1.58(m,2H),1.48(s,9H),1.30(d,J＝6.9Hz,6H)。
化合物17.8(61mg,0.10mmol)，化合物17.9(50mg,0.13mmol,1.3equiv)溶于1.5mL二甲亚砜，注入三乙胺(30μL,0.40mmol,4.0equiv)，30℃下反应16小时后，向反应液加入乙酸乙酯，用水和饱和NaCl洗涤多次，无水NaSO4干燥，过滤，柱层析得产物C123(30mg),收率38％。 1H NMR(400MHz,CD3OD)δ7.68(s,1H),7.65(dd,J＝5.4,3.2Hz,1H),7.49–7.45(m,2H),7.36(d,J＝8.6Hz,2H),7.31(d,J＝8.5Hz,2H),5.17(dd,J＝13.3,5.2Hz,1H),4.51(m,3H),4.45(d,J＝17.0Hz,1H),4.08(s,1H),3.69–3.60(m,4H),3.07(dt,J＝13.7,6.9Hz,1H),2.97–2.78(m,6H),2.76–2.67(m,4H),2.51(qd,J＝13.2,4.6Hz,1H),2.21–2.13(m,1H),2.02–1.92(m,2H),1.76–1.57(m,8H),1.50–1.39(m,4H),1.28(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 40H 56N 10O 4[M+H] +:789.45，实测值为789.64。
实施例18
[C124]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((5-(4-羟基哌啶-1-基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
Figure PCTCN2019100969-appb-000066
化合物18.1(350mg，0.568mmol，1.0equiv)和4-羟基哌啶18.2(201mg，1.99mmol，3.0equiv)溶于2mLNMP中，加入DIPEA(301μL，2.15mmol，3.5equiv)，在N 2保护下加热12小时，减压除去溶剂，柱层析，得产物18.3(230mg)，收率59％。
以化合物18.3为原料，参照实施例17中的合成路线，制备得C124。 1H NMR(400MHz,CD 3OD)δ7.66–7.64(m,2H),7.51-7.45(m,2H),7.37-7.31(m,4H),5.47(s,1H),5.34(t,J＝4.6Hz,1H),5.18(dd,J＝13.3,5.1Hz,1H),4.60–4.42(m,4H),4.14-4.06(m,2H),3.84-3.76(m,1H),3.53(d,J＝4.4Hz,4H),3.15-3.02(m,3H),2.97–2.86(m,1H),2.80(dd,J＝11.7,9.3Hz,1H),2.74(t,J＝7.6Hz,2H),2.61–2.46(m,5H),2.40(dd,J＝14.3,6.5Hz,2H),2.18(d,J＝7.7Hz,1H),2.08–1.97(m,2H),1.92–1.82(m,2H),1.79–1.67(m,2H),1.64-1.54(m,2H),1.50–1.39(m,4H),1.30(s,6H).UPLC-MS(ESI)理论值为C 44H 56N 10O 5[M+H] +:805.44,实测值为805.68.
[C125]N-(4-(((5-(((2R，3R)-1,3-二羟基丁-2-基)氨基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基基)苯基)-4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C125。 1H NMR(500MHz,CD 3OD)δ7.80(s,1H),7.65(d,J＝2.2Hz,1H),7.49(s,2H),7.38(d,J＝8.7Hz,2H),7.34(d,J＝8.7Hz,2H),5.46(s,1H),5.18(dd,J＝13.4,5.2Hz,1H),4.60(m,2H),4.53(d,J＝16.9Hz,1H),4.46(d,J＝16.9Hz,1H),4.09–4.03(m,1H),3.89–3.59(m,7H),3.27(m,4H),3.13–3.07(m,2H),3.05-2.98(m,1H),2.96-2.88(m,1H),2.83-2.79(m,1H),2.78–2.73(m,2H),2.58-2.48(m,1H),2.24–2.14(m,1H),1.82-1.72(m,4H),1.51–1.40(m,2H),1.30(t,J＝3.5Hz,6H),1.20(d,J＝6.4Hz,3H).UPLC-MS(ESI)理论值为C 43H 56N 10O 6[M+H] +:809.44,实测值为809.70.
[C126]N-(4-(((5-(((2S，3S)-1,3-二羟基丁-2-基)氨基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基基)苯基)-4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C126。 1H NMR(500MHz,MeOD)7.70(s,1H),7.66(dd,J＝6.2,2.2Hz,1H),7.53–7.45(m,2H),7.39-7.29(m,4H),5.37(s,1H),5.18(dd,J＝13.3,5.1Hz,1H),4.57-4.42(m,4H),4.08-4.01(m,1H),3.78–3.68(m,7H),3.10–2.99(m,5H),2.96–2.86(m,3H),2.82-2.71(m,3H),2.57-2.49(m,1H),2.27–2.14(m,1H),1.80-1.67(m,4H),1.48-1.39(m,2H),1.29(dd,J＝6.9,3.5Hz,6H),1.19(d,J＝6.4Hz,3H).UPLC-MS(ESI)理论值为C 43H 56N 10O 6[M+H] +:809.44,实测值为809.67.
[C127]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((3-异丙基-5-(吡咯烷-1-基)吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C127。 1H NMR(400MHz,CD3OD)δ7.68(s,1H),7.65(dd,J＝5.3,3.3Hz,1H),7.49–7.45(m,2H),7.36(d,J＝8.8Hz,2H),7.33(d,J＝8.8Hz,2H),5.21–5.12(m,2H),4.56–4.40(m,4H),3.75–3.64(m,4H),3.48-3.39(m,4H),3.17-3.07(m,1H),3.02-2.93(m,4H),2.91–2.77(m,4H),2.72(t,J＝7.5Hz,2H),2.51(m,1H),2.21–2.12(m,1H),2.03–1.92(m,4H),1.78–1.64(m,4H),1.45–1.37(m,2H),1.29(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 43H 54N 10O 4[M+H] +:775.43,实测值为775.68.
[C128]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((5-((S)-3-羟基哌啶-1-基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C128。 1H NMR(400MHz,CD 3OD)δ7.70–7.65(m,2H),7.48(dd,J＝6.9,5.2Hz,2H),7.37(d,J＝9.0Hz,2H),7.35(d,J＝9.0Hz,2H),5.46(s,1H),5.19(dd,J＝13.3,5.1Hz,1H),4.59–4.50(m,3H),4.47(d,J＝17.0Hz,1H),4.22(dd,J＝12.7,3.7Hz,1H),3.96(d,J＝13.1Hz,1H),3.72–3.60(m,5H),3.13–2.98(m,2H),2.93–2.81(m,7H),2.78-2.69(m,4H),2.53(qd,J＝13.2,4.6Hz,1H),2.24–2.13(m,1H),2.07–1.95(m,1H),1.84–1.62(m,5H),1.56–1.38(m,4H),1.32(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 44H 56N 10O 5[M+H] +:805.44,实测值为805.71.
[C129]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((3-异丙基-5-((1-(甲基磺酰基)哌啶-4-基)氨基)吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C129。 1H NMR(400MHz,CD 3OD)δ7.69–7.64(m,2H),7.50–7.45(m,2H),7.38(d,J＝8.6Hz,2H),7.32(d,J＝8.6Hz,2H),5.18(dd,J＝13.3,5.2Hz,1H),5.12(s,1H),4.56–4.42(m,4H),3.81–3.61(m,5H),3.63(d,J＝12.4Hz,2H),3.10–3.04(m,5H),2.96–2.87(m,5H),2.85(s,3H),2.81(dd,J＝4.4,2.2Hz,1H),2.77–2.73(t,2H),2.53(tt,J＝13.3,6.7Hz,1H),2.23–2.15(m,1H),2.07-1.94(m,2H),1.80–1.66(m,4H),1.54–1.42(m,J＝13.5,9.3Hz,4H),1.29(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 45H 59N 11O 6S[M+H] +:882.44,实测值为882.64.
[C130]N-(4-(((5-(1,1-二氧化硫)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)-4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C130。 1H NMR(400MHz,CD 3OD)δ7.71(s,1H),7.66(dd,J＝6.0,2.6Hz,1H),7.51–7.45(m,2H),7.39–7.31(m,4H),5.52(s,1H),5.18(dd, J＝13.3,5.2Hz,1H),4.58(s,2H),4.49(q,J＝17.0Hz,2H),4.14-4.16(m,4H),3.74-3.65(m,4H),3.08(dd,J＝13.9,6.9Hz,1H),3.03-2.95(m,8H),2.92–2.81(m,4H),2.77–2.73(m,2H),2.52(ddd,J＝18.1,13.1,4.5Hz,1H),2.20–2.14(m,1H),1.79–1.67(m,4H),1.49–1.39(m,2H),1.31(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 43H 54N 10O 6S[M+H] +:839.39,实测值为839.62.
[C131]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((5-((R)-3-羟基哌啶-1-基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C131。 1H NMR(400MHz,CD 3OD)δ7.68–7.64(m,2H),7.50–7.45(m,2H),7.38–7.32(m,4H),5.49(s,1H),5.18(dd,J＝13.3,5.1Hz,1H),4.55–4.42(m,4H),4.20(dd,J＝12.7,3.8Hz,1H),3.95(d,J＝12.6Hz,1H),3.73–3.57(m,5H),3.11-2.98(m,2H),2.94-2.85(m,6H),2.82–2.70(m,5H),2.52(qd,J＝13.2,4.7Hz,1H),2.23–2.14(m,1H),2.04–1.93(m,J＝8.1Hz,1H),1.82–1.63(m,5H),1.53–1.37(m,4H),1.30(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值C 44H 56N 10O 5[M+H] +:805.44,实测值为805.68.
实施例19.
[C132]6-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)哌嗪-1-基)-N-(4-(((5-(((R)-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)己酰胺的制备
Figure PCTCN2019100969-appb-000067
化合物19.1(1.00g,1.90mmol)，化合物19.2(793mg,3.90mmol,2.0equiv)，Cs 2CO 3(945mg,2.90mmol,1.5equiv),BINAP(187mg,0.30mmol,0.15equiv),Pd 2dba 3(92mg,0.10mmol,0.05equiv)加入干燥茄型瓶，抽换气，N 2保护，注入40mL无水甲苯，搅拌下再次抽换气，N 2保护，100℃下反应16小时后，向反应液中加入乙酸乙酯，分别用水和饱和NaCl洗涤，无水NaSO4干燥，过滤，柱层析得产物19.3(843mg),收率65％。
化合物19.3(312mg,0.46mmol)溶于6mL二氯甲烷，搅拌下缓慢滴加2mL三氟乙酸，室温反应2小时后，向反应液加入二氯甲烷，分别用饱和NaCHO 3和饱和NaCl洗涤，无水NaSO4干燥，过滤，旋干得产物19.4(161mg)，收率96％。
化合物19.4(52mg,0.14mmol)，化合物19.5(47mg,0.16mmol,1.1equiv)，HATU(59mg,0.16mmol,1.1equiv)溶于8mL DMF，搅拌下加入DIPEA(69μL,0.42mmol,3.0equiv),室温下反 应12小时后，向反应液中加入乙酸乙酯，用水洗涤多次，无水NaSO4干燥，过滤，柱层析得产物19.6(52mg),收率57％。 1H NMR(400MHz,DMSO)δ9.84(s,1H),7.70(s,1H),7.59(s,1H),7.53(d,J＝8.4Hz,2H),7.27(d,J＝8.5Hz,2H),6.34(d,J＝7.2Hz,1H),5.16(s,1H),4.71(t,J＝5.6Hz,1H),4.39–4.43(s,2H),3.87–3.76(m,2H),3.28–3.21(m,5H),2.97–2.89(m,1H),2.34–2.22(m,8H),1.65–1.52(m,4H),1.47–1.41(m,3H),1.38(s,9H),1.29–1.25(m,1H),1.23(d,J＝6.9Hz,6H),0.84(t,J＝7.4Hz,3H)。UPLC-MS(ESI)理论值为C 48H 66N 10O 5[M+H] +:651.43，实测值为651.62。
以化合物19.6为原料，参照实施例17中的合成路线，制备得C132。 1H NMR(400MHz,CD 3OD)δ8.44(s,1H),7.65–7.61(m,2H),7.53(d,J＝8.4Hz,2H),7.45(d,J＝4.2Hz,2H),7.33(d,J＝8.3Hz,2H),5.25(s,1H),5.16(dd,J＝13.3,5.1Hz,1H),4.50(m,3H),4.45(d,14.2Hz,1H),3.78(s,1H),3.62(dd,J＝10.9,4.0Hz,1H),3.55(dd,J＝10.9,6.0Hz,1H),3.05–2.78(m,11H),2.75–2.65(m,6H),2.56–2.44(m,1H),2.37(t,J＝7.2Hz,2H),2.20–2.10(m,1H),2.05–1.97(m,1H),1.69–1.65(m,5H),1.65–1.55(m,5H),1.44–1.36(m,4H),1.26(d,J＝6.9Hz,6H),0.94(t,J＝7.4Hz,3H).UPLC-MS(ESI)理论值C 48H 66N 10O 5[M+H] +:863.52,实测值为863.81
[C133]4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)哌嗪-1-基)-N-(4-(((5-(((R)-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)丁酰胺的制备
参照实施例19中的合成路线，制备得C133。 1H NMR(400MHz,CD 3OD)δ8.26(s,1H),7.68(s,1H),7.63(dd,8.4,3.6Hz,1H),7.56(d,J＝8.4Hz,2H),7.45(d,J＝3.6Hz,2H),7.35(d,J＝8.3Hz,2H),5.27(s,1H),5.16(dd,J＝13.3,5.1Hz,1H),4.48(s,1H),4.46(q,J＝16.7Hz,4H),3.75(s,1H),3.64(dd,J＝11.2,3.5Hz,1H),3.55(dd,J＝11.2,6.1Hz,1H),3.06–2.77(m,9H),2.76–2.63(m,9H),2.56–2.47(m,1H),2.43(t,J＝6.7Hz,2H),2.21–2.11(m,1H),1.97–1.86(m,2H),1.72–1.65(m,2H),1.64–1.43(m,4H),1.38–1.29(m,2H),1.26(d,J＝6.7Hz,6H),0.94(t,J＝7.4Hz,3H).UPLC-MS(ESI)理论值C 46H 62N 10O 5[M+H] +:835.49,实测值为835.72.
[C134]4-(4-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙基)哌嗪-1-基)-N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-α][1,3,5]三嗪-4-基)氨基)甲基)苯基)丁酰胺的制备
参照实施例2和实施例19中的合成路线，制备得C134。 1H NMR(400MHz,DMSO)δ11.02(s,1H),9.98(s,1H),7.95(s,1H),7.63–7.57(m,1H),7.53(d,J＝8.5Hz,2H),7.50–7.48(m,2H),7.27(d,J＝8.5Hz,2H),5.25–5.21(m,0.5H),5.16(dd,J＝13.3,5.0Hz,1H),5.08–4.99(m,0.5H),4.60(dd,J＝10.1,6.4Hz,2H),4.48(d,J＝17.1Hz,1H),4.32(d,J＝17.0Hz,1H),3.53–3.29(m,6H),3.23–3.08(m,4H),3.02–2.85(m,7H),2.85–2.76(m,4H),2.72–2.58(m,3H),2.44–2.32(m,3H),2.31–2.24(m,1H),2.22–2.14(m,1H),2.07–1.97(m,2H),1.97–1.84(m,4H),1.83–1.72(m,1H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值C 45H 59N 11O 5[M+H] +:834.47,实测值为834.67.
[C135]4-(4-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丁基)哌嗪-1-基)-N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-α][1,3,5]三嗪-4-基)氨基)甲基)苯基)丁酰胺的制备
参照实施例2和实施例19中的合成路线，制备得C135。 1H NMR(400MHz,DMSO)δ11.01(s,1H),9.97(s,1H),7.96(s,1H),7.61–7.57(m,1H),7.55–7.51(m,2H),7.48(d,J＝4.3Hz,2H), 7.27(d,J＝8.5Hz,2H),5.26–5.21(m,0.5H),5.16(dd,J＝13.1,5.0Hz,1H),5.08–5.00(m,0.5H),4.64–4.57(m,2H),4.47(d,J＝17.1Hz,1H),4.31(d,J＝17.2Hz,1H),3.53–3.28(m,6H),3.23–3.08(m,4H),3.04–2.86(m,6H),2.85–2.76(m,4H),2.71–2.58(m,4H),2.43–2.32(m,3H),2.31–2.24(m,1H),2.22–2.14(m,1H),2.08–1.95(m,2H),1.92–1.73(m,3H),1.63(s,4H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值C 46H 61N 11O 5[M+H] +:848.49,实测值为848.75.
[C136]4-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)哌嗪-1-基)-N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-α][1,3,5]三嗪-4-基)氨基)甲基)苯基)丁酰胺的制备
参照实施例2和实施例19中的合成路线，制备得C136。 1H NMR(400MHz,DMSO)δ11.00(s,1H),7.94(s,1H),7.59–7.55(m,1H),7.53(d,J＝8.5Hz,2H),7.47–7.44(m,2H),7.26(d,J＝8.5Hz,2H),5.17–5.04(m,2H),4.59(d,J＝6.1Hz,2H),4.46(d,J＝17.2Hz,1H),4.30(d,J＝17.2Hz,1H),3.51–3.46(m,1H),3.44–3.38(m,1H),3.38–3.26(m,14H),3.02–2.87(m,2H),2.73–2.57(m,6H),2.45–2.28(m,3H),2.18–2.07(m,2H),2.04–1.88(m,4H),1.82–1.71(m,1H),1.66–1.54(m,2H),1.32–1.18(m,10H).UPLC-MS(ESI)理论值C 47H 63N 11O 5[M+H] +:862.50,实测值为862.72.
[C137]5-(4-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙基)哌嗪-1-基)-N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-α][1,3,5]三嗪-4-基)氨基)甲基)苯基)戊酰胺的制备
参照实施例2和实施例19中的合成路线，制备得C137。 1H NMR(400MHz,DMSO)δ11.02(s,1H),9.93(s,1H),7.95(s,1H),7.62–7.58(m,1H),7.53(d,J＝8.5Hz,2H),7.50–7.47(m,2H),7.26(d,J＝8.5Hz,2H),5.26–5.21(m,0.5H),5.16(dd,J＝13.3,5.1Hz,1H),5.07–4.99(m,0.5H),4.60(dd,J＝10.0,6.5Hz,2H),4.48(d,J＝17.1Hz,1H),4.31(d,J＝17.1Hz,1H),3.59–3.28(m,6H),3.22–3.09(m,4H),3.08–2.86(m,7H),2.81(dd,J＝13.3,4.4Hz,3H),2.73–2.58(m,4H),2.43–2.31(m,3H),2.30–2.23(m,1H),2.22–2.14(m,1H),2.07–1.88(m,4H),1.84–1.72(m,1H),1.69–1.52(m,4H),1.25(d,J＝7.6Hz,6H).UPLC-MS(ESI)理论值C 46H 61N 11O 5[M+H] +:848.49,实测值为848.64.
[C138]5-(4-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丁基)哌嗪-1-基)-N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-α][1,3,5]三嗪-4-基)氨基)甲基)苯基)戊酰胺的制备
参照实施例2和实施例19中的合成路线，制备得C138。 1H NMR(400MHz,DMSO)δ11.03(s,1H),9.96(s,1H),7.98(s,1H),7.64–7.59(m,1H),7.55(d,J＝8.5Hz,2H),7.52–7.48(m,2H),7.32–7.26(m,2H),5.28–5.23(m,0.5H),5.18(dd,J＝13.2,5.1Hz,1H),5.10–5.01(m,0.5H),4.63(dd,J＝10.0,6.3Hz,2H),4.50(d,J＝17.2Hz,1H),4.33(d,J＝17.2Hz,1H),3.70–3.30(m,6H),3.27–2.90(m,12H),2.83(dd,J＝13.6,4.5Hz,3H),2.75–2.59(m,3H),2.45–2.34(m,3H),2.33–2.26(m,1H),2.25–2.17(m,1H),2.10–1.99(m,2H),1.88–1.75(m,1H),1.73–1.57(m,8H),1.28(d,J＝7.6Hz,6H).UPLC-MS(ESI)理论值C 47H 63N 11O 5[M+H] +:862.50,实测值为862.79.
[C139]5-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)哌嗪-1-基)-N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-α][1,3,5]三嗪-4-基)氨基)甲基)苯基)戊酰胺的制备
参照实施例2和实施例19中的合成路线，制备得C139。 1H NMR(400MHz,DMSO)δ11.00(s,1H),9.90(s,1H),7.94(s,1H),7.59–7.55(m,1H),7.53(d,J＝8.5Hz,2H),7.48–7.43(m,2H),7.26(d,J＝8.5Hz,2H),5.14(dd,J＝13.2,5.1Hz,1H),5.08–4.98(m,1H),4.59(d,J＝6.0Hz,2H), 4.46(d,J＝17.1Hz,1H),4.30(d,J＝17.2Hz,1H),3.52–3.19(m,10H),3.14–3.02(m,2H),3.01–2.87(m,2H),2.76–2.53(m,10H),2.44–2.35(m,1H),2.30(t,J＝7.1Hz,2H),2.14–1.96(m,2H),1.94–1.77(m,2H),1.66–1.44(m,7H),1.37–1.21(m,10H).UPLC-MS(ESI)理论值C 48H 65N 11O 5[M+H] +:876.52,实测值为876.73.
[C140]6-(4-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙基)哌嗪-1-基)-N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-α][1,3,5]三嗪-4-基)氨基)甲基)苯基)己酰胺的制备
参照实施例2和实施例19中的合成路线，制备得C140。 1H NMR(400MHz,DMSO)δ11.02(s,1H),9.89(s,1H),7.95(s,1H),7.63–7.58(m,1H),7.52(d,J＝8.5Hz,2H),7.50–7.46(m,2H),7.26(d,J＝8.5Hz,2H),5.25–5.21(m,0.5H),5.16(dd,J＝13.2,5.1Hz,1H),5.08–4.99(m,0.5H),4.60(dd,J＝9.7,6.7Hz,2H),4.47(d,J＝17.1Hz,1H),4.31(d,J＝17.1Hz,1H),3.56–3.27(m,6H),3.22–3.08(m,4H),3.05–2.86(m,7H),2.85–2.75(m,4H),2.72–2.58(m,3H),2.44–2.24(m,4H),2.22–2.14(m,1H),2.07–1.97(m,2H),1.96–1.86(m,2H),1.83–1.71(m,1H),1.65–1.53(m,4H),1.34–1.20(m,8H).UPLC-MS(ESI)理论值C 47H 63N 11O 5[M+H] +:862.50,实测值为862.76.
[C141]6-(4-(4-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基基)丁基)哌嗪-1-基)-N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-α][1,3,5]三嗪-4-基)氨基)甲基)苯基)己酰胺的制备
参照实施例2和实施例19中的合成路线，制备得C141。 1H NMR(400MHz,DMSO)δ11.01(s,1H),9.89(s,1H),7.96(s,1H),7.62–7.57(m,1H),7.53(d,J＝8.5Hz,2H),7.50–7.44(m,2H),7.26(d,J＝8.5Hz,2H),5.25–5.21(m,0.5H),5.16(dd,J＝13.3,5.1Hz,1H),5.08–4.99(m,0.5H),4.60(dd,J＝9.9,6.5Hz,2H),4.47(d,J＝17.2Hz,1H),4.31(d,J＝17.1Hz,1H),3.59–3.29(m,6H),3.22–3.08(m,4H),3.08–2.87(m,8H),2.81(dd,J＝13.4,4.5Hz,3H),2.72–2.57(m,3H),2.45–2.36(m,1H),2.34–2.24(m,3H),2.23–2.15(m,1H),2.08–1.95(m,2H),1.84–1.72(m,1H),1.69–1.51(m,8H),1.35–1.21(m,8H).UPLC-MS(ESI)理论值C 48H 65N 11O 5[M+H] +:876.52,实测值为876.73.
[C142]6-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)哌嗪-1-基)-N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-α][1,3,5]三嗪-4-基)氨基)甲基)苯基)己酰胺的制备
参照实施例2和实施例19中的合成路线，制备得C142。 1H NMR(400MHz,DMSO)δ11.00(s,1H),7.95(s,1H),7.59–7.55(m,1H),7.53(d,J＝8.5Hz,2H),7.48–7.43(m,2H),7.26(d,J＝8.5Hz,2H),5.24–5.01(m,2H),4.59(d,J＝5.7Hz,2H),4.46(d,J＝17.2Hz,1H),4.30(d,J＝17.1Hz,1H),3.52–3.24(m,8H),3.22–3.10(m,2H),3.06–2.84(m,8H),2.77(s,3H),2.68–2.57(m,3H),2.46–2.36(m,1H),2.36–2.10(m,4H),2.05–1.95(m,2H),1.89–1.77(m,1H),1.70–1.53(m,6H),1.49–1.39(m,2H),1.35–1.18(m,10H).UPLC-MS(ESI)理论值C 49H 67N 11O 5[M+H] +:890.53,实测值为890.84.
[C143]7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)-N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-α][1,3,5]三嗪-4-基)氨基)甲基)苯基)庚-6-炔酰胺的制备
参照实施例2和实施例9中的合成路线，制备得C143。 1H NMR(400MHz,DMSO)δ10.98(s,1H),9.90(s,1H),7.95(s,1H),7.70(d,J＝7.2Hz,1H),7.62(d,J＝7.2Hz,1H),7.56–7.48(m,3H),7.26(d,J＝8.5Hz,2H),5.26–5.20(m,0.5H),5.13(dd,J＝13.1,5.0Hz,1H),5.07–4.99(m, 0.5H),4.60(dd,J＝9.5,6.6Hz,2H),4.46(d,J＝17.8Hz,1H),4.31(d,J＝17.7Hz,1H),3.53–3.44(m,1H),3.38–3.29(m,1H),3.23–3.08(m,2H),2.98(dt,J＝14.2,7.0Hz,1H),2.93–2.84(m,1H),2.81(dd,J＝13.2,4.6Hz,3H),2.60–2.41(m,4H),2.35(t,J＝7.2Hz,2H),2.31–2.24(m,1H),2.22–2.14(m,1H),2.08–1.94(m,2H),1.83–1.71(m,3H),1.64–1.55(m,2H),1.26(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值C 41H 47N 9O 5[M+H] +:746.37,实测值为746.65.
[C144]8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(6-(((8-异丙基-2-((1-甲基哌-4-基)氧基)吡唑并[1,5-α][1,3,5]三嗪-4-基)氨基)甲基)吡啶-3-基)辛酰胺的制备
参照实施例2和实施例6中的合成路线，制备得C144。 1H NMR(400MHz,DMSO)δ11.10(s,1H),10.10(s,1H),8.66(s,1H),8.02–7.95(m,2H),7.83–7.77(m,1H),7.50(d,J＝8.6Hz,1H),7.43(d,J＝7.2Hz,1H),7.30(dd,J＝8.6,2.3Hz,1H),5.21–5.17(m,0.5H),5.07(dd,J＝12.7,5.3Hz,1H),5.02–4.94(m,0.5H),4.75–4.67(m,2H),4.20(t,J＝6.3Hz,2H),3.50–3.43(m,1H),3.34–3.26(m,1H),3.19–3.06(m,2H),2.99(dt,J＝13.6,6.7Hz,1H),2.92–2.76(m,4H),2.61–2.44(m,2H),2.33(t,J＝7.4Hz,2H),2.28–2.21(m,1H),2.20–2.11(m,1H),2.05–1.93(m,2H),1.80–1.69(m,3H),1.64–1.53(m,2H),1.51–1.42(m,2H),1.39–1.30(m,4H),1.27(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值C 41H 50N 10O 7[M+H] +:795.39,实测值为795.65.
[C145]6-(4-(3-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)丙-2-炔-1-基)哌嗪-1-基)-N-(4-(((8-异丙基-2-((1-甲基哌啶-4-基)氧基)吡唑并[1,5-α][1,3,5]三嗪-4-基)氨基)甲基)苯基)己酰胺的制备
参照实施例6和实施例19中的合成路线，制备得C145。 1H NMR(500MHz,DMSO)δ10.98(s,1H),9.90(s,1H),8.16(s,1H),7.92(s,1H),7.74(d,J＝7.6Hz,1H),7.69(d,J＝7.6Hz,1H),7.56–7.50(m,3H),7.25(d,J＝8.5Hz,2H),5.14(dd,J＝13.2,5.1Hz,1H),5.02–4.93(m,1H),4.58(d,J＝6.1Hz,2H),4.50(d,J＝17.7Hz,1H),4.35(d,J＝17.7Hz,1H),3.58(s,2H),3.51–3.32(m,2H),3.00–2.86(m,5H),2.69–2.54(m,9H),2.48–2.39(m,5H),2.28(t,J＝7.3Hz,2H),2.10–1.94(m,5H),1.89–1.77(m,2H),1.62–1.54(m,2H),1.53–1.43(m,2H),1.25(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值C 47H 59N 11O 5[M+H] +:858.47,实测值为858.81.
[C146]8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚-4-基)氧基)-N-(4-(((3-异丙基-5-((1-甲基哌-4-基)氨基)吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)辛酰胺的制备
参照实施例6和实施例17中的合成路线，制备得C146。 1H NMR(500MHz,DMSO)δ11.08(s,1H),9.86(s,1H),7.87–7.73(m,2H),7.54(d,J＝8.3Hz,2H),7.49(d,J＝8.5Hz,1H),7.43(d,J＝7.2Hz,1H),7.29(d,J＝7.4Hz,2H),5.32–5.16(m,1H),5.07(dd,J＝12.7,5.4Hz,1H),4.48(s,2H),4.19(t,J＝6.3Hz,2H),4.12–4.06(m,0.5H),3.92–3.82(m,1H),3.51–3.42(m,1.5H),3.35–3.28(m,0.5H),3.18–3.12(m,0.5H),3.10–2.98(m,2H),2.91–2.82(m,1H),2.80–2.72(m,3H),2.61–2.46(m,2H),2.28(t,J＝7.4Hz,2H),2.14–2.05(m,2H),2.05–1.91(m,2H),1.79–1.70(m,2H),1.68–1.52(m,3H),1.50–1.41(m,2H),1.40–1.27(m,4H),1.23(d,J＝6.8Hz,6H).UPLC-MS(ESI)理论值C 43H 53N 9O 6[M+H] +:792.41,实测值为792.62.
[C147]7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)-N-(4-(((3-异丙基-5-((1-甲基哌啶-4-基)氨基)吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)庚酰胺的制备
参照实施例9和实施例17中的合成路线，制备得C147。 1H NMR(500MHz,DMSO)δ10.98 (s,1H),9.88(s,1H),7.87(s,1H),7.59–7.51(m,3H),7.46–7.40(m,2H),7.31(d,J＝7.6Hz,2H),5.31(s,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.52(s,2H),4.45(d,J＝17.1Hz,1H),4.30(d,J＝17.1Hz,1H),4.14–4.08(m,0.5H),3.92–3.83(m,1H),3.54–3.43(m,1.5H),3.37–3.29(m,0.5H),3.20–3.13(m,0.5H),3.11–2.99(m,2H),2.96–2.87(m,1H),2.78(s,3H),2.66–2.55(m,3H),2.47–2.37(m,1H),2.28(t,J＝7.3Hz,2H),2.13–2.03(m,1H),2.03–1.93(m,2H),1.70–1.52(m,6H),1.36–1.28(m,4H),1.22(d,J＝6.7Hz,6H).UPLC-MS(ESI)理论值C 42H 53N 9O 4[M+H] +:748.42,实测值为748.85.
[C148]7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)-N-(4-(((5-(((S)-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)庚酰胺的制备
参照实施例9和实施例17中的合成路线，制备得C148。 1H NMR(500MHz,DMSO)δ10.97(s,1H),9.85(s,1H),7.94(s,1H),7.58–7.52(m,3H),7.46–7.41(m,2H),7.32(d,J＝8.0Hz,2H),5.44(s,1H),5.12(dd,J＝13.2,5.1Hz,1H),4.54(s,2H),4.45(d,J＝17.1Hz,1H),4.30(d,J＝17.1Hz,1H),3.88–3.73(m,1H),3.51–3.44(m,2H),3.07–2.98(m,1H),2.96–2.87(m,1H),2.67–2.55(m,3H),2.47–2.38(m,1H),2.27(t,J＝7.3Hz,2H),2.04–1.95(m,1H),1.65–1.52(m,5H),1.47–1.39(m,1H),1.37–1.29(m,4H),1.23(d,J＝6.9Hz,6H),0.86(t,J＝7.4Hz,3H).UPLC-MS(ESI)理论值C 40H 50N 8O 5[M+H] +:723.39,实测值为723.63.
[C149]7-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)-N-(4-(((5-(((R)-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)庚酰胺的制备
参照实施例9和实施例17中的合成路线，制备得C149。 1H NMR(500MHz,DMSO)δ10.97(s,1H),9.85(s,1H),7.94(s,1H),7.57–7.51(m,3H),7.45–7.41(m,2H),7.32(d,J＝8.0Hz,2H),5.44(s,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.54(s,2H),4.45(d,J＝17.1Hz,1H),4.30(d,J＝17.1Hz,1H),3.81–3.65(m,1H),3.52–3.44(m,2H),3.07–2.97(m,1H),2.96–2.86(m,1H),2.66–2.56(m,3H),2.43(ddd,J＝26.3,13.3,4.4Hz,1H),2.27(t,J＝7.4Hz,2H),2.04–1.96(m,1H),1.65–1.53(m,5H),1.47–1.38(m,1H),1.38–1.29(m,4H),1.23(d,J＝6.9Hz,6H),0.86(t,J＝7.4Hz,3H).UPLC-MS(ESI)理论值C 40H 50N 8O 5[M+H] +:723.39,实测值为723.59.
[C150]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((5-(((S)-1-羟基丁吡啶-2-基)氨基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C150。 1H NMR(400MHz,DMSO)δ11.02(s,1H),9.65(s,1H),8.78(s,1H),7.97(s,1H),7.61–7.58(m,1H),7.48(d,J＝4.2Hz,2H),7.42(d,J＝8.5Hz,2H),7.30(d,J＝7.9Hz,2H),5.48(s,1H),5.16(dd,J＝13.4,5.1Hz,1H),4.54(s,H),4.45(d,17.2Hz,1H),4.31(d,J＝17.2Hz,1H),4.22(d,J＝14.1Hz,2H),3.50(m,4H),3.21–3.06(m,5H),3.05–2.90(m,3H),2.93–2.87(m,1H),2.68(t,J＝7.6Hz,2H),2.62(d,17.2Hz,1H),2.45–2.35(m,1H),2.05–1.97(m,1H),1.73–1.56(m,5H),1.48–1.42(m,1H),1.40–1.29(m,2H),1.23(d,J＝6.9Hz,6H),0.88(t,J＝7.4Hz,3H).UPLC-MS(ESI)理论值C 43H 56N 10O 5[M+H] +:793.44,实测值为793.62.
[C151]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((5-(((R)-1-羟基丁吡啶-2-基)氨基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C151。 1H NMR(400MHz,DMSO)δ11.02(s,1H),9.68(s,1H),8.78(s,1H),7.97(s,1H),7.61–7.58(m,1H),7.48(d,J＝4.2Hz,2H),7.42(d,J＝8.6Hz,2H),7.30(d,J＝8.1Hz,2H),5.48(s,1H),5.16(dd,J＝13.3,5.1Hz,1H),4.54(s,2H),4.47(d,J＝17.0Hz,1H),4.31(d,J＝17.2Hz,1H),4.22(d,J＝12.7Hz,2H),3.50(m,4H),3.20–3.08(m,5H),3.03–2.95(m,3H),2.93–2.87(m,1H),2.69(t,J＝7.0Hz,2H),2.62(d,J＝17.1Hz,1H),2.45–2.27(m,1H),2.05–2.00(m,1H),1.72–1.56(m,5H),1.48–1.43(m,1H),1.36(d,J＝7.8Hz,2H),1.23(d,J＝6.9Hz,6H),0.88(t,J＝7.4Hz,3H).UPLC-MS(ESI)理论值C 43H 56N 10O 5[M+H] +:793.44,实测值为793.55.
[C152]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((3-异丙基-5-((1-甲基哌-4-基)氨基)吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C152。 1H NMR(500MHz,DMSO)δ10.99(s,1H),9.99(s,1H),9.67(s,1H),8.79(s,1H),7.76(s,1H),7.58(s,1H),7.52-7.35(m,3H),7.32-7.19(m,2H),5.14(d,J＝9.4Hz,2H),4.46(d,J＝15.5Hz,2H),4.31(d,J＝16.7Hz,1H),4.22(d,J＝12.8Hz,2H),4.07-3.64(m,7H),3.58-3.41(m,3H),3.23–2.84(m,8H),2.77(s,2H),2.71-2.57(m,3H),2.44-2.32(m,1H),2.20-2.06(m,1H),2.05-1.90(m,2H),1.77-1.55(m,5H),1.47-1.30(m,2H),1.21(s,6H).UPLC-MS(ESI)理论值C 45H 59N 11O 4[M+H] +:818.48,实测值为818.65.
[C153]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-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)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C153。 1H NMR(400MHz,DMSO)δ11.01(s,1H),9.89(s,1H),8.79(s,1H),7.97(s,1H),7.58(p,J＝3.8Hz,1H),7.47(d,J＝4.3Hz,2H),7.41(d,J＝8.6Hz,2H),7.30(d,J＝8.4Hz,2H),5.38(s,1H),5.15(dd,J＝13.3,5.1Hz,1H),4.56(s,2H),4.47(d,J＝17.2Hz,1H),4.30(d,J＝17.1Hz,1H),4.22(d,J＝13.8Hz,2H),3.91-3.81(m,3H),3.58-3.48(m,2H),3.41(t,J＝10.8Hz,2H),3.21–3.04(m,5H),3.03–2.86(m,3H),2.70-2.57(m,3H),2.47-2.33(m,1H),2.05–1.97(m,1H),1.81–1.57(m,6H),1.50–1.29(m,4H),1.21(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值C 44H 56N 10O 5[M+H] +:805.44,实测值为805.54.
[C154]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((2-(((S)-1-羟基丁吡啶-2-基)氨基)-8-异丙基吡唑并[1,5-α][1,3,5]三嗪-4-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例16和实施例17中的合成路线，制备得C154。 1H NMR(500MHz,DMSO)δ10.98(s,1H),7.67(s,1H),7.60–7.55(m,1H),7.49–7.43(m,2H),7.38(d,J＝8.5Hz,2H),7.30–7.19(m,2H),5.13(dd,J＝13.3,5.1Hz,1H),4.65–4.40(m,3H),4.31(d,J＝17.1Hz,1H),3.90–3.77(m,1H),3.54–3.21(m,12H),2.97–2.84(m,2H),2.69–2.57(m,3H),2.48–2.35(m,1H),2.07–1.97(m,1H),1.68–1.59(m,3H),1.56–1.40(m,3H),1.38–1.29(m,2H),1.28–1.15(m,6H),0.86(t,J＝7.2Hz,3H).UPLC-MS(ESI)理论值C 42H 55N 11O 5[M+H] +:794.44,实测值为794.70.
[C155]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((5-((R)-3-羟基吡咯-1-基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C155。 1H NMR(400MHz,CD 3OD)δ7.70(s,1H),7.67(dd,J＝5.3,3.3Hz,1H),7.53–7.43(m,2H),7.38(d,J＝8.8Hz,2H),7.35(d,J＝8.8Hz,2H),5.20–5.10(m,2H),4.85(s,1H)，4.58–4.45(m,4H),3.80–3.62(m,5H),3.46-3.37(m,4H), 3.15-3.04(m,1H),3.01-2.95(m,4H),2.91–2.79(m,4H),2.70(t,J＝7.5Hz,2H),2.52(m,1H),2.24–2.13(m,1H),2.03–1.85(m,2H),1.80–1.62(m,4H),1.45–1.35(m,2H),1.28(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 43H 54N 10O 5[M+H] +:791.43,实测值为791.70.
[C156]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((5-((S)-3-羟基吡咯-1-基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C156。 1H NMR(400MHz,CD 3OD)δ7.72(s,1H),7.68(dd,J＝5.3,3.3Hz,1H),7.55–7.45(m,2H),7.36(d,J＝8.8Hz,2H),7.34(d,J＝8.8Hz,2H),5.22–5.10(m,2H),4.86(s,1H)，4.58–4.44(m,4H),3.82–3.65(m,5H),3.48-3.35(m,4H),3.16-3.05(m,1H),3.03-2.96(m,4H),2.92–2.81(m,4H),2.72(t,J＝7.5Hz,2H),2.51(m,1H),2.25–2.14(m,1H),2.05–1.86(m,2H),1.82–1.64(m,4H),1.46–1.33(m,2H),1.30(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 43H 54N 10O 5[M+H] +:791.43,实测值为791.70.
[C157]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((5-((S)-2-(羟甲基)吡咯烷-1-基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C157。 1H NMR(400MHz,CD 3OD)δ7.70(s,1H),7.62(dd,J＝5.3,3.3Hz,1H),7.51–7.40(m,2H),7.35(d,J＝8.8Hz,2H),7.33(d,J＝8.8Hz,2H),5.20–5.11(m,2H),4.72(s,1H)，4.56–4.40(m,4H),3.82–3.64(m,5H),3.51-3.35(m,3H),3.19-3.08(m,1H),3.05-2.94(m,4H),2.92–2.79(m,4H),2.75(t,J＝7.5Hz,2H),2.53(m,1H),2.22–2.14(m,1H),2.02–1.80(m,4H),1.80–1.65(m,4H),1.48–1.33(m,2H),1.32(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 43H 56N 10O 5[M+H] +:805.44,实测值为805.72.
[C158]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((5-((R)-2-(羟甲基)吡咯烷-1-基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C158。 1H NMR(400MHz,CD 3OD)δ7.71(s,1H),7.61(dd,J＝5.3,3.3Hz,1H),7.52–7.42(m,2H),7.36(d,J＝8.8Hz,2H),7.35(d,J＝8.8Hz,2H),5.21–5.10(m,2H),4.73(s,1H)，4.56–4.42(m,4H),3.80–3.62(m,5H),3.53-3.32(m,3H),3.19-3.06(m,1H),3.08-2.96(m,4H),2.92–2.78(m,4H),2.76(t,J＝7.5Hz,2H),2.54(m,1H),2.24–2.14(m,1H),2.02–1.80(m,4H),1.81–1.64(m,4H),1.48–1.32(m,2H),1.35(d,J＝6.9Hz,6H).UPLC-MS(ESI)理论值为C 43H 56N 10O 5[M+H] +:805.44,实测值为805.72.
[C159]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((5-((R)-2-(2-羟乙基)哌啶-1-基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C159。 1H NMR(400MHz,CD 3OD)δ7.75(s,1H),7.70(dd,J＝5.3,3.3Hz,1H),7.55–7.40(m,2H),7.35(d,J＝8.8Hz,2H),7.32(d,J＝8.8Hz,2H),5.25–5.10(m,2H),4.75(s,1H)，4.56–4.42(m,4H),3.80–3.64(m,6H),3.52-3.33(m,4H),3.15-3.05(m,1H),3.08-2.90(m,3H),2.92–2.75(m,4H),2.73(t,J＝7.5Hz,2H),2.54(m,1H),2.24–2.10(m,1H),2.01–1.90(m,2H),1.82–1.60(m,8H),1.55–1.37(m,4H),1.33(d,J＝6.8Hz,6H).UPLC-MS(ESI)理论值为C 46H 60N 10O 5[M+H] +:833.47,实测值为833.72。
[C160]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((5-((S)-2-(2-羟乙基)哌啶-1-基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C160。 1H NMR(400MHz,CD 3OD)δ7.77 (s,1H),7.74(dd,J＝5.3,3.3Hz,1H),7.58–7.42(m,2H),7.36(d,J＝8.8Hz,2H),7.30(d,J＝8.8Hz,2H),5.21–5.12(m,2H),4.76(s,1H)，4.57–4.40(m,4H),3.85–3.60(m,6H),3.50-3.31(m,4H),3.15-3.03(m,1H),3.10-2.91(m,3H),2.95–2.72(m,4H),2.75(t,J＝7.5Hz,2H),2.57(m,1H),2.26–2.10(m,1H),2.04–1.92(m,2H),1.84–1.61(m,8H),1.58–1.36(m,4H),1.35(d,J＝6.8Hz,6H).UPLC-MS(ESI)理论值为C 46H 60N 10O 5[M+H] +:833.47,实测值为833.72。
[C161]N-(4-(((5-(((2S，3R)-1,3-二羟基丁-2-基)氨基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)甲基基)苯基)-4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C161。 1H NMR(500MHz,CD 3OD)δ7.82(s,1H),7.66(d,J＝2.1Hz,1H),7.51(s,2H),7.39(d,J＝8.7Hz,2H),7.35(d,J＝8.7Hz,2H),5.48(s,1H),5.20(dd,J＝13.2,5.0Hz,1H),4.61(m,2H),4.54(d,J＝16.9Hz,1H),4.45(d,J＝16.9Hz,1H),4.08–4.01(m,1H),3.90–3.56(m,7H),3.35-3.25(m,4H),3.15–3.04(m,2H),3.06-2.95(m,1H),2.98-2.86(m,1H),2.85-2.75(m,1H),2.76–2.72(m,2H),2.62-2.45(m,1H),2.25–2.13(m,1H),1.85-1.71(m,4H),1.55–1.42(m,2H),1.31(t,J＝3.6Hz,6H),1.21(d,J＝6.3Hz,3H).UPLC-MS(ESI)理论值为C 43H 56N 10O 6[M+H] +:809.44,实测值为809.70.
[C162]4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)-N-(4-(((3-异丙基-5-(((2S，3S)-1,3,4-三羟基丁-2-基)氨基)吡唑并[1,5-a]嘧啶-7-基)氨基)甲基)苯基)哌嗪-1-甲酰胺的制备
参照实施例17和实施例18中的合成路线，制备得C162。 1H NMR(500MHz,CD 3OD)7.75(s,1H),7.68(dd,J＝6.3,2.1Hz,1H),7.55–7.42(m,2H),7.41-7.27(m,4H),5.35(s,1H),5.16(dd,J＝13.3,5.1Hz,1H),4.60-4.41(m,4H),4.11-4.02(m,1H),3.78–3.55(m,9H),3.13–2.98(m,5H),2.98–2.83(m,3H),2.85-2.70(m,3H),2.59-2.45(m,1H),2.28–2.13(m,1H),1.82-1.65(m,4H),1.49-1.36(m,2H),1.30(dd,J＝6.9,3.5Hz,6H),UPLC-MS(ESI)理论值为C 43H 56N 10O 7[M+H] +:825.43,实测值为825.65.
[C163]2-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)哌嗪-1-基)-N-(4-(((5-(((R)-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)乙酰胺的制备
参照实施例17和实施例19中的合成路线，制备得C163。 1H NMR(400MHz,DMSO)δ10.97(s,1H),9.56(s,1H),8.60(s,1H),7.95(s,1H),7.62–7.55(m,1H),7.46(d,J＝4.2Hz,2H),7.42(d,J＝8.6Hz,2H),7.25(d,J＝8.1Hz,2H),5.50(s,1H),5.12(dd,J＝13.3,5.1Hz,1H),4.52(s,2H),4.46(d,J＝17.0Hz,1H),4.32(d,J＝17.2Hz,1H),4.21(d,J＝12.7Hz,2H),3.42(s,2H),3.30–3.05(m,9H),3.02–2.94(m,3H),2.92–2.86(m,1H),2.66(t,J＝7.0Hz,2H),2.61(d,J＝17.1Hz,1H),2.47–2.25(m,1H),2.08–2.01(m,1H),1.75–1.53(m,5H),1.50–1.42(m,1H),1.37(d,J＝7.7Hz,2H),1.25(d,J＝6.9Hz,6H),0.91(t,J＝7.3Hz,3H).UPLC-MS(ESI)理论值C 44H 58N 10O 5[M+H] +:807.46,实测值为807.73.
[C164]3-(4-(5-(2-(2,6-二氧代哌啶-3-基)-1-氧代异吲哚-4-基)戊基)哌嗪-1-基)-N-(4-(((5-(((R)-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)丙酰胺的制备
参照实施例17和实施例19中的合成路线，制备得C164。 1H NMR(400MHz,CD 3OD)δ8.28(s,1H),7.72(s,1H),7.65(dd,8.3,3.6Hz,1H),7.57(d,J＝8.3Hz,2H),7.46(d,J＝3.6Hz,2H),7.37 (d,J＝8.3Hz,2H),5.27(s,1H),5.18(dd,J＝13.3,5.1Hz,1H),4.54(s,1H),4.48(q,J＝16.5Hz,4H),3.78(s,1H),3.66(dd,J＝11.2,3.5Hz,1H),3.57(dd,J＝11.3,6.2Hz,1H),3.10–2.85(m,9H),2.81–2.65(m,9H),2.62–2.49(m,1H),2.46(t,J＝6.8Hz,2H),2.25–2.10(m,1H),1.78–1.69(m,2H),1.67–1.45(m,4H),1.39–1.31(m,2H),1.28(d,J＝6.8Hz,6H),0.96(t,J＝7.5Hz,3H).UPLC-MS(ESI)理论值C 45H 60N 10O 5[M+H] +:821.47,实测值为821.75.
实施例20：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-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1％双抗的L-15培养基，在37℃，不含CO 2的培养箱中培养MDA-MB-468细胞，使用加有20％FBS及1％双抗的DMEM/HIGH GLUCOSE培养基培养BT549，在37℃，5％CO 2的环境中生长。
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稀释的化合物加入到90μL的细胞中，然后在37℃，5％CO 2中培养者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。NT：表示未为测试。活性结果：***表述细胞活性IC 50>20μM，**表述细胞活性1μM<IC 50<20μM，*表述细胞活性IC 50<1μM。
2.实验结果
Figure PCTCN2019100969-appb-000068
Figure PCTCN2019100969-appb-000069
Figure PCTCN2019100969-appb-000070
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-468及BT549中，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降解剂。
实施例21：化合物对血液肿瘤细胞和其他实体瘤细胞的增殖生长抑制活性
实验方法同上述细胞测试方法，相关细胞活性测试结果如下表：
Figure PCTCN2019100969-appb-000071
从上表我们可以发现，本发明的化合物在血液肿瘤细胞株中，例如，弥漫大B细胞淋巴瘤细胞株(OCI-LY-10)、多发性骨髓瘤细胞株(MM.1S)、人急性淋巴细胞白血病T淋巴细胞株(CCRF-CEM)都具有较高的活性，细胞生长抑制活性IC 50<200nM。本发明的化合物分别在人前列腺癌细胞株(PC-3)和人结肠癌细胞株(HCT116)中也有较好的活性，可以作为新型的靶向CDK的降解剂，用于预防和治疗与CDK异常活性相关的疾病，如实体肿瘤和血液肿瘤。
实施例22：利用Western Blot检测化合物对CDK的降解
1.实验方法
在Western Bolt实验中，用6孔板培养细胞，用不同的药物浓度处理相应的细胞，收集细胞并用RIPA裂解液裂解细胞，取5-10μg裂解液跑SDS-PAGE，然后将蛋白转移到PVDF膜上，用相应的抗体检测目的蛋白，使用肌动蛋白actin或者微管蛋白Tubulin作为内参，以下是本论文中使用的抗体的信息：CDK1(Absin,abs132093)，CDK2(Absin,abs100510)，CDK4(CST,12790),CDK5(Absin,abs100524)，CDK9(CST,2316)，Actin(Absin,abs132001)，Tubulin(Absin,abs131993a)。
2.实验结果
从图1结果可以看到，本发明的化合物主要对CDK9有非常高的选择性且有很好的降解效果，而对CDK家族的其他蛋白没有发现有明显的降解效果。因此，本发明的化合物可以作为新型的三阴性乳腺癌细胞中靶向CDK9的降解剂。

Claims (13)

  1. 一种通式(I)所示的化合物、其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物：
    Figure PCTCN2019100969-appb-100001
    其中，
    Figure PCTCN2019100969-appb-100002
    选自以下基团：
    Figure PCTCN2019100969-appb-100003
    所述G 1、G 2、G 3各自独立地任选自–C(R b1)＝或–N＝；其中R b1选自氢、卤素和C 1-4烃基；
    Z为–CH 2–或–C(＝O)–；
    R a1为氢、氟或甲基；
    R a2为氢或甲基；
    R c1为氢或氟；
    R a3、R a4、R a5各自独立地为氢、卤素、氰基、硝基、羟基、氨基、取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基、取代或未取代的氨基、取代或未取代的C 2-6烷羰基，其中所述取代是指被如下一种或多种取代基所取代：卤素、羟基、C 1-6烷氧基、氰基、硝基、 C 1-6烷基、卤代C 1-6烷基、羟C 1-6烷基、C 3-10环烷基、含有1-3个选自N、O和S原子的3-6元杂环基；
    X为–O–、–NH–、–CH 2–、–NH–CO–、–CO–NH–、–CO–、–CH＝CH–、-C≡C-、–CO–NH–S(O) 2–、–NH–CO–NH–、–NH–CO–O–、–OCONH–、–SO 2–、––SO 2NH–、–NHSO 2–、
    Figure PCTCN2019100969-appb-100004
    或者X不存在；
    L选自–(CH 2) m1–(OCH 2CH 2) m2–、–(CH 2OCH 2) m3–、–(CH 2) m4–W1-(CH 2) m5–、–(CH 2) m4–W2-(CH 2CH 2O) m6–(CH 2) m7–，其中，W1、W2各自独立选自-O-、-CH 2-、五元杂芳环、六元杂芳环、C 3-10烷基环或3-6元杂烷基环；
    m1为0，1，2，3，4，5，6，7，8，9或10；
    m2为0，1，2，3，4，5或6；
    m3为0，1，2，3，4或5；
    m4为0，1，2，3，4或5；
    m5为0，1，2，3，4，5或6；
    m6为0，1，2，3或4；
    m7为0，1，2，3，4，5，6或7；
    Y为–CH 2–、–CH＝CH–、-C≡C-、–O–、–NR 2a–、–CO–NR 2b–、–NR 2c–CO–CH 2O–、–NR 2d–CO–CH 2NR 2e–或者Y不存在，其中–CO–NR 2b–、–NR 2c–CO–CH 2O–、–NR 2d–CO–CH 2NR 2e–与L连接的形式分别为–L–CO–NR 2b–、–L–NR 2c–CO–CH 2O–、–L–NR 2d–CO–CH 2NR 2e–；其中所述R 2a、R 2b、R 2c、R 2d、R 2e各自独立地任选自氢或者C 1-C 4烃基；
    Figure PCTCN2019100969-appb-100005
    选自C 6-12芳基、5-8元环烷基、含有1-3个选自N、O和S的杂原子的5-8元杂环基或杂芳基、5-8元环烷基并C 6-12芳基、含有1-3个选自N、O和S的杂原子的5-8元杂环基或杂芳基并C 6-12芳基；
    R 4选自氢原子、卤素、C 1-6烷氧基、氰基、氨基、硝基、C 1-6烷基、C 3-10环烷基、5-8元杂环基、C 6-10芳基、5-6元杂芳基、-NHC(O)R 5、-NHC(O)OR 6、-NR 7R 8、其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、C 1-C 6烷氧基、氰基、硝基取代基所取代；
    R 5、R 6、R 7和R 8各自独立地选自氢原子、C 1-6烷基、C 3-10环烷基、5-8元杂环基、C 6-10芳基或5-8元杂芳基，其中所述的烷基、环烷基、芳基或杂芳基任选进一步被一个或多个选 自卤素、羟基、C 1-C 6烷氧基、氰基、硝基取代基所取代；
    n为0，1，2，3，4；
    R 1为氢、氘或者CH 3；
    其中X 1-X 7各自独立地为C或者N，优选地，X 1-X 7所在的五元环并六元环与R 2、R 3和E所组成的结构选自：
    Figure PCTCN2019100969-appb-100006
    R 2为氢或者取代或未取代的C 1-8烃基，其中所述取代是指被选自如下的一种或多种取代基所取代：卤素、氰基、硝基、羟基和氨基；
    E选自–O–、–CO–NH–、–NH–CO–、–O–CH 2–、–CO–NH–CH 2–、–NR 6–、–NR 6–CH 2–、–CH 2–NR 6–、–S–、–CH(OH)–或–CH 2–；优选地E选自–O–或–NH–；
    R 3选自取代或未取代的C 1-6烷基、取代或未取代的C 1-6烷氧基、取代或未取代的氨基、取代或未取代的C 2-6烷羰基，其中所述取代是指被如下一种或多种取代基所取代：卤素、羟基、C 1-6烷氧基、氰基、硝基、C 1-6烷基、卤代C 1-6烷基、羟C 1-6烷基、C 3-10环烷基、含有1-3个选自N、O和S原子的3-8元杂环基。
  2. 如权利要求1所述的化合物以及其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物，其中通式(I)的化合物选自如下通式：
    Figure PCTCN2019100969-appb-100007
    其中，R 1、R 2、R 3、E、R 4、n、
    Figure PCTCN2019100969-appb-100008
    X、L、Y和
    Figure PCTCN2019100969-appb-100009
    的定义与权利要求1中相同。
  3. 如权利要求1所述的化合物以及其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物，其中通式(I)的化合物选自如下通式：
    Figure PCTCN2019100969-appb-100010
    其中，R 3-E所组成的基团选自以下基团：
    Figure PCTCN2019100969-appb-100011
    R 1为氢、氘或者CH 3；
    R 2为氢或者取代或未取代的C 1-C 3烷基，其中所述取代是指被选自如下的一种或多种取代基所取代：卤素、氰基、硝基、羟基和氨基；
    R 4选自氢原子、卤素、氰基、氨基、硝基、-NHC(O)CH 3、3-6元环烷基、C 1-4烷氧基、C 1-4烷基、其中所述的烷基或烷氧基任选进一步被一个或多个选自卤素、羟基、氰基、硝基的取代基所取代；
    n为0，1，2；
    Figure PCTCN2019100969-appb-100012
    选自苯基或萘环基、5-6元环烷基、含有1-3个选自N、O和S的杂原子的5-6元杂环基或5-6元杂芳基、5-6元环烷基并苯基、含有1-3个选自N、O和S的杂原子的5-8元杂环基或5-6元杂芳基并苯基；
    X、L、Y和
    Figure PCTCN2019100969-appb-100013
    的定义与权利要求1中相同。
  4. 如权利要求1所述的化合物以及其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物，其中通式(I)的化合物选自如下通式：
    Figure PCTCN2019100969-appb-100014
    R 3-E所组成的基团选自以下基团：
    Figure PCTCN2019100969-appb-100015
    R 1为氢、氘或者CH 3；
    R 2为氢或者取代或未取代的C 1-3烷基，其中所述取代是指被选自如下的一种或多种取代基所取代：卤素、氰基、硝基、羟基和氨基；
    R 4为氢原子、卤素、氰基、氨基、硝基、-NHC(O)CH 3、3-6元环烷基；
    n为0，1，2；
    Figure PCTCN2019100969-appb-100016
    选自以下基团：
    Figure PCTCN2019100969-appb-100017
    L选自–(CH 2) m1–(OCH 2CH 2) m2–、–(CH 2OCH 2) m3–、–(CH 2) m4–W1-(CH 2) m5–、–(CH 2) m4–W2-(CH 2CH 2O) m6–(CH 2) m7–；
    其中W1、W2各自独立优选自-O-、-CH 2-、
    Figure PCTCN2019100969-appb-100018
    X、Y、
    Figure PCTCN2019100969-appb-100019
    m1、m2、m3、m4、m5、m6、m7的定义与权利要求1中相同。
  5. 如权利要求1所述的化合物以及其互变异构体、对映体、非对映体、消旋体、代 谢前体、可药用的盐、酯、前药或其水合物，其中通式(I)的化合物选自如下通式：
    Figure PCTCN2019100969-appb-100020
    其中，R 1、R 2、R 3、E、X、L、Y和
    Figure PCTCN2019100969-appb-100021
    的定义与权利要求1中相同。
  6. 如权利要求1所述的化合物以及其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物，其中通式(I)的化合物选自如下通式：
    Figure PCTCN2019100969-appb-100022
    其中，R 1、R 2、R 3、E、R 4、n、
    Figure PCTCN2019100969-appb-100023
    X、L、Y、R c1、R a2、R a3和R a4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、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物，其中通式(I)的化合物选自如下通式：
    Figure PCTCN2019100969-appb-100024
    其中，R 1、R 2、R 3、E、R 4、n、
    Figure PCTCN2019100969-appb-100025
    X、L、Y和
    Figure PCTCN2019100969-appb-100026
    的定义与权利要求1中相同。
  8. 如权利要求1所述的化合物以及其互变异构体、对映体、非对映体、消旋体、代谢前体、可药用的盐、酯、前药或其水合物，其中通式(I)的化合物选自下列化合物：
    Figure PCTCN2019100969-appb-100027
    Figure PCTCN2019100969-appb-100028
    Figure PCTCN2019100969-appb-100029
    Figure PCTCN2019100969-appb-100030
    Figure PCTCN2019100969-appb-100031
    Figure PCTCN2019100969-appb-100032
    Figure PCTCN2019100969-appb-100033
    Figure PCTCN2019100969-appb-100034
    Figure PCTCN2019100969-appb-100035
    Figure PCTCN2019100969-appb-100036
    Figure PCTCN2019100969-appb-100037
    Figure PCTCN2019100969-appb-100038
  9. 一种制备通式(I)所示的化合物的方法，所述方法选自如下方法之一：合成方法一：
    Figure PCTCN2019100969-appb-100039
    其中，R 2、R 3、E、X 1、X 2和X 7的定义与权利要求1中的定义相同；
    n 1为0～12的整数；
    n 2为0～6的整数；
    步骤a:化合物1A与连接链1B通过缩合反应得到化合物1C；
    步骤b:化合物1C与1D在偶氮二甲酸二异丙酯和三苯基膦条件下反应得到1E；
    合成方法二：
    Figure PCTCN2019100969-appb-100040
    其中，R 2、R 3、E、X 1、X 2和X 7的定义与权利要求1中的定义相同；
    U为-O-或-CH 2-；
    n 3为0-9的整数，n 4为0-5的整数；
    步骤c:化合物2A与连接链2B在碘化亚铜和双三苯基膦二氯化钯条件下反应得到化合物2C；
    步骤d:化合物2C在氢气和钯碳加氢催化剂条件反应得到化合物2D；
    步骤e:化合物2D和1A通过缩合反应得到化合物2E；
    合成方法三：
    Figure PCTCN2019100969-appb-100041
    其中，R 2、R 3、E、X 1、X 2和X 7的定义与权利要求1中的定义相同；
    n 5为0-12的整数，n 6为0-6的整数；
    步骤f:连接链3A与化合物1A通过缩合反应得到化合物3B；
    步骤g:化合物3B在盐酸或三氟醋酸脱保护条件下得到化合物3C；
    步骤h:化合物3C与化合物3D通过缩合反应得到化合物3E；
    步骤i:化合物3C与化合物3F在N,N-二异丙基乙胺条件下反应得到化合物3G；
    合成方法四：
    Figure PCTCN2019100969-appb-100042
    其中，R 2、R 3、E、X 1、X 2和X 7的定义与权利要求1中的定义相同；
    Z为亚甲基或羰基；
    n 7为0-12的整数，n 8为0-6的整数；
    步骤j:化合物4A与4B在偶氮二甲酸二异丙酯和三苯基膦条件下反应得到4C；
    步骤k:化合物4C在四丁基氟化氨条件下反应得到化合物4D；
    步骤l:化合物4E在氢气和钯碳加氢催化剂条件反应得到化合物4F；
    步骤m:化合物1A与连接链4F通过缩合反应得到化合物4G；
    合成方法五：
    Figure PCTCN2019100969-appb-100043
    其中，R 2、R 3、E、X 1、X 2和X 7的定义与权利要求1中的定义相同；
    n 9为0-10的整数，n 10为0-6的整数；
    步骤n:化合物5A与连接链5B通过缩合反应得到化合物5C；
    步骤o:化合物5C在氢氧化锂条件下脱除保护基得到化合物5D；
    步骤p：化合物5D与化合物1A通过缩合反应得到化合物5E；
    合成方法六：
    Figure PCTCN2019100969-appb-100044
    其中，R 2、R 3、Ra3、Ra4、E、X 1、X 2和X 7的定义与权利要求1中的定义相同；
    n 11为0-6的整数，n 12为0-10的整数；
    步骤q:化合物6A与连接链6B通过缩合反应得到化合物6C；
    步骤r:化合物6C在氢氧化锂条件下脱除保护基得到化合物6D；
    步骤s：化合物6D与化合物1A通过缩合反应得到化合物6E；
    合成方法七：
    Figure PCTCN2019100969-appb-100045
    其中，R 2、R 3、E、X 1、X 2和X 7的定义与权利要求1中的定义相同；
    n 13为0-9的整数，n 14为0-5的整数；
    步骤u：化合物2A与连接链7A在碘化亚铜和双三苯基膦二氯化钯条件下反应得到化合物7B；
    步骤v：化合物7B在三氟乙酸条件下反应得到化合物7C；
    步骤w：化合物7C和化合物1A在2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯和N,N-二异丙基乙胺的条件下缩合得到化合物7D；
    步骤x：化合物2C在钯碳催化常压氢气条件下得到化合物7E；
    合成方法八：
    Figure PCTCN2019100969-appb-100046
    其中，R 2、R 3、E、X 1、X 2和X 7的定义与权利要求1中的定义相同；
    n 15为0-9的整数，n 16为0-5的整数；
    步骤y：化合物8A与8B在双三苯基膦二氯化钯与碘化亚铜的条件下反应得到化合物8C；
    步骤z1：化合物8C在雷尼镍催化下氢化得到化合物8D；
    步骤z2：化合物8D在咪唑和叔丁基二甲基氯硅烷的条件下反应得到化合物8E；
    步骤z3：以化合物8E与8F在碱性条件下通过亲核取代反应，制备得到化合物8G；
    步骤z4：化合物8G与R 3EH在碱性条件下通过亲核取代反应，制备得到化合物8H；
    步骤z5：化合物8H在四丁基氟化铵的条件下反应得到化合物8I；
    步骤z6：化合物8I在偶氮二甲酸二异丙酯和三苯基膦的条件下反应得到化合物8J。
  10. 一种药物组合物，其包含治疗有效量的选自权利要求1-8中任一项所述的通式(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、代谢前体、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. 权利要求1-8中任一项所述的通式(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、代谢前体、可药用的盐、酯、前药或其水合物或权利要求10所述的药物组合物作为靶向CDK降解剂的用途。
  12. 权利要求1-8中任一项所述的通式(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、代谢前体、可药用的盐、酯、前药或其水合物或权利要求10所述的药物组合物在制备用于预防和/或治疗与CDK的异常活性相关的疾病或者症状的药物中的用途。
  13. 如权利要求12所述的用途，其特征在于，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、非小细胞肺癌的实体肿瘤，以及急性淋巴细胞白血病、急性淋巴球白血病、B细胞淋巴瘤、T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的血液肿瘤。
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