WO2023169438A1 - 一类含氮杂环类细胞周期抑制剂化合物、制备方法和用途 - Google Patents

一类含氮杂环类细胞周期抑制剂化合物、制备方法和用途 Download PDF

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WO2023169438A1
WO2023169438A1 PCT/CN2023/080156 CN2023080156W WO2023169438A1 WO 2023169438 A1 WO2023169438 A1 WO 2023169438A1 CN 2023080156 W CN2023080156 W CN 2023080156W WO 2023169438 A1 WO2023169438 A1 WO 2023169438A1
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alkyl
compound
substituted
membered
independently selected
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French (fr)
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万惠新
王亚周
马金贵
查传涛
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上海凌达生物医药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry and discloses a class of nitrogen-containing heterocyclic cell cycle inhibitor compounds, their pharmaceutical compositions and uses.
  • Cyclin-dependent kinase is a type of serine/threonine kinase that plays a central role in the cell cycle and dominates the initiation, progression and progression of the cell cycle. Finish.
  • the CDK family is an important signal transduction molecule in cells. The CDK-cyclin complex formed by it and cyclin is involved in cell growth, proliferation, dormancy and apoptosis.
  • CDK kinases for tumor treatment has received widespread attention, such as Flavopiridol (Alvocidib), Seliciclib (CYC202), Dinaciclib (SCH727965) and Milciclib (PHA-848125), etc.
  • the clinical application of CDK inhibitors discovered early has limited inhibitory activity against various CDK family subtypes, lacks certain selectivity, or is poorly absorbed in the body.
  • due to the improvement of the selectivity of CDK inhibitors for various CDK family subtypes or the improvement of the inhibitory activity of CDK kinases, especially the discovery of selective inhibitors targeting CDK4/6 has been accelerated. Become a hot topic again.
  • CDK7 kinase of the CDK family has dual functions of regulating kinase and transcription: 1) In the cytoplasm, CDK7 exists in the form of a heterotrimeric complex and acts as an activating kinase (CAK) of CDK1/2, thereby Phosphorylation of conserved residues in CDK1/2 by CDK7 is required for full catalytic CDK activity and cell cycle progression; 2) In the nucleus, CDK7 forms the RNA polymerase (RNAP) II general transcription factor complex The kinase core is also responsible for phosphorylating the C-terminal domain (CTD) of RNAP II, a necessary step in the initiation of gene transcription.
  • CAK activating kinase
  • CTD C-terminal domain
  • CDK7 The two functions of CDK7, CAK and CTD phosphorylation, support key aspects of cell proliferation, cell cycle, and transcription. Studies have shown that CDK7 kinase plays a very important role in the regulation of triple-negative breast cancer, and inhibiting CDK7 kinase has a significant killing effect on the growth of triple-negative breast cancer cells.
  • CDK kinase inhibitor drugs Although significant progress has been made in the development of CDK kinase inhibitor drugs, there are still some unresolved problems, such as resistance to existing CDK kinase inhibitor drugs and subtypes of CDK kinase family targets. Selectivity, etc. Therefore, there is an urgent need in this field to research and develop new CDK kinase inhibitors with high efficiency, low toxicity, resistance to drug resistance, and clinical application value, such as specific CDK7 kinase inhibitors.
  • One of the technical problems to be solved by the present invention is to provide a new type of CDK7 inhibitor for preparing tumor treatment drugs.
  • the present invention provides nitrogen-containing heterocyclic compounds represented by general formula I, or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, and torsion isomers thereof. Conform, solvate, polymorph or prodrug,
  • W, X and M are each independently selected from CR w or N;
  • R w is independently selected from H, deuterium, halogen, cyano, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl;
  • Y and Z are independently selected from C or N;
  • R 2 is independently selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl or 3-6 membered heterocycloalkyl; R 2 may be further substituted by one or more R 2-1 independently selected from deuterium, halogen, hydroxyl, C 1 -C 3 alkyl , C 1 -C 3 haloalkyl;
  • R 3 is independently selected from acryloyl, substituted acryloyl, propynyl, substituted propynyl, vinylsulfonyl, substituted vinylsulfonyl or cyano; "substituted" in R 3 means further being substituted by one or Substituted with multiple R 3-1 , the R 3-1 is independently selected from: halogen, deuterium, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3- 6-membered cycloalkyl, 3-6-membered heterocycloalkyl, 3-6-membered heterocycloalkyl-substituted C 1 -C 3 alkyl, amino-substituted C 1 -C 3 alkyl, mono-C 1 -C 3 Alkyl substituted amino-C 1 -C 3 alkyl or bis C 1 -C 3 alkyl substituted amino - C 1 -C 3 alkyl; alternative
  • R 4 and R 5 are independently selected from hydrogen, deuterium, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, hydroxyl, amino, substituted amino or C 1 -C 3 alkoxy; said The substituents in the substituted amino group are 1-3, independently selected from: C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl. ;
  • R a and R b are independently selected from hydrogen, deuterium, halogen, and C 1 -C 3 alkyl; or R a and R b form a 3-6 membered saturated carbocyclic ring through a carbon chain, preferably cyclopropane or cyclobutane;
  • Ring A and Ring B are respectively selected from 4-10 membered nitrogen-containing heterocycles, preferably 5-6 membered nitrogen-containing heterocycles;
  • n is independently selected from an integer from 0 to 3;
  • alkyl, substituted alkyl or alkenyl groups may be substituted by substituents, and the substituents are independently selected from the following group: including but not limited to deuterium, halogen, hydroxyl, monoalkylamino, dialkylamino, C 1 -C 6 alkyl or haloalkyl, 3-10 membered cycloalkyl or heterocycloalkyl, cyano, C 1 -C 6 alkoxy or haloalkoxy;
  • the heterocycle contains 1-3 heteroatoms selected from the following group: N, O, P, S or Se
  • the heterocycloalkyl group contains 1-3 heteroatoms selected from the following group: N, O, P or S
  • the ring system includes saturated or partially unsaturated ring systems such as spiro ring, bridged ring, fused ring, and fused ring.
  • the nitrogen-containing heterocyclic compound represented by general formula I or a pharmaceutically acceptable salt thereof, or its enantiomers, diastereomers, tautomers, torsomers, solvates, polymorphs or prodrugs,
  • W, X and M are each independently selected from CR w or N;
  • R w is independently selected from H, halogen, cyano, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl;
  • Y and Z are selected from C or N respectively;
  • R 1 is independently selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl, 3-6 membered heterocycloalkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkoxy, 3-6-membered cycloalkyl-O-, 3-6-membered heterocycloalkyl-O-, C 1 -C 10 alkyl-NH- , C 1 -C 10 haloalkyl-NH-, 3-6-membered cycloalkyl-NH- or 3-6-membered heterocycloalkyl-NH-; the above alkyl, cycloalkyl, heterocycloalkyl can be replaced by one Or substituted by several R 1-1 , R 1-1 is independently selected from: halogen, deuterium, hydroxyl, amino, substituted amino, C 1 -C 6 alkyl,
  • R 2 is independently selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
  • R 3 is independently selected from acryloyl or substituted acryloyl, propynyl, vinylsulfonyl or substituted vinylsulfonyl, cyano, etc.; R 3 may be further substituted by one or more R 3-1 , R 3-1 is independently selected from: halogen, deuterium, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6 membered cycloalkyl, 3-6 membered hetero Cycloalkyl-substituted C 1 -C 3 alkyl, amino-substituted C 1 -C 3 alkyl, mono-C 1 -C 3 alkyl substituted amino-C 1 -C 3 alkyl or bis C 1 -C 3 alkyl A substituted amino-C 1 -C 3 alkyl group; alternatively, two R 3-1 together with the attached carbon atom form a 3-8 membered carbocyclic ring or a 3-8 member
  • R 4 and R 5 are independently selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, hydroxyl, amino, substituted amino, C 1 -C 3 alkyl Oxygen group; the substituents in the substituted amino group are 1-3, independently selected from: C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6 membered cycloalkyl or 3-6 One-membered heterocycloalkyl;
  • R a and R b are independently selected from hydrogen, halogen, and C 1 -C 3 alkyl; or R a and R b form a 3-6 membered saturated carbocyclic ring through a carbon chain, preferably cyclopropane or cyclobutane;
  • Ring A and Ring B are respectively selected from 4-10 membered nitrogen-containing heterocycles, preferably 5-6 membered nitrogen-containing heterocycles;
  • n is independently selected from an integer from 0 to 3;
  • alkyl or substituted alkyl and alkenyl groups can be substituted by substituents, and the substituents are independently selected from the following group: including but not limited to deuterium, halogen, hydroxyl, monoalkylamino, dialkylamino, C1 -C6 alkyl or haloalkyl, 3-10 membered cycloalkyl or heterocycloalkyl, cyano group, C 1 -C 6 alkoxy or haloalkoxy; wherein, the heteroaryl group contains 1-3 The heteroatom selected from the following group: N, O, P or S, the heterocycloalkyl group contains 1-3 heteroatoms selected from the following group: N, O, P or S, the ring system includes Saturated or partially unsaturated ring systems such as spiro ring, bridged ring, fused ring, and fused ring.
  • the nitrogen-containing heterocyclic compound represented by general formula I or a pharmaceutically acceptable salt thereof, or its enantiomers, diastereomers,
  • Certain groups in tautomers, torsion isomers, solvates, polymorphs or prodrugs are defined below, and unmentioned groups are the same as described in any aspect of the present invention (referred to as "in some preferred "In implementation"),
  • W, X and M are each independently selected from CR w or N;
  • R w is independently selected from H, halogen, cyano, C 1 -C 3 alkyl or C 1 -C 3 alkyl haloalkyl;
  • Y and Z are selected from C or N respectively;
  • R 1 is independently selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl, 3-6 membered heterocycloalkyl, C 1 -C 10 alkoxy, C 1 -C 10 haloalkoxy, 3-6-membered cycloalkyl-O-, 3-6-membered heterocycloalkyl-O-, C 1 -C 10 alkyl-NH- , C 1 -C 10 haloalkyl-NH-, 3-6-membered cycloalkyl-NH- or 3-6-membered heterocycloalkyl-NH-; the above alkyl, cycloalkyl, heterocycloalkyl can be replaced by one Or substituted by several R 1-1 , R 1-1 is independently selected from: halogen, deuterium, hydroxyl, amino, substituted amino, C 1 -C 6 alkyl,
  • R 2 is independently selected from C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered halocycloalkyl or 3-6 membered heterocycloalkyl; R 2 may be further substituted by one or more R 2-1 , which R 2-1 is independently selected from halogen, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl;
  • R 3 is independently selected from acryloyl or substituted acryloyl, propynyl, vinylsulfonyl or substituted vinylsulfonyl, cyano, etc.; R 3 may be further substituted by one or more R 3-1 independently selected from: halogen, deuterium, hydroxyl , cyano, amino, C 1 -C 6 alkyl , C 1 -C 6 -alkoxy, 3-6-membered cycloalkyl, 3-6-membered heterocycloalkyl-substituted C 1 -C 3 alkyl, amino-substituted C 1 -C 3 alkyl, mono-C 1 -C 3 alkyl Substituted amino-C 1 -C 3 alkyl or bis C 1 -C 3 alkyl substituted amino-C 1 -C 3 alkyl; alternatively, two R 3-1 together with the attached carbon atom form a 3-8 member Carbocyclic ring or 3-8 membered
  • R 4 and R 5 are independently selected from hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, hydroxyl, amino, substituted amino, C 1 -C 3 alkoxy; the substituted amino
  • the substituents in are 1-3, independently selected from: C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl;
  • R a and R b are independently selected from hydrogen, halogen, and C 1 -C 3 alkyl; or R a and R b form a 3-6 membered saturated carbocyclic ring through a carbon chain, preferably cyclopropane or cyclobutane;
  • Ring A and Ring B are respectively selected from 4-10 membered nitrogen-containing heterocycles, preferably 5-6 membered nitrogen-containing heterocycles;
  • n is independently selected from an integer from 0 to 3;
  • alkyl or substituted alkyl and alkenyl groups can be substituted by substituents, and the substituents are independently selected from the following group: including but not limited to deuterium, halogen, hydroxyl, monoalkylamino, dialkylamino, C 1 -C 6 alkyl or haloalkyl, 3-10 membered cycloalkyl or heterocycloalkyl, cyano, C 1 -C 6 alkoxy or haloalkoxy; wherein, the heteroaryl group includes 1- 3 heteroatoms selected from the following group: N, O, P or S, the heterocycloalkyl group contains 1-3 heteroatoms selected from the following group: N, O, P or S, the ring
  • the system includes saturated or partially unsaturated ring systems such as spiro rings, bridged rings, fused rings, and fused rings.
  • R 2 is methyl, ethyl, isopropyl, or cyclopropyl
  • R 3 is
  • R a and R b are preferably hydrogen or methyl
  • R 4 is hydrogen, halogen, hydroxyl, or methyl
  • R 5 is hydrogen, hydroxyl, halogen, or methyl
  • Ring A is preferably The * terminal is connected to -NH-; the N terminal is connected to -(CH 2 ) n- terminal;
  • Ring B is preferably The N terminal is connected to R 3 , and the * terminal is connected to -(CH 2 )n-terminal;
  • the configuration of the carbon atom connected to the carbon chain in ring B is preferably the R configuration.
  • the nitrogen-containing heterocyclic compounds represented by general formula I are compounds represented by general formulas (VI-1)-(VI-9),
  • R 1 is preferably from halogen, C 1 -C 3 alkyl Or haloalkyl, C 3 -C 6 cycloalkyl or halocycloalkyl;
  • R 3 is selected from the following groups: etc.;
  • R c , R d , Re , R f , R g , Rh , R k , R m are independently selected from hydrogen, deuterium , halogen, C 1 -C 6 alkyl, cyano; or any two of the above Adjacent groups can form a 3-8-membered carbocyclic ring or a 3-8-membered heterocyclic ring through carbon chains or heteroatoms; the scope of other groups is as defined above.
  • R 3 is selected from the following groups: R c , R d , Re , R f , R g , Rh , R k , R m are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 alkyl , or cyano group; or any two of the above Adjacent groups can form a 3-8-membered carbocyclic ring or a 3-8-membered heterocyclic ring through carbon chains or heteroatoms.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof, or its enantiomers, diastereomers, tautomers, torsion isomers, Solvates, polymorphs or prodrugs are compounds represented by general formulas (V-1)-(V-2):
  • R 1 is preferably selected from halogen, C 1 -C 3 alkyl or haloalkyl, C 3 -C 6 cycloalkyl or halocycloalkyl;
  • R 3 is selected from the following groups: etc.;
  • R c , R d , Re , R f , R g , Rh , R k , R m are independently selected from hydrogen, deuterium , halogen, C 1 -C 6 alkyl, cyano; or any two of the above Adjacent groups can form a 3-8-membered carbocyclic ring or a 3-8-membered heterocyclic ring through carbon chains or heteroatoms; the scope of other groups is as defined above.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof, or its enantiomers, diastereomers, tautomers, torsion isomers, Solvates, polymorphs or prodrugs are compounds represented by general formulas (V-1)-(V-2):
  • R 3 is selected from the following groups: R c , R d , Re , R f , R g , Rh , R k , R m are independently selected from hydrogen, deuterium, halogen, C 1 -C 6 alkyl , cyano; or any two of the above phases Neighboring groups can form a 3-8-membered carbocyclic ring or a 3-8-membered heterocyclic ring through carbon chains or heteroatoms.
  • the C 2 -C 6 alkenyl group may be a C 2 -C 4 alkenyl group; preferably vinyl or propenyl.
  • C 2 -C 6 alkynyl may be C 2 -C 4 alkynyl, preferably
  • the C 1 -C 3 alkyl group may be methyl, ethyl, n-propyl or isopropyl.
  • C 1 -C 6 alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl or tert-butyl ; Preferably isopropyl or tert-butyl.
  • the halogen in the C 1 -C 3 haloalkyl group is preferably fluorine, chlorine, bromine or iodine; the C 1 -C 3 haloalkyl group is preferably C 1 -C 3 fluoroalkyl.
  • the 3-6 membered cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexenyl or cyclohexyl; preferably cyclopropyl.
  • the halogen may be fluorine, chlorine, bromine or iodine; fluorine is preferred.
  • the 3-6 membered heterocycloalkyl group can be
  • the 4-10 membered nitrogen-containing heterocycle can be any organic compound.
  • the 4-10 membered nitrogen-containing heterocycle can be any organic compound.
  • Rw is independently selected from H.
  • the number of R 1-1 is 1, 2 or 3; R 1-1 is independently selected from halogen or hydroxyl; preferably it is hydroxyl.
  • R 2 may be C 1 -C 3 alkyl; preferably isopropyl.
  • R 3 can be acryloyl, substituted acryloyl, propiloyl, substituted propiloyl or vinylsulfonyl.
  • R 3-1 is independently selected from: halogen, cyano, C 1 -C 6 alkyl, 3-6 membered heterocycloalkyl substituted C 1 -C 3 alkyl, mono-C Amino -C 1 -C 3 alkyl is substituted by 1 -C 3 alkyl or amino-C 1 -C 3 alkyl is substituted by bis C 1 -C 3 alkyl.
  • R 3 may be acryloyl, substituted acryloyl, propiloyl, substituted propiloyl, or vinylsulfonyl; substituted acryloyl is represented by one or more R 3-1 Substituted, the R 3-1 is independently selected from: halogen, cyano, C 1 -C 6 alkyl, 3-6 membered heterocycloalkyl substituted C 1 -C 3 alkyl, single C 1 -C 3 Alkyl substituted amino-C 1 -C 3 alkyl or bis C 1 -C 3 alkyl substituted amino-C 1 -C 3 alkyl.
  • R 4 may be halogen, hydroxyl or C 1 -C 3 alkyl.
  • R 5 may be halogen, hydroxyl or C 1 -C 3 alkyl.
  • R a , R b are independently selected from hydrogen or C 1 -C 3 alkyl.
  • Ring A can be The * terminal is connected to -NH-; the N terminal is connected to end connected.
  • Ring B can be The N terminal is connected to R 3 , and the * terminal is connected to end connected.
  • the configuration of the carbon atoms connected to the carbon chain in ring B is preferably the R configuration.
  • R2 may be methyl, ethyl, isopropyl or cyclopropyl; isopropyl is preferred.
  • R 3 can be
  • the nitrogen-containing heterocyclic compound represented by general formula I has any of the following structures:
  • a method for preparing a compound of formula I characterized in that the compound of general formula (A) undergoes steps a-c to generate a compound of general formula (I):
  • Pg is a protective group on the amino group, such as tert-butyl carbonate, benzyl carbonate, benzyl, etc.
  • the definitions of each group shown are as above;
  • the reaction is carried out in a solvent
  • the solvent is selected from the following group: water, methanol, ethanol, isopropyl alcohol, butanol, ethylene glycol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethylpyrrolidone, Methyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or its composition.
  • the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, carbonic acid Potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, or a combination thereof;
  • the organic base is selected from the following group: pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] Undec-7-ene (DBU), lithium hexamethyldisilyl, sodium hexamethyldisilyl, lutidine, or combinations thereof.
  • the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, trifluoromethanesulfonic acid or combinations thereof.
  • Another object of the present invention is to provide a drug and a composition thereof for treating or preventing tumors or autoimmune diseases.
  • the technical solutions to achieve the above objectives are as follows:
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I, its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, or prodrugs, and Pharmaceutically acceptable carrier.
  • the pharmaceutical compositions are formulated for intravenous, intramuscular, oral, rectal, inhaled, nasal, topical, ocular, or otic administration.
  • the pharmaceutical composition is a tablet, pill, capsule, liquid, inhalant, nasal spray solution, suppository, solution, emulsion, ointment, eye drop, or ear drop agent.
  • they further comprise one or more additional therapeutic agents.
  • the present invention provides compounds of formula I, their stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, or prodrugs for use in the preparation of preventing, treating, or alleviating symptoms caused by Use of CDK kinases, especially CDK7 kinases, in drugs for disorders or diseases mediated by abnormal activity of CDK7 kinases.
  • the present invention provides the use of substance Z in the preparation of a medicament for preventing, treating, or alleviating disorders or diseases mediated by abnormal activity of CDK kinase;
  • the CDK kinase is preferably CDK7 kinase
  • the substance Z is a compound of formula I, its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, or prodrug, or a pharmaceutical composition as described above.
  • the nitrogen-containing heterocyclic compound represented by the general formula (I) provided by the present invention or a pharmaceutically acceptable salt thereof, or an enantiomer, a diastereoisomer, or an interaction thereof Isomers, torsomers, solvates, polymorphs or prodrugs or pharmaceutical compositions as described above are used to prepare for the treatment or prevention of proliferative diseases (e.g., cancer (e.g., leukemia, Methods involving the compounds or compositions (melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases and autoimmune diseases), said tumors being independently selected from non- Small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, bile duct cancer, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell Cancer
  • the present invention provides the use of substance Z in the preparation of medicines for treating or preventing proliferative diseases
  • the proliferative diseases can be cancer (for example, leukemia, melanoma, multiple myeloma), benign Neoplasia, angiogenesis, inflammatory disease, infectious disease, autoinflammatory disease or autoimmune disease
  • the cancer is independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer , prostate cancer, liver cancer, skin cancer, stomach cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, Nasopharyngeal cancer or pancreatic cancer
  • the autoimmune disease is independently selected from rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopen
  • the substance Z is a nitrogen-containing heterocyclic compound represented by general formula (I), or a pharmaceutically acceptable salt thereof, or its enantiomers, diastereomers, tautomers, torsion isomers, solvates, polymorphs or prodrugs or pharmaceutical compositions as described above.
  • the present invention provides a method for treating or preventing disorders or diseases mediated by abnormal activity of CDK kinase, which includes administering a therapeutically effective amount of substance Z as described above to a patient in need thereof;
  • the CDK kinase is preferably CDK7 kinase
  • the substance Z is a nitrogen-containing heterocyclic compound represented by general formula (I), or a pharmaceutically acceptable salt thereof, or its enantiomers, diastereomers, tautomers, torsion isomers, solvates, polymorphs or prodrugs or pharmaceutical compositions as described above.
  • the manufacturer's instructions for using the kit can be used, or the reaction and purification can be carried out in accordance with methods known in the art or the instructions of the present invention.
  • the above techniques and methods can generally be implemented in accordance with conventional methods well known in the art, as described in the various general and more specific documents cited and discussed in this specification.
  • groups and their substituents can be selected by those skilled in the art to provide a stable structure. parts and compounds.
  • substituents When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes substituents that are chemically equivalent when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.
  • C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified notation does not include carbons that may be present in substituents of the group in question.
  • halogen refers to fluorine, chlorine, bromine or iodine
  • hydroxy refers to the -OH group
  • hydroxyalkyl refers to an alkyl group as defined below substituted by a hydroxyl group (-OH) group
  • nitro refers to -NO 2
  • cyano refers to -CN
  • amino refers to -NH 2
  • substituted amino Refers to an amino group substituted by one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamino, aralkyl amino group, heteroaralkyl amino group
  • carbboxyl group refers to -COOH.
  • alkyl as a group or part of another group (for example, in a group such as a halogen-substituted alkyl group) means a group consisting only of carbon atoms and hydrogen atoms, without unsaturation.
  • Bond a straight or branched hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and connected to the rest of the molecule by a single bond.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc.
  • alkenyl as a group or part of another group, means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10 (more preferably 2 to 6) carbon atoms and a linear or branched hydrocarbon chain group connected to the rest of the molecule through a single bond, such as but not limited to vinyl, propenyl, allyl, but- 1-alkenyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.
  • alkynyl as a group or part of another group, means consisting exclusively of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having e.g. A straight or branched hydrocarbon chain group of 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by a single bond, such as but not limited to ethynyl , prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, etc.
  • cycloalkyl as a group or part of another group, means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, which may include fused Ring systems, bridged ring systems or spiro ring systems having, for example, 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and which are saturated or unsaturated and can be The appropriate carbon atom is connected to the rest of the molecule by a single bond. Unless otherwise specifically stated in this specification, the carbon atoms in the cycloalkyl group may optionally be oxidized.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-Dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10 -Hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]hept
  • heterocyclyl as a group or part of another group, means from 2 to 14 carbon atoms and from 1 to 6 heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen, sulfur and selenium. It consists of stable 3- to 20-membered non-aromatic cyclic groups.
  • the heterocyclyl group may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, which may include a fused ring system, a bridged ring system or a spirocyclic ring system; in its heterocyclic group
  • the nitrogen, carbon, or sulfur atoms may be optionally oxidized; the nitrogen atoms may be optionally quaternized; and the heterocyclyl may be partially or fully saturated.
  • Heterocyclyl groups can be connected to the rest of the molecule via a carbon atom or a heteroatom and by a single bond.
  • heterocyclyl groups containing fused rings one or more of the rings may be an aryl or heteroaryl group as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom.
  • heterocyclyl is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. group, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclyl examples include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonanyl Alk-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza cyclobutanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuryl, oxazinyl, dioxopentyl, tetrahydroisoquinolyl, decahydroisoquinolyl, imidazolinyl, Imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolyl
  • aryl as a group or part of another group means a conjugated hydrocarbon ring system group having from 6 to 18 carbon atoms, preferably from 6 to 10 carbon atoms.
  • an aryl group may be a monocyclic, bicyclic, tricyclic or multicyclic ring system and may also be fused to a cycloalkyl or heterocyclyl group as defined above, provided that the aryl group is via The atoms in the aromatic ring are connected to the rest of the molecule through single bonds.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-Benzoxazine-3(4H)-one-7-yl, etc.
  • arylalkyl refers to an alkyl group as defined above substituted by an aryl group as defined above.
  • heteroaryl as a group or part of another group means a ring having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 nitrogen atoms in the ring.
  • 5- to 16-membered conjugated ring system groups of heteroatoms of oxygen and sulfur Unless otherwise specified in this specification, a heteroaryl group can be a monocyclic, bicyclic, tricyclic or multicyclic ring system, and can also be condensed with a cycloalkyl or heterocyclyl group as defined above, provided that the heteroaryl group The aryl group is connected to the rest of the molecule by a single bond via an atom on the aromatic ring.
  • a nitrogen, carbon, or sulfur atom in a heteroaryl group may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • a heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 5- to 12-membered aromatic group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • a stable 5- to 10-membered aromatic group composed of heteroatoms of nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolinyl, isoindolyl, indazolyl, isoindazolyl , purinyl, quinolyl, Isoquinolinyl, diazonaphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl,
  • heteroarylalkyl refers to an alkyl group as defined above substituted by a heteroaryl group as defined above.
  • optional or “optionally” means that the subsequently described event or condition may or may not occur, and that the description includes both instances in which the event or condition does and does not occur.
  • optionally substituted aryl means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.
  • moiety refers to a specific fragment or functional group in a molecule.
  • chemical moieties are generally thought of as chemical entities embedded in or attached to a molecule.
  • Steps are compounds that are composed of the same atoms, bonded by the same bonds, but have different three-dimensional structures.
  • the present invention will cover various stereoisomers and mixtures thereof.
  • Tautomers are isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be included within the scope of the invention.
  • the compounds of the present invention may contain one or more chiral carbon atoms, and thus may give rise to enantiomeric, diastereomeric and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as racemic and optically pure forms thereof.
  • racemates, diastereomers or enantiomers can be selected as raw materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as crystallization and chiral chromatography.
  • pharmaceutically acceptable salts includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salts” refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include but are not limited to hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, etc.; organic acid salts include but are not limited to formates, acetates, and 2,2-dichloroacetates.
  • “Pharmaceutically acceptable base addition salts” refer to salts formed with inorganic or organic bases that can maintain the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following salts: primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperazine Biridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclo
  • Polymorph refers to the different solid crystal phases produced by the presence of two or more different molecular arrangements in the solid state of certain compounds of the present invention. Certain compounds of the present invention may exist in more than one crystalline form, and the present invention is intended to include each crystalline form and mixtures thereof.
  • solvate refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more molecules of a solvent.
  • the solvent may be water, in which case the solvate is a hydrate.
  • the solvent may be an organic solvent.
  • the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., as well as the corresponding solvated forms.
  • the compounds of the present invention can form true solvates, but in some cases, they can also remain only as adventitious water or as a mixture of water plus part of an adventitious solvent.
  • the compounds of the invention can be reacted in a solvent or precipitated or crystallized from the solvent. Solvates of the compounds of the invention are also included within the scope of the invention.
  • the present invention also includes prodrugs of the above compounds.
  • the term “prodrug” means a compound that can be converted into a bioactive compound of the invention under physiological conditions or by solvolysis.
  • the term “prodrug” refers to a pharmaceutically acceptable metabolic precursor of a compound of the invention.
  • the prodrug may be inactive when administered to an individual in need thereof, but is converted in the body to the active compound of the invention.
  • Prodrugs are typically rapidly converted in vivo to yield the parent compound of the invention, for example by hydrolysis in the blood.
  • Prodrug compounds often provide solubility, histocompatibility, or sustained release advantages in mammalian organisms.
  • Prodrugs include known amino and carboxyl protecting groups.
  • prodrug preparation methods please refer to Saulnier, M.G., et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, R. B., et al., J. Med. Chem. 2000, 43, 475.
  • pharmaceutical composition refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal, such as a human.
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of pharmaceutical compositions is to facilitate administration to organisms and facilitate the absorption of active ingredients to exert biological activity.
  • the term "pharmaceutically acceptable” refers to a material (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the invention and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesirable biological effects. React or react in an undesirable way with the composition any components contained interact with each other.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory authorities as acceptable for human or livestock use , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • the "tumors” and “diseases related to abnormal cell proliferation” mentioned in the present invention include but are not limited to leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.
  • prophylactic As used herein, the terms “prophylactic,” “prevention,” and “preventing” include reducing the likelihood of the occurrence or progression of a disease or condition in a patient.
  • treatment and other similar synonyms include the following meanings:
  • an "effective amount” for treatment is the amount of a composition containing a compound disclosed herein that is required to provide clinically significant relief of a condition.
  • the effective amount appropriate in any individual case can be determined using techniques such as dose escalation testing.
  • administering refers to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral route, transduodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
  • drug combination refers to drug treatments obtained by mixing or combining more than one active ingredient, They include fixed and non-fixed combinations of active ingredients.
  • fixed combination refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or a single dosage form.
  • variable combination means that at least one compound described herein and at least one synergistic formulation are administered to a patient simultaneously, jointly, or sequentially at variable intervals as separate entities. These also apply to cocktail therapies, such as the administration of three or more active ingredients.
  • the functional groups of the intermediate compounds may need to be protected by appropriate protecting groups.
  • Such functional groups include hydroxyl, amino, thiol and carboxylic acid.
  • Suitable hydroxyl protecting groups include trialkylsilyl or diaryl Alkylsilyl (such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, etc.
  • Suitable protecting groups for amino, amidino and guanidine groups include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable thiol protecting groups include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like.
  • Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is detailed in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organic Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymer resin.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the present invention relates to a new compound with the structural characteristics of general formula (I), which selectively inhibits the enzymatic activity of CDK7 and significantly inhibits the growth of various tumor cells. It is a new type of therapeutic drug with a new mechanism of action.
  • the experimental instrument description (for example, 1 H NMR was recorded by Varian Mercury-300 or Varian Mercury-400 nuclear magnetic resonance instrument, 13 C NMR was recorded by Varian Mercury-400, Varian Mercury-500 or Varian Mercury-600 nuclear magnetic resonance instrument).
  • the resonance instrument records, and the chemical shift is expressed in ⁇ (ppm); the mass spectrum is recorded by Finnigan/MAT-95 (EI) and Finnigan LCQ/DECA and Micromass Ultra Q-TOF (ESI) mass spectrometers; the silica gel used for reversed-phase preparative HPLC separation is 200-300 mesh).
  • iPrOH isopropyl alcohol; EtOH: ethanol; DCM: dichloromethane; TFA: trifluoroacetic acid; MeOH: methanol; NaOH: sodium hydroxide; HCl: hydrogen chloride; TEA: triethylamine; Raney Ni: Raney nickel; 1 ,4-dioxane: 1,4-dioxane; NaH: sodium hydride; H 2 O: water; Pd/C: palladium/carbon; H 2 : hydrogen; HATU: 2-(7-benzotriazine oxide Azole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DMF: N,N-dimethylformamide; THF: tetrahydrofuran; Boc 2 O: di-tert-butyl dicarbonate; NBS : N-bromosuccinimide; NCS: N-chlorosuccinimide; NIS: N-io
  • Fumaronitrile fumaronitrile; P(nBu) 3 : tri-n-butylphosphine; LDA: lithium diisopropylamide; LiOH: lithium hydroxide; MeI: methyl iodide; EtI: ethyl iodide; (CH 2 O) n : Paraformaldehyde; HCO 2 H: formic acid; CH 3 COCl: acetyl chloride; LCMS: liquid chromatography mass spectrometry; Xantphos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene ; TLC: thin layer chromatography; eq.: equivalent; DCE: 1,2-dichloroethane; HEPES: 4-hydroxyethylpiperazineethanesulfonic acid; EGTA: ethylene glycol bis(2-aminoethyl ether) )tetraacetic acid; DTT: dithiothreitol
  • Step 1 Dissolve intermediate A (490mg, 2.02mmol), 4-aminopiperidine-1-formyl tert-butyl ester (421mg, 2.12mmol) and DIEA (800mg, 6.21mmol) in acetonitrile ( 50 mL), react at 70°C for 4 hours.
  • Step 2 Add m-chloroperoxybenzoic acid (596 mg, 3.48 mmol) to the above intermediate product (700 mg, 1.72 mmol) in dichloromethane (50 mL) under ice-water bath cooling. The reaction mixture was stirred at room temperature for 2 hours. LC-MS detection showed that the raw materials basically disappeared. The reaction mixture was washed twice with saturated aqueous sodium bicarbonate solution (30 mL), and then washed once with aqueous sodium thiosulfate solution (30 mL) and saturated brine (30 mL).
  • Step 3 Add methylmagnesium bromide in tetrahydrofuran (1M, 1.6 mL, 1.6 mmol) to anhydrous tetrahydrofuran (20 mL) of the above intermediate product (180 mg, 0.41 mmol) at room temperature. The reaction was stirred for 3 hours at room temperature. The reaction solution dropped to zero, and the reaction solution was quenched with saturated aqueous sodium bicarbonate solution (30 mL). Ethyl acetate (30 mL) was added to the reaction mixture. The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate (30 mL). The combined organic phases were dried over MgSO4 , filtered and concentrated. The crude product was preparatively purified by HPLC to obtain the product as a yellow solid (84 mg). LC-MS[M+H] + :m/z 375.5.
  • Step 4 Add trifluoroacetic acid (1 mL) to the anhydrous dichloromethane solution (10 mL) of the above intermediate product (80 mg, 0.21 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. LC-MS detection reaction was basically complete. The reaction solution was directly concentrated under reduced pressure to obtain a crude white solid intermediate product (58 mg). LC-MS[M+H] + :m/z 275.4.
  • Step 5 To the DMF solution (10 mL) of the above intermediate product (58 mg, 0.21 mmol) at room temperature, add (S)-2-((p-toluenesulfonate)methyl)morpholine-4- Formyl tert-butyl ester (78 mg, 0.21 mmol). The reaction mixture was stirred at 80°C for 72 hours. LC-MS detection reaction was basically complete. Saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (30 mL). The combined organic phases were concentrated under reduced pressure to obtain crude white solid intermediate product (25 mg). LC-MS[M+H] + :m/z 474.6.
  • Step 6 Add trifluoroacetic acid (1 mL) to the anhydrous dichloromethane solution (5 mL) of the above intermediate product (25 mg, 0.05 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. LC-MS detection reaction was basically complete. The reaction solution was directly concentrated under reduced pressure to obtain a crude white solid intermediate product (15 mg). LC-MS[M+H] + :m/z 374.5.
  • Step 7 Add acryloyl chloride (10 mg, 0.11 mmol) to the anhydrous dichloromethane solution (5 mL) of the above intermediate product (8 mg, 0.04 mmol) and triethylamine (20 mg, 0.20 mmol) at room temperature. . The reaction mixture was stirred at room temperature for 1 hour. LC-MS detection reaction was basically complete. The reaction solution was directly concentrated under reduced pressure, and the crude product was prepared by HPLC to obtain the target product (10 mg) as a white solid. LC- MS[M+H] + :m/z 428.2.
  • Step 2 Under nitrogen protection, add phosphorus oxychloride (5 mL) to the acetonitrile solution (10 mL) of the above intermediate compound (525 mg, 1.59 mmol). The reaction mixture was heated to 80 degrees and reacted for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a yellow solid crude product (480 mg). LC-MS[M+H] + :m/z 349.5.
  • Step 4 Add isopropenylboronic acid (96 mg, 1.11 mmol) to the 1,4-dioxane/water (12 mL/4 mL) solution of the above intermediate (550 mg, 1.09 mmol) at room temperature, tetra( Triphenylphosphine palladium (240 mg, 0.2 mmol) and sodium carbonate powder (560 mg, 5.3 mmol), the reaction mixture was stirred at 100°C under argon overnight.
  • Step 5 Add 5% palladium/carbon (50 mg) to the methanol solution (20 mL) of the above intermediate compound (310 mg, 0.73 mmol) at room temperature. Stir at room temperature for 6 hours under a hydrogen atmosphere of 1 atmosphere. LC-MS detects that the reaction is complete. The reaction solution was filtered through diatomaceous earth and washed twice with methanol. The combined organic phases were concentrated under reduced pressure to obtain crude white solid product (210 mg). LC-MS m/z:429.4[M+H] + .
  • Step 6 Add trifluoroacetic acid (3 mL) to the anhydrous dichloromethane solution (10 mL) of the above intermediate product (201 mg, 0.47 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. LC-MS detection reaction was basically complete. The reaction solution was directly concentrated under reduced pressure to obtain a crude white solid intermediate product (140 mg). LC-MS[M+H] + :m/z 329.3.
  • Step 7 To the DMF solution (10 mL) of the above intermediate product (135 mg, 0.41 mmol) at room temperature, add (S)-2-((p-toluenesulfonate)methyl)morpholine-4- Formyl tert-butyl ester (156 mg, 0.42 mmol). The reaction mixture was stirred at 80°C for 72 hours. LC-MS detection reaction was basically complete. Saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (30 mL). The combined organic phases were concentrated under reduced pressure, and the obtained crude product was preparatively purified by HPLC to obtain a white solid intermediate product (65 mg). LC-MS[M+H] + :m/z 528.6.
  • Step 8 Add trifluoroacetic acid (3 mL) to the anhydrous dichloromethane solution (10 mL) of the above intermediate product (65 mg, 0.12 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. LC-MS detection reaction was basically complete. The reaction solution was directly concentrated under reduced pressure to obtain a crude white solid intermediate product (35 mg). LC-MS[M+H] + :m/z 528.5.
  • Step 9 Add acryloyl chloride (10 mg, 0.11 mmol) to the anhydrous dichloromethane solution (5 mL) of the above intermediate compound (35 mg, 0.08 mmol) and triethylamine (20 mg, 0.20 mmol) at room temperature. . The reaction mixture was stirred at room temperature for 1 hour. LC-MS detection reaction was basically complete. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC to obtain the target product (20 mg) as a white solid. LC-MS[M+H] + :m/z 482.5.
  • Step 1 To a DMF solution (15 mL) of compound C (500 mg, 2.18 mmol), add 4-aminopiperidine-1-formyl tert-butyl ester (480 mg, 2.40 mmol) and DIEA (844 mg, 6.55mmol). The reaction mixture was stirred at room temperature overnight. LCMS detection showed that the reaction was complete. A saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (30 mL).
  • Step 2 To the dichloromethane solution (20 mL) of the above intermediate compound (700 mg, 1.78 mmol), add trifluoroacetic acid (3 mL). The reaction mixture was stirred at room temperature for 2 hours. LCMS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a yellow solid crude intermediate product (520 mg). LC-MS[M+H] + :m/z 294.1/296.1.
  • Step 3 To the DMF solution (15 mL) of the above intermediate compound (520 mg, 1.77 mmol), add (S)-2-((p-toluenesulfonate)methyl)morpholine-4-formyl tert-butyl Ester (659 mg, 1.77 mmol) and DIEA (1.52 g, 11.78 mmol). The reaction mixture was stirred at 80°C for 70 hours. LCMS detection showed that the reaction was basically complete. A saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (30 mL). The combined organic phases were concentrated under reduced pressure, and the crude product was prepared by HPLC to obtain the yellow solid intermediate product (210 mg). LC-MS[M+H] + :m/z 493.3.
  • Step 4 Under nitrogen protection, add dimethylzinc (222mg, 2.31mmol) and Pd(dppf)Cl 2 (29mg) to the dichloromethane solution (20mL) of the above intermediate compound (190mg, 0.38mmol) ,0.04mmol). The reaction mixture was heated to 80°C and stirred overnight. LCMS detection showed that the reaction was basically complete. Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction solution. The separated organic phase was concentrated under reduced pressure, and the obtained crude product was prepared by HPLC to obtain a yellow solid intermediate product (52 mg). LC-MS[M+H] + :m/z 473.3.
  • Step 5 To the dichloromethane solution (5 mL) of the above intermediate compound (52 mg, 0.11 mmol), add trifluoroacetic acid (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The LCMS detection reaction was basically complete. The reaction solution was directly concentrated under reduced pressure to obtain a yellow solid intermediate product (40 mg). LC-MS[M+H] + :m/z 373.3.
  • Step 6 To the tetrahydrofuran/water mixed solution (1:1, 5mL) of the above intermediate compound (40mg, 0.11mmol), add acryloyl chloride (20mg, 0.21mmol) and sodium bicarbonate powder (47mg, 0.56mmol). The reaction mixture was stirred at room temperature overnight. LC-MS detection reaction was basically complete. To the reaction mixture were added ethyl acetate (20 mL) and water (20 mL). The separated organic phase was concentrated under reduced pressure, and the obtained crude product was preparatively purified by HPLC to obtain the compound of Example 4 (11 mg) as a white solid. LC-MS[M+H] + :m/z427.1.
  • Step 2 Under nitrogen protection, add phosphorus oxychloride (5 mL) to the DMF solution (20 mL) of the above intermediate compound (890 mg, 3.63 mmol). The reaction mixture was heated to 110 degrees and reacted for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was prepared by HPLC to obtain a yellow oily product (580 mg). LC-MS[M+H] + :m/z 264.6.
  • Step 4 To the dichloromethane solution (20 mL) of the above intermediate compound (670 mg, 1.57 mmol), trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. LCMS detection showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a yellow solid crude intermediate product (510 mg). LC-MS[M+H] + :m/z 328.3.
  • Step 5 To the DMF solution (15 mL) of the above intermediate compound (510 mg, 1.56 mmol), add (S)-2-((p-toluenesulfonate)methyl)morpholine-4-formyl tert-butyl Ester (579 mg, 1.56 mmol) and DIEA (1.52 g, 11.78 mmol). The reaction mixture was stirred at 80°C for 70 hours. LCMS detection showed that the reaction was basically complete. A saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (30 mL). The combined organic phases were concentrated under reduced pressure, and the obtained crude product was prepared by HPLC to obtain the yellow solid intermediate product (130 mg). LC-MS[M+H] + :m/z 527.6.
  • Step 6 To the dichloromethane solution (5 mL) of the above intermediate compound (65 mg, 0.12 mmol), add trifluoroacetic acid (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The LCMS detection reaction was basically complete. The reaction solution was directly concentrated under reduced pressure to obtain a yellow solid intermediate product (51 mg). LC-MS[M+H] + :m/z 426.5.
  • Step 7 Add the above intermediate compound (51 mg, 0.12 mmol) to a mixed solution of tetrahydrofuran/water (1:1, 5 mL) at room temperature, Acryloyl chloride (20 mg, 0.21 mmol) and sodium bicarbonate powder (47 mg, 0.56 mmol) were added. The reaction mixture was stirred at room temperature overnight. LC-MS detection reaction was basically complete. To the reaction mixture were added ethyl acetate (20 mL) and water (20 mL). The separated organic phase was concentrated under reduced pressure, and the obtained crude product was preparatively purified by HPLC to obtain the compound of Example 5 (15 mg) as a white solid. LC-MS[M+H] + :m/z481.3.
  • Step 1 Add (R)-2-((4-((5-chloro-3-isopropylpyrazolo[1,5,-a]pyrimidin-7-yl)amino) Cyclopropylboronic acid (23 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (240 mg, 0.2 mmol) and sodium carbonate powder (560 mg, 5.3 mmol), and the reaction mixture was stirred at 80°C under nitrogen overnight.
  • Step 2 To the dichloromethane solution (5 mL) of the above intermediate compound (45 mg, 0.09 mmol), add trifluoroacetic acid (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The LCMS detection reaction was basically complete. The reaction solution was directly concentrated under reduced pressure to obtain a yellow solid intermediate product (35 mg). LC-MS[M+H] + :m/z 398.5.
  • Step 3 To the tetrahydrofuran/water mixed solution (1:1, 5mL) of the above intermediate compound (36mg, 0.09mmol), add acrylic chloride (15mg, 0.15mmol) and sodium bicarbonate powder (47mg, 0.56mmol). The reaction mixture was stirred at room temperature overnight. LC-MS detection reaction was basically complete. To the reaction mixture were added ethyl acetate (20 mL) and water (20 mL). The separated organic phase was concentrated under reduced pressure, and the obtained crude product was preparatively purified by HPLC to obtain the compound of Example 6 (5 mg) as a white solid. LC-MS[M+H] + :m/z 453.6.
  • Step 1 To a solution of compound D (500 mg, 1.82 mmol) in 1,4-dioxane (15 mL) at room temperature, add 4-aminopiperidine-1-formyl tert-butyl ester (385 mg, 1.92 mmol) and DIEA (844mg, 6.55mmol). The reaction mixture was heated to 90 degrees and stirred for 8 hours. LCMS detection showed that the reaction was complete. A saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (30 mL).
  • Step 2 Under nitrogen protection, add trimethylcyclotriboroxane to the 1,4-dioxane/water mixed solution (3:1, 4mL) of the above intermediate compound (300mg, 0.76mmol) (190 mg, 1.51 mmol), tetrakis(triphenylphosphine)palladium (240 mg, 0.2 mmol) and sodium carbonate powder (280 mg, 2.64 mmol).
  • the reaction mixture was heated to 90 degrees under microwave for 6 hours. After adding water (10 mL) to the reaction solution, the mixture was extracted twice with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel flash column chromatography to obtain a white solid product (145 mg). LC-MS m/z:374.5[M+H] + .
  • Step 3 To the dichloromethane solution (5 mL) of the above intermediate compound (145 mg, 0.39 mmol), add trifluoroacetic acid (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The LCMS detection reaction was basically complete. The reaction solution was directly concentrated under reduced pressure to obtain a yellow solid intermediate product (95 mg). LC-MS[M+H] + :m/z 274.3.
  • Step 4 To the DMF solution (15 mL) of the above intermediate compound (95 mg, 0.35 mmol), add (S)-2-((p-toluenesulfonate)methyl)morpholine-4-formyl tert-butyl Ester (130 mg, 0.35 mmol) and DIEA (200 mg, 1.55 mmol). The reaction mixture was stirred at 80°C for 64 hours. LCMS detection showed that the reaction was basically complete. A saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (30 mL). The combined organic phases were concentrated under reduced pressure, and the crude product was prepared by HPLC to obtain the yellow solid intermediate product (45 mg). LC-MS[M+H] + :m/z 473.6.
  • Step 5 To the dichloromethane solution (5 mL) of the above intermediate compound (44 mg, 0.09 mmol), add trifluoroacetic acid (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The LCMS detection reaction was basically complete. The reaction solution was directly concentrated under reduced pressure to obtain a yellow solid intermediate product (30 mg). LC-MS[M+H] + :m/z 373.5.
  • Step 6 To the tetrahydrofuran/water mixed solution (1:1, 5mL) of the above intermediate compound (30mg, 0.08mmol), add acryloyl chloride (15mg, 0.15mmol) and sodium bicarbonate powder (24mg, 0.29mmol). The reaction mixture was stirred at room temperature overnight. LC-MS detection reaction was basically complete. To the reaction mixture were added ethyl acetate (20 mL) and water (20 mL). The separated organic phase was concentrated under reduced pressure, and the obtained crude product was preparatively purified by HPLC to obtain the white compound of Example 7 (9 mg). LC-MS[M+H] + :m/z 427.3.
  • Step 1 To a methanol solution (10 mL) of 6-(trifluoromethyl)pyridazin-3-amine (960 mg, 5.89 mmol) and sodium bicarbonate (600 mg, 7.14 mmol) at room temperature, add liquid bromine ( 950mg, 5.94mmol). The reaction mixture was stirred at room temperature for 2 hours. After adding saturated aqueous sodium bicarbonate solution (50 mL) to the reaction liquid, the mixture was extracted twice with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine and concentrated under reduced pressure to obtain a yellow crude intermediate compound (1.3 g). LC-MS[M+H] + :m/z 243.
  • Step 2 Dissolve the above intermediate compound (1.3g, 5.37mmol) and 2-bromo-3-methylbutyraldehyde (886mg, 5.37mmol) in absolute ethanol (100mL), and heat the reaction mixture to 100 degrees to reflux overnight.
  • Step 3 Refer to the first step synthesis method in Example 7, use the above intermediate (600 mg, 1.94 mmol) to react with 4-aminopiperidine-1-formyl tert-butyl ester to obtain a white solid intermediate compound (480 mg) .
  • Step 4 Referring to the synthesis method of the third step in Example 7, react the above intermediate (480 mg, 1.12 mmol) with trifluoroacetic acid to obtain a white solid intermediate compound (360 mg).
  • Step 5 Refer to the fourth step synthesis method of Example 7, use the above intermediate (360 mg, 1.10 mmol) and (S)-2-((p-toluenesulfonate)methyl)morpholine-4-formyl The tert-butyl ester was reacted to obtain a white solid intermediate compound (120 mg). LC-MS[M+H] + :m/z527.6.
  • Step 6 Referring to the synthesis method of the fifth step in Example 7, react the above intermediate (42 mg, 0.08 mmol) with trifluoroacetic acid to obtain a white solid intermediate compound (30 mg).
  • Step 7 Referring to the synthesis method of Step 6 of Example 7, react the above intermediate (30 mg, 0.07 mmol) with acryloyl chloride to obtain the compound of Example 8 (10 mg) as a white solid.
  • Step 1 To the ethanol solution (20 mL) of 3-chloro-5-(trifluoromethyl)pyridazin-2-amine (580 mg, 2.93 mmol), slowly add chloroacetaldehyde aqueous solution (50%, 10 mL) . The reaction mixture was heated to 150 degrees under microwave for 30 minutes. The LC-MS detection reaction is basically completed. The reaction solution was concentrated under reduced pressure. After the residue was dissolved in dichloromethane (20 mL), saturated aqueous sodium bicarbonate solution (30 mL) was added, and the organic phase was separated. The organic phase was washed once with saturated brine and then dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure.
  • Step 2 Under nitrogen protection, add N-iodosuccinimide (434 mg, 1.93 mmol) to the DMF solution (10 mL) of the above intermediate compound (428 mg, 1.93 mmol). The reaction mixture was reacted at room temperature for 20 hours. The LC-MS detection reaction is basically completed. Saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution, and the organic phase was separated. The organic phase was washed once with saturated brine and then dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure.
  • Step 3 Refer to the third step of synthesis in Example 2, react the above intermediate (520 mg, 1.50 mmol) with 4-aminopiperidine-1-formyl tert-butyl ester to generate a white solid intermediate compound (420 mg).
  • Step 4 Refer to the fourth step of synthesis in Example 2, react the above intermediate (420 mg, 0.82 mmol) with isopropenylboronic acid to generate a white solid intermediate compound (220 mg).
  • Step 5 Refer to the fifth step of synthesis in Example 2, and use the above intermediate (220 mg, 0.52 mmol) to undergo a hydrogenation reaction under palladium/carbon catalysis to generate a white solid intermediate compound (130 mg).
  • Step 6 Refer to the synthesis in step 6 of Example 2, react the above intermediate (120 mg, 0.28 mmol) with trifluoroacetic acid to generate a white solid intermediate compound (88 mg).
  • Step 7 Refer to the seventh step of synthesis in Example 2, using the above intermediate (85 mg, 0.26 mmol) and (S)-2-((p-toluenesulfonate)methyl)morpholine-4-formyl tert. Butyl ester reacted to produce a white solid intermediate compound (43 mg). LC-MS[M+H] + :m/z 527.6.
  • Step 8 Refer to the synthesis in Step 8 of Example 2, react the above intermediate (43 mg, 0.08 mmol) with trifluoroacetic acid to generate a white solid intermediate compound (23 mg).
  • Step 9 Refer to the synthesis in Step 9 of Example 2, react the above intermediate (23 mg, 0.05 mmol) with acrylic acid chloride to generate a white solid intermediate compound (12 mg).
  • Step 1 To an ethanol solution (20 mL) of 1-amino-1H-imidazole-2-carboxylic acid ethyl ester (1.61 g, 10.4 mmol), add ethylamidine (10 mL). The reaction mixture was heated to 95 degrees and reacted for 96 hours. The LC-MS detection reaction is basically completed. The reaction solution cools to room temperature and becomes white. Solids precipitated. After the solid was filtered, it was dried to obtain a white solid intermediate product (528 mg). LC-MS[M+H] + :m/z 151.1.
  • Second step Referring to the first step synthesis method in Example 2, react the above intermediate compound (528 mg, 3.52 mmol) with N-iodosuccinimide to obtain a white solid intermediate (620 mg). LC-MS[M+H] + :m/z 277.0.
  • Step 3 Referring to the second step synthesis method of Example 2, react the above-mentioned intermediate compound (652 mg, 2.36 mmol) with phosphorus oxychloride to obtain a white solid intermediate (660 mg). LC-MS[M+H] + :m/z 294.9.
  • Step 4 Refer to the third step synthesis method of Example 2, react with the above-mentioned intermediate compound (660 mg, 2.24 mmol) and 4-aminopiperidine-1-formyl tert-butyl ester to obtain a white solid intermediate (760 mg) .
  • Step 5 Referring to the synthesis method of the fourth step in Example 2, react the above-mentioned intermediate compound (760 mg, 1.66 mmol) with isopropenylboronic acid to obtain a white solid intermediate (460 mg).
  • Step 6 Referring to the synthesis method of the fifth step in Example 2, use the above-mentioned intermediate compound (460 mg, 1.23 mmol) to undergo a hydrogenation reduction reaction under palladium/carbon catalysis to obtain a white solid intermediate (310 mg).
  • Step 7 Referring to the synthesis method of Step 6 of Example 2, react the above intermediate compound (310 mg, 0.83 mmol) with trifluoroacetic acid to obtain a white solid intermediate (225 mg).
  • Step 8 Refer to the synthesis method of the seventh step in Example 2, use the above-mentioned intermediate compound (310 mg, 0.83 mmol) and (S)-2-((p-toluenesulfonate)methyl)morpholine-4-methyl The acyl tert-butyl ester was reacted to obtain a white solid intermediate (72 mg). LC-MS[M+H] + :m/z 474.3.
  • Step 9 Referring to the synthesis method in step 8 of Example 2, react the above intermediate compound (72 mg, 0.15 mmol) with trifluoroacetic acid to obtain a white solid intermediate (43 mg).
  • Step 10 Referring to the synthesis method of step 9 in Example 2, react the above intermediate compound (38 mg, 0.10 mmol) with trifluoroacetic acid to obtain a white solid intermediate (16 mg).
  • Step 1 To a solution of 3,4,6-trichloropyridazine (460mg, 2.49mmol) in N-methylpyrrolidone (20mL), add (4-aminopiperidine-1-formyl tert-butyl ester (385mg ,1.92mmol) and DIEA (422mg, 3.27mmol). The reaction mixture was reacted at room temperature for 24 hours. After adding water (50mL) to the reaction solution, it was extracted twice with ethyl acetate (50mL), and the combined organic phases were subtracted Concentrate under pressure.
  • 4-aminopiperidine-1-formyl tert-butyl ester 385mg ,1.92mmol
  • DIEA 422mg, 3.27mmol
  • Step 2 Add hydrazine hydrate (10 mL) to the ethanol solution (20 mL) of the above intermediate compound (650 mg, 1.87 mmol). The reaction mixture was heated to 60°C for 2 hours. The LC-MS detection reaction is basically completed. The reaction solution dropped to room temperature, and a white solid precipitated. After the solid was filtered, it was dried to obtain a white solid intermediate product (560 mg). LC-MS[M+H] + :m/z 344.2/346.2.
  • Step 4 Referring to the second step reaction in Example 4, react the above-mentioned intermediate compound (475 mg, 1.21 mmol) with trifluoroacetic acid to generate a white solid intermediate compound (350 mg).
  • Step 5 Refer to the third step reaction of Example 4, using the above intermediate compound (350 mg, 1.19 mmol) and (S)-2-((p-toluenesulfonate)methyl)morpholine-4-formyl Tert-butyl ester reacted to produce a white solid intermediate (120 mg).
  • Step 6 Referring to the reaction in the fourth step of Example 4, use the above-mentioned intermediate compound (120 mg, 0.24 mmol) to react with dimethylzinc to generate a white solid intermediate compound (30 mg).
  • Step 7 Referring to the reaction in the fifth step of Example 4, react the above-mentioned intermediate compound (30 mg, 0.06 mmol) with trifluoroacetic acid to generate a white solid intermediate compound (15 mg).
  • Step 8 Referring to the reaction in Step 6 of Example 4, react the above-mentioned intermediate compound (15 mg, 0.04 mmol) with acryloyl chloride to generate a white solid intermediate compound (5 mg).
  • Step 2 Under nitrogen protection, add the toluene solution (20 mL) of the above intermediate compound (310 mg, 1.17 mmol) and (4-aminopiperidine-1-formyl tert-butyl ester (600 mg, 3.01 mmol) 4,5-bisdiphenylphosphine-9,9-dimethylxantphos (240mg, 0.42mmol), tris(dibenzylideneacetone)dipalladium (201mg, 0.22mmol) and tert-butanol Sodium (490 mg, 5.0 mmol). The reaction mixture was heated to 120 degrees and reacted for 4 hours.
  • Step 3 Referring to the synthesis method of the fourth step in Example 5, react the above intermediate compound (110 mg, 0.26 mmol) with trifluoroacetic acid to obtain a yellow solid compound (80 mg).
  • Step 4 Refer to the synthesis method of the fifth step in Example 5, using the above-mentioned intermediate compound (80 mg, 0.24 mmol) and (S)-2-((p-toluenesulfonate)methyl)morpholine-4-methyl The acyl tert-butyl ester was reacted to obtain a white solid intermediate product (30 mg). LC-MS[M+H] + :m/z527.3.
  • Step 5 Referring to the synthesis method of Step 6 of Example 5, react the above intermediate compound (30 mg, 0.06 mmol) with trifluoroacetic acid to obtain a yellow solid compound (22 mg).
  • Step 6 Referring to the synthesis method of Step 7 of Example 5, react the above intermediate compound (22 mg, 0.05 mmol) with acryloyl chloride to obtain the compound of Example 20 (4 mg) as a white solid.
  • Example 4 the compound of Example 26 was prepared as a white solid by using diethylzinc reagent instead of dimethylzinc.
  • Example 27 1-((2R)-2-((4-((5-(1-hydroxyethyl))-3-isopropylpyrazolo[1,5,-a]pyrimidin-7-yl )amino)piperidin-1-yl)methyl)morpholin)prop-2-enyl-1-one
  • the first step to the intermediate compound (R)-2-4-((5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidine-1-
  • Step 2 To the acetonitrile solution (3 mL) of the above intermediate compound (80 mg, 0.15 mmol), add 1 M aqueous hydrochloric acid solution (1 mL). The reaction mixture was stirred at room temperature for 2 hours. LCMS detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain a crude yellow oily intermediate compound (60 mg). LC-MS[M+H] + :m/z 501.3.
  • Step 3 Add NaBH 4 (10 mg, 0.23 mmol) to the methanol solution (4 mL) of the above intermediate compound (50 mg, 0.10 mmol) under cooling in an ice-water bath. The reaction solution was slowly raised to room temperature, and the reaction was continued to stir for 30 minutes. LCMS detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. The crude product was dissolved in ethyl acetate (20 mL), washed twice with saturated brine, and the separated organic phase was concentrated under reduced pressure to obtain the crude product as a yellow oil (50 mg). LC-MS[M+H] + :m/z 503.2.
  • Step 4 To the dichloromethane solution (4 mL) of the above intermediate compound (50 mg, 0.10 mmol), add trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 30 minutes. LCMS detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain a crude yellow solid intermediate compound (30 mg). LC-MS[M+H] + :m/z 403.2.
  • Step 5 Referring to the synthesis method of Step 7 of Example 5, react the above intermediate compound (30 mg, 0.07 mmol) with acryloyl chloride to obtain the compound of Example 27 (5 mg) as a white solid.
  • Example 28 1-((2R)-2-((4-((5-(1-fluoroethyl))-3-isopropylpyrazolo[1,5,-a]pyrimidin-7-yl )amino)piperidin-1-yl)methyl)morpholin)prop-2-enyl-1-one
  • Step 1 Under cooling in an ice water bath, add to the intermediate compound (2R)-2-4-((5-(1-hydroxyethyl)-3-isopropylpyrazolo[1,5-a]pyrimidine -To a solution (4 mL) of -7-yl)amino)piperidin-1-yl)methyl)morpholine-4-tert-butyl carbonate (50 mg, 0.10 mmol) in dichloromethane, add diethylamine trifluoride Sulfur (0.4 mL, 2.3 mmol). The reaction mixture was stirred at room temperature for 2 hours. LC-MS detects that the reaction is complete.
  • Step 2 Add trifluoroacetic acid (1 mL) to the dichloromethane solution (5 mL) of the above intermediate compound (42 mg, 0.08 mmol) under ice-water bath cooling. The reaction mixture was stirred at room temperature for 2 hours. LCMS detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure to obtain a crude yellow oily intermediate (30 mg). LC-MS[M+H] + :m/z 405.1.
  • Step 3 To the dichloromethane solution (5 mL) of the above intermediate compound (30 mg, 0.07 mmol), add acryloyl chloride (10 mg, 0.11 mmol) and triethylamine (23 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 2 hours. LC-MS detects that the reaction is complete. The reaction solution was concentrated under reduced pressure, and the crude product obtained was prepared by HPLC to obtain the compound of Example 28 (6 mg) as a white solid. LC-MS[M+H] + :m/z459.15.
  • Example 28-P1 and 28-P2 1-((R)-2-((4-((5-((S or R)-1-fluoroethyl))-3-isopropylpyrazolo[1 ,5,-a]pyrimidin-7-yl)amino)piperidin-1-yl)methyl)morpholin)prop-2-enyl-1-one and 1-((R)-2-((4 -((5-((R or S)-1-fluoroethyl)-3-isopropylpyrazolo[1,5,-a]pyrimidin-7-yl)amino)piperidin-1-yl) Methyl)morpholin)prop-2-enyl-1-one
  • Step 1 Combine the racemate mixture (2R)-2-((4-((5-(1-fluoroethyl)-3-isopropylpyrazolo[1,5,-a]pyrimidine-7- Base)amino)piperidin-1-yl)methyl)morpholine)-4-formyl tert-butyl ester (28a) (150 mg, 0.3 mmol) was chiral prepared by supercritical fluid chromatography to obtain two components with a single structure. Compound 28a-P1 (60 mg, shorter retention time) and single configuration compound 28a-P2 (53 mg, longer retention time), LC-MS (ESI): m/z: 505.3[M+H] + .
  • Mobile phase A supercritical CO2
  • Mobile phase B isopropylamine (add 0.1% 7.0mol/l ammonia/methanol solution)
  • Mobile phase A supercritical CO2
  • Mobile phase B isopropylamine (add 0.1% diethylamine)
  • Step 2 Referring to the method in the second step of Example 28, 28a-P1 (60 mg, 0.12 mmol) and 28a-P2 (53 mg, 0.1 mmol)) react with TFA respectively to generate white solid compounds 28b-P1 (33 mg) and 28b- P2(25mg). LC-MS(ESI):m/z:405.2[M+H] + .
  • Step 3 Referring to the method in the third step of Example 28, 28b-P1 (33 mg, 0.12 mmol) and 28b-P2 (25 mg, 0.1 mmol)) react with acryloyl chloride to generate white solid compounds 28-P1 (17 mg) and 28 respectively. -P2(13mg). LC-MS(ESI):m/z:459.5[M+H] + .
  • Step 1 Under nitrogen protection and cooling in an ice-water bath, add the intermediate compound (R)-2-((4-((5-acetyl-3-isopropylpyrazolo[1,5-a]pyrimidine To a solution of -7-yl)amino)piperidin-1-yl)methyl)morpholine-4-tert-butyl carbonate (70 mg, 0.140 mmol) in tetrahydrofuran (5 mL), add methylmagnesium bromide (33 mg, 0.28 mmol). The reaction mixture was slowly warmed to room temperature and stirring was continued for 30 minutes. LCMS detection showed that the reaction was complete.
  • Step 2 Referring to the preparation method of the second step of Example 29, react the above intermediate compound (50 mg, 0.10 mmol) with trifluoroacetic acid to obtain a yellow solid compound (40 mg).
  • Step 3 Refer to the preparation method in the third step of Example 29, use the above intermediate compound (40 mg, 0.10 mmol) and trifluoroacetic acid After reaction, a yellow solid compound (7 mg) was obtained. LC-MS[M+H] + :m/z 471.20.
  • the first step refer to the preparation method of the first step of Example 28, use the above intermediate (R)-2-((4-((5-(2-hydroxyisoprop-2-yl)-3-isopropyl) Pyrazolo[1,5-a]pyrimidin-7-yl)amino)piperidin-1-yl)methyl)morpholine-4-carbonate tert-butyl ester (80 mg, 0.15 mmol) was reacted with DAST to obtain a yellow solid compound (60 mg). LC-MS[M+H] + :m/z 519.3.
  • Step 2 Referring to the preparation method of the second step of Example 28, react the above intermediate compound (58 mg, 0.11 mmol) with trifluoroacetic acid to obtain a yellow solid compound (45 mg).
  • Step 3 Referring to the preparation method of the third step of Example 28, react the above intermediate compound (42 mg, 0.10 mmol) with trifluoroacetic acid to obtain the compound of Example 30 (9 mg) as a yellow solid.
  • Example 32 1-((2R)-2-((4-((2-(1-hydroxyethyl-8-isopropylpyrimido[1,5,-a][1,3,5] triazin-4-yl)amino)piperidin-1-yl) Methyl)morpholin)prop-2-enyl-1-one
  • Step 1 To the DMF solution (15 mL) of intermediate compound G (230 mg, 1.0 mmol), add 4-aminopiperidine-1-formyl tert-butyl ester (200 mg, 1.0 mmol) and DIEA ( 420mg, 3.3mmol). The reaction mixture was stirred at room temperature overnight. LCMS detection showed that the reaction was complete. A saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (30 mL).
  • Step 2 To the 1,4-dioxane solution (20mL) of the above intermediate compound (240mg, 0.6mmol), add tributyl(1-ethoxyvinyl)tin (1.4mL, 0.7mmol) ), Pd(PPh 3 ) 2 Cl 2 (111 mg, 0.158 mmol) and triethylamine (126 mg, 1.2 mmol). The reaction mixture was heated to 80°C under nitrogen protection and stirred for 12 hours. LCMS detection showed that the reaction was complete. After the reaction mixture was cooled to room temperature, 2M aqueous hydrochloric acid (5 mL) was added to the reaction solution. The reaction solution was continued to stir for 3 hours.
  • Step 3 To the DMF solution (10 mL) of the above intermediate product (125 mg, 0.41 mmol), add (S)-2-((p-toluenesulfonate)methyl)morpholine-4- at room temperature. Formyl tert-butyl ester (156 mg, 0.42 mmol). The reaction mixture was stirred at 80°C for 72 hours. LC-MS detection reaction was basically complete. Saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (30 mL). The combined organic phases were concentrated under reduced pressure, and the crude product was preparatively purified by HPLC to obtain a white solid intermediate product (63 mg). LC-MS[M+H] + :m/z 502.3.
  • Step 4 Add NaBH 4 (10 mg, 0.23 mmol) to the methanol solution (4 mL) of the above intermediate compound (60 mg, 0.12 mmol) under cooling in an ice-water bath. The reaction solution was slowly raised to room temperature, and the reaction was continued to stir for 30 minutes. LCMS detected that the reaction was complete, and the reaction solution was concentrated under reduced pressure. The crude product was dissolved in ethyl acetate (20 mL), washed twice with saturated brine, and the separated organic phase was concentrated under reduced pressure to obtain the crude product as a yellow oil (48 mg). LC-MS[M+H] + :m/z 504.3.
  • Step 5 Referring to the synthesis method of the fourth step in Example 27, react the above intermediate compound (48 mg, 0.07 mmol) with trifluoroacetic acid to obtain a white solid (29 mg).
  • Step 6 Referring to the synthesis method of the fifth step of Example 27, react the above intermediate compound (29 mg, 0.07 mmol) with acryloyl chloride to obtain the compound of Example 32 (5 mg) as a white solid.
  • Example 33 the intermediate (2R)-2-((4-((2-(1-hydroxyethyl))-8-isopropylpyrazolo[1,5-a][1 ,3,5]triazin-4-yl)amino)piperidin-1-yl)methyl)morpholine-4-tert-butyl carbonate as raw material, a white solid
  • Example 33 compound was prepared through three-step reaction. LC-MS[M+H] + :m/z 460.2.
  • Example 33-P1 and 33-P2 1-((R)-2-((4-((2-((S or R)-1-fluoroethyl))-8-isopropylpyrazolo[1 ,5,-a]triazin-4-yl)amino)piperidin-1-yl)methyl)morpholin)prop-2-enyl-1-one and 1-((R)-2-(( 4-((2-((R or S)-1-fluoroethyl)-8-isopropylpyrazolo[1,5,-a]triazin-4-yl)amino)piperidine-1- base)methyl)morpholin)prop-2-enyl-1-one
  • 33a 100 mg was prepared and separated by chiral SFC, and two single configuration intermediate compounds 33a-P1 (shorter retention time) and 33a-P2 (shorter retention time) were separated. long retention time), and then prepared and synthesized through two-step reactions to obtain white solid compounds 33-P1 (15 mg) and 33-P2 (11 mg).
  • Example 32 4-((6-chloro-3-isopropylimidazole[1,2-b]pyridazin-8-yl)amino)piperidine-1-carbonate tert-butyl ester was used. Starting materials, the compound of Example 36 was prepared as a white solid. LC-MS[M+H] + :m/z 457.30.
  • Step 1 To the intermediate compound (2R)-2-((4-((6-(1-hydroxyethyl))-3-isopropylimidazo[1,2-b]pyridazin-8-yl )Amino)piperidin-1-yl)methyl)morpholine-4-tert-butyl carbonate (90 mg, 0.16 mmol) in methanol solution (5 mL), 5% Pd/C (10 mg) was added. The reaction mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for 5 hours. LC-MS detects that the reaction is complete, add 20 mL of methanol to the reaction solution, and filter with diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain a gray crude solid compound (50 mg). LC-MS[M+H] + :m/z 487.3.
  • Step 2 Referring to the synthesis method of the fourth step in Example 27, react the above intermediate compound (48 mg, 0.07 mmol) with trifluoroacetic acid to obtain a white solid (29 mg).
  • Step 3 Referring to the synthesis method of the fifth step of Example 27, react the above intermediate compound (29 mg, 0.07 mmol) with acryloyl chloride to obtain the compound of Example 37 (5 mg) as a white solid.
  • Example 38 the intermediate (2R)-2-((4-((6-(1-hydroxyethyl))-3-isopropylimidazo[1,2-b]pyridazine- 8-yl)Amino)piperidin-1-yl)methyl)morpholine-4-tert-butyl carbonate was used as the starting material, and a white solid Example 38 compound was prepared through three steps of reaction. LC-MS[M+H] + :m/z 459.3.
  • Example 41 1-((2R)-2-((4-((6-(1-hydroxyethyl))-3-isopropylimidazo[1,2,-a]pyrazin-8-yl )amino)piperidin-1-yl)methyl)morpholin)prop-2-enyl-1-one
  • Example 32 Refer to the synthesis method of Example 32, starting from 4-((6-chloro-3-isopropylimidazole[1,2-a]pyrazin-8-yl)amino)piperidine-1-carbonate tert-butyl ester Starting materials were used to prepare the compound of Example 41 as a white solid. LC-MS[M+H] + :m/z 457.3.
  • Example 42 1-((2R)-2-((4-((6-ethyl-3-isopropylimidazo[1,2,-a]pyrazin-8-yl)amino)piperidine -1-yl)methyl)morpholin)prop-2-enyl-1-one
  • Example 43 1-((2R)-2-((4-((6-(1-fluoroethyl))-3-isopropylimidazo[1,2,-a]pyrazin-8-yl )amino)piperidin-1-yl)methyl)morpholin)prop-2-enyl-1-one
  • Example 38 the intermediate (2R)-2-((4-((6-(1-hydroxyethyl))-3-isopropylimidazo[1,2-a]pyrazine- 8-yl)amino)piperidin-1-yl)methyl)morpholine-4-tert-butyl carbonate was used as the starting material, and the compound of Example 43 was prepared as a white solid through three-step reactions.
  • LC-MS[M+H] + :m/z 457.3
  • Example 44 1-((2R)-2-((4-((6-(2-hydroxyisoprop-2-yl)-3-isopropylimidazo[1,2,-a]pyrazine -8-yl)amino)piperidin-1-yl)methyl)morpholin)prop-2-enyl-1-one
  • Example 44 (2R)-2-((4-((6-acetyl-3-isopropylimidazo[1,2-a]pyrazin-8-yl)amino) Using tert-butyl (din-1-yl)methyl)morpholine-4-carbonate as the starting material, the compound of Example 44 was prepared as a white solid. LC-MS[M+H] + :m/z471.3.
  • Example 45 1-((2R)-2-((4-((6-(2-fluoroisoprop-2-yl)-3-isopropylimidazo[1,2,-a]pyrazine -8-yl)amino)piperidin-1-yl)methyl)morpholin)prop-2-enyl-1-one
  • Example 47 1-((2R)-2-((4-((2-(1-hydroxyethyl))-7-isopropylimidazo[2,1,-f][1,2,4 ]triazin-4-yl)amino)piperidin-1-yl)methyl)morpholin)prop-2-enyl-1-one
  • the first step refer to the third step of synthesis in Example 2, react with intermediate compound H (537 mg, 2.01 mmol) and 4-aminopiperidine-1-formyl tert-butyl ester to generate a white solid intermediate compound (480 mg) .
  • Step 2 Refer to the fourth step of synthesis in Example 2, react with the above-mentioned intermediate compound (480 mg, 1.11 mmol) and isopropenyl borate pinacol ester to generate a white solid intermediate compound (395 mg).
  • Step 3 Refer to the second step of synthesis in Example 32, react with the above-mentioned intermediate compound (398 mg, 1.01 mmol) and tributyl (1-ethoxyvinyl) tin to generate a white solid intermediate compound (278 mg) .
  • Step 4 Refer to the third step of synthesis in Example 32, using the above intermediate compound (278 mg, 0.93 mmol) and (S)-2-((p-toluenesulfonate)methyl)morpholine-4-formyl
  • the reaction of tert-butyl ester produced a white solid intermediate compound (128 mg).
  • Step 5 Refer to the fifth step of synthesis in Example 2, and use the above-mentioned intermediate compound (128 mg, 0.26 mmol) to undergo hydrogenation reduction under Pd/C catalysis to generate a white solid intermediate compound (95 mg).
  • Step 6 Refer to the fourth step of synthesis in Example 32, react the above-mentioned intermediate compound (95 mg, 0.19 mmol) with sodium borohydride to generate a white solid intermediate compound (78 mg).
  • Step 7 Refer to the fifth step of synthesis in Example 32, react the above-mentioned intermediate compound (78 mg, 0.15 mmol) with trifluoroacetic acid to generate a white solid intermediate compound (45 mg).
  • Step 8 Refer to the synthesis in step 6 of Example 32, react the above intermediate compound (45 mg, 0.11 mmol) with acryloyl chloride to generate the compound of Example 47 (15 mg) as a white solid.
  • Example 48 1-((2R)-2-((4-((2-(1-fluoroethyl))-7-isopropylimidazo[2,1,-f][1,2,4 ]triazin-4-yl)amino)piperidin-1-yl)methyl)morpholin)prop-2-enyl-1-one
  • Example 48 the intermediate (2R)-2-((4-((2-(1-hydroxyethyl))-7-isopropylimidazo[2,1-f][1, 2,4]Triazin-4-yl)amino)piperidin-1-yl)methyl)morpholine-4-tert-butyl carbonate was used as the starting material, and a white solid Example 48 compound was prepared through three steps of reaction. LC-MS[M+H] + :m/z 460.3.
  • Example 38 Refer to the synthesis method of Example 38, using different reagents as raw materials instead of 4-aminopiperidine-1-formyl tert-butyl ester or (S)-2-((p-toluenesulfonyl)methyl)morpholine-4 -Formyl tert-butyl ester to prepare compounds of Examples 66-70:
  • Example 28 Refer to the synthesis method of Example 28, using different reagents as raw materials instead of 4-aminopiperidine-1-formyl tert-butyl ester or (S)-2-((p-toluenesulfonyl)methyl)morpholine-4 -Formyl tert-butyl ester to prepare compounds of Examples 71-75:
  • Example 33 Refer to the synthesis method of Example 33, using different reagents as raw materials instead of 4-aminopiperidine-1-formyl tert-butyl ester or (S)-2-((p-toluenesulfonyl)methyl)morpholine-4 -Formyl tert-butyl ester to prepare compounds of Examples 76-80:
  • Example 81 (R)-1-(2-(((4-((8-isopropyl-2-vinylpyrimido[1,5,-a][1,3,5]triazine-4 -yl)amino)piperidin-1-yl)methyl)morpholin)prop-2-enyl-1-one
  • Example 84 (R)-1-(2-((4-((2-(difluoromethyl)-8-isopropylpyrimido[1,5,-a][1,3,5] Triazin-4-yl)amino)piperidin-1-yl)methyl)morpholin)prop-2-enyl-1-one
  • Step 1 Refer to the synthesis method in the third step of Example 1, use 4-((8-isopropyl-2-(methylsulfone)pyrimido[1,5,-a][1,3,5]tri Azin-4-yl)amino)piperidine-1-formyl tert-butyl ester (1.5g, 3.42mmol) was reacted with vinylmagnesium bromide (1M in THF, 3.5mL, 3.5mmol) to obtain a light yellow oily compound (0.83 g). LC-MS[M+H] + :m/z 387.2.
  • Step 3 Referring to the synthesis method in the first step of Example 29, react the above intermediate (560 mg, 1.44 mmol) with methylmagnesium bromide to prepare a white solid compound (455 mg). LC-MS[M+H] + :m/z 405.2.
  • Step 5 Referring to the synthesis method of the fourth step in Example 1, react the above intermediate (385 mg, 0.96 mmol) with trifluoroacetic acid to prepare a white solid compound (242 mg). LC-MS[M+H] + :m/z 303.2.
  • Step 6 Refer to the fifth step synthesis method of Example 1, use the above intermediate (240 mg, 0.79 mmol) and (S)-2-((p-toluenesulfonate)methyl)morpholine-4-formyl tert. Butyl ester was reacted to prepare a white solid compound (128 mg). LC-MS[M+H] + :m/z 502.3.
  • Step 7 Referring to the synthesis method in step 6 of Example 1, react the above intermediate (125 mg, 0.25 mmol) with trifluoroacetic acid to prepare a white solid compound (85 mg).
  • Step 8 Referring to the seventh step synthesis method of Example 1, react the above intermediate (125 mg, 0.25 mmol) with acryloyl chloride to prepare a white solid compound (23 mg).
  • Step 1 Add diethylaminosulfur trifluoride (664mg, 4.12mmol) to 4-((2-aldehyde-8-isopropylpyrimido[1,5,-a][1, 3,5]triazin-4-yl)amino)piperidine-1-formyl tert-butyl ester (320 mg, 0.824 mmol) in dichloromethane (5 mL). After the reaction solution rose to room temperature, stirring was continued for 2 hours. The reaction was quenched by adding saturated sodium bicarbonate solution to the reaction solution. The reaction solution was washed with saturated sodium chloride solution, and the aqueous phase was extracted with dichloromethane.
  • Step 3 At room temperature, add potassium carbonate (270 mg, 1.95 mmol), (S)-2-( (p-Toluenesulfonate)methyl)morpholine-4-formyl tert-butyl ester (480 mg, 1.29 mmol).
  • the reaction mixture was heated to 90°C for 16 hours under nitrogen protection.
  • LCMS detection showed that the reaction was complete.
  • After adding 20 mL of water to the reaction solution, the mixture was extracted three times with ethyl acetate (10 mL). The combined organic phases were concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/anhydrous methanol 20:1) to obtain a light yellow solid compound (100 mg).
  • Step 5 To the dichloromethane solution (5 mL) of the above intermediate compound (70 mg, 0.171 mmol), add triethylamine (35 mg, 0.342 mmol) and acryloyl chloride (20 mg, 0.222 mmol) at zero temperature. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction solution was washed with saturated sodium chloride solution, and the separated organic phase was concentrated under reduced pressure. The obtained crude product was purified by HPLC to obtain Example 85 compound (18.7 mg) as a white solid. LCMS[M+H] + :m/z 464.4.
  • Example 85 Referring to the synthesis method of Example 85, using different reagents as raw materials instead of acrylic acid chloride, the compounds of Examples 86-93 were prepared:
  • Example 94 2-fluoro-1-((2R)-2-((4-((2-(1-fluoroethyl))-8-isopropylpyrimido[1,5,-a][1 ,3,5]triazin-4-yl)amino)piperidin-1-yl)methyl)morpholin)prop-2-enyl-1-one
  • Step 1 Under nitrogen protection, 4-((2-aldehyde-8-isopropylpyrimido[1,5,-a][1,3,5]triazin-4-yl)amino)piperidine - A solution of 1-formyl tert-butyl ester (1.1g, 2.83mmol) in tetrahydrofuran (30mL), cooled to minus -70 degrees. At this temperature, a solution of methylmagnesium bromide in tetrahydrofuran (3M, 2.36 mL, 7.08 mmol) was slowly added, and the reaction was continued at this temperature for 1 hour. The LCMS detection reaction was basically complete.
  • Step 3 To the N, N-dimethylformamide solution (25 mL) of the above intermediate compound (900 mg, 2.96 mmol), add potassium carbonate (270 mg, 1.95 mmol) and (S)-2-( (p-Toluenesulfonate)methyl)morpholine-4-formyl tert-butyl ester (2.75 g, 7.39 mmol). Under nitrogen protection, the reaction mixture was heated to 90°C for 16 hours. LCMS detection showed that the reaction was basically complete. After adding saturated aqueous sodium chloride solution (50 mL) to the reaction mixture, the mixture was extracted three times with ethyl acetate (20 mL).
  • Step 6 To the dichloromethane solution (5 mL) of the above intermediate compound (45 mg, 0.11 mmol), add 2-fluoroacryloyl chloride (12 mg, 0.13 mmol) and triethylamine (22 mg, 0.22 mmol) at zero temperature. . After the reaction mixture warmed to room temperature, stirring was continued for 2 hours. After adding methylene chloride (10 mL) to the reaction solution, the organic phase was washed with saturated aqueous sodium chloride solution. The separated organic phase was concentrated under reduced pressure, and the obtained crude product was preparatively purified by HPLC to obtain the compound of Example 94 (9.73 mg) as a white solid. LCMS[M+H] + :m/z478.2.
  • Example 95 Referring to the synthesis method of Example 94, using different reagents as raw materials instead of 2-fluoroacryloyl chloride, the compounds of Examples 95-100 were prepared:
  • the specific operation process is as follows: (1) Preparation of 1 ⁇ Kinase buffer; (2) Preparation of compound concentration gradient: The test concentration of the test compound is 10000nM starting, diluted in the 384source plate to a 100% DMSO solution of 100 times the final concentration, 3 Dilute compounds 10 times to 10 concentrations. Use the Dispenser Echo 550 to transfer 250 nL of compound at 100x the final concentration to the destination 384-well-plate. Prepare a kinase solution with 2.5 times the final concentration using 1 ⁇ Kinase buffer. (3) Add 10 ⁇ L of 2.5 times the final concentration of kinase solution to the compound wells and positive control wells respectively; add 10 ⁇ L of 1 ⁇ Kinase buffer to the negative control wells.
  • results see Table 1: Most of the example compounds of the present invention have high CDK7 kinase inhibitory activity, and still show high inhibitory activity (inhibition rate greater than 95%) at concentrations as low as 100 nM; and most of the example compounds The inhibitory activity against CDK9 is weak, and it still shows low inhibitory activity at a concentration of 1000nM (inhibition rate is less than 10%). Most of the example compounds showed higher CDK7/CDK9 kinase selectivity. (The inhibition rate means ++++ ⁇ 90%; 80% ⁇ +++ ⁇ 60%;60% ⁇ ++ ⁇ 30%;+ ⁇ 10%; IC 50 means A ⁇ 50nM; 50nM ⁇ B ⁇ 500nM;500nM ⁇ C ⁇ 1000nM;D>1000nM.)
  • Table 1 Kinase inhibitory activity and kinase inhibition rate of the patented compound CDK7/CDK9 of the present invention
  • NT means not done.
  • the IC 50 of the CDK7 kinase of most of the compounds in the examples is less than 50 nM, and some compounds are even less than 20 nM, such as Example 4 (IC50, 7.1 nM), 27 (IC50 , 13.5nM), 28 (IC 50 , 19.8nM), 28-P2 (IC 50 , 2.8nM), etc.
  • Results (see Table 2): Most of the compounds of the present invention have strong cell proliferation inhibitory activity, with an IC 50 of less than 1000 nM.
  • the IC 50 of some of the compounds of the present invention is less than 50 nM.
  • the IC 50 of some of the compounds of the present invention inhibits cell proliferation.
  • the activity IC50 is even less than 10nM.
  • the specific results are shown in the table below: (IC 50 means A ⁇ 50nM; 50nM ⁇ B ⁇ 500nM;500nM ⁇ C ⁇ 1000nM;D>1000nM).
  • control compound is a compound reported in the patent of Eli Lilly and Company (see WO2021242602, Example 8).
  • Metabolic stability test Use a system of 150 ⁇ L of liver microsomes (final concentration 0.5 mg/mL) for metabolic stability incubation.
  • the system contains NADPH (final concentration 1 mM), 1 ⁇ M test compound and positive control midazole. or negative control atenolol, terminate the reaction with acetonitrile containing tinidazole at 0 min, 5 min, 10 min, 20 min and 30 min respectively, vortex for 10 min, centrifuge at 15000 rpm for 10 min, take 50 ⁇ L of the supernatant and inject it into a 96-well plate.
  • the metabolic stability of the compound was calculated by determining the relative reduction of the original drug.
  • the compounds of the present invention have high stability to liver microsomes of various genera (rat, mouse, dog, monkey, human).
  • the data of some of the compounds of the examples are as follows:
  • NT means not done.
  • Test Example 4 Test of pharmacokinetic parameters of the example compounds in mice
  • mice Six male SPF-grade Balbc mice (Shanghai Sipur-Bika Laboratory Animals) were divided into two groups. The test compounds were prepared into appropriate solutions or suspensions; one group was administered intravenously (1 mg/kg), and the other group was administered orally. medicine (5mg/kg). Blood was collected via jugular venipuncture. Each sample was collected at about 0.2 mL/time point. Heparin sodium was used for anticoagulation. The blood collection time points were as follows: before administration and 5, 15 and 30 minutes after administration, 1, 2, 4, 6, 8 and 24h; place blood samples on ice after collection, and centrifuge to separate plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8°C). The collected plasma is stored at -80°C before analysis. Plasma samples were analyzed by LC-MS/MS.
  • the pharmacokinetic calculation software WinNonlin5.2 non-compartmental model was used to calculate the pharmacokinetic parameters AUC 0-t , AUC 0- ⁇ , MRT 0- ⁇ , and C max of the test product. , T max , T 1/2 and V d and other parameters and their average values and standard deviations.
  • bioavailability (F) will be calculated by the following formula.
  • samples sampled before reaching Cmax should be calculated as zero values, and samples at sampling points after reaching Cmax should be calculated as unquantifiable (BLQ).
  • the compound of the present invention shows high drug exposure and bioavailability, and has good pharmacokinetic properties in vivo.
  • Test Example 5 Effect of Example Compounds on the Growth of Xenograft Tumors in Nude Mice
  • HCT116 HCC1806, OVCAR-3
  • xenograft tumor models e.g., HCT116, HCC1806, OVCAR-3
  • Experimental nude mice were subcutaneously inoculated with 2-8 ⁇ 10 7 tumor cells on the right back. The cells were resuspended in 1:1 PBS and Matrigel.
  • mice were randomly divided into groups for administration according to tumor size and body weight.
  • the day when tumor cells were inoculated was defined as day 0. Before the start of dosing, all animals were weighed and tumor volumes were measured using vernier calipers. 3) The compound of the example (prepared with purified water of 1% hydroxyethyl cellulose, 0.25% polysorbate 80, and 0.05% antifoaming agent to the required concentration and then ready for use) is orally administered at a given dose every day, continuously. After three weeks of administration, the solvent control group was given the same amount of solvent. During the entire experiment, the diameter of the transplanted tumors was measured twice a week, and the body weight of the mice was also weighed.
  • V 0 is the tumor volume measured when the drug is administered in separate cages (i.e. d 0 )
  • V t is the tumor volume at each measurement.
  • Example compounds 28 and 33 showed obvious anti-tumor activity in HCT116, HCC1806, and OVCAR-3 tumor models.
  • Example compounds 28 and 33 showed significant anti-tumor activity at 15 mg/ kg, 30 mg/kg, 60 mg/kg, the tumor inhibition rate is greater than 70%, and the tumor inhibition rate in the medium and high dose groups is even greater than 90%, and the test animals can tolerate it well.

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Abstract

涉及一类含氮杂环类化合物、制备方法和用途，具体为一种如通式（I）所示的含氮杂环类化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药、其制备方法及在药学上的应用，其中各基团的定义如说明书中所述。

Description

一类含氮杂环类细胞周期抑制剂化合物、制备方法和用途
本申请要求申请日为2022/3/7的中国专利申请2022102172115和申请日为2022/8/27的中国专利申请2022110361903的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于药物化学领域，公开了一类含氮杂环类细胞周期抑制剂化合物、其药物组合物和用途。
背景技术
细胞周期异常是癌症的一个标志性特征，周期蛋白依赖性激酶(cyclin-dependent kinase,CDK)是一类丝氨酸/苏氨酸激酶，在细胞周期中起中心作用，主导细胞周期的启动、进行和结束。CDK家族是细胞内重要的信号转导分子，其与周期素(cyclin)形成的CDK-cyclin复合物，参与细胞的生长、增殖、休眠和凋亡。
在过去的20年中，以CDK激酶为肿瘤治疗靶点的药物开发已经得到了广泛的关注，如Flavopiridol(Alvocidib),Seliciclib(CYC202),Dinaciclib(SCH727965)和Milciclib(PHA-848125)等都进入不同阶段临床研究。但是由于早期发现的CDK抑制剂对各CDK家族亚型抑制活性不高，或者缺乏一定的选择性，或者体内吸收不佳等情况而限制了临床应用。近几年，由于提高了CDK抑制剂对于各CDK家族亚型的选择性或者提高了CDK激酶的抑制活性，尤其是靶向CDK4/6的选择性抑制剂的发现，使得这一领域的药物研发再次成为热点。
最新研究发现CDK家族的CDK7激酶同时具有调控激酶和转录的双重功能：1)在胞质中，CDK7以异三聚体复合体的形式存在并且充当CDK1/2的激活激酶(CAK)，借此CDK7对CDK1/2中的保守残基进行的磷酸化是为完全的催化CDK活性和细胞周期进展所必需的；2)在核中，CDK7形成RNA聚合酶(RNAP)II通用转录因子复合物的激酶核心并且负责将RNAP II的C末端结构域(CTD)磷酸化，这是基因转录起始中的一个必要的步骤。CDK7的两个功能，即CAK和CTD磷酸化支持了细胞增殖、细胞循环、以及转录的关键方面。研究表明,CDK7激酶对于三阴性乳腺癌的调控具有非常重要的作用，抑制CDK7激酶对于三阴性乳腺癌细胞的生长具有显著的杀伤作用。
CDK激酶抑制剂类药物研发尽管已经取得了非常重大的进展，但是同时还存在一些未能解决的问题，如已有CDK激酶抑制剂类药物的耐药性、对CDK激酶家族靶点的亚型选择性等，因此，本领域迫切需要研究和开发新的高效低毒、抗耐药性、具有临床应用价值的新型CDK激酶抑制剂，如特异性CDK7激酶抑制剂。
发明内容
本发明需要解决的技术问题之一是提供一种新型的CDK7抑制剂，用于制备肿瘤治疗药物。
本发明是通过下述技术方案来解决上述技术问题：
本发明提供了如通式I所示的含氮杂环类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，
式中：
W、X和M各自独立地选自CRw或N；Rw独立地选自H、氘、卤素、氰基、C1-C3烷基或C1-C3卤代烷基；
Y、Z独立地选自C或者N；
R1独立地选自C2-C6烯基、C2-C6炔基、C1-C6烷基-(C＝O)-、C1-C3烷基、C1-C3卤代烷基、3-6元环烷基、3-6元卤代环烷基，3-6元杂环烷基、C1-C10烷氧基、C1-C10卤代烷氧基、3-6元环烷基-O-、3-6元杂环烷基-O-、C1-C10烷基-NH-、C1-C10卤代烷基-NH-、3-6元环烷基-NH-或3-6元杂环烷基-NH-；上述烯基、炔基、烷基、环烷基、杂环烷基可以被一个或数个R1-1所取代，R1-1独立地选自：卤素、氘、羟基、氨基、取代的氨基、C1-C6烷基、羟基取代的C1-C6烷基、氨基取代的C1-C6烷基、C1-C6烷氧基、3-10元环烷基或3-10元杂环烷基取代的C1-C6烷基；所述取代氨基中的取代基为1-3个，独立地选自：C1-C6烷基、C1-C6烷氧基、3-6元环烷基或3-6元杂环烷基；
R2独立地选自C1-C3烷基、C1-C3卤代烷基、3-6元环烷基、3-6元卤代环烷基或3-6元杂环烷基；R2可进一步被一个或多个R2-1取代，所述R2-1独立地选自氘、卤素、羟基、C1-C3烷基、C1-C3卤代烷基；
R3独立地选自丙烯酰基、取代的丙烯酰基、丙炔酰基、取代的丙炔酰基、乙烯磺酰基、取代的乙烯磺酰基或氰基；R3中所述“取代”为进一步被一个或多个R3-1所取代，所述R3-1独立地选自：卤素、氘、羟基、氰基、氨基、C1-C6烷基、C1-C6烷氧基、3-6元环烷基、3-6元杂环烷基、3-6元杂环烷基取代的C1-C3烷基、氨基取代的C1-C3烷基、单C1-C3烷基取代氨基-C1-C3烷基或双C1-C3烷基取代氨基-C1-C3烷基；或者，两个R3-1与所连接的碳原子一起形成3-8元碳环或3-8元杂环，优选为
R4、R5独立地选自氢、氘、卤素、C1-C3的烷基、C1-C3卤代烷基、羟基、氨基、取代氨基或C1-C3烷氧基；所述取代氨基中的取代基为1-3个，独立地选自：C1-C6烷基、C1-C6烷氧基、3-6元环烷基或3-6元杂环烷基；
Ra、Rb独立地选自氢、氘、卤素、C1-C3烷基；或者Ra、Rb通过碳链形成3-6元饱和碳环，优选为环丙烷或环丁烷；
环A和环B分别选自4-10元含氮杂环，优选为5-6元含氮杂环；
n独立地选自0-3的整数；
上述的烷基、取代烷基或烯基可以被取代基取代，所述取代基分别独立地选自下组：包括但不限于氘、卤素、羟基、单烷基氨基、双烷基氨基、C1-C6烷基或卤代烷基、3-10元环烷基或杂环烷基、氰基、C1-C6烷氧基或卤代烷氧基；
其中，所述的杂环包含1-3个选自下组的杂原子：N、O、P、S或Se，所述的杂环烷基包含1-3个选自下组的杂原子：N、O、P或S，所述的环系包含螺环、桥环、稠环、并环等饱和或部分不饱和的环系。
在本发明某些优选实施方案中，所述如通式I所示的含氮杂环类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，
式中：
W、X和M各自独立地选自CRw或N；Rw独立地选自H、卤素、氰基、C1-C3烷基或C1-C3卤代烷基；
Y,Z分别选自C或者N；
R1独立地选自C1-C3烷基、C1-C3卤代烷基、3-6元环烷基、3-6元卤代环烷基，3-6元杂环烷基、C1-C10烷氧基、C1-C10卤代烷氧基、3-6元环烷基-O-、3-6元杂环烷基-O-、C1-C10烷基-NH-、C1-C10卤代烷基-NH-、3-6元环烷基-NH-或3-6元杂环烷基-NH-；上述烷基、环烷基、杂环烷基可以被一个或数个R1-1所取代，R1-1独立地选自：卤素、氘、羟基、氨基、取代的氨基、C1-C6烷基、羟基取代的C1-C6烷基、氨基取代的C1-C6烷基、C1-C6烷氧基、3-10元环烷基或3-10元杂环烷基取代的C1-C6烷基；所述取代氨基中的取代基为1-3个，独立地选自：C1-C6烷基、C1-C6烷氧基、3-6元环烷基或3-6元杂环烷基；
R2独立地选自C1-C3烷基、C1-C3卤代烷基、3-6元环烷基或3-6元杂环烷基；
R3独立地选自丙烯酰基或取代的丙烯酰基，丙炔酰基，乙烯磺酰基或取代的乙烯磺酰基、氰基等；R3可进一步被一个或多个R3-1所取代，所述R3-1独立地选自：卤素、氘、羟基、氰基、氨基、C1-C6烷基、C1-C6烷氧基、3-6元环烷基、3-6元杂环烷基取代的C1-C3烷基、氨基取代的C1-C3烷基、单C1-C3烷基取代氨基-C1-C3烷基或双C1-C3烷基取代氨基-C1-C3烷基；或者，两个R3-1与所连接的碳原子一起形成3-8元碳环或3-8元杂环，优选为
R4、R5独立地选自氢、卤素、C1-C3的烷基、C1-C3卤代烷基、羟基、氨基、取代氨基、C1-C3烷 氧基；所述取代氨基中的取代基为1-3个，独立地选自：C1-C6烷基、C1-C6烷氧基、3-6元环烷基或3-6元杂环烷基；
Ra、Rb独立地选自氢、卤素、C1-C3烷基；或者Ra、Rb通过碳链形成3-6元饱和碳环，优选为环丙烷、环丁烷；
环A和环B分别选自4-10元含氮杂环，优选为5-6元含氮杂环；
n独立地选自0-3的整数；
上述的烷基或取代烷基，烯基可以被取代基取代，所述取代基分别独立地选自下组：包括但不限于氘、卤素、羟基、单烷基氨基、双烷基氨基、C1-C6烷基或卤代烷基、3-10元环烷基或杂环烷基、氰基、C1-C6烷氧基或卤代烷氧基；其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O、P或S，所述的杂环烷基包含1-3个选自下组的杂原子：N、O、P或S，所述的环系包含螺环、桥环、稠环、并环等饱和或部分不饱和的环系。
在本发明某些优选实施方案中，所述如通式I所示的含氮杂环类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药中的某些基团如下定义，未提及的基团同本发明任一方案所述(简称“在一些优选实施方式中”)，
式中：
W、X和M各自独立地选自CRw或N；Rw独立地选自H、卤素、氰基、C1-C3烷基或C1-C3烷基卤代烷基；
Y、Z分别选自C或者N；
R1独立地选自C1-C3烷基、C1-C3卤代烷基、3-6元环烷基、3-6元卤代环烷基，3-6元杂环烷基、C1-C10烷氧基、C1-C10卤代烷氧基、3-6元环烷基-O-、3-6元杂环烷基-O-、C1-C10烷基-NH-、C1-C10卤代烷基-NH-、3-6元环烷基-NH-或3-6元杂环烷基-NH-；上述烷基、环烷基、杂环烷基可以被一个或数个R1-1所取代，R1-1独立地选自：卤素、氘、羟基、氨基、取代的氨基、C1-C6烷基、羟基取代的C1-C6烷基、氨基取代的C1-C6烷基、C1-C6烷氧基、3-10元环烷基或3-10元杂环烷基取代的C1-C6烷基；所述取代氨基中的取代基为1-3个，独立地选自：C1-C6烷基、C1-C6烷氧基、3-6元环烷基或3-6元杂环烷基；
R2独立地选自C1-C3烷基、C1-C3卤代烷基、3-6元环烷基、3-6元卤代环烷基或3-6元杂环烷基；R2可进一步被一个或多个R2-1取代，所述R2-1独立地选自卤素、羟基、C1-C3烷基、C1-C3卤代烷基；
R3独立地选自丙烯酰基或取代的丙烯酰基，丙炔酰基，乙烯磺酰基或取代的乙烯磺酰基、氰基等； R3可进一步被一个或多个R3-1所取代，所述R3-1独立地选自：卤素、氘、羟基、氰基、氨基、C1-C6烷基、C1-C6烷氧基、3-6元环烷基、3-6元杂环烷基取代的C1-C3烷基、氨基取代的C1-C3烷基、单C1-C3烷基取代氨基-C1-C3烷基或双C1-C3烷基取代氨基-C1-C3烷基；或者，两个R3-1与所连接的碳原子一起形成3-8元碳环或3-8元杂环，优选为
R4、R5独立地选自氢、卤素、C1-C3的烷基、C1-C3卤代烷基、羟基、氨基、取代氨基、C1-C3烷氧基；所述取代氨基中的取代基为1-3个，独立地选自：C1-C6烷基、C1-C6烷氧基、3-6元环烷基或3-6元杂环烷基；
Ra、Rb独立地选自氢、卤素、C1-C3烷基；或者Ra、Rb通过碳链形成3-6元饱和碳环，优选为环丙烷、环丁烷；
环A和环B分别选自4-10元含氮杂环，优选为5-6元含氮杂环；
n独立地选自0-3的整数；
上述的烷基或取代烷基，烯基可以被取代基取代，所述取代基分别独立地选自下组：包括但不限于氘、卤素、羟基、单烷基氨基、双烷基氨基、C1-C6烷基或卤代烷基、3-10元环烷基或杂环烷基、氰基、C1-C6烷氧基或卤代烷氧基；其中，所述的杂芳基包含1-3个选自下组的杂原子：N、O、P或S，所述的杂环烷基包含1-3个选自下组的杂原子：N、O、P或S，所述的环系包含螺环、桥环、稠环、并环等饱和或部分不饱和的环系。
在一些优选实施方式中，不为
在一些优选实施方式中，当Y为N时，W、X和M中至少有一个为N。
在一些优选实施方式中，具有通式(I)所述的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其中，R1为CH3、CF3、CH3O-、NH2或CH3NH-、CH3CH2、
或者，R2为甲基、乙基、异丙基、环丙基；
或者，R3为
或者，Ra、Rb优选为氢、甲基；
或者，R4为氢、卤素、羟基、甲基；
或者，R5为氢、羟基、卤素、甲基；
或者，环A优选为其中*端与-NH-相连；N端与-(CH2)n-端相连；
或者，环B优选为其中N端与R3相连，*端与-(CH2)n-端相连；
或者，环B中与碳链相连的碳原子的构型优选为R构型。
在一些优选的实施方式中，所述式(I)化合物或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其优选为通式(II)所示的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药：
其中W、X、Y、Z、M、R1、R2、R3、R4、Ra、Rb基团的范围如上文所定义。
在一些优选的实施方式中，所述式(I)化合物或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其优选为通式(III-1)-(III-9)所示的化合物，

其它基团的范围如上文所定义。
在一些优选的实施方式中，所述通式I所示的含氮杂环类化合物为通式(VI-1)-(VI-9)所示的化合物，
其它基团(R1、R2、R3、Ra、Rb)的范围如上文所定义。
在一些优选的实施方式中，所述式(I)化合物或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其优选为通式(IV-1)-(IV-2)所示的化合物，
其中，R1优选自卤素、C1-C3烷基 或卤代烷基，C3-C6的环烷基或卤代环烷基；R3选自下面基团：等；Rc、Rd、Re、Rf、Rg、Rh、Rk、Rm独立地选自氢、氘、卤素、C1-C6烷基、氰基；或者上述任意两个相邻基团之间可以通过碳链或杂原子形成3-8元碳环或3-8元杂环；其它基团的范围如上文所定义。
在一些优选的实施方式中，所述式(I)化合物或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其优选为通式(IV-1)-(IV-2)所示的化合物，
其中，R1优选自C2-C6烯基、C2-C6炔基、C1-C6烷基-(C＝O)-、卤素、C1-C3烷基、卤代烷基、C3-C6的环烷基或卤代环烷基；更优选自乙烯基、乙炔基、C1-C3烷基、卤代烷基、C3-C6的环烷基或卤代环烷基；
R3选自下面基团：Rc、Rd、Re、Rf、Rg、Rh、Rk、Rm独立地选自氢、氘、卤素、C1-C6烷基、或氰基；或者上述任意两个相邻基团之间可以通过碳链或杂原子形成3-8元碳环或3-8元杂环。
在一些优选的实施方式中，所述式(I)化合物或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其为通式(V-1)-(V-2)所示的化合物：
其中，R1优选自卤素、C1-C3烷基或卤代烷基，C3-C6的环烷基或卤代环烷基；R3选自下面基团：等；Rc、Rd、Re、Rf、Rg、Rh、Rk、Rm独立地选自氢、氘、卤素、C1-C6烷基、氰基；或者上述任意两个相邻基团之间可以通过碳链或杂原子形成3-8元碳环或3-8元杂环；其它基团的范围如上文所定义。
在一些优选的实施方式中，所述式(I)化合物或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其为通式(V-1)-(V-2)所示的化合物：
其中，R1优选自C2-C6烯基、C2-C6炔基、C1-C6烷基-(C＝O)-、卤素、C1-C3烷基、卤代烷基、C3-C6的环烷基或卤代环烷基；更优选自乙烯基、乙炔基、C1-C3烷基、卤代烷基、C3-C6的环烷基或卤代环烷基；
R3选自下面基团：Rc、Rd、Re、Rf、Rg、Rh、Rk、Rm独立地选自氢、氘、卤素、C1-C6烷基、氰基；或者上述任意两个相邻基团之间可以通过碳链或杂原子形成3-8元碳环或3-8元杂环。
在一些优选的实施方式中，C2-C6烯基可为C2-C4烯基；优选为乙烯基或丙烯基。
在一些优选的实施方式中，C2-C6炔基可为C2-C4炔基，优选为
在一些优选的实施方式中，C1-C3烷基可为甲基、乙基、正丙基或异丙基。
在一些优选的实施方式中，C1-C6烷基可为甲基、乙基、正丙基、异丙基、正丁基、异丁基、伯丁基、仲丁基或叔丁基；优选为异丙基或叔丁基。
在一些优选的实施方式中，C1-C3卤代烷基中的卤素优选为氟、氯、溴或碘；所述C1-C3卤代烷基优选为C1-C3氟代烷基。
在一些优选的实施方式中，3-6元环烷基可为环丙基、环丁基、环戊基、环己烯基或环己基；优选为环丙基。
在一些优选的实施方式中，卤素可为氟、氯、溴或碘；优选为氟。
在一些优选的实施方式中，3-6元杂环烷基可为
在一些优选的实施方式中，4-10元含氮杂环可为
在一些优选的实施方式中，Rw独立地选自H。
在一些优选的实施方式中，R1可为C2-C6烯基、C2-C6炔基、C1-C6烷基-(C＝O)-、C1-C3烷基、C1-C3卤代烷基或3-6元环烷基。
在一些优选的实施方式中，R1-1的个数为1、2或3个；R1-1独立地选自卤素或羟基；优选为羟基。
在一些优选的实施方式中，R1可为C2-C6烯基、C2-C6炔基、C1-C6烷基-(C＝O)-、C1-C3烷基、C1-C3卤代烷基或3-6元环烷基；上述烷基可以被一个或数个R1-1所取代，R1-1独立地选自羟基。
在一些优选的实施方式中，R2可为C1-C3烷基；优选为异丙基。
在一些优选的实施方式中，R3可为丙烯酰基、取代的丙烯酰基、丙炔酰基、取代的丙炔酰基或乙烯磺酰基。
在一些优选的实施方式中，R3-1独立地选自：卤素、氰基、C1-C6烷基、3-6元杂环烷基取代的C1-C3烷基、单C1-C3烷基取代氨基-C1-C3烷基或双C1-C3烷基取代氨基-C1-C3烷基。
在一些优选的实施方式中，R3可为丙烯酰基、取代的丙烯酰基、丙炔酰基、取代的丙炔酰基、或乙烯磺酰基；取代的丙烯酰基为被一个或多个R3-1所取代，所述R3-1独立地选自：卤素、氰基、C1-C6烷基、3-6元杂环烷基取代的C1-C3烷基、单C1-C3烷基取代氨基-C1-C3烷基或双C1-C3烷基取代氨基-C1-C3烷基。
在一些优选的实施方式中，R4可为卤素、羟基或C1-C3的烷基。
在一些优选的实施方式中，R5可为卤素、羟基或C1-C3的烷基。
在一些优选的实施方式中，Ra、Rb独立地选自氢或C1-C3烷基。
在一些优选的实施方式中，环A可为其中*端与-NH-相连；N端与端相连。
在一些优选的实施方式中，环B可为其中N端与R3相连，*端与端相连。
在一些优选的实施方式中，环B中与碳链相连的碳原子的构型优选为R构型。
在一些优选的实施方式中，R1可为乙烯基、乙炔基、CH3(C＝O)-、-CH3、-CHF2、CF3、CH3O-、-NH2、CH3NH-、CH3CH2-、
在一些实施方式中，R2可为甲基、乙基、异丙基或环丙基；优选为异丙基。
在一些优选的实施方式中，R3可为
在一些优选的实施方式中，可为
在一些优选的实施方式中，可为
在一些优选的实施方式中，可为
在一些优选的实施方式中，所述如通式I所示的含氮杂环类化合物为如下任一结构：


一种制备式I化合物的方法，其特征在于通式(A)化合物经过步骤a-c，生成通式(I)化合物:
a)将通式(A)化合物与适当的烷基化试剂发生取代或者还原胺化反应生成中间体化合物(B)；
b)将通式(B)化合物，在适当反应条件下，脱除氨基上的保护基生成通式(C)中间体化合物；
c)将通式(C)化合物与适当的试剂,在碱或适当的试剂催化下反应，生成通式(I)化合物。
Pg为氨基上的保护基，如碳酸叔丁基，碳酸苄酯，苄基等，所示各基团的定义如上所述；
优选地，所述反应在溶剂中进行，且所述溶剂选自下组：水、甲醇、乙醇、异丙醇、丁醇、乙二醇、乙二醇甲醚、N-甲基吡咯烷酮、二甲基亚砜，四氢呋喃、甲苯、二氯甲烷、1，2-二氯乙烷、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氧六环，或其组合物。
优选地，所述无机碱选自下组：氢化钠、氢氧化钾、醋酸钠、醋酸钾、叔丁醇钾、叔丁醇钠、氟化钾、氟化铯、磷酸钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠，或其组合物；所述有机碱选自下组：吡啶，三乙胺，N，N-二异丙基乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、六甲基二硅基锂、六甲基二硅基钠、二甲基吡啶，或其组合物。
优选地，所述酸选自下组：盐酸、硫酸、磷酸、甲磺酸、甲苯磺酸、三氟乙酸、甲酸、乙酸，三氟甲磺酸或其组合物。
本发明的另一目的是提供一种治疗或预防肿瘤或自身免疫性疾病的药物及其组合物。实现上述目的的技术方案如下：
一方面，本发明提供了药物组合物，其包含治疗有效量的式I化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、或前药，以及药学上可接受的载体。在所述药物组合物的某些实施方案中，药物组合物被配制用于静脉内施用、肌内施用、口服施用、直肠施用、吸入施用、鼻施用、局部施用、眼睛施用或耳施用。在所述药物组合物的其它实施方案中，药物组合物是片剂、丸剂、胶囊、液体剂、吸入剂、鼻喷雾溶液剂、栓剂、溶液剂、乳剂、软膏剂、滴眼剂或滴耳剂。在所述药物组合物的其它实施方案中，其还包含一种或多种另外的治疗剂。
另一方面，本发明提供了式I化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、或前药在制备用于预防、治疗、或减轻由CDK激酶尤其CDK7激酶异常活性介导的障碍或疾病的药物中的用途。
另一方面，本发明提供了物质Z在制备用于预防、治疗、或减轻由CDK激酶异常活性介导的障碍或疾病的药物中的用途；
所述CDK激酶优选为CDK7激酶；
所述物质Z为式I化合物、其立体异构体、几何异构体、互变异构体、药学上可接受的盐、或前药，或者如上所述的药物组合物。
另一方面，本发明提供的所述通式(I)所示的含氮杂环类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药或者如上所述的药物组合物用于制备治疗或预防受试者的增殖性疾病(例如，癌症(例如，白血病、黑素瘤、多发性骨髓瘤)、良性赘生物、血管发生、炎性疾病、自身炎性疾病和自身免疫性疾病)的涉及该化合物或组合物的方法，所述的肿瘤独立地选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、纤维瘤、肉瘤、基底细胞癌、胶质瘤、肾癌、黑色素瘤、骨癌、甲状腺癌、鼻咽癌、胰腺癌等；所述的自身免疫疾病独立地选自类风湿性关节炎、系统性红斑狼疮、特发性血小板减少性紫癜、溶血性贫血或银屑病；所述的炎症疾病独立地选自骨关节炎、痛风性关节炎、溃疡性结肠炎和/或炎性肠病等；所述的感染疾病独立地选自败 血症、脓毒性休克、内毒素性休克、革兰氏阴性败血症和/或中毒性休克综合征。
另一方面，本发明提供了一种物质Z在制备治疗或预防增殖性疾病的药物中的应用；所述增殖性疾病可为癌症(例如，白血病、黑素瘤、多发性骨髓瘤)、良性赘生物、血管发生、炎性疾病、感染疾病、自身炎性疾病或自身免疫性疾病；所述的癌症独立地选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、纤维瘤、肉瘤、基底细胞癌、胶质瘤、肾癌、黑色素瘤、骨癌、甲状腺癌、鼻咽癌或胰腺癌；所述的自身免疫疾病独立地选自类风湿性关节炎、系统性红斑狼疮、特发性血小板减少性紫癜、溶血性贫血或银屑病；所述的炎性疾病独立地选自骨关节炎、痛风性关节炎、溃疡性结肠炎和/或炎性肠病；所述的感染疾病独立地选自败血症、脓毒性休克、内毒素性休克、革兰氏阴性败血症和/或中毒性休克综合征；
所述物质Z为通式(I)所示的含氮杂环类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药或者如上所述的药物组合物。
另一方面，本发明提供了一种治疗或预防由CDK激酶异常活性介导的障碍或疾病的方法，其包括向有此需要的患者给予治疗有效量的如上所述的物质Z；
所述CDK激酶优选为CDK7激酶；
所述物质Z为通式(I)所示的含氮杂环类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药或者如上所述的药物组合物。
术语
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解，上述简述和下文的详述为示例性且仅用于解释，而不对本发明主题作任何限制。在本申请中，除非另有具体说明，否则使用单数时也包括复数。必须注意，除非文中另有清楚的说明，否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构 部分和化合物。
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH2O-等同于-OCH2-。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。
在本申请中，术语“卤素”是指氟、氯、溴或碘；“羟基”是指-OH基团；“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基；“羰基”是指-C(＝O)-基团；“硝基”是指-NO2；“氰基”是指-CN；“氨基”是指-NH2；“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基；“羧基”是指-COOH。
在本申请中，作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中)，术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。
在本申请中，作为基团或是其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
在本申请中，作为基团或是其它基团的一部分，术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙炔基、丙-1-炔基、丁-1-炔基、戊-1-烯-4-炔基等。
在本申请中，作为基团或是其它基团的一部分，术语“环烷基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基，其可包括稠合环体系、桥环体系或螺环体系，具有例如3至15个碳原子，优选具有3至10个碳原子，更优选具有3至8个碳原子，且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明，环烷基中的碳原子可以任选地被氧化。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、 8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。
在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧、硫和硒的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中，作为基团或是其它基团的一部分，术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中，术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、 异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中，术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
在本申请中，“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
“立体异构体”是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。
在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、 月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型，本发明旨在包括各种晶型及其混合物。
通常，结晶化作用会产生本发明化合物的溶剂化物。本发明中使用的术语“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。溶剂可以是水，该情况下的溶剂化物为水合物。或者，溶剂可以是有机溶剂。因此，本发明的化合物可以以水合物存在，包括单水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等，以及相应的溶剂化形式。本发明化合物可形成真实的溶剂化物，但在某些情况下，也可以仅保留不定的水或者水加上部分不定溶剂的混合物。本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。本发明化合物的溶剂化物也包含在本发明的范围之内。
本发明还包括上述化合物的前药。在本申请中，术语“前药”表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。因此，术语“前药”是指本发明的化合物的药学上可接受的代谢前体。当被给予有需要的个体时，前药可以不具有活性，但在体内被转化成本发明的活性化合物。前药通常在体内迅速转化，而产生本发明的母体化合物，例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。前药包括已知的氨基保护基和羧基保护基。具体的前药制备方法可参照Saulnier,M.G.,et al.,Bioorg.Med.Chem.Lett.1994,4,1985-1990；Greenwald,R.B.,et al.,J.Med.Chem.2000,43,475。
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包 含的任意组分相互作用。
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“肿瘤”，“细胞增殖异常相关疾病”等包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义：
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；
(ii)抑制疾病或病症，即遏制其发展；
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳 基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organic Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明涉及具有通式(I)结构特征的新型化合物,选择性抑制CDK7的酶活，显著抑制多种肿瘤细胞的生长，是一类全新作用机制的治疗药物。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。除非另外说明、否则百分比和份数是重量百分比和重量份数。
各实施例中，实验仪器说明(例如1H NMR由Varian Mercury-300或Varian Mercury-400型核磁共振仪记录，13C NMR由Varian Mercury-400或Varian Mercury-500型或Varian Mercury-600型核磁共振仪记录，化学位移以δ(ppm)表示；质谱由Finnigan/MAT-95(EI)与Finnigan LCQ/DECA and Micromass Ultra Q-TOF(ESI)型质谱仪记录；反相制备HPLC分离用硅胶为200-300目)。
其中，化学式或英文字母缩写代表的试剂中文名称表如下：
iPrOH：异丙醇；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；Raney Ni：雷尼镍；1,4-dioxane：1,4-二氧六环；NaH：氢化钠；H2O：水；Pd/C：钯/炭；H2：氢气；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；Boc2O：二碳酸二叔丁酯；NBS：N-溴代丁二酰亚胺；NCS：N-氯代丁二酰亚胺；NIS：N-碘代丁二酰亚胺；MeCN：乙腈；DIPEA/DIEA：N,N-二异丙基乙胺；NaBH4：硼氢化钠；AcOH：醋酸；ethyl acetate：乙酸乙酯；NaBH3CN：氰基硼氢化钠；K2CO3：碳酸钾；Cs2CO3：碳酸铯；nBuLi：正丁基锂；LiAlH4：氢化铝锂；Pd(dppf)Cl2：[1,1’-双(二苯基膦基)二茂铁]二氯化钯；KOAc：醋酸钾。Fumaronitrile：富马酸腈；P(nBu)3：三正丁基膦；LDA：二异丙基氨基锂；LiOH：氢氧化锂；MeI：碘甲烷；EtI：碘乙烷；(CH2O)n：多聚甲醛；HCO2H：甲酸；CH3COCl：乙酰氯；LCMS：液相色谱质谱联用；Xantphos：4,5-双二苯基膦-9,9-二甲基氧杂蒽；TLC：薄层色谱法；eq.：当量；DCE：1，2-二氯乙烷；HEPES：4-羟乙基哌嗪乙磺酸；EGTA：乙二醇双(2-氨基乙基醚)四乙酸；DTT：二硫苏糖醇
关键中间体的制备：
实施例制备
实施例1：(R)-1-(2-((4-((8-异丙基-2-甲基嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
第一步：在氮气保护下将中间体A(490mg,2.02mmol)，4-氨基哌啶-1-甲酰基叔丁酯(421mg,2.12mmol)，DIEA(800mg,6.21mmol)溶于乙腈(50mL)中，70℃下反应4h。反应液减压浓缩，粗产品经硅胶柱层析(PE:EA＝2:1)纯化得到白色固体中间体产物(710mg)。LC-MS[M+H]+:m/z 407.6。
第二步：在冰水浴冷却下，向上述中间体产物(700mg,1.72mmol)的二氯甲烷(50mL)中，加入间氯过氧苯甲酸(596mg,3.48mmol)。反应混合物在室温下搅拌2个小时。LC-MS检测，原料基本消失。反应混合物用饱和碳酸氢钠水溶液(30mL)洗涤两次，然后依次用硫代硫酸钠水溶液(30mL)和饱和食盐水(30mL)各洗涤一次。分离的有机相减压浓缩，所得粗产品经硅胶柱层析(PE:EA＝1:1)纯化得到黄色固体中间体产物(320mg)。LC-MS[M+H]+:m/z 439.6。
第三步：在室温下，向上述中间体产物(180mg,0.41mmol)的无水四氢呋喃(20mL)中,加入甲基溴化镁的四氢呋喃溶液(1M，1.6mL，1.6mmol)。室温下，搅拌反应3小时。反应液降到零度，用饱和碳酸氢钠水溶液(30mL)淬灭反应液。向反应混合物中加入乙酸乙酯(30mL)。分离有机相，水相用乙酸乙酯(30mL)萃取两次。合并的有机相经MgSO4干燥，过滤，浓缩。粗产物经HPLC制备纯化得到黄色固体产物(84mg)。LC-MS[M+H]+:m/z 375.5。
第四步：在室温下，向上述中间体产物(80mg,0.21mmol)的无水二氯甲烷溶液(10mL)中,加入三氟醋酸(1mL)。反应混合物在室温下搅拌反应1小时。LC-MS检测反应基本完全。直接减压浓缩反应液，得到粗品白色固体中间体产物(58mg)。LC-MS[M+H]+:m/z 275.4。
第五步：在室温下，向上述中间体产物(58mg,0.21mmol)的DMF溶液(10mL)中,加入(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯(78mg，0.21mmol)。反应混合物在80度搅拌反应72小时。LC-MS检测反应基本完全。向反应液中加入饱和碳酸氢钠水溶液(30mL),用乙酸乙酯(30mL)萃取两次。合并的有机相减压浓缩，得到粗品白色固体中间体产物(25mg)。LC-MS[M+H]+:m/z 474.6。
第六步：在室温下，向上述中间体产物(25mg,0.05mmol)的无水二氯甲烷溶液(5mL)中,加入三氟醋酸(1mL)。反应混合物在室温下搅拌反应1小时。LC-MS检测反应基本完全。直接减压浓缩反应液，得到粗品白色固体中间体产物(15mg)。LC-MS[M+H]+:m/z 374.5。
第七步：在室温下，向上述中间体产物(8mg,0.04mmol)和三乙胺(20mg,0.20mmol)的无水二氯甲烷溶液(5mL)中,加入丙烯酰氯(10mg,0.11mmol)。反应混合物在室温下搅拌反应1小时。LC-MS检测反应基本完全。直接减压浓缩反应液，粗产物经HPLC制备得到白色固体目标产物(10mg)。LC- MS[M+H]+:m/z 428.2。1H NMR(400MHz,DMSO-d6):δ9.51(s,1H),8.76(d,J＝8.0Hz,1H),8.02(d,J＝6.8Hz,1H),6.85-6.77(m,1H),6.16(d,J＝16.8Hz,1H),5.75(d,J＝12.4Hz,1H),4.37-4.32(m,2H),4.28-4.04(m,5H),3.97-3.88(m,3H),3.55-3.12(m,5H),2.40(s,3H),2.07-1.97(m,4H),1.27(d,J＝7.2Hz,6H)。
实施例2：(R)-1-(2-((4-((-8-异丙基-2-(三氟甲基)嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
第一步：在氮气保护下，向中间体B(500mg,2.25mmol)的DMF溶液(10mL)中，加入N-碘代丁二酰亚胺(506mg，2.25mmol)。该反应混合物在室温下反应20个小时。LC-MS检测反应基本完成。向反应液加入饱和碳酸氢钠水溶液(30mL)，分离有机相。有机相经饱和食盐水洗涤一次，然后用无水硫酸钠干燥。过滤有机相，减压浓缩后，所得粗品经硅胶柱层析(石油醚/乙酸乙酯＝4:1)纯化得到黄色固体中间体产物(528mg)。LC-MS[M+H]+:m/z 331.0。
第二步：在氮气保护下，向上述中间体化合物(525mg,1.59mmol)的乙腈溶液(10mL)中，加入三氯氧磷(5mL)。该反应混合物加热到80度，反应2个小时。减压浓缩反应液，得到黄色固体粗产物(480mg)。LC-MS[M+H]+:m/z 349.5。
第三步：在氮气保护下将上述中间体化合物(480mg,1.38mmol)，4-氨基哌啶-1-甲酰基叔丁酯(410mg,2.05mmol)，DIEA(800mg,6.21mmol)溶于乙腈(50mL)中，70℃下反应4h。反应液减压浓缩，粗产品经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝2:1)纯化得到白色固体中间体产物(560mg)。LC-MS[M+H]+:m/z 513.3。
第四步：在室温下，向上述中间体(550mg，1.09mmol)的1,4-二氧六环/水(12mL/4mL)溶液中加入异丙烯基硼酸(96mg,1.11mmol)，四(三苯基膦)钯(240mg,0.2mmol)和碳酸钠粉末(560mg,5.3mmol)，反应混合物在100℃在氩气下搅拌过夜。反应完毕，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水Na2SO4干燥，过滤，减压浓缩，硅胶快速柱色谱法纯化得到白色固体产物(310mg)。LC-MS  m/z:427.2[M+H]+。
第五步：在室温下，向上述中间体化合物(310mg,0.73mmol)的甲醇溶液(20mL)中，加入5％钯/碳(50mg)。在1个大气压的氢气氛围下，室温搅拌6个小时。LC-MS检测反应完成。硅藻土过滤反应液，甲醇洗涤两次。合并的有机相减压浓缩，得到粗品白色固体产物(210mg)。LC-MS m/z:429.4[M+H]+。
第六步：在室温下，向上述中间体产物(201mg,0.47mmol)的无水二氯甲烷溶液(10mL)中,加入三氟醋酸(3mL)。反应混合物在室温下搅拌反应2小时。LC-MS检测反应基本完全。直接减压浓缩反应液，得到粗品白色固体中间体产物(140mg)。LC-MS[M+H]+:m/z 329.3。
第七步：在室温下，向上述中间体产物(135mg,0.41mmol)的DMF溶液(10mL)中,加入(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯(156mg，0.42mmol)。反应混合物在80度搅拌反应72小时。LC-MS检测反应基本完全。向反应液中加入饱和碳酸氢钠水溶液(30mL),用乙酸乙酯(30mL)萃取两次。合并的有机相减压浓缩，所得粗产物经HPLC制备纯化得到白色固体中间体产物(65mg)。LC-MS[M+H]+:m/z 528.6。
第八步：在室温下，向上述中间体产物(65mg,0.12mmol)的无水二氯甲烷溶液(10mL)中,加入三氟醋酸(3mL)。反应混合物在室温下搅拌反应1小时。LC-MS检测反应基本完全。直接减压浓缩反应液，得到粗品白色固体中间体产物(35mg)。LC-MS[M+H]+:m/z 528.5。
第九步：在室温下，向上述中间体化合物(35mg,0.08mmol)和三乙胺(20mg,0.20mmol)的无水二氯甲烷溶液(5mL)中,加入丙烯酰氯(10mg,0.11mmol)。反应混合物在室温下搅拌反应1小时。LC-MS检测反应基本完全。减压浓缩反应液，粗产物经HPLC制备得到白色固体目标产物(20mg)。LC-MS[M+H]+:m/z 482.5。1H NMR(400MHz,MeOD)δ7.56(s,1H),6.75(dd,J＝16.7,9.5Hz,1H),6.27(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.66-2.51(m,2H),2.35(m,2H),2.15-2.03(m,2H),1.88-1.49(m,2H),1.31(d,J＝6.9Hz,6H).
实施例3：(R)-1-(2-((4-((2-环丙基-8-异丙基-嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例1的合成方法，用环丙基溴化镁代替甲基溴化镁制备得到白色固体实施例3化合物。LC-MS[M+H]+:m/z 454.2。1H NMR(400MHz,DMSO-d6):δ9.51(s,1H),8.76(d,J＝8.0Hz,1H),7.98(d,J＝6.8Hz,1H),6.95-6.65(m,1H),6.17(m,1H),5.75(m,1H),4.37-4.30(m,2H),4.28-4.04(m,5H),3.97-3.88(m,3H),3.20-2.98(m,5H),2.49-1.97(m,5H),1.27(d,J＝7.2Hz,6H),1.18-0.96(m,2H),0.95-0.85(m,2H)。
实施例4：(R)-1-(2-((4-((3-异丙基-5-甲基吡唑并[1,5,-a]嘧啶-7-基)氨基)哌啶-1-基)甲基)吗啡啉)丙 -2-烯基-1-酮
第一步：在室温下，向化合物C(500mg,2.18mmol)的DMF溶液(15mL)中，加入4-氨基哌啶-1-甲酰基叔丁酯(480mg,2.40mmol)和DIEA(844mg,6.55mmol)。该反应混合物室温搅拌过夜。LCMS检测反应完全。向反应液中加入饱和碳酸氢钠水溶液(30mL)后，用乙酸乙酯(30mL)萃取两次。合并的有机相减压浓缩，所得粗产品经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1:2)纯化得到产品黄色固体中间体产物(790mg)。LC-MS[M+H]+:m/z 394.2/396.2。
第二步：向上述中间体化合物(700mg,1.78mmol)的二氯甲烷溶液(20mL)中，加入三氟乙酸(3mL)。反应混合物在室温下搅拌反应2个小时。LCMS检测反应完全。减压浓缩反应液，得到黄色固体粗品中间体产物(520mg)。LC-MS[M+H]+:m/z 294.1/296.1。
第三步：向上述中间体化合物(520mg,1.77mmol)的DMF溶液(15mL)中，加入(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯(659mg,1.77mmol)和DIEA(1.52g,11.78mmol)。该反应混合物在80℃下搅拌反应70小时。LCMS检测基本反应完全。向反应液中加入饱和碳酸氢钠水溶液(30mL)后，用乙酸乙酯(30mL)萃取两次。合并的有机相减压浓缩，所得粗产物经HPLC制备得到产品黄色固体中间体产物(210mg)。LC-MS[M+H]+:m/z 493.3。
第四步：在氮气保护下，向上述中间体化合物(190mg,0.38mmol)的二氯甲烷溶液(20mL)中，加入二甲基锌(222mg,2.31mmol)和Pd(dppf)Cl2(29mg,0.04mmol)。反应混合物加热到80℃搅拌反应过夜。LCMS检测基本反应完全。向反应液中加入饱和碳酸氢钠水溶液(10mL)。分离的有机相减压浓缩，所得粗产品经HPLC制备得到黄色固体中间体产物(52mg)。LC-MS[M+H]+:m/z 473.3。
第五步：室温下，向上述中间体化合物(52mg,0.11mmol)的二氯甲烷溶液(5mL)中，加入三氟乙酸(1mL)。该反应混合物在室温下搅拌反应2个小时。LCMS检测反应基本完全。直接减压浓缩反应液得到黄色固体中间体产物(40mg)。LC-MS[M+H]+:m/z 373.3。
第六步：室温下，向上述中间体化合物(40mg,0.11mmol)的四氢呋喃/水混合溶液(1:1,5mL)中，加入丙烯酰氯(20mg,0.21mmol)和碳酸氢钠粉末(47mg,0.56mmol)。该反应混合物在室温下搅拌过夜。LC-MS检测反应基本完全。向反应混合物中加入乙酸乙酯(20mL)和水(20mL)。分离的有机相减压浓缩，所得粗产物经HPLC制备纯化得到白色固体实施例4化合物(11mg)。LC-MS[M+H]+:m/z427.1。1H NMR(400MHz,MeOD)δ7.87(s,1H),6.75(dd,J＝16.5,9.5Hz,1H),6.23(dd,J＝16.8,1.9Hz,1H),6.05(s,1H),5.77(d,J＝10.8Hz,1H),4.41(m,1H),3.99(m,2H),3.72-3.44(m,3H),3.24(d,J＝6.8Hz, 1H),2.98(m,3H),2.66-2.53(m,2H),2.48(s,3H),2.35(m,2H),2.12-2.01(m,2H),1.88-1.49(m,2H),1.31(d,J＝6.9Hz,6H)。
实施例5：(R)-1-(2-((4-((3-异丙基-5-(三氟甲基)吡唑并[1,5,-a]嘧啶-7-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
第一步：将4-异丙基-1H-吡唑-5-氨(1.25g,10.0mmol)和4,4,4-三氟-3-氧代丁酸乙酯(2.31g,12.5mmol)溶于冰乙酸溶液(100mL)中。该反应混合物加热到110度反应6个小时。LCMS检测反应基本完全。减压浓缩反应液，所得粗产品经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1:4)纯化得到产品黄色固体中间体产物(890mg)。LC-MS[M+H]+:m/z 246.2。
第二步：在氮气保护下，向上述中间体化合物(890mg,3.63mmol)的DMF溶液(20mL)中，加入三氯氧磷(5mL)。该反应混合物加热到110度，反应2个小时。减压浓缩反应液，所得粗产物经HPLC制备得到黄色油状产物(580mg)。LC-MS[M+H]+:m/z 264.6。
第三步：在室温下，向上述中间体化合物(550mg,2.09mmol)的DMF溶液(20mL)中，加入4-氨基哌啶-1-甲酰基叔丁酯(480mg,2.40mmol)和DIEA(844mg,6.55mmol)。该反应混合物室温搅拌过夜。向反应液中加入饱和碳酸氢钠水溶液(30mL)后，用乙酸乙酯(40mL)萃取两次。合并的有机相减压浓缩，所得粗产品经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1:2)纯化得到产品黄色固体中间体产物(670mg)。LC-MS[M+H]+:m/z 428.5。
第四步：向上述中间体化合物(670mg,1.57mmol)的二氯甲烷溶液(20mL)中，加入三氟乙酸(3mL)。反应混合物在室温下搅拌反应2个小时。LCMS检测反应完全。减压浓缩反应液，得到黄色固体粗品中间体产物(510mg)。LC-MS[M+H]+:m/z 328.3。
第五步：向上述中间体化合物(510mg,1.56mmol)的DMF溶液(15mL)中，加入(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯(579mg,1.56mmol)和DIEA(1.52g,11.78mmol)。该反应混合物在80℃下搅拌反应70小时。LCMS检测基本反应完全。向反应液中加入饱和碳酸氢钠水溶液(30mL)后，用乙酸乙酯(30mL)萃取两次。合并的有机相减压浓缩，所得粗产物经HPLC制备得到产品黄色固体中间体产物(130mg)。LC-MS[M+H]+:m/z 527.6。
第六步：室温下，向上述中间体化合物(65mg,0.12mmol)的二氯甲烷溶液(5mL)中，加入三氟乙酸(1mL)。该反应混合物在室温下搅拌反应2个小时。LCMS检测反应基本完全。直接减压浓缩反应液得到黄色固体中间体产物(51mg)。LC-MS[M+H]+:m/z 426.5。
第七步：室温下，向上述中间体化合物(51mg,0.12mmol)的四氢呋喃/水混合溶液(1:1,5mL)中， 加入丙烯酰氯(20mg,0.21mmol)和碳酸氢钠粉末(47mg,0.56mmol)。该反应混合物在室温下搅拌过夜。LC-MS检测反应基本完全。向反应混合物中加入乙酸乙酯(20mL)和水(20mL)。分离的有机相减压浓缩，所得粗产物经HPLC制备纯化得到白色固体实施例5化合物(15mg)。LC-MS[M+H]+:m/z481.3。1H NMR(400MHz,MeOD)δ7.97(s,1H),6.75(dd,J＝16.5,9.5Hz,1H),6.27(dd,J＝16.8,1.9Hz,1H),6.15(s,1H),5.77(d,J＝10.8Hz,1H),4.41(m,1H),3.99(m,2H),3.72-3.44(m,3H),3.24(d,J＝6.8Hz,1H),2.98(m,3H),2.66-2.53(m,2H),2.35(m,2H),2.12-2.01(m,2H),1.88-1.45(m,2H),1.29(d,J＝7.2Hz,6H)。
实施例6：(R)-1-(2-((4-((5-环丙基-3-异丙基吡唑并[1,5,-a]嘧啶-7-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
第一步：在室温下，向(R)-2-((4-((5-氯-3-异丙基吡唑并[1,5,-a]嘧啶-7-基)氨基)哌啶-1-基)甲基)吗啡啉-4-甲酸叔丁酯(95mg,0.19mmol)的1,4-二氧六环/水(10mL/2mL)溶液中加入环丙基硼酸(23mg,0.26mmol)，四(三苯基膦)钯(240mg,0.2mmol)和碳酸钠粉末(560mg,5.3mmol)，反应混合物在80℃在氮气下搅拌过夜。反应完毕，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水Na2SO4干燥，过滤，减压浓缩，硅胶快速柱色谱法纯化得到白色固体产物(45mg)。LC-MS m/z:499.6[M+H]+。
第二步：室温下，向上述中间体化合物(45mg,0.09mmol)的二氯甲烷溶液(5mL)中，加入三氟乙酸(1mL)。该反应混合物在室温下搅拌反应2个小时。LCMS检测反应基本完全。直接减压浓缩反应液得到黄色固体中间体产物(35mg)。LC-MS[M+H]+:m/z 398.5。
第三步：室温下，向上述中间体化合物(36mg,0.09mmol)的四氢呋喃/水混合溶液(1:1,5mL)中，加入丙烯酰氯(15mg,0.15mmol)和碳酸氢钠粉末(47mg,0.56mmol)。该反应混合物在室温下搅拌过夜。LC-MS检测反应基本完全。向反应混合物中加入乙酸乙酯(20mL)和水(20mL)。分离的有机相减压浓缩，所得粗产物经HPLC制备纯化得到白色固体实施例6化合物(5mg)。LC-MS[M+H]+:m/z 453.6。1H NMR(400MHz,MeOD):δ7.83(s,1H),6.75(dd,J＝16.5,9.5Hz,1H),6.25(dd,J＝16.8,1.9Hz,1H),6.05(s,1H),5.77(d,J＝10.8Hz,1H),4.41(m,1H),3.99(m,2H),3.72-3.44(m,3H),3.24(d,J＝6.8Hz,1H),2.98(m,3H),2.66-2.53(m,2H),2.48(m,1H),2.35(m,2H),2.12-2.01(m,2H),1.88-1.49(m,2H),1.31(d,J＝6.9Hz,6H),0.68(m,2H),0.54(m,2H)。
实施例7：(R)-1-(2-((4-((3-异丙基-6-甲基咪唑并[1,2,-b]嘧啶-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
第一步：在室温下，向化合物D(500mg,1.82mmol)的1,4-二氧六环溶液(15mL)中，加入4-氨基哌啶-1-甲酰基叔丁酯(385mg,1.92mmol)和DIEA(844mg,6.55mmol)。该反应混合物加热到90度搅拌反应8个小时。LCMS检测反应完全。向反应液中加入饱和碳酸氢钠水溶液(30mL)后，用乙酸乙酯(30mL)萃取两次。合并的有机相减压浓缩，所得粗产品经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1:2)纯化得到产品黄色固体中间体产物(620mg)。LC-MS[M+H]+:m/z 394.2/396.2。
第二步：氮气保护下，向上述中间体化合物(300mg,0.76mmol)的1,4-二氧六环/水的混合溶液(3:1，4mL)中加入三甲基环三硼氧烷(190mg,1.51mmol)，四(三苯基膦)钯(240mg,0.2mmol)和碳酸钠粉末(280mg,2.64mmol)。反应混合物在微波下，加热到90度下反应6个小时。向反应液加入水(10mL)后，用乙酸乙酯(10mL)萃取两次。合并的有机相用饱和食盐水洗涤，无水Na2SO4干燥，过滤，减压浓缩。所得粗产物经硅胶快速柱色谱法纯化得到白色固体产物(145mg)。LC-MS m/z:374.5[M+H]+。
第三步：室温下，向上述中间体化合物(145mg,0.39mmol)的二氯甲烷溶液(5mL)中，加入三氟乙酸(1mL)。该反应混合物在室温下搅拌反应2个小时。LCMS检测反应基本完全。直接减压浓缩反应液得到黄色固体中间体产物(95mg)。LC-MS[M+H]+:m/z 274.3。
第四步：向上述中间体化合物(95mg,0.35mmol)的DMF溶液(15mL)中，加入(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯(130mg,0.35mmol)和DIEA(200mg,1.55mmol)。该反应混合物在80℃下搅拌反应64小时。LCMS检测基本反应完全。向反应液中加入饱和碳酸氢钠水溶液(30mL)后，用乙酸乙酯(30mL)萃取两次。合并的有机相减压浓缩，所得粗产物经HPLC制备得到产品黄色固体中间体产物(45mg)。LC-MS[M+H]+:m/z 473.6。
第五步：室温下，向上述中间体化合物(44mg,0.09mmol)的二氯甲烷溶液(5mL)中，加入三氟乙酸(1mL)。该反应混合物在室温下搅拌反应2个小时。LCMS检测反应基本完全。直接减压浓缩反应液得到黄色固体中间体产物(30mg)。LC-MS[M+H]+:m/z 373.5。
第六步：室温下，向上述中间体化合物(30mg,0.08mmol)的四氢呋喃/水混合溶液(1:1,5mL)中，加入丙烯酰氯(15mg,0.15mmol)和碳酸氢钠粉末(24mg,0.29mmol)。该反应混合物在室温下搅拌过夜。LC-MS检测反应基本完全。向反应混合物中加入乙酸乙酯(20mL)和水(20mL)。分离的有机相减压浓缩，所得粗产物经HPLC制备纯化得到白色实施例7化合物(9mg)。LC-MS[M+H]+:m/z 427.3。1H NMR(400MHz,MeOD)δ7.57(s,1H),6.75(dd,J＝16.8,9.5Hz,1H),6.65(s,1H),6.25(dd,J＝16.8,1.9 Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.66-2.51(m,2H),2.37(m,2H),2.24(s,3H),2.15-2.01(m,2H),1.88-1.49(m,2H),1.28(d,J＝6.9Hz,6H).
实施例8：(R)-1-(2-((4-((3-异丙基-6-(三氟甲基)咪唑并[1,2,-b]嘧啶-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
第一步：室温下，向6-(三氟甲基)哒嗪-3-胺(960mg,5.89mmol)和碳酸氢钠(600mg,7.14mmol)的甲醇溶液(10mL)中，加入液溴(950mg，5.94mmol)。该反应混合物在室温下搅拌2个小时。向反应液加入饱和碳酸氢钠水溶液(50mL)后，用乙酸乙酯(50mL)萃取两次。合并的有机相饱和食盐水洗涤后，减压浓缩，得到黄色粗品中间体化合物(1.3g)。LC-MS[M+H]+:m/z 243。
第二步：将上述中间体化合物(1.3g,5.37mmol)和2-溴-3-甲基丁醛(886mg,5.37mmol)溶于无水乙醇(100mL)中，反应混合物加热到100度回流过夜。减压浓缩反应液，粗产品经硅胶柱层析(石油醚/乙酸乙酯＝2:1)纯化得到白色固体化合物(1.25g)。LC-MS[M+H]+:m/z 308.1/310.1。
第三步：参考实施例7的第一步合成方法，用上述中间体(600mg,1.94mmol)与4-氨基哌啶-1-甲酰基叔丁酯反应，得到白色固体中间体化合物(480mg)。LC-MS[M+H]+:m/z 428.4。
第四步：参考实施例7的第三步合成方法，用上述中间体(480mg,1.12mmol)与三氟乙酸反应，得到白色固体中间体化合物(360mg)。LC-MS[M+H]+:m/z 328.3。
第五步：参考实施例7的第四步合成方法，用上述中间体(360mg,1.10mmol)与(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯反应，得到白色固体中间体化合物(120mg)。LC-MS[M+H]+:m/z527.6。
第六步：参考实施例7的第五步合成方法，用上述中间体(42mg,0.08mmol)与三氟乙酸反应，得到白色固体中间体化合物(30mg)。LC-MS[M+H]+:m/z 427.5。
第七步：参考实施例7的第六步合成方法，用上述中间体(30mg,0.07mmol)与丙烯酰氯反应，得到白色固体实施例8化合物(10mg)。LC-MS[M+H]+:m/z 481.2。1H NMR(400MHz,MeOD)δ7.67(s,1H),6.73(dd,J＝16.8,9.5Hz,1H),6.35(s,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.66-2.51(m,2H),2.37(m,2H),2.15-2.01(m,2H),1.88-1.49(m,2H),1.28(d,J＝6.9Hz,6H).
实施例9：(R)-1-(2-((4-((6-环丙基-3-异丙基咪唑并[1,2,-b]嘧啶-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例7的合成方法，用环丙基溴化镁代替三甲基环三硼氧烷制备得到白色固体实施例9化合物。LC-MS[M+H]+:m/z 453.2。1H NMR(400MHz,MeOD)δ7.55(s,1H),6.78(dd,J＝16.8,9.5Hz,1H),6.69(s,1H),6.27(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.66-2.51(m,2H),2.37(m,2H),2.29(s,3H),2.15-2.01(m,2H),1.88-1.49(m,2H),1.28(d,J＝6.9Hz,6H),0.65(m,2H),0.52(m,2H)。
实施例10：(R)-1-(2-((4-((3-异丙基-6-甲基咪唑并[1,2,-a]吡嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例7的合成方法，用中间体E代替中间体D制备得到白色固体实施例10化合物。LC-MS[M+H]+:m/z 427.2。1H NMR(400MHz,MeOD)δ7.65(s,1H),6.73(dd,J＝16.8,9.5Hz,1H),6.73(s,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.66-2.51(m,2H),2.48(s,3H),2.37(m,2H),2.15-2.01(m,2H),1.88-1.45(m,2H),1.32(d,J＝6.9Hz,6H)。
实施例11：(R)-1-(2-((4-((3-异丙基-6-(三氟甲基)咪唑并[1,2,-a]吡嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
第一步：向3-氯-5-(三氟甲基)哒嗪-2-胺(580mg,2.93mmol)的乙醇溶液(20mL)中，缓慢加入氯代乙醛水溶液(50％，10mL)。该反应混合物在微波下加热到150度反应30分钟。LC-MS检测反应基本完成。减压浓缩反应液，残余物溶于二氯甲烷(20mL)后，加入饱和碳酸氢钠水溶液(30mL)，分离有机相。有机相经饱和食盐水洗涤一次，然后用无水硫酸钠干燥。过滤有机相，减压浓缩后，所得粗品经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝4:1)纯化得到黄色固体中间体产物(428mg)。LC-MS[M+H]+:m/z 222.0/224.0。
第二步：在氮气保护下，向上述中间体化合物(428mg,1.93mmol)的DMF溶液(10mL)中，加入N-碘代丁二酰亚胺(434mg，1.93mmol)。该反应混合物在室温下反应20个小时。LC-MS检测反应基本完成。向反应液加入饱和碳酸氢钠水溶液(30mL)，分离有机相。有机相经饱和食盐水洗涤一次，然后用无水硫酸钠干燥。过滤有机相，减压浓缩后，所得粗品经硅胶柱层析(石油醚/乙酸乙酯＝4:1)纯化得到黄色固体中间体产物(520mg)。LC-MS[M+H]+:m/z 347.8/349.8。
第三步：参照实施例2的第三步合成，用上述中间体(520mg,1.50mmol)与4-氨基哌啶-1-甲酰基叔丁酯反应，生成白色固体中间体化合物(420mg)。LC-MS[M+H]+:m/z 512.3。
第四步：参照实施例2的第四步合成，用上述中间体(420mg,0.82mmol)与异丙烯基硼酸反应，生成白色固体中间体化合物(220mg)。LC-MS[M+H]+:m/z 426.4。
第五步：参照实施例2的第五步合成，用上述中间体(220mg,0.52mmol)在钯/碳催化下发生氢化反应，生成白色固体中间体化合物(130mg)。LC-MS[M+H]+:m/z 428.4。
第六步：参照实施例2的第六步合成，用上述中间体(120mg,0.28mmol)与三氟乙酸反应，生成白色固体中间体化合物(88mg)。LC-MS[M+H]+:m/z 328.2。
第七步：参照实施例2的第七步合成，用上述中间体(85mg,0.26mmol)与(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯反应，生成白色固体中间体化合物(43mg)。LC-MS[M+H]+:m/z 527.6。
第八步：参照实施例2的第八步合成，用上述中间体(43mg,0.08mmol)与三氟乙酸反应，生成白色固体中间体化合物(23mg)。LC-MS[M+H]+:m/z 427.4。
第九步：参照实施例2的第九步合成，用上述中间体(23mg,0.05mmol)与丙烯基酰氯反应，生成白色固体中间体化合物(12mg)。LC-MS[M+H]+:m/z 481.4。1H NMR(400MHz,MeOD)δ7.69(s,1H),6.73(dd,J＝16.8,9.5Hz,1H),6.53(s,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.66-2.51(m,2H),2.37(m,2H),2.15-2.01(m,2H),1.88-1.45(m,2H),1.30(d,J＝7.2Hz,6H)。
实施例12：(R)-1-(2-((4-((3-异丙基-6-(三氟甲基)咪唑并[1,2,-a]吡嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例10的合成方法，用环丙基硼酸代替三甲基环三硼氧烷制备得到白色固体实施例12化合物。LC-MS[M+H]+:m/z 427.2。1H NMR(400MHz,MeOD)δ7.65(s,1H),6.73(dd,J＝16.8,9.5Hz,1H),6.73(s,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.66-2.51(m,2H),2.40-2.37(m,3H),2.15-2.01(m,2H),1.88-1.45(m,2H),1.30(d,J＝6.9Hz,6H),0.68(m,2H),0.53(m,2H)。
实施例13：(R)-1-(2-((4-((7-异丙基-6-甲基咪唑并[2,1,-f][1,2,4]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
第一步：向1-氨基-1H-咪唑-2-甲酸乙酯(1.61g,10.4mmol)的乙醇溶液(20mL)中，加入乙基脒(10mL)。该反应混合物加热到95度反应96小时。LC-MS检测反应基本完成。反应液降至室温，有白色 固体析出。固体过滤后，干燥得到白色固体中间体产物(528mg)。LC-MS[M+H]+:m/z 151.1。
第二步：参照实施例2的第一步合成方法，用上述中间体化合物(528mg,3.52mmol)与N-碘代丁二酰亚胺反应，得到白色固体中间体(620mg)。LC-MS[M+H]+:m/z 277.0。
第三步：参照实施例2的第二步合成方法，用上述中间体化合物(652mg,2.36mmol)与三氯氧磷反应，得到白色固体中间体(660mg)。LC-MS[M+H]+:m/z 294.9。
第四步：参照实施例2的第三步合成方法，用上述中间体化合物(660mg,2.24mmol)与4-氨基哌啶-1-甲酰基叔丁酯反应，得到白色固体中间体(760mg)。LC-MS[M+H]+:m/z 459.1。
第五步：参照实施例2的第四步合成方法，用上述中间体化合物(760mg,1.66mmol)与异丙烯基硼酸反应，得到白色固体中间体(460mg)。LC-MS[M+H]+:m/z 373.2。
第六步：参照实施例2的第五步合成方法，用上述中间体化合物(460mg,1.23mmol)在钯/碳催化下，发生氢化还原反应，得到白色固体中间体(310mg)。LC-MS[M+H]+:m/z 375.2。
第七步：参照实施例2的第六步合成方法，用上述中间体化合物(310mg,0.83mmol)与三氟乙酸反应，得到白色固体中间体(225mg)。LC-MS[M+H]+:m/z 275.2。
第八步：参照实施例2的第七步合成方法，用上述中间体化合物(310mg,0.83mmol)与(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯反应，得到白色固体中间体(72mg)。LC-MS[M+H]+:m/z 474.3。
第九步：参照实施例2的第八步合成方法，用上述中间体化合物(72mg,0.15mmol)与三氟乙酸反应，得到白色固体中间体(43mg)。LC-MS[M+H]+:m/z 374.2。
第十步：参照实施例2的第九步合成方法，用上述中间体化合物(38mg,0.10mmol)与三氟乙酸反应，得到白色固体中间体(16mg)。LC-MS[M+H]+:m/z 428.3。1H NMR(400MHz,MeOD)δ7.65(s,1H),6.71(dd,J＝16.8,9.5Hz,1H),6.28(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.68(s,3H),2.63-2.51(m,2H),2.37(m,2H),2.15-2.01(m,2H),1.88-1.41(m,2H),1.30(d,J＝6.9Hz,6H)。
实施例14：(R)-1-(2-((4-((7-异丙基-6-(三氟甲基)咪唑并[2,1,-f][1,2,4]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例13的合成方法，用三氟乙基脒代替乙基脒制备得到白色固体实施例14化合物。LC-MS[M+H]+:m/z 482.2。1H NMR(400MHz,MeOD)δ7.65(s,1H),6.73(dd,J＝16.8,9.5Hz,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.63-2.51(m,2H),2.37(m,2H),2.15-2.01(m,2H),1.88-1.45(m,2H),1.30(d,J＝6.9Hz,6H)。
实施例15：(R)-1-(2-((4-((7-异丙基-6-(三氟甲基)咪唑并[2,1,-f][1,2,4]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例13的合成方法，用环丙基甲脒代替乙基脒制备得到白色固体实施例15化合物。LC-MS[M+H]+:m/z 482.2。1H NMR(400MHz,MeOD)δ7.69(s,1H),6.75(dd,J＝16.8,9.5Hz,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.96(m,3H),2.69-2.51(m,3H),2.37(m,2H),2.15-2.01(m,2H),1.88-1.45(m,2H),1.30(d,J＝6.9Hz,6H),0.65(m,2H),0.52(m,2H)。
实施例16：(R)-1-(2-((4-((3-异丙基-6-甲基-[1,2,4]三氮唑并[4,3,-a]吡嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例7的合成方法，用中间体F代替中间体D制备得到白色固体实施例16化合物。LC-MS[M+H]+:m/z 428.2。1H NMR(400MHz,MeOD)δ7.95(s,1H),6.73(dd,J＝16.8,9.5Hz,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.66-2.51(m,2H),2.58(s,3H),2.37(m,2H),2.15-2.01(m,2H),1.90-1.42(m,2H),1.31(d,J＝6.9Hz,6H)。
实施例17：(R)-1-(2-((4-((6-环丙基-3-异丙基-[1,2,4]三氮唑并[4,3,-a]吡嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例9的合成方法，用中间体F代替中间体D制备得到白色固体实施例17化合物。LC-MS[M+H]+:m/z 428.2。1H NMR(400MHz,MeOD)δ7.95(s,1H),6.78(dd,J＝16.8,9.5Hz,1H),6.27(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H), 2.98(m,3H),2.66-2.51(m,2H),2.37(m,2H),2.29(s,3H),2.15-2.01(m,2H),1.78-1.49(m,2H),1.25(d,J＝6.9Hz,6H),0.62(m,2H),0.48(m,2H)。
实施例18：(R)-1-(2-((4-((3-异丙基-6-甲基-[1,2,4]三氮唑并[4,3,-b]哒嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
第一步：向3,4,6-三氯哒嗪(460mg,2.49mmol)的N-甲基吡咯烷酮(20mL)溶液中，加入(4-氨基哌啶-1-甲酰基叔丁酯(385mg,1.92mmol)和DIEA(422mg,3.27mmol)。该反应混合物在室温下反应24小时。向反应液中加入水(50mL)后，用乙酸乙酯(50mL)萃取两次，合并的有机相减压浓缩。所得粗产物经硅胶柱层析(石油醚/乙酸乙酯＝3:1)纯化，得到白色固体中间体化合物(650mg)。LC-MS[M+H]+:m/z 347.1/349.1。
第二步：向上述中间体化合物(650mg,1.87mmol)的乙醇溶液(20mL)中，加入水合肼(10mL)。该反应混合物加热到60度反应2小时。LC-MS检测反应基本完成。反应液降至室温，有白色固体析出。固体过滤后，干燥得到白色固体中间体产物(560mg)。LC-MS[M+H]+:m/z 344.2/346.2。
第三步：向上述中间体化合物(550mg,1.60mmol)的异丁酸溶液(10mL)中，加入异丁酸肝(1.61g,10.2mmol)。该反应混合物在室温下搅拌3个小时。向反应液中加入饱和碳酸氢钠水溶液(50mL),室温下搅拌20分钟，然后加入乙酸乙酯(100mL)萃取。分离的有机相减压浓缩，所得粗产物经硅胶柱层析(石油醚/乙酸乙酯＝1:1)纯化，得到白色固体中间体化合物(480mg)。LC-MS[M+H]+:m/z 395.1/397.1。
第四步：参考实施例4的第二步反应，用上述中间体化合物(475mg,1.21mmol)与三氟乙酸反应，生成白色固体中间体化合物(350mg)。LC-MS[M+H]+:m/z 295.0/297.0。
第五步：参考实施例4的第三步反应，用上述中间体化合物(350mg,1.19mmol)与(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯反应，生成白色固体中间体(120mg)。LC-MS[M+H]+:m/z494.2/496.2。
第六步：参考实施例4的第四步反应，用上述中间体化合物(120mg,0.24mmol)与二甲基锌反应，生成白色固体中间体化合物(30mg)。LC-MS[M+H]+:m/z 474.3。
第七步：参考实施例4的第五步反应，用上述中间体化合物(30mg,0.06mmol)与三氟乙酸反应，生成白色固体中间体化合物(15mg)。LC-MS[M+H]+:m/z 374.2。
第八步：参考实施例4的第六步反应，用上述中间体化合物(15mg,0.04mmol)与丙烯酰氯反应，生成白色固体中间体化合物(5mg)。LC-MS[M+H]+:m/z 428.2。1H NMR(400MHz,MeOD)δ6.89(s, 1H),6.75(dd,J＝16.8,9.5Hz,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.69(s,3H),2.66-2.51(m,2H),2.37(m,2H),2.15-2.01(m,2H),1.90-1.42(m,2H),1.26(d,J＝6.9Hz,6H)。
实施例19：(R)-1-(2-((4-((6-环丙基-3-异丙基-[1,2,4]三氮唑并[4,3,-b]哒嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例6的合成方法，用环丙基硼酸代替甲基硼酸制备得到白色固体实施例19化合物。LC-MS[M+H]+:m/z 454.2。1H NMR(400MHz,MeOD)δ6.95(s,1H),6.75(dd,J＝16.8,9.5Hz,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.69-2.51(m,3H),2.37(m,2H),2.15-2.01(m,2H),1.90-1.42(m,2H),1.26(d,J＝6.9Hz,6H)，0.65(m,2H),0.48(m,2H)。
实施例20：(R)-1-(2-((4-((3-异丙基6-(三氟甲基)-[1,2,4]三氮唑并[4,3,-a]吡啶-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
第一步：将3-氯-5-(三氟甲基)吡啶-2-基肼(443mg,2.1mmol)和异丁酸(185mg,2.1mmol)溶于三氯氧磷(2mL)中。该反应混合物在微波下，加热到140度反应20分钟。反应混合物加入到碳酸氢钠水溶液(20mL)中，用乙酸乙酯(50mL)萃取两次，合并的有机相减压浓缩。所得粗产物经硅胶柱层析(石油醚/乙酸乙酯＝4:1)纯化，得到白色固体中间体化合物(310mg)。LC-MS[M+H]+:m/z 264.0/266.0。
第二步：在氮气保护下，向上述中间体化合物(310mg,1.17mmol)和(4-氨基哌啶-1-甲酰基叔丁酯(600mg,3.01mmol)的甲苯溶液(20mL)中，加入4,5-双二苯基膦-9,9-二甲基氧杂蒽(xantphos)(240mg,0.42mmol),三(二亚苄基丙酮)二钯(201mg,0.22mmol)和叔丁醇钠(490mg,5.0mmol)。该反应混合物加热到120度反应4个小时。向反应混合物加入到水(40mL)中，用乙酸乙酯(50mL)萃取两次，合并的有机相减压浓缩。所得粗产物经硅胶柱层析(石油醚/乙酸乙酯＝1:1)纯化，得到黄色固体中间体化合 物(110mg)。LC-MS[M+H]+:m/z 428.2。
第三步：参考实施例5的第四步合成方法，用上述中间体化合物(110mg,0.26mmol)与三氟乙酸反应，得到黄色固体化合物(80mg)。LC-MS[M+H]+:m/z 328.2。
第四步：参考实施例5的第五步合成方法，用上述中间体化合物(80mg,0.24mmol)与(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯反应，得到白色固体中间体产物(30mg)。LC-MS[M+H]+:m/z527.3。
第五步：参考实施例5的第六步合成方法，用上述中间体化合物(30mg,0.06mmol)与三氟乙酸反应，得到黄色固体化合物(22mg)。LC-MS[M+H]+:m/z 426.2。
第六步：参考实施例5的第七步合成方法，用上述中间体化合物(22mg,0.05mmol)与丙烯酰氯反应得到白色固体实施例20化合物(4mg)。LC-MS[M+H]+:m/z 481.3。1H NMR(400MHz,MeOD)δ6.97(s,1H),6.73(dd,J＝16.5,9.5Hz,1H),6.25(dd,J＝16.8,1.9Hz,1H),6.35(s,1H),5.77(d,J＝10.8Hz,1H),4.41(m,1H),3.99(m,2H),3.72-3.44(m,3H),3.24(d,J＝6.8Hz,1H),2.98(m,3H),2.66-2.53(m,2H),2.35(m,2H),2.12-2.01(m,2H),1.88-1.45(m,2H),1.24(d,J＝6.8Hz,6H)。
实施例21：(R)-3-异丙基-5-甲基-N-(1-((4-(乙烯基磺酰基)吗啡啉-2-基)甲基)哌啶-4-基)吡唑并[1,5,-a]嘧啶-7-胺
参考实施例1的第七步合成方法，用乙烯基磺酰氯代替丙烯酰氯制备得到白色固体实施例21化合物。LC-MS[M+H]+:m/z 463.2。1H NMR(400MHz,MeOD)δ7.57(s,1H),6.25(m,1H),5.77(m,1H),4.48(m,1H),4.05-3.95(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98-2.86(m,3H),2.66-2.51(m,2H),2.48(s,3H),2.37(m,2H),2.15-2.01(m,2H),1.88-1.49(m,2H),1.32(d,J＝6.9Hz,6H)。
参照实施例1第七步的方法合成，用取代的丙烯酰氯(或酸)或取代的丁烯酰氯(或酸)反应，制备得到实施例22～25化合物；

实施例26：(R)-1-(2-((4-((3-异丙基-5-乙基吡唑并[1,5,-a]嘧啶-7-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参照实施例4的合成方法，用二乙基锌试剂代替二甲基锌制备得到白色固体实施例26化合物。LC-MS[M+H]+:m/z 441.20。1H NMR(400MHz,MeOD)δ7.90(s,1H),6.76(m,1H),6.25(m,1H),6.12(s,1H),5.79(m,1H),4.71-4.36(m,2H),4.01(d,J＝12.4Hz,2H),3.85(m,2H),3.60(m,1H),3.26(d,J＝6.9Hz,1H),3.03(m,2H),2.94(m,2H),2.76(m,2H),2.66(m,1H),2.20(m,2H),1.99(m,2H),1.32(d,J＝6.6Hz,6H).
实施例27：1-((2R)-2-((4-((5-(1-羟基乙基)-3-异丙基吡唑并[1,5,-a]嘧啶-7-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
第一步：向中间体化合物(R)-2-4-((5-氯-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯(390mg,0.791mmol)的1,4-二氧六环溶液(20mL)中，加入三丁基(1-乙氧基乙烯基)锡(2.6mL,1.187mmol),Pd(PPh3)2Cl2(111mg,0.158mmol)和三乙基胺(240mg,2.373mmol)。反应混合物在氮气保护下，加热到80℃下搅拌反应12小时。LCMS检测反应完全，减压浓缩反应液，粗产物溶于乙酸乙酯(20mL)中,水洗两次，浓缩分离的有机相。所得粗产物经硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝30:1)纯化得到粗品黄色油状中间体产物(410mg)。LC-MS[M+H]+:m/z 529.5。
第二步：向上述中间体化合物(80mg,0.15mmol)的乙腈溶液(3mL)中，加入1M的盐酸水溶液(1mL)。该反应混合物在室温下搅拌反应2小时。LCMS检测反应完全，减压浓缩反应液，得到粗品黄色油状中间体化合物(60mg)。LC-MS[M+H]+:m/z 501.3。
第三步：冰水浴冷却下，向上述中间体化合物将(50mg,0.10mmol)的甲醇溶液(4mL)中，加入NaBH4(10mg,0.23mmol)。反应液缓慢升至室温，继续搅拌反应30分钟。LCMS检测反应完全，减压浓缩反应液。粗产物溶于乙酸乙酯(20mL)，用饱和食盐水洗涤两次，分离的有机相减压浓缩得到粗产品黄色油状(50mg)。LC-MS[M+H]+:m/z 503.2。
第四步：向上述中间体化合物(50mg,0.10mmol)的二氯甲烷溶液(4mL)中，加入三氟乙酸(1mL)。反应混合物在室温下搅拌反应30分钟。LCMS检测反应完全，减压浓缩反应液，得到粗产品黄色固体中间体化合物(30mg)。LC-MS[M+H]+:m/z 403.2。
第五步：参考实施例5的第七步合成方法，用上述中间体化合物(30mg,0.07mmol)与丙烯酰氯反应得到白色固体实施例27化合物(5mg)。LC-MS[M+H]+:m/z 457.2。1H NMR(400MHz,MeOD)δ7.89(s,1H),6.76(m,1H),6.28(s,1H),6.27-6.21(m,1H),5.77(d,J＝10.8Hz,1H),4.41(m,2H),3.99(m,2H),3.76-3.60(m,2H),3.54(m,1H),3.02-2.45(m,6H),2.37(m,2H),2.10(m,2H),1.80(m,2H),1.49(d,J＝6.6Hz,3H),1.33(d,J＝6.9Hz,6H).
实施例28：1-((2R)-2-((4-((5-(1-氟乙基)-3-异丙基吡唑并[1,5,-a]嘧啶-7-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
第一步：在冰水浴冷却下，向中间体化合物(2R)-2-4-((5-(1-羟基乙基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯(50mg,0.10mmol)的二氯甲烷溶液(4mL)中，加入二乙胺基三氟化硫(0.4mL,2.3mmol)。该反应混合物在室温下搅拌反应2个小时。LC-MS检测反应完成。用20mL的二氯甲烷稀释反应溶液后，加入饱和碳酸氢钠水溶液10mL。分离的有机相经水洗后，减压浓缩，得到粗品黄色油状中间体(42mg)。LC-MS[M+H]+:m/z 505.2。
第二步：在冰水浴冷却下，向上述中间体化合物(42mg,0.08mmol)的二氯甲烷溶液(5mL)中，加入三氟乙酸(1mL)。反应混合物在室温下搅拌反应2小时。LCMS检测反应完全，减压浓缩反应液得到粗品黄色油状中间体(30mg)。LC-MS[M+H]+:m/z 405.1。
第三步：向上述中间体化合物(30mg,0.07mmol)的二氯甲烷溶液(5mL)中，加入丙烯酰氯(10mg,0.11mmol)和三乙胺(23mg,0.22mmol)。反应混合物在室温下搅拌2个小时。LC-MS检测反应完成。减压浓缩反应液，所得粗产物经HPLC制备得到白色固体实施例28化合物(6mg)。LC-MS[M+H]+:m/z459.15。1H NMR(400MHz,DMSO)δ7.96(s,1H),7.71-7.60(m,1H),6.79(dd,J＝16.4,10.5Hz,1H),6.23(s,1H),6.13(dd,J＝16.7,2.2Hz,1H),5.70(d,J＝10.6Hz,1H),5.58(m,1H),4.27(m,1H),3.94(m,1H),3.84(m,1H),3.63(m,1H),3.55-3.34(m,2H),3.14(m,2H),3.00-2.73(m,3H),2.41(m,2H),2.26-2.09(m,2H),1.79(m,4H),1.62(m,3H),1.30(d,J＝6.9Hz,6H).
实施例28-P1和28-P2 1-((R)-2-((4-((5-((S或R)-1-氟乙基)-3-异丙基吡唑并[1,5,-a]嘧啶-7-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮和1-((R)-2-((4-((5-((R或S)-1-氟乙基)-3-异丙基吡唑并[1,5,-a]嘧啶-7-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
步骤一：将消旋体混合物(2R)-2-((4-((5-(1-氟乙基)-3-异丙基吡唑并[1,5,-a]嘧啶-7-基)氨基)哌啶-1-基)甲基)吗啡啉)-4-甲酰基叔丁酯(28a)(150mg,0.3mmol)经超临界流体色谱手性制备得到两个组分，单一构型化合物28a-P1(60mg，较短的保留时间)和单一构型化合物28a-P2(53mg，较长的保留时间)，LC-MS(ESI):m/z:505.3[M+H]+。
28a的手性SFC制备条件：
色谱柱型号：色谱柱规格：250*25mm 10μm
流动相A：超临界CO2 流动相B:异丙胺(添加0.1％7.0mol/l氨/甲醇溶液)
流动相梯度配比：A:B＝80:20 检测波长：214nM 流动相流速：70mL/Min
循环时间：5Min 柱温：室温 压力：100bar
28a-P1(Rt＝6.684min)和28a-P2(Rt＝7.607min)的手性分析条件：
色谱柱型号：色谱柱规格：100*3.0mm 3.0μm
流动相A：超临界CO2 流动相B:异丙胺(添加0.1％二乙胺)
流动相梯度配比：A:B＝90:10 检测波长：214nM 流动相流速：1.5mL/Min
运行时间：10Min 柱温：35度 压力：1800psi
步骤二：参考实施例28第二步的方法，28a-P1(60mg，0.12mmol)和28a-P2(53mg,0.1mmol))分别与TFA反应生成白色固体化合物28b-P1(33mg)和28b-P2(25mg)。LC-MS(ESI):m/z:405.2[M+H]+。
步骤三：参考实施例28第三步的方法，28b-P1(33mg，0.12mmol)和28b-P2(25mg,0.1mmol))分别与丙烯酰氯反应生成白色固体化合物28-P1(17mg)和28-P2(13mg)。LC-MS(ESI):m/z:459.5[M+H]+。
1H NMR for 28-P1(400MHz,DMSO)δ7.96(s,1H),7.71-7.60(m,1H),6.79(dd,J＝16.4,10.5Hz,1H),6.23(s,1H),6.13(dd,J＝16.7,2.2Hz,1H),5.70(d,J＝10.6Hz,1H),5.58(m,1H),4.27(m,1H),3.94(m,1H),3.84(m,1H),3.63(m,1H),3.55-3.34(m,2H),3.14(m,2H),3.00-2.73(m,3H),2.41(m,2H),2.26-2.09(m,2H),1.79(m,4H),1.62(m,3H),1.30(d,J＝6.9Hz,6H).
1H NMR for 28-P2(400MHz,DMSO)δ7.96(s,1H),7.65(dd,J＝15.4,9.2Hz,1H),6.88-6.71(m,1H),6.23(s,1H),6.13(dd,J＝16.7,1.8Hz,1H),5.70(d,J＝10.7Hz,1H),5.64(m,1H),5.52(m,1H),4.27(m,1H),3.94(m,1H),3.84(m,1H),3.69-3.58(m,1H),3.56-3.35(m,2H),3.14(m,2H),3.00-2.72(m,3H),2.41(m,2H),2.25-2.10(m,2H),1.88-1.71(m,4H),1.62(m,3H),1.30(d,J＝6.9Hz,6H).
实施例29：(R)-1-(2-((4-((5-(2-羟基异丙-2-基)-3-异丙基吡唑并[1,5,-a]嘧啶-7-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
第一步：在氮气保护和冰水浴冷却下，向中间体化合物(R)-2-((4-((5-乙酰基-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯(70mg,0.140mmol)的四氢呋喃溶液(5mL)中，加入甲基溴化镁(33mg,0.28mmol)。反应混合物缓慢升至室温并继续搅拌反应30分钟。LCMS检测反应完全。向反应液中加入10mL水，减压浓缩反应液去除四氢呋喃。用乙酸乙酯(20mL)萃取两次,合并的有机相减压浓缩得到粗品黄色油状中间体(50mg)。LC-MS[M+H]+:m/z 517.5。
第二步：参照实施例29的第二步制备方法，用上述中间体化合物(50mg,0.10mmol)与三氟乙酸反应，得到黄色固体化合物(40mg)。LC-MS[M+H]+:m/z 417.3。
第三步：参照实施例29的第三步制备方法，用上述中间体化合物(40mg,0.10mmol)与三氟乙酸 反应，得到黄色固体化合物(7mg)。LC-MS[M+H]+:m/z 471.20。1H NMR(400MHz,MeOD)δ7.88(s,1H),6.76(dd,J＝16.8,10.6Hz,1H),6.38(s,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.79(dd,J＝10.6,1.9Hz,1H),4.44(m,1H),4.16-3.95(m,2H),3.84(m,2H),3.61(m,1H),3.36(m,2H),3.24(m,1H),3.02(m,2H),2.90(m,2H),2.87-2.62(m,2H),2.23(m,2H),1.93(s,2H),1.57(s,6H),1.36(d,J＝6.9Hz,6H).
实施例30：(R)-1-(2-((4-((5-(2-氟异丙-2-基)-3-异丙基吡唑并[1,5,-a]嘧啶-7-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
第一步：参照实施例28的第一步制备方法，用上述中间体(R)-2-((4-((5-(2-羟基异丙-2-基)-3-异丙基吡唑并[1,5-a]嘧啶-7-基)氨基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯(80mg,0.15mmol)与DAST反应，得到黄色固体化合物(60mg)。LC-MS[M+H]+:m/z 519.3。
第二步：参照实施例28的第二步制备方法，用上述中间体化合物(58mg,0.11mmol)与三氟乙酸反应，得到黄色固体化合物(45mg)。LC-MS[M+H]+:m/z 419.3。
第三步：参照实施例28的第三步制备方法，用上述中间体化合物(42mg,0.10mmol)与三氟乙酸反应，得到黄色固体实施例30化合物(9mg)。LC-MS[M+H]+:m/z 473.30。1H NMR(400MHz,MeOD)δ7.89(s,1H),6.77(m,1H),6.38(s,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.79(dd,J＝10.6,1.9Hz,1H),4.44(m,1H),4.16-3.95(m,2H),3.84(m,2H),3.61(m,1H),3.36-3.02(m,5H),2.90(m,2H),2.87-2.62(m,2H),2.25(m,2H),1.95(m,2H),1.91(s,6H),1.36(d,J＝6.9Hz,6H).
实施例31：(R)-1-(2-((4-((2-乙基-8-异丙基嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例1的合成方法，用乙基溴化镁代替甲基溴化镁，制备得到白色固体实施例31化合物。LC-MS[M+H]+:m/z 442.15。1H NMR(400MHz,MeOD)δ7.90(s,1H),6.75(d,J＝6.2Hz,1H),6.23(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.3Hz,1H),4.57(s,1H),4.41(m,1H),4.18(m,1H),4.06-3.96(m,1H),3.94(m,1H),3.57(m,2H),3.22(m,1H),3.24-3.12(m,1H),2.99(m,3H),2.72(q,J＝7.6Hz,2H),2.67-2.46(m,3H),2.35(m 2H),2.05(m,2H),1.92-1.74(m,2H),1.35-1.30(m,9H).
实施例32：1-((2R)-2-((4-((2-(1-羟基乙基-8-异丙基嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基) 甲基)吗啡啉)丙-2-烯基-1-酮
第一步：在室温下，向中间体化合物G(230mg,1.0mmol)的DMF溶液(15mL)中，加入4-氨基哌啶-1-甲酰基叔丁酯(200mg,1.0mmol)和DIEA(420mg,3.3mmol)。该反应混合物室温搅拌过夜。LCMS检测反应完全。向反应液中加入饱和碳酸氢钠水溶液(30mL)后，用乙酸乙酯(30mL)萃取两次。合并的有机相减压浓缩，所得粗产品经硅胶柱层析(洗脱剂：乙酸乙酯/石油醚＝1:2)纯化得到产品黄色固体中间体产物(240mg)。LC-MS[M+H]+:m/z 395.2/397.2。
第二步：向上述中间体化合物(240mg,0.6mmol)的1,4-二氧六环溶液(20mL)中，加入三丁基(1-乙氧基乙烯基)锡(1.4mL,0.7mmol),Pd(PPh3)2Cl2(111mg,0.158mmol)和三乙基胺(126mg,1.2mmol)。反应混合物在氮气保护下，加热到80℃下搅拌反应12小时。LCMS检测反应完全。反应混合物冷却到室温后，向反应溶液中加入2M盐酸水溶(5mL)。反应溶液继续搅拌3个小时。减压浓缩反应液，粗产物溶于乙酸乙酯(20mL)中,水洗两次，浓缩分离的有机相。所得粗产物经硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝10:1)纯化得到粗品黄色油状中间体产物(110mg)。LC-MS[M+H]+:m/z 303.2。
第三步：在室温下，向上述中间体产物(125mg,0.41mmol)的DMF溶液(10mL)中,加入(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯(156mg，0.42mmol)。反应混合物在80度搅拌反应72小时。LC-MS检测反应基本完全。向反应液中加入饱和碳酸氢钠水溶液(30mL),用乙酸乙酯(30mL)萃取两次。合并的有机相减压浓缩，所得粗产物经HPLC制备纯化得到白色固体中间体产物(63mg)。LC-MS[M+H]+:m/z 502.3。
第四步：冰水浴冷却下，向上述中间体化合物将(60mg,0.12mmol)的甲醇溶液(4mL)中，加入NaBH4(10mg,0.23mmol)。反应液缓慢升至室温，继续搅拌反应30分钟。LCMS检测反应完全，减压浓缩反应液。粗产物溶于乙酸乙酯(20mL)，用饱和食盐水洗涤两次，分离的有机相减压浓缩得到粗产品黄色油状(48mg)。LC-MS[M+H]+:m/z 504.3。
第五步：参考实施例27的第四步合成方法，用上述中间体化合物(48mg,0.07mmol)与三氟乙酸反应得到白色固体(29mg)。LC-MS[M+H]+:m/z 404.2。
第六步：参考实施例27的第五步合成方法，用上述中间体化合物(29mg,0.07mmol)与丙烯酰氯反应得到白色固体实施例32化合物(5mg)。LC-MS[M+H]+:m/z 458.3。1H NMR(400MHz,DMSO)δ8.53(m,1H),8.03(s,1H),6.82-6.76(m,1H),6.15-6.11(d,J＝16.6Hz,1H),5.72-5.69(d,J＝12.4Hz,1H),4.92(m,1H),4.54-4.51(m,1H),4.09-3.99(m,1H),3.94-3.83(m,2H),3.49-3.37(m,2H),3.24-2.91(m,4H), 2.40(m,2H),2.11-2.08(m,2H),1.79(m,4H),1.39(d,J＝4.8Hz,3H),1.29-1.27(d,J＝6.8Hz,6H)。
实施例33：1-((2R)-2-((4-((2-(1-氟乙基-8-异丙基嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例28的合成方法，以中间体(2R)-2-((4-((2-(1-羟基乙基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯为原料，经三步反应制备得到白色固体实施例33化合物。LC-MS[M+H]+:m/z 460.2。1H NMR(400MHz,DMSO)δ8.68(m,1H),8.08(s,1H),6.92-6.64(m,1H),6.13(d,J＝16.6Hz,1H),5.70(d,J＝10.4Hz,1H),5.45(m,1H),4.27(m,1H),4.11-3.99(m,1H),3.98-3.89(m,1H),3.88-3.80(m,1H),3.57-3.37(m,2H),3.24-3.02(m,2H),2.86(m,3H),2.40(m,2H),2.19-2.01(m,2H),1.80(m,4H),1.61(m,3H),1.29(d,J＝6.9Hz,6H)。
实施例33-P1和33-P2 1-((R)-2-((4-((2-((S或R)-1-氟乙基)-8-异丙基吡唑并[1,5,-a]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮和1-((R)-2-((4-((2-((R或S)-1-氟乙基)-8-异丙基吡唑并[1,5,-a]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例28-P1和28-P2的合成方法，通过手性SFC制备分离33a(100mg),分离得到两个单一构型中间体化合物33a-P1(较短保留时间)和33a-P2(较长保留时间),然后分别经两步反应制备合成得到白色固体化合物33-P1(15mg)和33-P2(11mg)。LC-MS(ESI):m/z:460.2[M+H]+。
1H NMR for 33-P1(400MHz,DMSO)δ8.69(m,1H),8.05(s,1H),6.95-6.64(m,1H),6.13(d,J＝16.6Hz,1H),5.70(d,J＝10.4Hz,1H),5.44(m,1H),4.27(m,1H),4.11-3.99(m,1H),3.98-3.89(m,1H),3.89-3.78(m,1H),3.57-3.37(m,2H),3.24-3.02(m,2H),2.86(m,3H),2.40(m,2H),2.19-2.01(m,2H),1.80(m,4H),1.61(m,3H),1.28(d,J＝6.9Hz,6H)。
1H NMR for 33-P2(400MHz,DMSO)δ8.69(m,1H),8.05(s,1H),6.95-6.64(m,1H),6.15(d,J＝16.6Hz,1H),5.70(d,J＝10.4Hz,1H),5.44(m,1H),4.27(m,1H),4.12-3.95(m,1H),3.98-3.89(m,1H),3.89-3.75(m,1H),3.54-3.35(m,2H),3.24-3.01(m,2H),2.86(m,3H),2.40(m,2H),2.19-2.05(m,2H),1.80(m,4H),1.61(m,3H),1.28(d,J＝6.9Hz,6H)。
实施例34：(R)-1-(2-((4-((2-(2-羟基异丙-2-基)-8-异丙基嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例29的合成方法，以中间体(R)-2-((4-((2-乙酰基-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯为起始原料，经三步反应制备得到白色固体实施例34化合物。LC-MS[M+H]+:m/z 472.20。1H NMR(400MHz,DMSO)：δ8.58(m,1H),8.04(s,1H),6.77(m,1H),6.13(m1H),5.71(m,1H),4.82(s,1H),4.28(m,1H),4.07(m,1H),4.00-3.80(m,2H),3.51-3.39(m,2H),3.24-3.03(m,2H),2.99-2.76(m,3H),2.41(m,2H),2.21-2.04(m,2H),1.79(m,4H),1.46(s,6H),1.30(d,J＝6.9Hz,6H)。
实施例35：(R)-1-(2-((4-((2-(2-羟基异丙-2-基)-8-异丙基嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例30的合成方法，以中间体(R)-2-((4-((2-(2-羟基异丙-2-基)-8-异丙基吡唑并[1,5-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯为起始原料，经三步反应制备得到白色固体实施例35化合物。LC-MS[M+H]+:m/z 474.2。1H NMR(400MHz,DMSO)δ8.65(m,1H),8.06(s,1H),6.87-6.72(m,1H),6.13(d,J＝16.7Hz,1H),5.70(d,J＝10.5Hz,1H),4.27(m,1H),4.06-3.80(m,3H),3.45(m,3H),3.12(m,1H),2.90(m,3H),2.40(m,2H),2.19-2.01(m,2H),1.81(m,4H),1.72(s,3H),1.66(s,3H),1.29(d,J＝6.9Hz,6H).
实施例36：(R)-1-(2-((4-((6-(1-羟基乙基)-3-异丙基咪唑并[1,2,-b]嘧啶-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例32的合成方法，以4-((6-氯-3-异丙基咪唑[1,2-b]哒嗪-8-基)胺基)哌啶-1-碳酸叔丁酯为起始原料，制备得到白色固体实施例36化合物。LC-MS[M+H]+:m/z 457.30。1H NMR(400MHz,MeOD)δ7.57(s,1H),6.75(dd,J＝16.8,9.5Hz,1H),6.65(s,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.42(m,4H),3.26(m,1H),2.98(m,3H),2.66-2.51(m,2H),2.37(m,2H),2.15-2.01(m,2H),1.94(d,J＝6.6Hz,3H),1.88-1.49(m,2H),1.28(d,J＝6.9Hz,6H).
实施例37：(R)-1-(2-((4-((6-乙基-3-异丙基咪唑并[1,2,-b]嘧啶-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
第一步：向中间体化合物(2R)-2-((4-((6-(1-羟基乙基)-3-异丙基咪唑并[1,2-b]哒嗪-8-基)胺基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯(90mg,0.16mmol)的甲醇溶液(5mL)中，加入5％Pd/C(10mg)。反应混合物在氢气氛围下(1atm)，室温搅拌5个小时。LC-MS检测反应完全，向反应液中加入20mL甲醇，用硅藻土过滤。滤液减压浓缩，得到灰色粗品固体化合物(50mg)。LC-MS[M+H]+:m/z 487.3。
第二步：参考实施例27的第四步合成方法，用上述中间体化合物(48mg,0.07mmol)与三氟乙酸反应得到白色固体(29mg)。LC-MS[M+H]+:m/z 387.3。
第三步：参考实施例27的第五步合成方法，用上述中间体化合物(29mg,0.07mmol)与丙烯酰氯反应得到白色固体实施例37化合物(5mg)。LC-MS[M+H]+:m/z 441.3。1H NMR(400MHz,MeOD)δ7.57(s,1H),6.75(dd,J＝16.8,9.5Hz,1H),6.65(s,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.42(m,4H),3.26(m,1H),2.98(m,3H),2.66-2.37(m,5H),2.15-2.01(m,2H),1.94-1.39(m,5H),1.28(d,J＝6.9Hz,6H).
实施例38：(R)-1-(2-((4-((6-(1-氟乙基)-3-异丙基咪唑并[1,2,-b]嘧啶-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例28的合成方法，以中间体(2R)-2-((4-((6-(1-羟基乙基)-3-异丙基咪唑并[1,2-b]哒嗪-8-基)胺基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯为起始原料，经三步反应制备得到白色固体实施例38化合物。LC-MS[M+H]+:m/z 459.3。1H NMR(400MHz,MeOD)δ7.57(s,1H),6.75(dd,J＝16.8,9.5Hz,1H),6.65(s,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45-3.99(m,4H),3.74-3.42(m,3H),3.26(m,1H),2.98(m,3H),2.66-2.51(m,2H),2.37(m,2H),2.15-2.01(m,2H),1.94(m,3H),1.88-1.49(m,2H),1.28(d,J＝6.9Hz,6H).
实施例39：(R)-1-(2-((4-((6-(2-羟基异丙-2-基)-3-异丙基咪唑并[1,2,-b]嘧啶-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例29的合成方法，以中间体(R)-2-((4-((6-乙酰基-3-异丙基咪唑并[1,2-b]哒嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯为起始原料，经三步反应制备得到白色固体实施例39化合物。LC-MS[M+H]+:m/z 471.30。1H NMR(400MHz,MeOD)δ7.56(s,1H),6.72(m,1H),6.63(s,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.42(m,4H),3.26(m,1H),2.98(m,3H),2.66-2.51(m,2H),2.37(m,2H),2.15-2.01(m,2H),1.89(s,6H),1.85-1.49(m,2H),1.34(d,J＝6.9Hz,6H).
实施例40：(R)-1-(2-((4-((6-(2-氟异丙-2-基)-3-异丙基咪唑并[1,2,-b]嘧啶-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例30的合成方法，以中间体(R)-2-((4-((6-(2-羟基异丙-2-基)-3-异丙基咪唑并[1,2-b]哒嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯为起始原料，经三步反应制备得到白色固体实施例40化合物。LC-MS[M+H]+:m/z 473.30。1H NMR(400MHz,MeOD)δ7.56(s,1H),6.72(m,1H),6.65(s,1H),6.27(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.42(m,4H),3.26(m,1H),2.98(m,3H),2.66-2.51(m,2H),2.37(m,2H),2.15-2.01(m,2H),1.93-1.49(m,8H),1.33(d,J＝6.8Hz,6H).
实施例41：1-((2R)-2-((4-((6-(1-羟基乙基)-3-异丙基咪唑并[1,2,-a]吡嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例32的合成方法，以4-((6-氯-3-异丙基咪唑[1,2-a]吡嗪-8-基)氨基)哌啶-1-碳酸叔丁酯为起始原料，制备得到白色固体实施例41化合物。LC-MS[M+H]+:m/z 457.3。1H NMR(400MHz,MeOD)δ7.65(s,1H),6.73(m,1H),6.75(s,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.76(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,4H),3.26(m,1H),2.98(m,3H),2.66-2.41(m,2H),2.37(m,2H),2.15-2.01(m,2H),1.89(d,J＝7.2Hz,3H),1.85-1.45(m,2H),1.32(d,J＝6.9Hz,6H)。
实施例42：1-((2R)-2-((4-((6-乙基-3-异丙基咪唑并[1,2,-a]吡嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例37的合成方法，以中间体(2R)-2-((4-((6-(1-羟基乙基)-3-异丙基咪唑并[1,2-a]吡嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯为起始原料，经三步反应制备得到白色固体实施例42化合物。LC-MS[M+H]+:m/z 441.3。1H NMR(400MHz,MeOD)δ7.65(s,1H),6.73(dd,J＝16.8,9.5Hz,1H),6.73(s,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.66-2.45(m,4H),2.37(m,2H),2.15-2.01(m,2H),1.88-1.45(m,5H),1.32(d,J＝6.9Hz,6H)。
实施例43：1-((2R)-2-((4-((6-(1-氟乙基)-3-异丙基咪唑并[1,2,-a]吡嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例38的合成方法，以中间体(2R)-2-((4-((6-(1-羟基乙基)-3-异丙基咪唑并[1,2-a]吡嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯为起始原料，经三步反应制备得到白色固体实施例43化合物。LC-MS[M+H]+:m/z 459.3。LC-MS[M+H]+:m/z 457.3。1H NMR(400MHz,MeOD)δ7.65(s,1H),6.73(m,1H),6.75(s,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.76(d,J＝10.8Hz,1H),4.45-3.99(m,4H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.66-2.41(m,2H),2.37(m,2H),2.17-1.93(m,5H),1.88-1.45(m,2H),1.32(d,J＝6.9Hz,6H)。
实施例44：1-((2R)-2-((4-((6-(2-羟基异丙-2-基)-3-异丙基咪唑并[1,2,-a]吡嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例39的合成方法，以(2R)-2-((4-((6-乙酰基-3-异丙基咪唑并[1,2-a]吡嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯为起始原料，制备得到白色固体实施例44化合物。LC-MS[M+H]+:m/z471.3。1H NMR(400MHz,MeOD)δ7.65(s,1H),6.73(m,1H),6.75(s,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.76(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.66-2.41(m,2H),2.37(m,2H),2.15-2.01(m,2H),1.85-1.65(m,2H),1.48(s,6H),1.32(d,J＝6.9Hz,6H)。
实施例45：1-((2R)-2-((4-((6-(2-氟异丙-2-基)-3-异丙基咪唑并[1,2,-a]吡嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例40的合成方法，以(2R)-2-((4-((6-(2-羟基异丙-2基)-3-异丙基咪唑并[1,2-a]吡嗪-8-基)氨基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯为起始原料，制备得到白色固体实施例45化合物。LC-MS[M+H]+:m/z 473.3。1H NMR(400MHz,DMSO)δ8.65(s,1H),8.06(s,1H),6.87-6.72(m,1H),6.13(d,J＝16.7Hz,1H),5.70(d,J＝10.5Hz,1H),4.27(m,1H),4.06-3.80(m,3H),3.45(m,3H),3.12(m,1H),2.90(m,3H),2.40(m,2H),2.19-2.01(m,2H),1.81(m,4H),1.72(s,3H),1.66(s,3H),1.29(d,J＝6.9Hz,6H)。
实施例46：(R)-1-(2-((4-((7-异丙基-6-乙基咪唑并[2,1,-f][1,2,4]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例13的合成方法，用丙基脒代替乙基脒制备得到白色固体实施例46化合物。LC-MS[M+H]+:m/z 442.3。1H NMR(400MHz,MeOD)δ7.65(s,1H),6.73(m,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.77(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.63-2.51(m,4H),2.37(m,2H),2.15-2.01(m,2H),1.88-1.45(m,5H),1.30(d,J＝6.9Hz,6H)。
实施例47：1-((2R)-2-((4-((2-(1-羟基乙基)-7-异丙基咪唑并[2,1,-f][1,2,4]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
第一步：参照实施例2的第三步合成，用中间体化合物H(537mg,2.01mmol)与4-氨基哌啶-1-甲酰基叔丁酯反应，生成白色固体中间体化合物(480mg)。LC-MS[M+H]+:m/z 431.0/433.0。
第二步：参照实施例2的第四步合成，用上述中间体化合物(480mg,1.11mmol)与异丙烯基硼酸频哪醇酯反应，生成白色固体中间体化合物(395mg)。LC-MS[M+H]+:m/z 393.0/395.0。
第三步：参照实施例32的第二步合成，用上述中间体化合物(398mg,1.01mmol)与三丁基(1-乙氧基乙烯基)锡反应，生成白色固体中间体化合物(278mg)。LC-MS[M+H]+:m/z 301.1。
第四步：参照实施例32的第三步合成，用上述中间体化合物(278mg,0.93mmol)与(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯反应，生成白色固体中间体化合物(128mg)。LC-MS[M+H]+:m/z500.3。
第五步：参照实施例2的第五步合成，用上述中间体化合物(128mg,0.26mmol)在Pd/C催化下氢化还原，生成白色固体中间体化合物(95mg)。LC-MS[M+H]+:m/z 502.3。
第六步：参照实施例32的第四步合成，用上述中间体化合物(95mg,0.19mmol)与硼氢化钠反应，生成白色固体中间体化合物(78mg)。LC-MS[M+H]+:m/z 504.3。
第七步：参照实施例32的第五步合成，用上述中间体化合物(78mg,0.15mmol)与三氟乙酸反应，生成白色固体中间体化合物(45mg)。LC-MS[M+H]+:m/z 404.3。
第八步：参照实施例32的第六步合成，用上述中间体化合物(45mg,0.11mmol)与丙烯酰氯反应，生成白色固体实施例47化合物(15mg)。LC-MS[M+H]+:m/z 458.3。1H NMR(400MHz,DMSO)：δ8.53(m,1H),8.03(s,1H),6.82-6.76(m,1H),6.15-6.11(m,1H),5.72-5.69(d,J＝12.4Hz,1H),4.92-4.91(d,J＝4.8Hz,1H),4.54-4.51(m,1H),4.28-4.09(m,2H),3.91-3.83(m,2H),3.49-3.41(m,2H),3.14-3.09(m,1H),2.91-2.55(m,3H),2.41(m,2H),2.11-2.08(m,2H),1.79(m,4H),1.38(d,J＝4.8Hz,3H),1.29-1.27(d,J＝6.9Hz,6H)。
实施例48：1-((2R)-2-((4-((2-(1-氟乙基)-7-异丙基咪唑并[2,1,-f][1,2,4]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例38的合成方法，以中间体(2R)-2-((4-((2-(1-羟基乙基)-7-异丙基咪唑并[2,1-f][1,2,4]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯为起始原料，经三步反应制备得到白色固体实施例48化合物。LC-MS[M+H]+:m/z 460.3。1H NMR(400MHz,MeOD)δ7.65(s,1H),6.73(m,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.76(d,J＝10.8Hz,1H),4.45-3.99(m,4H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.66-2.41(m,2H),2.37(m,2H),2.17-1.83(m,5H),1.88-1.45(m,2H),1.32(d,J＝6.8Hz,6H)。
实施例49：(R)-1-(2-((4-((2-(2-羟基异丙-2-基)-7-异丙基咪唑并[2,1,-f][1,2,4]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例39的合成方法，以(R)-2-((4-((2-乙酰基-7-异丙基咪唑并[2,1-f][1,2,4]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯为起始原料制备得到白色固体实施例49化合物。LC-MS[M+H]+:m/z 472.3。1H NMR(400MHz,MeOD)δ7.65(s,1H),6.73(m,1H),6.25(dd,J＝16.8,1.9Hz,1H),5.76(d,J＝10.8Hz,1H),4.45(m,1H),3.99(m,2H),3.74-3.49(m,3H),3.26(m,1H),2.98(m,3H),2.66-2.35(m,4H),2.15-2.01(m,2H),1.85-1.65(m,2H),1.48(s,6H),1.35(d,J＝6.8Hz,6H)。
实施例50：(R)-1-(2-((4-((2-(2-氟异丙-2-基)-7-异丙基咪唑并[2,1,-f][1,2,4]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参考实施例40的合成方法，以(R)-2-((4-((2-(2-羟基异丙-2基)-7-异丙基咪唑并[2,1-f][1,2,4]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉-4-碳酸叔丁酯为起始原料制备得到白色固体实施例50化合物。LC-MS[M+H]+:m/z 474.2。1H NMR(400MHz,DMSO)δ8.65(m,1H),8.06(s,1H),6.87-6.72(m,1H),6.13(d,J＝16.7Hz,1H),5.70(d,J＝10.5Hz,1H),4.27(m,1H),4.06-3.80(m,3H),3.45(m,3H),3.12(m,1H),2.90(m,3H),2.40(m,2H),2.19 2.01(m,2H),1.81(m,4H),1.72(s,3H),1.66(s,3H),1.29(d,J＝6.9Hz, 6H).
参考实施例4和26的合成方法，以不同的试剂为原料代替4-氨基哌啶-1-甲酰基叔丁酯或(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯，制备得到实施例51-65化合物:


参考实施例38的合成方法，以不同的试剂为原料代替4-氨基哌啶-1-甲酰基叔丁酯或(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯，制备得到实施例66-70化合物:

参考实施例28的合成方法，以不同的试剂为原料代替4-氨基哌啶-1-甲酰基叔丁酯或(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯，制备得到实施例71-75化合物:

参考实施例33的合成方法，以不同的试剂为原料代替4-氨基哌啶-1-甲酰基叔丁酯或(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯，制备得到实施例76-80化合物:

实施例81：(R)-1-(2-((4-((8-异丙基-2-乙烯基嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参照实施例1的合成方法，用乙烯基溴化镁代替甲基溴化镁制备得到实施例81化合物。LC-MS[M+H]+:m/z 440.2。1H NMR(400MHz,DMSO)：δ8.19(s,1H),6.78(dd,J＝16.8,12.4Hz,1H),6.63(m,1H),6.15(d,J＝16.6Hz,1H),5.89(d,J＝16.4Hz,1H),5.72(d,J＝12.4Hz,1H),5.44(d,J＝12.2Hz,1H),4.38-4.14(m,2H),3.94-3.85(m,2H),3.49-3.39(m,3H),3.19-3.16(m,1H),2.94(m,3H),2.41(m,2H),2.13-2.10(m,2H),1.81(m,4H),1.32(d,J＝6.9Hz,6H).
实施例82：(R)-2-氟-1-(2-((4-((8-异丙基-2-乙烯基嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参照实施例81的合成方法，用2-氟丙烯酰氯代替丙烯酰氯制备得到实施例82化合物。LC-MS[M+H]+:m/z 458.2。1H NMR(400MHz,DMSO)：δ8.17(s,1H),6.63(m,1H),6.15(m,1H),6.05(d,J＝16.4Hz,1H),5.72(m,1H),5.44(d,J＝12.2Hz,1H),4.38-4.14(m,2H),3.94-3.85(m,2H),3.49-3.39(m,3H),3.19-3.16(m,1H),2.94(m,3H),2.41(m,2H),2.13-2.10(m,2H),1.81(m,4H),1.32(d,J＝6.9Hz,6H).
实施例83：(R)-1-(2-((4-((2-乙炔基8-异丙基嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
参照实施例1的合成方法，用乙炔基溴化镁代替甲基溴化镁制备得到实施例83化合物。LC-MS[M+H]+:m/z 438.2。1H NMR(400MHz,DMSO)：δ8.17(s,1H),6.78(dd,J＝16,12Hz,1H),6.17-6.13(d,J＝16.6Hz,1H),5.72(d,J＝12.4Hz,1H),4.38-4.16(m,2H),3.94-3.85(m,3H),3.49-3.39(m,3H),3.19-3.16(m,1H),2.94(m,3H),2.40(m,2H),2.13-2.11(m,2H),1.82-1.79(m,4H),1.32(d,J＝6.9Hz,6H).
实施例84：(R)-1-(2-((4-((2-(二氟甲基)-8-异丙基嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
步骤一：参考实施例1第三步的合成方法，用4-((8-异丙基-2-(甲基砜)嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-甲酰基叔丁酯(1.5g,3.42mmol)与乙烯基溴化镁(1M in THF,3.5mL，3.5mmol)反应得到浅黄色油状化合物(0.83g)。LC-MS[M+H]+:m/z 387.2。
步骤二：向上述中间体(0.83g,2.15mmol)的二氯甲烷溶液(30mL)中通入臭氧，反应4个小时后，LC-MS检测反应基本完全。向反应液中加入30mL饱和碳酸氢钠水溶液，分离的有机相减压浓缩，所得粗产物经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝3:1)纯化得到浅黄色油状化合物(560mg)。LC-MS[M+H]+:m/z 389.2。
步骤三：参考实施例29第一步的合成方法，用上述中间体(560mg,1.44mmol)与甲基溴化镁反应，制备得到白色固体化合物(455mg)。LC-MS[M+H]+:m/z 405.2。
步骤四：向上述中间体(450mg,1.11mmol)的四氢呋喃溶液(30mL)中加入戴斯马丁氧化剂(708mg,1.76mmol)。该反应混合物在室温下搅拌反应过夜。减压浓缩反应，残余物溶于乙酸乙酯(30mL)。依次用饱和碳酸氢钠水溶液和饱和食盐水洗涤，分离的有机相减压浓缩，粗产物经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝4:1)纯化得到白色固体化合物(387mg)。LC-MS[M+H]+:m/z 403.2。
步骤五：参考实施例1的第四步合成方法，用上述中间体(385mg,0.96mmol)与三氟乙酸反应，制备得到白色固体化合物(242mg)。LC-MS[M+H]+:m/z 303.2。
步骤六：参考实施例1的第五步合成方法，用上述中间体(240mg,0.79mmol)与(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯反应，制备得到白色固体化合物(128mg)。LC-MS[M+H]+:m/z 502.3。
步骤七：参考实施例1的第六步合成方法，用上述中间体(125mg,0.25mmol)与三氟乙酸反应，制备得到白色固体化合物(85mg)。LC-MS[M+H]+:m/z 402.2。
步骤八：参考实施例1的第七步合成方法，用上述中间体(125mg,0.25mmol)与丙烯酰氯反应，制备得到白色固体化合物(23mg)。LC-MS[M+H]+:m/z 456.2。1H NMR(400MHz,DMSO)δ8.19(s,1H),6.85-6.70(m,1H),6.13(d,J＝16.7Hz,1H),5.70(d,J＝10.2Hz,1H),4.41-4.06(m,2H),4.00-3.79(m,2H),3.58-3.32(m,3H),3.20-3.14(m,1H),2.94(s,3H),2.61(s,3H),2.41(m,2H),2.12(m,2H),1.81(m,4H),1.33(d,J＝6.9Hz,6H)。
实施例85：(R)-1-(2-((4-((2-(二氟甲基)-8-异丙基嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
步骤一：在零度下，将二乙氨基三氟化硫(664mg，4.12mmol)加入到4-((2-醛基-8-异丙基嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-甲酰基叔丁酯(320mg，0.824mmol)的二氯甲烷(5mL)中。反应液升至室温后，继续搅拌2小时。向反应液中饱和碳酸氢钠溶液淬灭反应。反应液用饱和氯化钠溶液洗涤，水相用二氯甲烷萃取。合并的有机相减压浓缩，粗产品经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝10:1)得到白色固体中间体化合物(300mg)。LCMS[M+H]+:m/z 411.2
步骤二：在室温下，向上述中间体化合物(300mg,0.731mmol)的二氯甲烷溶液(5mL)中加入三氟乙酸(5mL)。反应混合物在室温下反应2小时。减压浓缩反应液，粗产物经硅胶柱层析(洗脱剂：二氯甲烷/无水甲醇＝20:1)纯化得到淡黄色固体化合物(200mg)。LCMS[M+H]+:m/z 311.0。
步骤三：在室温下，向上述中间体化合物(200mg,0.65mmol)的N，N-二甲基甲酰胺溶液(5mL)中加入碳酸钾(270mg,1.95mmol)，(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯(480mg,1.29mmol)。反应混合物在氮气保护下，加热到90℃反应16小时。LCMS检测反应完全。向反应液中加入20mL水后，用乙酸乙酯(10mL)萃取三次。合并的有机相减压浓缩，所得粗产物经硅胶柱层析(洗脱剂：二氯甲烷/无水甲醇＝20:1)纯化得到淡黄色固体化合物(100mg)。LCMS[M+H]+:m/z 510.3。
步骤四：室温下，向上述中间体化合物(100mg,0.196mmol)的二氯甲烷溶液(2mL)中加入三氟乙酸(2mL)。反应混合物在室温下反应2小时。减压浓缩反应液，所得粗产物经硅胶柱层析(洗脱剂：二氯甲烷/无水甲醇＝20:1)纯化得到淡黄色固体化合物(70mg)。LCMS[M+H]+:m/z 410.0。
步骤五：在零度下，加入向上述中间体化合物(70mg，0.171mmol)的二氯甲烷溶液(5mL)中,加入三乙胺(35mg，0.342mmol)和丙烯酰氯(20mg,0.222mmol)。反应混合物升至室温，并搅拌2小时。反应液用饱和氯化钠溶液洗涤，分离的有机相减压浓缩，所得粗产物经HPLC制备纯化得到白色固体实施例85化合物(18.7mg)。LCMS[M+H]+:m/z 464.4。1H NMR(400MHz,DMSO-d6):δ9.03(m,1H),8.18(s,1H),6.84-6.54(m,2H),6.13(d,J＝16.6Hz,1H),5.70(d,J＝10.7Hz,1H),4.27(m,1H),4.06(m,1H),3.99-3.80(m,2H),3.55-3.36(m,2H),3.30-3.05(m,2H),2.86(m,3H),2.43(m,2H),2.12(m,2H),1.89-1.74(m,4H),1.30(d,J＝6.9Hz,6H).
19F NMR(377MHz,DMSO-d6):δ-118.97(s,2H).
参考实施例85的合成方法，以不同的试剂为原料代替丙烯基酰氯，制备得到实施例86-93化合物:

实施例94：2-氟-1-((2R)-2-((4-((2-(1-氟乙基)-8-异丙基嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-基)甲基)吗啡啉)丙-2-烯基-1-酮
步骤一：在氮气保护，将4-((2-醛基-8-异丙基嘧啶并[1,5,-a][1,3,5]三嗪-4-基)氨基)哌啶-1-甲酰基叔丁酯(1.1g,2.83mmol)的四氢呋喃溶液(30mL),降温至零下-70度。在此温度下，缓慢加入甲基溴化镁的四氢呋喃溶液(3M，2.36mL,7.08mmol)，并继续在该温度下反应1小时。LCMS检测反应基本完全。向反应液中加入饱和氯化铵溶液(50mL)淬灭反应后，用乙酸乙酯(30mL)萃取两次，分离的有机相减压浓缩，所得粗产物经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝10:1到4:1)纯化得淡黄色油状化合物(1.05g)。LCMS[M+H]+:m/z 405.2。
步骤二：在室温下，向上述中间体化合物(1.05g，2.60mmol)的二氯甲烷溶液(10mL)中，加入三氟乙酸(5ml)。该反应混合物在室温下继续搅拌2小时。减压浓缩反应液，所得粗产物经硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝7:1)纯化得到白色油状化合物(900mg)。LCMS[M+H]+:m/z 305.2。
步骤三：室温下，向上述中间体化合物(900mg,2.96mmol)的N，N-二甲基甲酰胺溶液(25mL)中，加入碳酸钾(270mg,1.95mmol)和(S)-2-((对甲苯磺酸基)甲基)吗啡啉-4-甲酰基叔丁酯(2.75g,7.39mmol)。在氮气保护，该反应混合物加热到90℃反应16小时。LCMS检测基本反应完全。向反应混合物中加入饱和氯化钠水溶液(50mL)后，用乙酸乙酯(20mL)萃取三次。合并的有机相减压浓缩，所得粗产物经硅胶柱层析(洗脱剂：二氯甲烷/无水甲醇＝10:1)纯化得到淡黄色固体化合物(914mg)。LCMS[M+H]+:m/z 504.2。
步骤四：在零下70度下，向上述中间体化合物(300mg，0.596mmol)的二氯甲烷(5mL)中,加入二乙氨基三氟化硫(288mg，1.787mmol)。该反应混合物继续在室温下搅拌2小时。向反应液中加入饱和碳酸氢钠溶液(30mL)和二氯甲烷(30mL)。分离的有机相用饱和氯化钠水溶液洗涤后减压浓缩，所得粗产物经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝10:1)纯化得到无色油状物化合物(110mg)。LCMS[M+H]+:m/z 506.4。
步骤五：在室温下，向上述中间体化合物(110mg，0.218mmol)的二氯甲烷溶液(4mL)中,加入三氟乙酸(2mL)。该反应混合物在室温下继续搅拌2小时。反应混合物减压浓缩后，所得粗产品经硅胶柱层析(洗脱剂：二氯甲烷/甲醇＝9:1)纯化得到白色固体化合物(45mg)。LCMS[M+H]+:m/z 406.3。
步骤六：在零度下，向上述中间体化合物(45mg，0.11mmol)的二氯甲烷溶液(5mL)中，加入2-氟丙烯酰氯(12mg,0.13mmol)和三乙胺(22mg，0.22mmol)。该反应混合物升至室温后，继续搅拌2小时。向反应液中加入二氯甲烷(10mL)后，用饱和氯化钠水溶液洗涤有机相。分离的有机相减压浓缩，所得粗产品经HPLC制备纯化得到白色状固体实施例94化合物(9.73mg)。LCMS[M+H]+:m/z478.2。1H NMR(400MHz,DMSO)δ8.68(m,1H),8.08(s,1H),6.33(m,1H),5.87(m,1H),5.45(m,1H), 4.27(m,1H),4.11-3.99(m,1H),3.98-3.89(m,1H),3.88-3.80(m,1H),3.57-3.37(m,2H),3.24-3.05(m,2H),2.86(m,3H),2.40(m,2H),2.19-2.01(m,2H),1.80(m,4H),1.61(m,3H),1.27(d,J＝6.9Hz,6H)。
参考实施例94的合成方法，以不同的试剂为原料代替2-氟丙烯酰氯，制备得到实施例95-100化合物:

测试例1酶活性测试
检测实施例化合物在CDK7/CycH/MAT1(Carna)和CDK9/CycT1(Carna)激酶上的抑制率，以PHA-793887和Dinaciclib作为阳性对照化合物。利用Mobility shift assay的方法，在2种激酶上进行实施例化合物的活性测试。
具体操作流程如下：(1)配制1×Kinase buffer；(2)化合物浓度梯度的配制：受试化合物测试浓度为10000nM起始，在384source板中稀释成100倍终浓度的100％DMSO溶液,3倍稀释化合物，10个浓度。使用分液器Echo 550向目的板384-well-plate转移250nL 100倍终浓度的化合物。用1×Kinase buffer配制2.5倍终浓度的激酶溶液。(3)在化合物孔和阳性对照孔分别加10μL的2.5倍终浓度的激酶溶液；在阴性对照孔中加10μL的1×Kinase buffer。(4)1000rpm离心30秒，反应板振荡混匀后室温孵育10分钟。(5)用1×Kinase buffer配制5/3倍终浓度的ATP和Kinase substrate的混合溶液。(6)加入15μl的5/3倍终浓度的ATP和底物的混合溶液，起始反应。(7)将384孔板1000rpm离心30秒，振荡混匀后室温孵育相应的时间。(8)加入30μl终止检测液停止激酶反应，1000rpm离心30秒，振荡混匀。(9)用Caliper EZ Reader读取转化率。(10)计算公式％Inhibition＝Conversion％_max-Conversion％_sample/Conversion％_max-Conversion％_min×100,其中：Conversion％_sample是样品的转化率读数；Conversion％_min是阴性对照孔均值，代表没有酶活孔的转化率读数；Conversion％_max是阳性对照孔均值，代表没有化合物抑制孔的转化率读数。拟合量效曲线以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response–Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC50值。计算公式是Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope))。
结果(见表一)：本发明大部分实施例化合物具有较高的CDK7激酶抑制活性，在低至100nM浓度下仍然显示较高的抑制活性(抑制率大于95％)；并且大部分实施例化合物对CDK9的抑制活性较弱，在1000nM浓度下仍然显示较低的抑制活性(抑制率小于10％)。大部分实施例化合物显示了较高的CDK7/CDK9激酶选择性。(其中抑制率表示++++≥90％；80％<+++≤60％；60％<++≤30％；+<10％；IC50表示A≤50nM；50nM<B≤500nM；500nM<C≤1000nM；D>1000nM。)
表1：本发明专利化合物CDK7/CDK9的激酶抑制活性和激酶抑制率


NT表示未做。
本发明绝大部分实施例化合物对CDK7激酶具有较强的抑制活性，大部分实施例化合物CDK7激酶IC50小于50nM,部分化合物甚至小于20nM，比如实施例4(IC50，7.1nM)，27(IC50，13.5nM)，28(IC50，19.8nM)，28-P2(IC50,2.8nM)等。
测试例2抗OVCAR-3细胞增殖活性测试
1)、将状态良好的OVCAR-3细胞(ATCC)消化后离心，重悬后计数并接种于96孔板(Corning)中，每孔1000细胞。
2)、培养箱预培养24h(37℃，5％CO 2)后，给予不同浓度的实施例化合物处理72h；实验组与对照组均设置6个复孔，并设加入DMSO溶剂的对照孔及不加入细胞的空白孔(纯培养基)。
3)、药物处理后，利用发光法进行细胞活力检测。测量前将培养板平衡至室温，每孔加入50uL试剂(Promega)，在轨道振荡器上混合2分钟以诱导细胞裂解，继续室温下孵育60分钟以稳定发光信号，随后在Envision(PerkinElmer)上记录发光值。
4)、计算细胞活力抑制率(％)＝[A(DMSO)-A(加药)]/[A(DMSO)-A(空白)]×100％。(A(加药)：具有细胞和药物溶液的孔的吸光度；A(空白)：具有培养基而没有细胞的孔的吸光度；A(DMSO)：铺种细胞并加入DMSO的孔的吸光度)。三次重复实验，Graghpad软件统计。
结果(见表2)：本发明大部分实施例化合物具有较强的细胞增殖抑制活性，IC50小于1000nM，部分实施例化合物的细胞增殖抑制活性IC50小于50nM，部分实施例化合物的细胞增殖抑制活性IC50甚至小于10nM。具体结果如下表所示：(IC50表示A≤50nM；50nM<B≤500nM；500nM<C≤1000nM；D>1000nM)。
表2：本发明化合物抗OVCAR-3细胞增殖活性数据结果

对照化合物为礼来公司专利报道的化合物(参见WO2021242602，Example 8)。
测试例3：实施例化合物的ADME测试
(1)代谢稳定性试验：用体系为150μL的肝微粒体(终浓度0.5mg/mL)进行代谢稳定性温孵，体系含NADPH(终浓度1mM)、1μM受试化合物和阳性对照咪达唑仑或阴性对照阿替洛尔，分别在0min、5min、10min、20min和30min用含替硝唑的乙腈终止反应，涡旋10min，15000rmp离心10min，取50μL上清于96孔板中进样。通过测定原药的相对减少量计算化合物代谢稳定性。
结果(见表3)：本发明实施例化合物对各种属(大鼠、小鼠、狗、猴、人)肝微粒体稳定性较高，部分实施例化合物数据如下:
表3：本发明专利化合物肝微粒体代谢稳定性测试结果
NT表示未做。
测试例4：实施例化合物在小鼠体内药代动力学参数测试
6只雄性SPF级Balbc小鼠(上海西普尔-必凯实验动物)分成两组，受试化合物配置成合适溶液或混悬液；一组静脉注射给药(1mg/kg)，一组口服给药(5mg/kg)。经颈静脉穿刺采血，每个样品采集约0.2mL/时间点，肝素钠抗凝，采血时间点如下：给药前及给药后5、15和30min，1、2、4、6、8和24h；血液样本采集后置于冰上，离心分离血浆(离心条件：8000转/分钟，6分钟，2-8℃)，收集的血浆分析前存放于-80℃。血浆样品采用LC-MS/MS进行分析。
根据药物的血药浓度数据，使用药代动力学计算软件WinNonlin5.2非房室模型分别计算供试品的药代动力学参数AUC0-t、AUC0-∞、MRT0-∞、Cmax、Tmax、T1/2和Vd等参数及其平均值和标准差。此外，生物利用度(F)将通过下面的公式进行计算。
对于浓度低于定量下限的样品，在进行药代动力学参数计算时，在达到Cmax以前取样的样品应以零值计算，在达到Cmax以后取样点样品应以无法定量(BLQ)计算。
表4：本发明化合物在小鼠体内的口服药代动力学参数结果
结论：本发明化合物体现了较高的药物暴露量和生物利用度，具有良好的体内药物代谢动力学性质。
测试例5：实施例化合物对裸鼠异种移植肿瘤生长的影响
为了评估测试化合物的体内功效，使用多种异种移植肿瘤模型(如HCT116,HCC1806,OVCAR-3)。1)将HCT116、HCC1806、OVCAR-3细胞培养在含10％胎牛血清的培养液中。收集指数生长期的肿瘤细胞，PBS重悬至适合浓度用于裸小鼠皮下肿瘤接种。2)实验裸小鼠于右侧背部皮下接种2-8×107肿瘤细胞，细胞重悬在1：1的PBS与基质胶中，定期观察肿瘤生长情况，待肿瘤生长至平均体积120mm3-180mm3时根据肿瘤大小和小鼠体重随机分组给药。3)肿瘤细胞接种当天定义为第0天。在给药开始前，称量所有动物的体重，并用游标卡尺测量肿瘤体积。3)实施例化合物(用1％羟乙基纤维素、0.25％聚山梨醇酯80、0.05％消泡剂的纯化水配置到所需浓度后待用)以给定剂量每天口服给药，连续给药三周，溶剂对照组给等量溶剂。整个实验过程中，每周2次测量移植瘤直径，同时称量小鼠体重。
肿瘤体积(tumor volume,TV)的计算公式为：TV＝1/2×a×b2，其中a、b分别表示长、宽。根据测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为：RTV＝Vt/V0。其中V0为分笼给药时(即d0)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积。抗肿瘤活性的评价指标为1)相对肿瘤增殖率T/C(％)，计算公式如下：T/C(％)＝(TRTV/CRTV)×100％，TRTV：治疗组RTV；CRTV：阴性对照组RTV；2)肿瘤体积增长抑制率GI％，计算公式如下：GI％＝[1-(TVt-TV0)/(CVt-CT0)]×100％，TVt为治疗组每次测量的瘤体积；TV0为治疗组分笼给药时所得瘤体积；CVt为对照组每次测量的瘤体积；CV0为对照组分笼给药时所得瘤体积。
结果显示，本发明部分化合物,如实施例28和33等，在HCT116,HCC1806,OVCAR-3肿瘤模型中均显示出明显的抗肿瘤活性，相比对照组，实施例化合物28和33在15mg/kg，30mg/kg,60mg/kg剂量下抑瘤率大于70％，在中高剂量组抑瘤率甚至大于90％，并且试验动物能较好耐受。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (12)

  1. 一种如通式I所示的含氮杂环类化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，
    式中：
    W、X和M各自独立地选自CRw或N；Rw独立地选自H、氘、卤素、氰基、C1-C3烷基或C1-C3卤代烷基；
    Y、Z独立地选自C或者N；
    R1独立地选自C2-C6烯基、C2-C6炔基、C1-C6烷基-(C＝O)-、C1-C3烷基、C1-C3卤代烷基、3-6元环烷基、3-6元卤代环烷基，3-6元杂环烷基、C1-C10烷氧基、C1-C10卤代烷氧基、3-6元环烷基-O-、3-6元杂环烷基-O-、C1-C10烷基-NH-、C1-C10卤代烷基-NH-、3-6元环烷基-NH-或3-6元杂环烷基-NH-；上述烯基、炔基、烷基、环烷基、杂环烷基可以被一个或数个R1-1所取代，R1-1独立地选自：卤素、氘、羟基、氨基、取代的氨基、C1-C6烷基、羟基取代的C1-C6烷基、氨基取代的C1-C6烷基、C1-C6烷氧基、3-10元环烷基或3-10元杂环烷基取代的C1-C6烷基；所述取代氨基中的取代基为1-3个，独立地选自：C1-C6烷基、C1-C6烷氧基、3-6元环烷基或3-6元杂环烷基；
    R2独立地选自C1-C3烷基、C1-C3卤代烷基、3-6元环烷基、3-6元卤代环烷基或3-6元杂环烷基；R2可进一步被一个或多个R2-1取代，所述R2-1独立地选自氘、卤素、羟基、C1-C3烷基、C1-C3卤代烷基；
    R3独立地选自丙烯酰基、取代的丙烯酰基、丙炔酰基、取代的丙炔酰基、乙烯磺酰基、取代的乙烯磺酰基或氰基；R3中所述“取代”为进一步被一个或多个R3-1所取代，所述R3-1独立地选自：卤素、氘、羟基、氰基、氨基、C1-C6烷基、C1-C6烷氧基、3-6元环烷基、3-6元杂环烷基、3-6元杂环烷基取代的C1-C3烷基、氨基取代的C1-C3烷基、单C1-C3烷基取代氨基-C1-C3烷基或双C1-C3烷基取代氨基-C1-C3烷基；或者，两个R3-1与所连接的碳原子一起形成3-8元碳环或3-8元杂环，优选为
    R4、R5独立地选自氢、氘、卤素、C1-C3的烷基、C1-C3卤代烷基、羟基、氨基、取代氨基或C1-C3烷氧基；所述取代氨基中的取代基为1-3个，独立地选自：C1-C6烷基、C1-C6烷氧基、3-6元环烷基或3-6元杂环烷基；
    Ra、Rb独立地选自氢、氘、卤素、C1-C3烷基；或者Ra、Rb通过碳链形成3-6元饱和碳环，优选 为环丙烷或环丁烷；
    环A和环B分别选自4-10元含氮杂环，优选为5-6元含氮杂环；
    n独立地选自0-3的整数；
    上述的烷基、取代烷基或烯基可以被取代基取代，所述取代基分别独立地选自下组：包括但不限于氘、卤素、羟基、单烷基氨基、双烷基氨基、C1-C6烷基或卤代烷基、3-10元环烷基或杂环烷基、氰基、C1-C6烷氧基或卤代烷氧基；
    其中，所述的杂环包含1-3个选自下组的杂原子：N、O、P、S或Se，所述的杂环烷基包含1-3个选自下组的杂原子：N、O、P或S，所述的环系包含螺环、桥环、稠环、并环等饱和或部分不饱和的环系。
  2. 如权利要求1所述的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其特征在于，其满足以下条件中的一个或多个：
    (1)当Y为N时，W、X和M中至少有一个为N；
    (2)C2-C6烯基为C2-C4烯基，优选为乙烯基或丙烯基；
    (3)C2-C6炔基为C2-C4炔基，优选为
    (4)C1-C3烷基为甲基、乙基、正丙基或异丙基；
    (5)C1-C6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、伯丁基、仲丁基或叔丁基；优选为异丙基或叔丁基；
    (6)C1-C3卤代烷基中的卤素为氟、氯、溴或碘；所述C1-C3卤代烷基优选为C1-C3氟代烷基；
    (7)3-6元环烷基为环丙基、环丁基、环戊基、环己烯基或环己基；优选为环丙基；
    (8)卤素为氟、氯、溴或碘；优选为氟；
    (9)3-6元杂环烷基为
    (10)4-10元含氮杂环为
  3. 如权利要求1所述的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其特征在于，其满足以下条件中的一个或多个：
    (1)Rw独立地为H；
    (2)R1为C2-C6烯基、C2-C6炔基、C1-C6烷基-(C＝O)-、C1-C3烷基、C1-C3卤代烷基或3-6元环烷基；
    (3)R1-1的个数为1、2或3个；R1-1独立地为氘、卤素或羟基；优选为羟基；
    (4)R2为C1-C3烷基；优选为异丙基；
    (5)R3为丙烯酰基、取代的丙烯酰基、丙炔酰基、取代的丙炔酰基或乙烯磺酰基；
    (6)R3-1独立地选自氘、卤素、氰基、C1-C6烷基、3-6元杂环烷基取代的C1-C3烷基、单C1-C3烷基取代氨基-C1-C3烷基和双C1-C3烷基取代氨基-C1-C3烷基；
    (7)R4为氘、卤素、羟基或C1-C3的烷基；
    (8)R5为氘、卤素、羟基或C1-C3的烷基；
    (9)Ra、Rb独立地为氢、氘、或C1-C3烷基；
    (10)环A为其中*端与-NH-相连；N端与端相连；
    (11)环B为其中N端与R3相连，*端与端相连；
    (12)环B中与碳链相连的碳原子构型优选为R构型；
    (13)不为
  4. 如权利要求1所述的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其特征在于：
    R1为乙烯基、乙炔基、CH3(C＝O)-、CH3、CH2F、CHF2、CF3、CH3O-、NH2或CH3NH-、CH3CH2、
    或者，R2为甲基、乙基、异丙基或环丙基；优选为异丙基；
    或者，R3为
    或者，Ra、Rb优选为氢、氘、甲基；
    或者，R4为氢、氘、卤素、羟基、甲基；
    或者，R5为氢、氘、羟基、卤素、甲基；
    或者，环A为其中*端与-NH-相连；
    或者，环B为其中N端与R3相连；
    或者，环B中与碳链相连的碳原子构型优选为R构型。
  5. 如权利要求1所述的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其特征在于，其满足以下条件中的一个或多个：
    (1)为
    (2)为
    (3)为
  6. 如权利要求1所述的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其特征在于：所述通式I所示的含氮杂环类化合物为通式(II)所示的化合物，
    其中，W、X、Y、Z、M、R1、R2、R3、R4、Ra、Rb基团的范围如权利要求1所定义。
  7. 如权利要求1所述的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其特征在于：所述通式I所示的含氮杂环类化合物为通式(VI-1)-(VI-9)所示的化合物，
    R1、R2、R3、Ra、Rb的范围如权利要求1所定义；
    例如通式(III-1)-(III-9)所示的化合物，
  8. 如权利要求1所述的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变 异构体、扭转异构体、溶剂化物、多晶型物或前药，其特征在于：所述通式I所示的含氮杂环类化合物为通式(IV-1)-(IV-2)所示的化合物，
    其中，R1选自C2-C6烯基、C2-C6
    炔基、C1-C6烷基-(C＝O)-、卤素、C1-C3烷基、卤代烷基、C3-C6的环烷基或卤代环烷基；更优选自乙烯基、乙炔基、C1-C3烷基、卤代烷基、C3-C6的环烷基或卤代环烷基；
    R3选自下面基团：
    Rc、Rd、Re、Rf、Rg、Rh、Rk、Rm独立地选自氢、氘、卤素、C1-C6烷基和氰基；或者上述任意两个相邻基团之间可以通过碳链或杂原子形成3-8元碳环或3-8元杂环；
    更优选地，所述通式I所示的含氮杂环类化合物为通式(V-1)-(V-2)所示的化合物，
    其中，R1优选自C2-C6烯基、C2-C6炔
    基、C1-C6烷基-(C＝O)-、卤素、C1-C3烷基、卤代烷基、C3-C6的环烷基或卤代环烷基；更优选自乙烯基、乙炔基、C1-C3烷基、卤代烷基、C3-C6的环烷基或卤代环烷基；
    R3选自下面基团：
    Rc、Rd、Re、Rf、Rg、Rh、Rk、Rm独立地选自氢、氘、卤素、C1-C6烷基和氰基；或者上述任意两个相邻基团之间可以通过碳链或杂原子形成3-8元碳环或3-8元杂环。
  9. 如权利要求1所述的化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、扭转异构体、溶剂化物、多晶型物或前药，其特征在于：所述的化合物为如下任一结构：


  10. 一种药物组合物，其特征在于，所述药物组合物包括：
    (i)有效量的如权利要求1-9中任一项所述化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药；和
    (ii)药学上可接受的载体。
  11. 一种物质Z在制备用于预防、治疗、或减轻由CDK激酶异常活性介导的障碍或疾病的药物中的用途；
    所述CDK激酶优选为CDK7激酶；
    所述物质Z为如权利要求1-9中任一项所述化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，或如权利要求10所述的药物组合物。
  12. 一种物质Z在制备治疗或预防增殖性疾病的药物中的应用；所述增殖性疾病可为癌症、良性赘生物、血管发生、炎性疾病、感染疾病、自身炎性疾病或自身免疫性疾病；所述的癌症独立地选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、肝癌、皮肤癌、胃癌、肠癌、胆管癌、脑癌、白血病、淋巴癌、纤维瘤、肉瘤、基底细胞癌、胶质瘤、肾癌、黑色素瘤、骨癌、甲状腺癌、鼻咽癌或胰腺癌；所述的自身免疫疾病独立地选自类风湿性关节炎、系统性红斑狼疮、特发性血小板减少性紫癜、溶血性贫血或银屑病；所述的炎性疾病独立地选自骨关节炎、痛风性关节炎、溃疡性结肠炎和/或炎性肠病；所述的感染疾病独立地选自败血症、脓毒性休克、内毒素性休克、革兰氏阴性败血症和/或中毒性休克综合征；
    所述物质Z为如权利要求1-9中任一项所述化合物，或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药，或如权利要求10所述的药物组合物。
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CN101772500A (zh) * 2007-06-14 2010-07-07 先灵公司 作为蛋白质激酶抑制剂的咪唑并吡嗪
WO2020180907A1 (en) * 2019-03-05 2020-09-10 Bristol-Myers Squibb Company Imidazopyridazine compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
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