WO2011113293A1 - Dérivés de dihydroptéridinone, procédé de préparation et utilisation pharmaceutique associés - Google Patents

Dérivés de dihydroptéridinone, procédé de préparation et utilisation pharmaceutique associés Download PDF

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Publication number
WO2011113293A1
WO2011113293A1 PCT/CN2011/000062 CN2011000062W WO2011113293A1 WO 2011113293 A1 WO2011113293 A1 WO 2011113293A1 CN 2011000062 W CN2011000062 W CN 2011000062W WO 2011113293 A1 WO2011113293 A1 WO 2011113293A1
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group
fluorenyl
substituted
aryl
methyl
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PCT/CN2011/000062
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English (en)
Chinese (zh)
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邓炳初
张农
董正
曾祥全
舒思杰
刘伦俊
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江苏恒瑞医药股份有限公司
上海恒瑞医药有限公司
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Priority to CN201180002067.3A priority Critical patent/CN102421779B/zh
Priority to TW100115019A priority patent/TW201229050A/zh
Publication of WO2011113293A1 publication Critical patent/WO2011113293A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—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
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a novel dihydroacridone derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same and its use as a therapeutic agent, particularly as a Plk kinase inhibitor. Background technique
  • the cyclin-dependent kinase family (Cdks) has long been recognized as the most important regulator of the cell cycle, but as the research progresses, more and more other protein kinases are found to be critical to the cell cycle progression. effect.
  • the Polo-like kinase (Plks) family is one of them.
  • Plks are a class of serine/threonine kinases that are important in regulating the cell cycle. According to the literature, Plks are involved in the regulation of many steps in the process of mitosis, including the activation of Cdc25C and Cdkl/Cyclin B during G2-M phase transformation, centrosome maturation and spindle formation and assembly. In the later stages of mitosis, Plks are also involved in the separation of sister chromatids, which promote the activation of complex components and the regulation of septiii during cytokinesis.
  • Plks family of subtypes
  • Plkl is particularly important for the regulation of mitosis (see Glover et al, Dev. 1998, 12:3777-87; Qian et al, ⁇ Biol Cell., 2001, 12: 1791 -9).
  • Plkl expression and activity levels It is closely related to the degree of growth of tumor cells (see WO 2004/014899 Al).
  • Overexpression of Plk1 has been shown to be associated with a variety of high-proliferation types of tumors, such as non-small cell lung cancer, squamous cell carcinoma, breast cancer, ovarian cancer.
  • a number of dihydroacridone derivatives have been disclosed in the prior art as Plkl inhibitors, and such compounds have been reported to have antiproliferative activity.
  • the patents WO 03/020722, WO 2004/076454 and WO2008050096 disclose dihydroacridone derivatives, processes for their preparation and their use in pharmaceutical compositions for the treatment of cell cycle kinase activity and are characterized by excessive or Use of diseases with abnormal cell proliferation.
  • Patent WO 01/019825 discloses the use of pteridin derivatives as therapeutics for tumors and viral diseases. Due to the resistance of various types of tumors, there is an urgent need to develop new drugs to overcome tumors.
  • An object of the present invention is to provide a medicament having Plk1 kinase inhibitory activity which can be used for the treatment of cell proliferation diseases such as cancer, infection, inflammation and autoimmune diseases. Summary of the invention
  • R 1 and R 2 are each independently selected from a hydrogen atom or an alkyl group
  • R 1 and R 2 together with the atoms to which they are bonded form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains 0 to 2 N, 0 or 8 (0)
  • the 3 to 8 membered ring is optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, halogen, hydroxy, cyano, nitro, aryl, heteroaryl, carbonyl, -S(0)ONR 7 R 8, -CONR 7 R 8, -NR 7 R 8, -S (0) oR 9, - COR 9 , or - C (0) oR 9 is substituted with a substituent;
  • R 3 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cyclodecyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the fluorenyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group Or an aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of alkyl, decyloxy, halogen, hydroxy, cyano, nitro, aryl, -S(0)ONR 7 R 8 , - CONR Substituted by a substituent of 7 R 8 , —NR 7 R 8 , —S(0)OR 9 , —COR 9 or —C(0)OR 9 ;
  • R 2 and R 3 together with the atoms to which they are attached form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains 1 to 2 N, 0 or 8 (0) 111 heteroatoms, and
  • the 3 to 8 membered ring is optionally further selected from one or more selected from the group consisting of fluorenyl, alkoxy, halogen, hydroxy, cyano, nitro, aryl, heteroaryl, carbonyl, -S(0)ONR 7 R 8 Substituted with a substituent of -CONR 7 R 8 , -NR 7 R 8 , -S(0)OR 9 , -COR 9 or -C(0)OR 9 ;
  • R 4 and R 5 are each independently selected from a hydrogen atom, a fluorenyl group, a halogen, a cyano group or a nitro group;
  • L is selected from an alkylene group, optionally further substituted with one or more substituents selected from halogen, cyano, nitro or alkyl, wherein said thiol is optionally further substituted by one or more halogens ;
  • R 6 is selected from a fluorenyl group, wherein the thiol group is optionally further substituted with a heterocyclic group;
  • R 6 is selected from an unsubstituted alkyl group
  • A is selected from a bicycloalkyl group, a heteroheterocyclyl group, a spirocycloalkyl group or a spiroheterocyclyl group, wherein the bicyclononyl group, the biheterocyclyl group, the spirocycloalkyl group Or a spiroheterocyclyl optionally further substituted with one or more R 12 ;
  • R 6 is selected from heterocyclyl-substituted indenyl
  • A is selected from cyclodecyl, heterocyclyl, bicyclononyl, biheterocyclyl, bridged cycloalkyl, hetero bridged fluorenyl, spirocycloalkyl or Spiroheterocyclyl, wherein the cycloalkyl, heterocyclyl, Bicyclic fluorenyl, bicyclohetero, bridged fluorenyl, heterobridged fluorenyl, spirocycloalkyl or spiroheterocyclyl optionally substituted with one or more R 12 ;
  • R 7 and R 8 are each independently selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cyclodecyl group, heterocyclic group, aryl group or heteroaryl group Further optionally further selected from one or more selected from the group consisting of fluorenyl, alkoxy, heterocyclic, aryl, heteroaryl, halogen, hydroxy, cyano, -S(0)OR 9 , -COR 9 , -C Substituting (0) a substituent of OR 9 , -SCOjONR ⁇ R 11 , -CONRWR 11 or -NR 1 Q R";
  • R 7 and R 8 together with the N atom to which they are bonded form a 3 to 8 membered heterocyclic group, wherein the 3 to 8 membered heterocyclic group contains one or more N, 0 or S(0) m hetero An atom, and the 3 to 8 membered heterocyclic group is optionally further selected from one or more selected from the group consisting of an alkyl group, a decyloxy group, a heterocyclic group, an aryl group, a heteroaryl group, a halogen, a hydroxyl group, a cyano group, and -S ( 0) 0R 9 , -COR 9 , -C(0)0R 9 , -S(O)ONR 10 U .
  • R 9 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group, wherein the cycloalkyl group or aryl group is optionally further substituted with one or more mercapto groups;
  • R 1Q and R 11 are selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group or an aryl group;
  • R 12 is selected from the group consisting of alkyl, alkoxy, cyclodecyl, halogen, hydroxy, cyano, nitro, carbonyl, -S(0)ONR 7 R 8 , -CON 7 R 8 . -C(0)0R 9 , -0C(0)R 9 , -0(CH 2 ) R C(0)OR 9 , - OC(0)NR 7 R 8 , -S(0) M R 9 , -0S(0)0R 9 , Substituted with a substituent of NHC(0)R 9 or -COR 9 wherein said fluorenyl, decyloxy, cycloalkyl or heterocyclyl is optionally further selected from one or more selected from the group consisting of alkyl, cycloalkane Substituted by a substituent of a heterocyclic group, an aryl group or a heteroaryl group;
  • n 0 or 1
  • n 0, 1 or 2;
  • r is 1, 2 or 3.
  • the compounds of the formula (I) are tautomers, racemates, enantiomers, diastereomers, mixtures thereof, and pharmaceutically acceptable Salt: Where:
  • R 1 is selected from a hydrogen atom
  • R 2 is selected from a thiol group
  • R 3 is selected from a decyl group or a cycloalkyl group
  • R 2 and R 3 together with the atoms to which they are bonded form a 3 to 8 membered heterocyclic group wherein the 3 to 8 membered heterocyclic group contains 1 to 2 N, 0 or S(0) n heteroatoms.
  • the 3 to 8 membered heterocyclic group is optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, halogen, hydroxy, cyano, nitro, carbonyl, aryl, -S(0)ONR 7 Substituted by a substituent of R 8 , —CONR 7 R 8 , —NR 7 R 8 , —S(0)0R 9 , —COR 9 or —C(0)0R 9 ;
  • R 4 and R 5 are each independently selected from a hydrogen atom, a halogen or a fluorenyl group
  • R 6 is selected from a fluorenyl group, wherein the thiol group is optionally further substituted with a heterocyclic group;
  • A is selected from a bicycloalkyl group, a biheterocyclyl group, a spirocyclic fluorenyl group or a spiroheterocyclic ring. And wherein said bicycloalkyl, bicyclohetero, bridged fluorenyl, bridged heterocyclyl, spiro fluorenyl or spiroheterocyclyl is optionally substituted with one or more R 12 ;
  • R 6 is selected from heterocyclic substituted alkyl
  • A is selected from cyclodecyl, heterocyclyl, bicycloalkyl, biheterocyclyl, bridged fluorenyl, bridged heterocyclyl, spiro fluorenyl or spiro a heterocyclic group, wherein said cyclodecyl, heterocyclyl, bicyclononyl, diheterocyclyl, bridged fluorenyl, bridged heterocyclyl, spirocycloalkyl or spiroheterocyclyl is optionally further substituted by one or Substituted by multiple R 1 2 ;
  • R 7 and R 8 are each independently selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the fluorenyl group, cyclodecyl group, heterocyclic group, aryl group or heteroaryl group Further optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, heterocyclyl, aryl, heteroaryl, halogen, hydroxy, cyano, carboxylic acid, carboxylic acid ester, -S(0)OR 9 Substituting -COR 9 , -S(0)ONR 1 Q R ] 1 , - CONR 1 G R" or - NRWR 1 1 ;
  • R 7 and R 8 together with the N atom to which they are bonded form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains one or more N, 0 or S(0) m heteroatoms, and
  • the 3 to 8 membered heterocyclic ring is further selected from one or more selected from the group consisting of an anthracenyl group, a decyloxy group, a heterocyclic group, an aryl group, a heteroaryl group, a halogen, a hydroxyl group, a cyano group, a carboxylic acid, a carboxylic acid ester, Substituted by a substituent of a carbonyl group, -S(0)OR 9 , -COR 9 , -S ⁇ ONR'V ⁇ - CONR' GR 11 or -NRWR 1 1 ;
  • R 9 is selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group or an aryl group, wherein the cycloalkyl group or the aryl group is optionally further substituted with one or more alkyl groups;
  • R 1 Q and R 1 1 are selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group or an aryl group;
  • R 1 2 is selected from the group consisting of alkyl, decyloxy, cycloalkyl, hydroxy, cyano, nitro, carbonyl, -S(0)ONR 7 R 8 , - CONR 7 R 8 , -C(0)OR 9 - - OC(0)R 9 , -0(CH 2 ) R C(0)OR 9 , - OC(0)NR 7 R 8 , -S(0) M R 9 , -OS(0)OR 9 Substituted with a substituent of -NHC(0)R 9 or -COR 9 wherein the alkyl, decyloxy, cyclodecyl or heterocyclic group is further optionally further selected from one or more selected from the group consisting of fluorenyl and cyclo Substituted by a substituent of an alkyl group, a heterocyclic group, an aryl group or a heteroaryl group;
  • n 0 or 1
  • n 0, 1 or 2;
  • r is 1, 2 or 3.
  • a preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable compound An acceptable salt, wherein: R 1 and R 2 are each independently selected from a hydrogen atom or an alkyl group;
  • R 3 is selected from a hydrogen atom, a decyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkenyl group, the alkynyl group, the cyclodecyl group, the heterocyclic group Or an aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano, nitro, aryl, -S(0)ONR 7 R 8 , -CONR 7 Substituted by a substituent of R 8 , —NR 7 R 8 , —S(0)0R 9 , —COR 9 or —C(0)OR 9 ;
  • R 2 and R 3 together with the atoms to which they are attached form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains 1 to 2 N, 0 or S(0) m heteroatoms, and 3 ⁇ 8 yuan ring optional further by one or a plurality of selected thiol groups, decyloxy groups, halogens, light groups, cyano groups, nitro groups, aryl groups, heteroaryl groups, carbonyl groups, -S(0)ONR 8 , -CONR 7 R s , -NR 7 R 8 , Substituted by a substituent of -S(0)OR 9 , - COR 9 or -C(0)OR 9 ;
  • R 4 and R 5 are each independently selected from a hydrogen atom, an alkyl group, a halogen, a cyano group or a nitro group;
  • L is selected from the group consisting of an anthracenylene group, optionally further substituted with one or more substituents selected from halogen, cyano, nitro or alkyl, wherein the alkyl group is optionally further substituted by one or more halogens ;
  • R 6 is selected from a thiol group
  • A is selected from a bicyclononyl group, a bicyclic heterocyclic group, a spirocyclic fluorenyl group or a spiroheterocyclyl group, wherein the bicyclic fluorenyl group, the bicyclic heterocyclic group, the spiro fluorenyl group or the spiroheterocyclic group is optionally further substituted by one or Substituted by a plurality of R 12 ;
  • R 7 and R s are each independently selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the fluorenyl group, cyclodecyl group, heterocyclic group, aryl group or heteroaryl group group optionally further substituted with one or more groups selected from the embankment, embankment group, a heterocyclic group, an aryl group, a heteroaryl group, halogen, hydroxy, cyano, -S (0) 0R 9, -COR 9, C ( 0) 0R 9 , -SiC ONR 1 °R' 1 , -CONR 1 °R' 1 or - NR 1 °R ! 1 substituted by a substituent;
  • R 7 and R 8 together with the N atom to which they are bonded form a 3 to 8 membered heterocyclic group, wherein the 3 to 8 membered heterocyclic group contains one or more N, 0 or 8 (0), ⁇ atom, and the 3 to 8 membered heterocyclic group is optionally further selected from one or more selected from the group consisting of an alkyl group, a decyloxy group, a heterocyclic group, an aryl group, a heteroaryl group, a halogen group, a hydroxyl group, a cyano group, Substituted by a substituent of -S(0)0R 9 , -COR 9 , C(0)0R 9 , -S(0)0NR 1 Q R M , -CONI ⁇ R 1 1 or -NR 10 R";
  • R 9 is selected from a hydrogen atom, an alkyl group, a cyclodecyl group or an aryl group, wherein the cycloalkyl or aryl group is optionally further substituted with one or more alkyl groups;
  • R 1Q and R 11 are selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group or an aryl group;
  • R 12 is selected from the group consisting of alkyl, nonyloxy, cyclodecyl, halogen, hydroxy, cyano, nitro, carbonyl, -S(0)ONR 7 R 8 , -CONR 7 R 8 , -C(0)0R 9 , -OC(0)R 9 , -0(CH 2 ) r C(0)OR 9 , - 0C(0)NR 7 R s , -S(0) m R 9 , -0S(0)0R 9 , Substituted by a substituent of -NHC(0)R 9 or -COR 9 wherein said alkyl, decyloxy, cyclodecyl or heterocyclyl is optionally further selected from one or more selected from the group consisting of alkyl, cyclo Substituted with a substituent of a heterocyclic group, an aryl group or a heteroaryl group;
  • n 0 or 1
  • n 0, 1 or 2;
  • r is 1, 2 or 3.
  • a preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable compound An acceptable salt, wherein: R 1 and R 2 are each independently selected from a hydrogen atom or an alkyl group;
  • R 3 is selected from a hydrogen atom, a decyl group, an alkenyl group, an alkynyl group, a cyclodecyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the fluorenyl group, the alkenyl group, the alkynyl group, the cyclodecyl group, the heterocyclic group Or an aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of alkyl, decyloxy, halogen, hydroxy, cyano, nitro, aryl, -S(0)ONR 7 R 8 , -CONR 7 Substituted by a substituent of R 8 , —NR 7 R 8 , —S(0)0R 9 , —COR 9 or —C(0)0R 9 ; Alternatively, R 2 and R 3 together with the atoms to which they are attached form a 3 to 8 membered ring, wherein
  • R 4 and R 5 are each independently selected from a hydrogen atom, a fluorenyl group, a halogen, a cyano group or a nitro group;
  • L is selected from an alkylene group, optionally further substituted with one or more substituents selected from halogen, cyano, nitro or fluorenyl, wherein said alkyl group is optionally further substituted by one or more halogens Replace
  • R 6 is selected from a fluorenyl group, wherein the alkyl group is further substituted with a heterocyclic group;
  • R 6 is selected from heterocyclyl-substituted indenyl
  • A is selected from cycloalkyl, heterocyclyl, bicyclononyl, biheterocyclyl, bridged fluorenyl, hetero bridged fluorenyl, spiro fluorenyl or a spiroheterocyclyl group, wherein the cyclodecyl, heterocyclyl, bicycloalkyl, biheterocyclyl, bridged cycloalkyl, hetero bridged fluorenyl, spirocycloalkyl or spiroheterocyclyl is optionally substituted Substituted by one or more R 12 ;
  • R 7 and R 8 are each independently selected from a hydrogen atom, an alkyl group, a cyclodecyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cyclodecyl group, heterocyclic group, aryl group or heteroaryl group Further optionally further selected from one or more selected from the group consisting of fluorenyl, alkoxy, heterocyclic, aryl, heteroaryl, halogen, hydroxy, cyano, -S(0)OR 9 , -COR 9 , C ( 0) 0R 9 , -S(O)ONR ] 0 R' -CONK ER 1 1 or a substituent of -NRWR 11 substituted;
  • R 7 and R 8 together with the N atom to which they are bonded form a 3 to 8 membered heterocyclic group, wherein the 3 to 8 membered heterocyclic group contains one or more N, 0 or 8 (0) faced 1 a hetero atom, and the 3 to 8 membered heterocyclic group is further optionally further selected from one or more selected from the group consisting of fluorenyl, decyloxy, heterocyclic, aryl, heteroaryl, halogen, hydroxy, cyano, -S (0)0R 9 , -COR 9 . C(0)0R 9 , -S(O)ONR 10 R N . Substituted by a substituent of -CONR ⁇ R 1 1 or -NR ⁇ R";
  • R 9 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group, wherein the cycloalkyl or aryl group is optionally further substituted with one or more mercapto groups;
  • R 1Q and R 1 1 are selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group or an aryl group;
  • R 12 is selected from the group consisting of fluorenyl, decyloxy, cyclodecyl, halogen, hydroxy, cyano, nitro, carbonyl, -S(0)ONR 7 R 8 , - CONR 7 R 8 , -C(0)0R 9 -OC(0)R 9 , -0(CH 2 ) R C(0)OR 9 , -OC(0)NR 7 R 8 , -S(0),”R 9 , -0S(0)0R 9 , -NHC (0) R 9 or -COR 9 group substituted with substituents, wherein the embankment group, an alkoxy group, a cycloalkyl group or a heterocyclyl group optionally further substituted with one or more groups selected from alkyl with ring Substituted with a substituent of a fluorenyl, heterocyclyl, aryl or heteroaryl group;
  • n 0 or 1
  • n 0, 1 or 2;
  • r is 1, 2 or 3.
  • a preferred embodiment of the invention a compound of the formula (I.) or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and A pharmaceutically acceptable salt, wherein R 1 is selected from a hydrogen atom, R 2 is selected from a thiol group, and R 2 is preferably an ethyl group.
  • a preferred embodiment of the invention a compound of the formula (I) or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable compound An acceptable salt wherein R 3 is selected from decyl or cyclodecyl, preferably isopropyl or cyclopentyl.
  • R 3 is selected from decyl or cyclodecyl, preferably isopropyl or cyclopentyl.
  • the compound of the formula (I) may contain an asymmetric carbon atom and may therefore exist in the form of an optically pure diastereomer, a mixture of diastereomers, a diastereomeric racemate, a mixture of diastereomeric racemates. Or exist as a meso compound.
  • the invention includes all of these forms. Mixtures of diastereomeric mixtures, diastereomeric racemates or diastereomeric racemates can be separated by conventional methods, for example by column chromatography, thin layer chromatography and HPLC.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention provides a compound of the formula (IA) which is an intermediate for the preparation of a compound of the formula (I), wherein:
  • G is selected from a leaving group, preferably selected from the group consisting of halogen, methanesulfonyl, p-toluenesulfonyl, trifluoromethanesulfonyl or decyloxy;
  • R is selected from a hydrogen atom or a sulfhydryl group
  • R 1 is selected from a hydrogen atom or a fluorenyl group
  • R 2 and R 3 together with the atoms to which they are attached form a 3 to 8 membered ring, wherein the 3 to 8 membered ring contains! ⁇ 2 N, 0 or S(0) n heteroatoms, and the 3 to 8 membered ring is optionally further further selected from one or more selected from the group consisting of fluorenyl, decyloxy, aryl, halogen, hydroxy, cyano, Substituted by a substituent of a carbonyl group, a carboxylic acid, a carboxylic acid ester, -S(0)ONR 7 R 8 , -CONR 7 R 8 , -NR 7 R 8 , -S(0)OR 9 or -COR 9 .
  • n, R 7 to R 9 are as defined in the general formula (J)
  • Typical compounds of formula (IA) include, but are not limited to:
  • the present invention provides a process for the preparation of a compound of the formula (I), which comprises:
  • the compound of the formula (IA:) is reacted with a compound of the formula (IB) or a salt of the compound of the formula (IB) to give a compound of the formula (I).
  • R is selected from a methyl group
  • R ⁇ R 3 is as defined for the compound of formula (IA);
  • A, n, L, R 4 to R 6 are as defined for the compound of the formula (I).
  • Another aspect of the invention relates to a compound of the formula (I) of the invention or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable
  • the use of the accepted salt for the preparation of a medicament for a cell proliferative disorder wherein the cell proliferative disorder is cancer, infection, inflammation, and autoimmune disease, and the cancer is cervical cancer or colon cancer.
  • Another aspect of the invention relates to a method of treating a cell proliferative disorder, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a tautomer, racemate, enantiomer thereof Isomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts, wherein the cell proliferation diseases are cancer, infection, inflammation, and autoimmune diseases, and the cancer is cervical Cancer or colon cancer.
  • Another aspect of the invention relates to a compound of the formula (I) of the invention or a tautomer, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable
  • the accepted salt is a drug for treating a cell proliferation disease, wherein the cell proliferation disease is cancer, infection, inflammation, and autoimmune disease, and the cancer is cervical cancer or colon cancer.
  • the present invention relates to the compound of the formula (I) of the present invention or a tautomer, a racemate, an enantiomer, a diastereomer thereof, a mixture thereof, and a pharmaceutically acceptable form thereof.
  • Use of a salt in the preparation of a Plk kinase inhibitor Use of a salt in the preparation of a Plk kinase inhibitor.
  • Another aspect of the invention relates to a method of inhibiting Plk kinase comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a tautomer, racemate, enantiomer thereof , diastereomers, mixtures thereof, and pharmaceutically acceptable salts.
  • the invention further relates to the compounds of the formula (I) or the tautomers, racemates, enantiomers thereof, Diastereomers, mixtures thereof, and pharmaceutically acceptable salts are useful as drugs for inhibiting Plk kinase.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention or a tautomer, racemate, enantiomer, diastereomer thereof, and In the form of a mixture, and a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient therefor.
  • the pharmaceutical composition is a medicament for treating cancer, infection, inflammation, and autoimmune diseases, and the cancer is cervical cancer or colon cancer.
  • Another aspect of the invention relates to a method of treating a cell proliferative disorder, comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a tautomer thereof, a racemate, a pair thereof a pharmaceutical composition of a conjugate, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt, wherein the cell proliferative disorder is cancer, infection, inflammation, and autoimmune disease,
  • the cancer described is cervical cancer or colon cancer.
  • the compounds of the invention and their pharmaceutically acceptable salts can be administered orally, dermally or parenterally (e.g., by injection, inhalation, spray, sublingual, rectal or vaginal).
  • “Injectable administration” includes intravenous injection, joint injection, intramuscular injection, subcutaneous injection, parenteral injection, and infusion. Dermal administration includes topical or cross-administration. Oral administration is carried out according to methods well known to those skilled in the art, and one or more adjuvants such as diluents, sweeteners, flavoring agents, colorants and preservatives may also be present in such formulations.
  • the amount of the pharmaceutically active compound in each case should be in the range of from 0.1 to 90% by weight of the total composition, preferably from 0.5 to 50% by weight, i.e., in an amount sufficient to achieve the metering range provided below. If necessary, multiple specified doses can be provided daily.
  • the active ingredient is mixed with non-toxic, pharmaceutically acceptable excipients.
  • excipients include: inert diluents (such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulation or disintegrants (such as corn starch, alginic acid) and binders (such as magnesium stearate) , stearic acid, talc).
  • the tablets may be uncoated or they may be coated by a known method to alleviate the decomposition and absorption in the gastrointestinal tract to prolong the efficacy, such as glyceryl stearate or glyceryl distearate.
  • These compounds can also be prepared in a solid, rapid release mode.
  • the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or china clay; in a soft capsule, the active ingredient is mixed with water or an oil vehicle such as peanut oil, paraffin or olive oil.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or china clay
  • the active ingredient is mixed with water or an oil vehicle such as peanut oil, paraffin or olive oil.
  • the active ingredient is mixed with excipients which are suitable for pharmaceutical use.
  • excipients are suspending agents (such as hydroxymethyl cellulose sodium, methyl cellulose, hydroxypropyl-methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum arabic), dispersing agents or wetting agents [ Including naturally occurring phospholipids (such as egg pity) or condensates of alkylenes and fatty acids (such as polyoxyethylene stearate) or condensates of ethylene and long-chain fatty alcohols (such as heptadecylene oxide ten A condensate of hexaol) or ethylene oxide and a partial ester derived from a fatty acid and a hexitol (such as polyethylene sorbitan monooleate):
  • the aqueous suspension may also mean a plurality of preservatives (such as ethyl p-hydroxybenzoate or propyl p-hydroxybenzoate); one or more colorants; one or more fragrances and one or A variety of sweeteners (such as sucrose or saccharin:).
  • preservatives such as ethyl p-hydroxybenzoate or propyl p-hydroxybenzoate
  • colorants such as ethyl p-hydroxybenzoate or propyl p-hydroxybenzoate
  • fragrances such as sucrose or saccharin:
  • Dispersible powders or granules suitable for the preparation of aqueous suspensions are prepared by admixing water, active ingredient and dispersing or wetting agents, suspending agents and one or more preservatives. Other excipients such as sweeteners, colorants or fragrances may also be added thereto.
  • the syrup comprising the active ingredient material of the present invention or a composition thereof may additionally include a sweetener such as saccharin, sweetener, glycerin or sugar, and a flavoring agent.
  • a sweetener such as saccharin, sweetener, glycerin or sugar
  • a flavoring agent such as sweeteners such as vanilla or orange extracts.
  • it may also include a suspending aid or a thickening agent (such as sodium carboxymethylcellulose), a wetting agent (such as a condensation product of a fatty alcohol with ethylene oxime:) or a preservative (such as p-hydroxybenzoic acid). ester;).
  • Injection or infusion solutions are prepared in a conventional manner, for example, by adding isotonic agents, preservatives (such as parabens) or stabilizers (such as alkali metal salts of ethylenediaminetetraacetic acid), if necessary, using emulsifiers And/or a dispersing agent, when water is used as a diluent, that is, an organic solvent may be used as a dissolving agent or a co-solvent as needed, and transferred to an injection vial or an ampoule or a perfusion bottle.
  • isotonic agents such as parabens
  • stabilizers such as alkali metal salts of ethylenediaminetetraacetic acid
  • emulsifiers And/or a dispersing agent when water is used as a diluent, that is, an organic solvent may be used as a dissolving agent or a co-solvent as needed, and transferred to an injection vial or an ampoule or a perfusion bottle
  • Suitable suppositories are, for example, admixed with a carrier for this purpose, such as a neutral lipid or polyethylene glycol or a derivative thereof.
  • Suitable excipients can be, for example, water, in pharmaceutically acceptable organic solvents (such as paraffin, for example, petroleum fractions), vegetable oils (for example, peanut oil or sesame oil), mono- or polyfunctional alcohols (for example, ethanol or glycerol).
  • organic solvents such as paraffin, for example, petroleum fractions
  • vegetable oils for example, peanut oil or sesame oil
  • mono- or polyfunctional alcohols for example, ethanol or glycerol
  • carrier such as natural mineral powder (for example, kaolin, clay, talc), synthetic mineral powder (for example, highly dispersible silica and silicate)], sugar (for example, raw sugar, lactose and glucose), emulsifier (eg, lignin, sulfite waste, methylcellulose, starch, and polyvinylpyrrolidone) and lubricants (eg, magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).
  • natural mineral powder for example, kaolin, clay, talc
  • synthetic mineral powder for example, highly dispersible silica and silicate
  • sugar for example, raw sugar, lactose and glucose
  • emulsifier eg, lignin, sulfite waste, methylcellulose, starch, and polyvinylpyrrolidone
  • lubricants eg, magnesium stearate, talc, stearic acid, and sodium lauryl sulf
  • the formulations may be administered in a conventional manner, preferably by the oral or dermal route, preferably orally.
  • the tablets may of course include additives (e.g., sodium citrate, calcium carbonate, and dicalcium phosphate) in addition to the above-described carriers, and other additives (e.g., starch, preferably potato starch, gelatin, and the like). It is also possible to use a lubricant to form tablets such as magnesium fatty acid, sodium lauryl sulfate and talc.
  • the active substance may be mixed with various flavoring or coloring agents in addition to the above-mentioned excipients. Suitable liquid carrier materials can be used for the solution of the active substance for parenteral use.
  • the intravenous dose is from 1 to 1000 mg per hour, preferably from 5 to 500 mg per hour.
  • the dosage of the drug depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the patient's The route, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal mode of treatment such as the mode of treatment, the daily dose of the compound of formula (I) or pharmaceutically acceptable
  • the type of salt can be verified according to traditional treatment options. ⁇ Detailed description of the invention
  • Mercapto refers to a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms.
  • a mercapto group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, a 2-propyl group, a n-butyl group, an isobutyl group, a t-butyl group or a pentyl group or the like is preferable.
  • lower fluorenyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like.
  • the fluorenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of a decyloxy group, an alkenyl group, an alkynyl group, a halogen, a hydroxyl group, an amino group, a nitro group, and a cyano group.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. For example, vinyl, 1-propenyl, 2-propenyl, 2-, 2- or 3-butenyl, and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of an indenyl group, a decyloxy group, an alkynyl group, a halogen group, a hydroxyl group, an amino group, a nitro group, and a cyano group.
  • Alkynyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of a decyl group, an alkoxy group, an alkenyl group, a halogen, a hydroxyl group, an amino group, a nitro group, and a cyano group.
  • a carboxylic acid or a carboxylic acid ester A carboxylic acid or a carboxylic acid ester.
  • Cycloalkyl refers to a non-aromatic monocyclic or polycyclic cyclic system comprising from 3 to 20 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably the cycloalkyl ring contains from 3 to 8 carbon atoms.
  • monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexane, cyclohexadienyl, cycloheptyl, cycloheptatrienyl Wait.
  • Polycyclic fluorenyl groups include spiro, fused, and bridged cycloalkyl groups, and non-limiting examples include 1-naphthoquinone, norbornyl, adamantyl, and the like.
  • the cycloalkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy, Amino, nitro, cyano, carbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, bicyclononyl, biheterocyclyl, -S(0)ONR 7 R 8 , -CONR 7 R 8 , -NR 7 R 8 , -S(0)OR 9 , -COR 9 , carboxylic acid or carboxylic acid ester.
  • Heterocyclyl means a non-aromatic monocyclic or polycyclic ring system comprising from 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S(0)n (where n is An integer of 0 to 2) of a hetero atom, but excluding the ring moiety of -0- 0-, -0-S- or -SS-, the remaining ring atoms being carbon.
  • the heterocyclic group contains 3 to 10 ring atoms, of which 1 to 4 are hetero atoms, and more preferably the heterocyclic group contains 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl
  • the polycyclic heterocyclic group includes a bicyclic or polycyclic spiro ring, a fused ring, and a bridged heterocyclic group.
  • the heterocyclic group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, independently selected from the group consisting of fluorenyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy, amino, nitro, cyano, carbonyl, naphthenic , heterocyclyl, aryl, heteroaryl, bicycloalkyl, biheterocyclyl, -S(0)ONR 7 R 8 , - CONR 7 R s , -NR 7 R 8 , -S(0)OR 9 , -COR 9 , a carboxylic acid or a carboxylic acid ester.
  • groups independently selected from the group consisting of fluorenyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy, amino, nitro, cyano, carbonyl, naphthenic , heterocyclyl, aryl, heteroaryl, bicycloalkyl, biheterocyclyl, -S(0)ONR 7
  • Bicyclic fluorenyl means a 5 to 14 membered all-carbon fused ring ("fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with other rings in the system), one of which Multiple rings may contain one or more double one rings with a fully conjugated pi-electron system.
  • Bicycloalkyl groups can be substituted or unsubstituted.
  • the substituent is preferably one or more, independently selected from the group consisting of fluorenyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy, amino, nitro, cyano, carbonyl, cyclodecyl, hetero Cyclo, aryl, heteroaryl, bicycloindenyl, biheterocyclyl, -S(0)ONR 7 R 8 , -CONR 7 R 8 , -NR 7 R 8 , -S(0)OR 9 , COR 9 , a carboxylic acid or a carboxylic acid ester.
  • “Biheterocyclyl” refers to a 12-membered fused ring ("fused" ring system means each ring in the system shares an adjacent pair of carbon atoms with other rings in the system), one or more of which The ring atoms are selected from nitrogen, oxygen or a hetero atom of S(0)n (where n is an integer from 0 to 2), and the remaining ring atoms are carbon. These can contain one or more double bonds but no ⁇ electronic system. It is preferably 7 to 0 yuan. E.g
  • the bicyclic heterocyclic group may be substituted or unsubstituted.
  • the substituent is preferably one or more, independently selected from the group consisting of fluorenyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy, amino, nitro, cyano, carbonyl, cycloalkyl, hetero Cyclo, aryl, heteroaryl, bicycloindenyl, biheterocyclyl, -S(0)ONR 7 R 8 , -CONR 7 R 8 , -NR 7 R 8 , -S(0)OR 9 , COR 9 , carboxylic acid or carboxylic acid ester.
  • spirocycloalkyl refers to a polycyclic group of 5 to 14 members, which shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a complete conjugation. ⁇ electronic system. It is preferably 7 to 10 yuan.
  • the spirocycloalkyl group is divided into a monospirocycloalkyl group, a double according to the number of common spiro atoms between the ring and the ring.
  • the spirocyclic fluorenyl or polyspiro is preferably a monospiroindole and a bispirocycloalkyl group.
  • it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospirocycloalkyl.
  • the spirocycloalkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of fluorenyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy , amino, nitro, cyano, carbonyl, cyclodecyl, heterocyclyl, aryl, heteroaryl, bicyclononyl, biheterocyclyl, -S(0)ONR 7 R 8 , -CONR 7 R 8 -NR 7 R 8 , - S(0)OR 9 , -COR 9 , a carboxylic acid or a carboxylic acid ester.
  • the substituent is preferably one or more of the following groups, independently selected from the group consisting of fluorenyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy , amino, nitro, cyano, carbonyl
  • spiroheterocyclyl means a polycyclic hydrocarbon of 5 to 4 members, which shares an atom (called a spiro atom) between the monocyclic rings, wherein one or two ring atoms are selected from nitrogen, oxygen or S(0)n (wherein n is an integer 0 to 2) hetero atom, and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electron system. It is preferably from 7 to 10.
  • the spirocyclic fluorenyl group is classified into a monospirocycloalkyl group, a bispirocyclic fluorenyl group or a polyspirocycloalkyl group, preferably a monospiroheterocyclic group and a bisspiroheterocyclic group, depending on the number of common snail atoms between the ring and the ring. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiroheterocyclic group.
  • the spiroheterocyclyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of fluorenyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy , amino, nitro, cyano, carbonyl, cyclodecyl, heterocyclyl, aryl, heteroaryl, bicyclononyl, diheterocyclyl, -S(0)ONR 7 R 8 , -CONR 7 R 8 -NR 7 R 8 , -S(0)OR 9 , -COR 9 , carboxylic acid or carboxylic acid ester.
  • the substituent is preferably one or more of the following groups, independently selected from the group consisting of fluorenyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy , amino, nitro, cyano, carbonyl, cycl
  • 3 to 8 membered heterocyclic group means that the number of ring atoms is 3 to 8 yuan, and the atoms constituting the ring contain one or more N, 0 or S(0) n hetero atoms, and the ring may contain 1 to 2
  • the double bond is a monocyclic or bicyclic non-aromatic ring group, and when the atom constituting the ring contains a nitrogen atom, a bond may be extended from the nitrogen atom. It is preferably a 4- to 6-membered heterocyclic group, and more preferably 5 to 6 members, such as a pyrrolidinyl group, a piperidinyl group or a piperazinyl group.
  • the 3- to 8-membered heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of an indenyl group, a decyloxy group, an alkenyl group, an alkynyl group, Halogen, hydroxy, amino, nitro, cyano, carbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, bicyclononyl, biheterocyclyl, -S(0)ONR 7 R 8 , -CONR 7 R 8 , -NR 7 R 8 , -S(0)OR 9 , -COR 9 , a carboxylic acid or a carboxylic acid ester.
  • the substituent is preferably one or more of the following groups, independently selected from the group consisting of an indenyl group, a decyloxy group, an alkenyl group, an alkynyl group, Halogen,
  • a p-membered/q-membered bicycloalkyl group a biheterocyclyl group, a monospirocycloalkyl group or a monospiroheterocyclyl group, which refers to a bicyclononyl group, a biheterocyclic group, a monospirocycloalkyl group or a monospiroheterocyclic group.
  • the number of ring atoms of each ring is p and q, respectively, and p or q is selected from an integer of 3 to 8, preferably an integer of 4 to 7.
  • Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms), a polycyclic ring having a conjugated ⁇ -electron system (ie, having adjacent pairs)
  • the ring group of a carbon atom is preferably 6 to 10 members such as a phenyl group, a naphthyl group and an anthracenyl group.
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of alkyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy, and independently.
  • Heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 or 6 members.
  • furyl thienyl, pyridyl, pyrrole, N-fluorenylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of fluorenyl, alkoxy, alkenyl, alkynyl, halogen, hydroxy. , amino, nitro, cyano, cyclodecyl, heterocyclyl, aryl, heteroaryl, bicyclononyl, biheterocyclyl, -COR 9 , -CONR 9 R 1 Q , -NR 9 R 1Q , Carboxylic acid or carboxylic acid ester.
  • Mercaptooxy means -0-(; fluorenyl) and -0-(unsubstituted cycloalkyl). For example, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • the alkoxy group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of fluorenyl, decyloxy, alkenyl, alkynyl, halogen, hydroxy.
  • Aryloxy means -0-aryl and -0-heteroaryl, and aryl and heteroaryl are as defined above. For example, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy and the like and derivatives thereof. .
  • Halogen means fluoro, chloro, bromo or iodo.
  • Amino means -N3 ⁇ 4.
  • Neitro means -N0 2 .
  • Hydrocarbonyl means -(alkyl)-OH.
  • Benzyl refers to -CH 2 - (phenyl).
  • heterocyclic group optionally substituted by a thiol group means that a fluorenyl group may be, but is not necessarily, present, including the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by a thiol group.
  • “Pharmaceutical composition” means one or more compounds described herein or a physiologically/pharmaceutically acceptable salt thereof or Mixtures of prodrugs with other chemical components, other components such as physiological/pharmaceutically acceptable carriers and excipients ; the purpose of the pharmaceutical compositions is to facilitate administration of the compounds to the organism.
  • the method for preparing the compound of the formula (I) or a salt thereof of the present invention comprises the following steps:
  • the compound of the formula (IA) is condensed with a salt of a compound of the formula (IB;) or a compound of the formula (IB;) to give a compound of the formula (I).
  • condensation reaction is carried out between an acid and an amine group, under a condensation reagent and basic conditions, and the condensation reagent used is selected from the group consisting of ruthenium, ⁇ -dicyclohexylcarbodiimide, ruthenium, osmium-diisopropyl carbon.
  • R is selected from a methyl group
  • G, ⁇ 3 is as defined for the compound of formula (IA);
  • A, n, L, R 4 to R 6 are as defined for the compound of the formula (I). detailed description
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in parts per million (ppm).
  • the NMR was measured by a Bmker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated chloroform (CDC1 3 ).
  • the internal standard was tetramethylsilyl (TMS), and the chemical shift was given in units of 10 _ 0 (ppm).
  • the MS was measured using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • HPLC measurements were performed using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the average inhibition rate of the kinase and the IC 5 o value were determined using a NovoStar plate reader (BMG, Germany).
  • the silica gel plate used has a specification of 0.15 mm to 0.2 mm, and the thin layer chromatography separation and purification product has a specification of 0.4 ram-0.5 mm.
  • the starting materials of the present invention are known and commercially available from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Chemical Companies such as products may be synthesized by or according to methods known in the art.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction uses a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction was carried out using a CEM Discover-S Model 908860 microwave reactor.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • the optimum temperature for the reaction at room temperature is from 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: chloroform and methanol system, B: n-hexane and ethyl acetate system, C: petroleum Ether and ethyl acetate system, D: acetone.
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • Column chromatography chromatographic eluent systems include: A: chloroform and methanol systems, B: n-hexyl and ethyl acetate systems, C: dichloromethane and acetone systems, D: n-hexyl and acetone systems.
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and it may be adjusted by adding a small amount of ammonia water and acetic acid.
  • EtOAc EtOAc
  • EtOAc EtOAc
  • EtOAc EtOAc
  • EtOAc EtOAc
  • EtOAc EtOAc
  • EtOAc EtOAc
  • the residue was purified by silica gel column chromatography elut elut elut elut elut elut elut elut elut Methyl ester-4-yl-amino)-5-methyl-7,8-dihydro-5H-acridin-6-one lk (550 mg, white solid), yield: 73%.
  • N-(l-methyl-(c-pyridin-4-yl)-4-nitro-3-(tetrahydro-furan-3-yl-methoxy)-benzamide 4-nitro-3- (tetrahydro-furan-3-yl-methoxy)-benzoic acid 6d (170 mg, 0.67 mmol), 1-methyl-piperidine-4-yl-amine (77 mg, 0.67 mmol), 0-benzene
  • triazole-oxime, hydrazine, hydrazine, ⁇ '-tetramethyluronium tetrafluoroborate (215 mg, 0.67 mmol) and diisopropylethylamine (25 ⁇ g, 1.47 mmol) dissolved in 40 mL In dichloromethane, the reaction was stirred for 2 hours.
  • W is) - 8 - cyclopentyl-7-ethyl --5 _-6-oxo - 5, 6, 7, 8 - tetrahydro - pteridin-2-ylamino) - N - (1 - A Base-piperidine
  • EtOAc (EtOAc) (EtOAcjjjjjjjj 4-(7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-methoxy)-benzene
  • EtOAcjjjjjjj 4-(7-ethyl-8-isopropyl-5-methyl-6-oxo-5,6,7,8-tetrahydro-acridin-2-ylamino)-methoxy)-benzene
  • Formic acid 12f (2.24 g, white solid), Yield: 91.8 %.
  • 3-methoxy-N-(l-methyl-piperidin-4-yl)-4-nitro-benzamide 3-methoxy-4-nitro-benzoic acid la (9.86 g, 50 Ment) dissolved in 200 mL of dichloromethane, followed by 0-benzotriazole-oxime, hydrazine, ⁇ ', ⁇ '-tetramethyluronium tetrafluoroborate (16.1 g, 50 mmol), Isopropylethylamine (18.2 mL, 110 mmol) and 1-methyl-piperidin-4-yl-amine (5.7 g, 50 mmol), stirred for 2 h, added 200 mL dichloromethane, 1 M aqueous ammonia The organic layer was dried (MgSO4) 10 g, yellow solid), Yield: 68%.
  • reaction mixture was concentrated under reduced pressure. ⁇ , triethylamine was added dropwise to the pH of the reaction mixture was 8-9, acetone (0.4 g, 7.1 mmol) was added, the reaction was stirred for 1 hour, sodium triacetoxyborohydride (2.5 g, 11.8 mmol) was added, and the reaction was stirred 12 hour. Add 30 mL of water and dilute with dichloromethane (50 mL x 3).
  • EtOAc (EtOAc m. 2-Chloro-5-methyl-8-phenyl-7,8,9,] 0-tetrahydro-5H-pyrazine[2,1 -A]acridine-6(6aH)-one 23k (80 mg , yellow solid), Yield: 78.4%.
  • the following in vitro assay was used to determine the proliferation inhibitory activity of the compounds of the present invention against one human cervical cancer cell line Hda in a cell line highly expressing Plk.
  • the in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound on tumor cells that express Plk in high, and the activity can be expressed by the IC 5Q value.
  • the general protocol for such an assay is as follows: First, Hela cells (purchased in Institute of biochemistry and cell biology) are seeded at a suitable cell concentration (eg 3000 cells/mL medium) on a 96-well culture plate, and then the cells are placed in a carbon dioxide incubator. The culture is carried out, and they are allowed to grow overnight. The medium is changed to a medium containing a series of concentration (usually 7 to 9 concentrations) of the test compound solution, and the plate is returned to the incubator for 72 hours. . After 72 hours, the test compound can be tested for its ability to inhibit cell proliferation using the CCK8 method.
  • the IC 5 o value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations.
  • the biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC 5 o values are shown in the following table.
  • the compounds of the present invention all have significant proliferation inhibitory activity against Hela cells.
  • Test Example 2 Inhibition of proliferation of Plk high expressing cells by the compound of the present invention
  • the following in vitro assay was conducted to determine the proliferation inhibitory activity of the compound of the present invention against human colon cancer cell HCT-116 in a cell line highly expressing Plk.
  • the in vitro cell assay described below can determine the proliferation inhibitory activity of the test compound on highly proliferating digestive tumor cells, and the inhibitory activity of the compound can be expressed by the IC 5Q value.
  • the experimental protocol is briefly described as follows: First, HCT-116 cells (purchased in Institute of biochemistry and cell biology) supplemented with 10% FCS (purchased from Gibco) as DMEM in DMEM, at a suitable cell concentration (eg 3000 cells/mL) The medium was inoculated on a 96-well culture plate, and then cultured overnight in a constant temperature incubator at 37 ° C under 5% CO 2 . After the cells are attached, the medium is replaced with fresh medium containing a gradient of the test compound (typically 7 or 9 concentration points).
  • the cell culture plate was continuously cultured for 72 hours under the aforementioned conditions. After 72 hours, the inhibitory activity of the compound on cell proliferation was measured by the method of CCK8 (Cell Counting Kit- 8, Cat. No.: CK04, purchased from Dojindo). The IC 5Q value of the compound can be calculated from the inhibition of cell proliferation by the test compound at various concentrations.
  • the biochemical activity of the compound of the present invention was measured by the above test, and the measured IC 5Q value is shown in the following table.
  • Test Example 3 Determination of Plkl kinase inhibitory activity by the compound of the present invention
  • the method described below can be used to assay the compounds of the present invention, and expressed PIk] ability to inhibit kinase activity by 50 value IC.
  • the half-inhibitory concentration of the compound, IC 5Q (the concentration of the compound required to inhibit the enzymatic activity to 50%), is determined by mixing a certain amount of the kinase with a specific substrate and a different concentration of the test compound. To a series of inhibition rates, and then use the calculation tool to calculate.
  • the Plk1 kinase used in this experiment was a recombinant human protein, and the reaction system was purchased from Poly-Like kinase 1 Assay/Inhibitor Screening Kit (#CY-]J 63).
  • the Pjk] enzyme reacts with the polypeptide substrate and different concentrations of the test compound in the reaction system (25 ° C, 30 minutes), followed by an anti-Anti- Phospho-Serine/Threonine Polyclonal Antibody (PPT-07) and The secondary antibody HRP-conjugated Anti-rabbit IgG labels the phosphorylated substrate and finally measures the A450 nM reading to quantify Plkl kinase activity.
  • the biochemical activity of the compound of the present invention was measured by the above test, and the measured IC 5Q value is shown in the following table.
  • Example 2 compound, a mixture of Examples 8-1 and 8-2
  • the pharmacokinetic parameters of the compounds of the invention are as follows:
  • Example 2 The compound of Example 2, the mixture of Examples 8-1 and 8-2, had good pharmacological absorption.

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Abstract

La présente invention concerne des dérivés de dihydroptéridinone, leur procédé de préparation et leur utilisation pharmaceutique. La présente invention concerne spécifiquement de nouveaux dérivés de dihydroptéridinone représentés par la formule générale (I), leur procédé de préparation, des compositions pharmaceutiques comprenant lesdits dérivés et leur utilisation en tant qu'agents thérapeutiques, notamment des inhibiteurs de la kinase PLK, chaque substituant de formule générale (I) ayant la définition proposée dans la description.
PCT/CN2011/000062 2010-03-19 2011-01-14 Dérivés de dihydroptéridinone, procédé de préparation et utilisation pharmaceutique associés WO2011113293A1 (fr)

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TW100115019A TW201229050A (en) 2011-01-14 2011-04-28 Dihydropteridinone derivatives, preparation process and pharmaceutical use thereof

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102017005091A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substituierte 3,4-Dihydropyrido[2,3-b]pyrazin-2(1H)-one
DE102017005089A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substitulerte 3,4-Dihydrochinoxalin-2(1H)-one

Families Citing this family (1)

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CN114276349B (zh) * 2021-12-13 2024-04-09 复旦大学 2-氨基喋啶酮类衍生物或其盐及其制备方法和用途

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CN1745081A (zh) * 2003-02-26 2006-03-08 贝林格尔英格海姆法玛两合公司 二氢蝶啶酮、其制法及作为药物制剂的用途
CN101039676A (zh) * 2004-08-14 2007-09-19 贝林格尔·英格海姆国际有限公司 具有长贮存期的二氢蝶啶酮的输注溶液
CN101541800A (zh) * 2006-10-25 2009-09-23 色品疗法有限公司 用于治疗癌症的作为plk抑制剂的蝶啶衍生物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1745081A (zh) * 2003-02-26 2006-03-08 贝林格尔英格海姆法玛两合公司 二氢蝶啶酮、其制法及作为药物制剂的用途
CN101039676A (zh) * 2004-08-14 2007-09-19 贝林格尔·英格海姆国际有限公司 具有长贮存期的二氢蝶啶酮的输注溶液
CN101541800A (zh) * 2006-10-25 2009-09-23 色品疗法有限公司 用于治疗癌症的作为plk抑制剂的蝶啶衍生物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102017005091A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substituierte 3,4-Dihydropyrido[2,3-b]pyrazin-2(1H)-one
DE102017005089A1 (de) 2016-05-30 2017-11-30 Bayer Pharma Aktiengesellschaft Substitulerte 3,4-Dihydrochinoxalin-2(1H)-one

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