WO2021121276A1 - Dérivé tétracyclique fusionné, son procédé de préparation et son utilisation médicale - Google Patents

Dérivé tétracyclique fusionné, son procédé de préparation et son utilisation médicale Download PDF

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WO2021121276A1
WO2021121276A1 PCT/CN2020/136846 CN2020136846W WO2021121276A1 WO 2021121276 A1 WO2021121276 A1 WO 2021121276A1 CN 2020136846 W CN2020136846 W CN 2020136846W WO 2021121276 A1 WO2021121276 A1 WO 2021121276A1
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alkyl
group
general formula
aryl
heteroaryl
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PCT/CN2020/136846
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English (en)
Chinese (zh)
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李心
董平
付纪强
贺峰
陶维康
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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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Publication of WO2021121276A1 publication Critical patent/WO2021121276A1/fr

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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present disclosure belongs to the field of medicine, and relates to a fused tetracyclic derivative represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as AKT1/
  • AKT1/ The use of 2/3 (AKT pan) inhibitors and the use in the preparation of drugs for the treatment and prevention of tumors.
  • PKT Protein kinase B
  • AKT Protein kinase B
  • AKT can be activated by a series of signals, including growth factors.
  • receptor tyrosine kinase receptor tyrosine kinase
  • PIP2 phosphatidylinositol-4,5-biphosphate
  • PIP3 phosphatidylinositol-4,5-biphosphate
  • the mutation of PI3K and the deletion and mutation of the homologous Phosphatase and tensin homolog (PTEN) will continue to activate the AKT protein, so that the pathway is continuously activated.
  • the role of AKT in cells is mainly to promote cell proliferation, cause cells to transform from benign to malignant, and promote cell movement and invasion, thereby causing tumor cell metastasis and dissemination.
  • the highly active phosphorylated AKT can also inhibit cell apoptosis, and participate in the mechanism of chemotherapy resistance, which affects the effect of clinical treatment. In clinical statistics, tumors with high activity of AKT account for 40% or more of different tumors.
  • AKT1 AKT1
  • AKT2 AKT2
  • AKT3 AKT3 gene knockout mice only show functions related to embryonic brain development, clinical studies have found that the expression of AKT3 is significantly increased in breast cancer and other tumors.
  • preclinical in vitro studies have shown that breast cancer cells will develop drug resistance in the treatment of long-term AKT1/2 selective inhibitor MK2206, and the expression of AKT3 is significantly increased in the drug-resistant cells.
  • Inhibitors for AKT targets have been studied clinically for many years.
  • the selective inhibitors of AKT1/2, MK2206 (Merck) and BAY1125976 (Bayer) have not been successful clinically due to curative effects and toxicity.
  • AKT1/2/3 (AKT pan) inhibitors AZD5363 (AZ) and GDC0068 (Roche) have achieved breakthrough results in phase 2 clinical trials.
  • the combination of them and other anticancer drugs can treat triple-negative breast cancer and ER+ breast cancer.
  • the treatment of prostate cancer has produced obvious effects.
  • the two AKT1/2/3 (AKT pan) inhibitors AZD5363 and GDC0068 have successfully advanced to the phase 3 clinical phase.
  • Prostate cancer is a high-incidence cancer in the United States. It is estimated that there will be 11 million prostate cancer patients worldwide in 2022, of which about 3 million (28%) in the United States.
  • Patent applications for AKT inhibitors that have been published include WO2006/071819, US8377937, WO2008/075109, US2010120801 and WO2009006040.
  • the purpose of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or Mixture form, or its pharmaceutically acceptable salt:
  • Y is N atom or CR 2 ;
  • Q is a CH or N atom; the condition is that when Y is CR 2 , Q is a N atom;
  • Z is O atom or NR 3 ;
  • G 1 and G 2 are the same or different, and are each independently selected from CR 4 or N atoms;
  • R 0 is -C(O)CHR 5 R 6 or -C(O)NHCHR 5 R 6 ;
  • R 1 is selected from hydrogen atom, halogen, alkyl and haloalkyl
  • R 2 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -NR 7 R 8 , nitro, hydroxyl, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl is optionally selected from amino, -NR 7 R 8 , halogen, alkoxy, haloalkyl, cyano, nitro, hydroxy, Substituted by one or more substituents in hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 3 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl;
  • R 5 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected From -NR 9 R 10 , oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, Substituted by one or more substituents in the aryl group and heteroaryl group;
  • R 6 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected From oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl And one or more substituents in the heteroaryl group;
  • R 7 and R 8 are the same or different and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkyl, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyl Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 9 and R 10 are the same or different and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkyl, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyl Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl is optionally substituted by one or more selected from cycloalkyl, heterocyclyl, aryl and heteroaryl Substitution;
  • n 0, 1, 2, 3, or 4.
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Q is a N atom.
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer The conformer, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G 1 is a N atom; G 2 is CR 4 ; R 4 is as defined in the general formula (I).
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Conformer, or its mixture form, or its pharmaceutically acceptable salt which is a compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer , Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • Z, Y, R 0 , R 1 , R 4 and n are as defined in the general formula (I).
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Conformer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (IIaa) or general formula (IIbb) or its tautomer, meso form, and racemate , Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • Z, Y, R 0 , R 1 , R 4 and n are as defined in the general formula (I).
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Conformer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (III) or a tautomer, meso, racemate, or enantiomer , Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R 0 is -C(O)CHR 5 R 6 ; preferably
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Conformer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (IIIaa) or general formula (IIIbb) or its tautomer, meso form, and racemate , Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer A structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (IV) or a tautomer, meso, racemate, or enantiomer , Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R 0 is -C(O)NHCHR 5 R 6 ;
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer R 2 is -NR 7 R 8 ;
  • R 7 and R 8 are the same or different, and each independently is a hydrogen atom or an alkyl group; preferably, R 7 and R 8 are the same or different.
  • R 8 is the same or different and is each independently a hydrogen atom or a C 1-6 alkyl group.
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a compound, a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z is an O atom.
  • a 6-membered heterocyclic group, a 6- to 10-membered aryl group and a 5- to 10-membered heteroaryl group are substituted by one or more substituents;
  • R 6 is a 6 to 10-membered aryl group or a 5- to 10-membered heteroaryl group, wherein The 6 to 10 membered aryl group or 5 to 10 membered heteroaryl group is optionally selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 One or more substituents in the halogenated alkoxy group are substituted.
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Conformer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (V) or a tautomer, meso, racemate, or enantiomer , Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
  • R 1 , R 4 , R 6 , R 9 and n are as defined in the general formula (I).
  • the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer Conformer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (Vaa) or general formula (Vbb) or its tautomer, meso, racemate , Enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
  • R 1 , R 4 , R 6 , R 9 and n are as defined in the general formula (I).
  • the compound represented by the general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer R 1 is a hydrogen atom; R 4 is a hydrogen atom; R 2 is -NR 7 R 8 ; R 7 and R 8 are the same or different, and are each independently A hydrogen atom or a C 1-6 alkyl group; R 0 is -C(O)NHCHR 5 R 6 ; R 5 is a C 1-6 alkyl group, wherein the C 1-6 alkyl group is optionally substituted by a hydroxy group; R 6 is a 6 to 10 membered aryl group or a 5 to 10 membered heteroaryl group, wherein the 6 to 10 membered aryl group or 5 to 10 membered heteroaryl group is optionally selected from halogen, C 1-6 alkyl, C One or more substituents of 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 halo
  • Typical compounds of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form, or its pharmaceutically acceptable salt,
  • R w is an amino protecting group, preferably (trimethylsilyl)ethoxymethyl
  • Y is N atom or CR 2 ;
  • Q is a CH or N atom; the condition is that when Y is CR 2 , Q is a N atom;
  • Z is O atom or NR 3 ;
  • G 1 and G 2 are the same or different and are each independently selected from CR 4 or N atom;
  • R 0 is -C(O)CHR 5 R 6 or -C(O)NHCHR 5 R 6 ;
  • R 1 is selected from hydrogen atom, halogen, alkyl and haloalkyl
  • R 2 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -NR 7 R 8 , nitro, hydroxyl, hydroxyalkyl, ring Alkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl is optionally selected from amino, -NR 7 R 8 , halogen, alkoxy, haloalkyl, cyano, nitro, hydroxy, Substituted by one or more substituents in hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 3 is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;
  • R 4 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl;
  • R 5 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected From -NR 9 R 10 , -OR 11 , oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, One or more substituents in heterocyclic group, aryl group and heteroaryl group;
  • R 6 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected From oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl And one or more substituents in the heteroaryl group;
  • R 7 and R 8 are the same or different and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, halogenated alkyl, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyl Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 9 and R 10 are the same or different, and are each independently selected from a hydrogen atom, R m , halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, Hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl is optionally selected from one of cycloalkyl, heterocyclyl, aryl and heteroaryl or Replaced by multiple substituents;
  • R 11 is selected from hydrogen atom, R n , alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;
  • R m is an amino protecting group; preferably, R m is tert-butoxycarbonyl;
  • R n is a hydroxy protecting group; preferably, R n is a tert-butyldimethylsilyl group;
  • n 0, 1, 2, 3, or 4.
  • R 6 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected From oxo, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Is substituted by one or more substituents in;
  • R 9 and R 10 are the same or different, and are each independently selected from a hydrogen atom, R m , halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, Hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R m is an amino protecting group, preferably, R m is a tert-butoxycarbonyl group.
  • the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (IIA) or a tautomer, meso, racemate, enantiomer, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • Z, Y, R 0 , R 1 , R 4 , R w and n are as defined in the general formula (IA).
  • the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (IIaaA) or general formula (IIbbA) or its tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • Z, Y, R 0 , R 1 , R 4 , R w and n are as defined in the general formula (IA).
  • the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (IIIA) or a tautomer, meso, racemate, enantiomer, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • R 0 is -C(O)CHR 5 R 6 ; preferably
  • the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (IVA) or a tautomer, meso, racemate, enantiomer, Diastereoisomers, or mixtures thereof or pharmaceutically acceptable salts thereof,
  • R 0 is -C(O)NHCHR 5 R 6 ;
  • the compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer Form, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by the general formula (VA) or a tautomer, meso, racemate, enantiomer, Diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • R m is an amino protecting group, preferably tert-butoxycarbonyl
  • R 1 , R 4 , R 6 , R 9 , R w and n are as defined in the general formula (IA).
  • the compounds of the typical general formula (IA) of the present disclosure include, but are not limited to:
  • Boc is tert-butoxycarbonyl
  • SEM is (trimethylsilyl)ethoxymethyl
  • TBS is tert-butyldimethylsilyl.
  • Another aspect of the present disclosure relates to a preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IA) removes the amino protecting group to obtain the compound of general formula (I),
  • R w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl
  • G 1 , G 2 , Q, Z, Y, R 0 , R 1 and n are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of the general formula (IIA) removes the amino protecting group to obtain the compound of the general formula (II),
  • R w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl
  • Z, Y, R 0 , R 1 , R 4 and n are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing compounds represented by general formula (IIaa) and general formula (IIbb) or tautomers, mesosomes, racemates, enantiomers, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, the method comprising:
  • Z, Y, R 0 , R 1 , R 4 and n are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:
  • R w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl
  • Another aspect of the present disclosure relates to a preparation of compounds represented by general formula (IIIaa) and general formula (IIIbb) or tautomers, mesosomes, racemates, enantiomers, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, the method comprising:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (IVA) removes the amino protecting group to obtain the compound of general formula (IV),
  • R w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:
  • the compound of general formula (VA) removes the amino protecting group to obtain the compound of general formula (V),
  • R w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl
  • R m is an amino protecting group; preferably tert-butoxycarbonyl
  • R 1 , R 4 , R 6 , R 9 and n are as defined in the general formula (V).
  • Another aspect of the present disclosure relates to a preparation of compounds represented by general formula (Vaa) and general formula (Vbb) or tautomers, mesosomes, racemates, enantiomers, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, the method comprising:
  • R 1 , R 4 , R 6 , R 9 and n are as defined in the general formula (V).
  • Another aspect of the present disclosure relates to a pharmaceutical composition containing the compound represented by the general formula (I) of the present disclosure or its tautomers, mesosomes, racemates, and enantiomers. Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure further relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or The use of the pharmaceutically acceptable salt or the pharmaceutical composition containing the same in the preparation of a medicine for inhibiting AKT1/2/3 (AKTpan).
  • AKT1/2/3 AKT1/2/3
  • the present disclosure further relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Use of its pharmaceutically acceptable salt or pharmaceutical composition containing it in the preparation of a medicament for the treatment and/or prevention of tumors.
  • the present disclosure further relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or The use of its pharmaceutically acceptable salt or a pharmaceutical composition containing it in the preparation of a medicament for the treatment and/or prevention of cancer; wherein the cancer is preferably selected from ovarian cancer, breast cancer, prostate cancer, glioma, Glioma, stomach cancer, fallopian tube cancer, lung cancer, peritoneal tumor, melanoma, brain cancer, esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, cervical cancer, skin cancer, neuroblastoma, sarcoma , Bone cancer, uterine cancer, endometrial cancer, head and neck cancer, multiple myeloma, lymphoma, non-Hodgkin's lymphoma, non-small cell lung cancer, polycythemia vera, leukemia
  • the present disclosure also relates to a method for inhibiting AKT1/2/3 (AKT pan), which comprises administering to a desired patient a therapeutically effective amount of a compound represented by general formula (I) or a tautomer or meso , Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • AKT1/2/3 AKT1/2/3
  • the present disclosure also relates to a method for the treatment and/or prevention of tumors, which comprises administering to a desired patient a therapeutically or preventively effective amount of a compound represented by the general formula (I) or its tautomer, mesosome, exo Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • the present disclosure also relates to a method for the treatment and/or prevention of cancer, which comprises administering to a desired patient a therapeutically or preventively effective amount of a compound represented by general formula (I) or its tautomer, mesosome, Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, wherein the cancer is preferably selected from ovarian cancer, breast cancer, Prostate cancer, glioma, glioma, stomach cancer, fallopian tube cancer, lung cancer, peritoneal tumor, melanoma, brain cancer, esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, cervical cancer, skin Cancer, neuroblastoma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck tumors, multiple myeloma, lymphoma, non-Hodgkin’s lymphoma, non-small cell lung
  • the present disclosure further relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicine.
  • the present disclosure also relates to a compound represented by general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used as an AKT1/2/3 (AKTpan) inhibitor.
  • a compound represented by general formula (I) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used as an AKT1/2/3 (AKTpan) inhibitor.
  • the present disclosure further relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used as a drug for treating tumors.
  • the tumor described in the present disclosure is selected from melanoma, brain tumor, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, nerves Blastoma, glioma, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, head and neck tumor, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor , Bladder cancer and gallbladder cancer.
  • the present disclosure further relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used as a medicine for the treatment of cancer; wherein the cancer is preferably selected from ovarian cancer, breast cancer, prostate cancer, glioma, glioma, Gastric cancer, fallopian tube cancer, lung cancer, peritoneal cancer, melanoma, brain cancer, esophageal cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, cervical cancer, skin cancer, neuroblastoma, sarcoma, bone cancer, uterus Cancer, endometrial cancer, head and neck tumors, multiple myeloma, lymphoma, non-Hodgkin’s lymphoma, non-small cell lung cancer, polycythemia vera, leukemia, thyroid tumor,
  • the active compound can be formulated into a form suitable for administration by any appropriate route, and the active compound is preferably in a unit dose form, or in a form in which the patient can self-administer in a single dose.
  • the unit dose of the compound or composition of the present disclosure can be expressed in the form of a tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, rejuvenated powder or liquid preparation.
  • the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait.
  • the composition may contain 0.1 to 99% by weight of the active compound.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs.
  • Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, To provide pleasing and delicious medicinal preparations.
  • the tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
  • excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.
  • Oral preparations can also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient is mixed with a water-soluble carrier or oil vehicle.
  • Aqueous suspensions contain the active substance and excipients for mixing suitable for preparing aqueous suspensions. Such excipients are suspending agents, dispersing agents or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
  • Oil suspensions can be formulated by suspending the active ingredients in vegetable oil or mineral oil.
  • the oil suspension may contain thickeners.
  • the above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.
  • dispersible powders and granules suitable for preparing water suspensions can provide active ingredients and dispersing agents, wetting agents, suspending agents or one or more preservatives for mixing. Suitable dispersing agents, wetting agents and suspending agents may also be added with other excipients such as sweetening agents, flavoring agents and coloring agents. These compositions are preserved by adding antioxidants such as ascorbic acid.
  • the pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion.
  • the oil phase can be vegetable oil, mineral oil or a mixture thereof.
  • Suitable emulsifiers can be naturally occurring phospholipids, and the emulsions can also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution.
  • Acceptable solvents or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution.
  • the sterile injection preparation can be a sterile oil-in-water injection microemulsion in which the active ingredient is dissolved in the oil phase, and the injection or microemulsion can be injected into the patient's bloodstream by local mass injection.
  • a continuous intravenous delivery device can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
  • the pharmaceutical composition of the present disclosure may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be formulated according to known techniques using those suitable dispersing agents, wetting agents and suspending agents mentioned above.
  • the sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent.
  • sterile fixed oil can be conveniently used as a solvent or suspending medium. For this purpose, any blended fixed oil can be used.
  • fatty acids can also be used to prepare injections.
  • the compounds of the present disclosure can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient. , The patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.
  • the optimal treatment method such as the treatment mode, the daily dosage of the compound (I), or the type of pharmaceutically acceptable salt, can be verified according to the traditional treatment plan.
  • the dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound. However, as a general guide, a suitable unit dose may be 0.1-1000 mg.
  • the present disclosure provides a fused four-ring AKT1/2/3 (AKTpan) inhibitor with a novel structure, which has a good inhibitory effect on AKT1, AKT2 and AKT3 enzymes.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) alkyl groups are more preferably alkyl groups containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms More preferred are lower alkyl groups containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.
  • alkyl group 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably independently selected from the group consisting of H atom, D atom, halogen, and alkane. Is substituted by one or more substituents in the group, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where the definition of alkyl is as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from H atom, D atom, halogen, alkyl group, alkoxy group , Haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more substituents.
  • alkylene refers to a saturated linear or branched aliphatic hydrocarbon group, which has two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 ), more preferably an alkylene group containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 -) CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc.
  • the alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl
  • alkenyl refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above.
  • alkenyl groups containing 2 to 12 for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12
  • alkenyl groups containing 2 to 6 carbon atoms are preferred.
  • Alkenyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, and halogenated alkoxy groups.
  • One or more substituents in the group cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl .
  • alkynyl refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above. Preference is given to alkynyl groups containing 2 to 12 (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and alkynyl groups containing 2 to 6 carbon atoms are more preferred.
  • the alkynyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a halogenated alkyl group, and a halogenated alkoxy group.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (e.g., 3, 4, 5). , 6, 7, 8, 9, 10, 11, and 12), more preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings, which may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 5-membered and 6-membered/6-membered bicyclic alkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro ring, fused ring and bridged ring) fused on an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure
  • the ring together is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably indanyl, tetrahydronaphthyl.
  • Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, sulfur, S( O) or S(O) 2 heteroatoms, but not including the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • It preferably contains 3 to 12 ring atoms (for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12), of which 1 to 4 (for example, 1, 2, 3, and 4) are hetero Atom; more preferably contains 3 to 8 ring atoms (such as 3, 4, 5, 6, 7 and 8), of which 1-3 (such as 1, 2 and 3) are heteroatoms; more preferably contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably contain 5 or 6 ring atoms, of which 1-3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl and so on.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5- to 20-membered monocyclic rings, in which one or more ring atoms are selected from nitrogen, oxygen, sulfur, and S (O) or S(O) 2 heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered, or 6-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclic groups include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bonds, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, sulfur, S(O) or S(O) 2 and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan double ring, 6 yuan/3 yuan, 6 yuan/4 yuan, 6-membered/5-membered and 6-membered/6-membered fused heterocyclic groups.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, one or more of the ring atoms It is a heteroatom selected from nitrogen, oxygen, sulfur, S(O) or S(O) 2 , and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • bridged heterocyclic groups include:
  • the heterocyclyl ring includes the heterocyclic group as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) fused on an aryl, heteroaryl or cycloalkyl ring, wherein it is combined with the parent
  • the rings linked together in the structure are heterocyclic groups, non-limiting examples of which include:
  • the heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more substituents in the group.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic ring is a ring that shares adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 membered , Such as phenyl and naphthyl.
  • the aryl ring includes the aryl ring as described above fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include :
  • Aryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, and alkyl groups. Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more substituents in.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4), 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members (for example, 5, 6, 7, 8, 9 or 10 members), more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkane Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like.
  • the heteroaryl ring includes the above-mentioned heteroaryl group fused on an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected with the parent structure is a heteroaryl ring, and non-limiting examples thereof include :
  • Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available point of attachment.
  • the substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more substituents in the group.
  • cycloalkyl, heterocyclic, aryl and heteroaryl groups have one residue derived from the removal of one hydrogen atom from the parent ring atom, or two residues derived from the same ring atom or two different ring atoms of the parent
  • residues derived from the removal of two hydrogen atoms are "divalent cycloalkyl", “divalent heterocyclic group", “arylene”, and "heteroarylene”.
  • amino protecting group is to keep the amino group unchanged when other parts of the molecule react, and to protect the amino group with a group that is easy to remove.
  • Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy and nitro.
  • the amino protecting group is preferably (trimethylsilyl)ethoxymethyl (SEM) and tert-butoxycarbonyl (Boc).
  • hydroxyl protecting group is a suitable group for protecting a hydroxyl group known in the art, see the document “Protective Groups in Organic Synthesis", 5th edition, TW Greene & P. GMWuts for the hydroxyl protecting group.
  • the hydroxy protecting group can be (C 1-10 alkyl or aryl) 3 silyl group, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethyl Silyl group (TBS), tert-butyldiphenylsilyl, etc.; can be C 1-10 alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C 1-6 alkoxy Substituted C 1-6 alkyl or phenyl substituted C 1-6 alkyl, most preferably C 1-4 alkoxy substituted C 1-4 alkyl, for example: methyl, tert-butyl, allyl , Benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), etc.; can be (C 1-10 alkyl or aryl) acyl, such as formyl , Ace
  • cycloalkyloxy refers to cycloalkyl-O-, where cycloalkyl is as defined above.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.
  • alkylthio refers to alkyl-S-, where alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.
  • hydroxy refers to the -OH group.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, where the alkyl group is as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • the compounds of the present disclosure may also include isotopic derivatives thereof.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • isotopic derivative refers to a compound that differs in structure only in the presence of one or more isotopically enriched atoms.
  • carbon atoms 11 C-, 13 C- or 14 C-carbon labels; 11 C-, 13 C- or 14 C- isotopes
  • Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies.
  • the present disclosure also includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom.
  • deuterated compounds can generally retain activity comparable to that of non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but does not have to be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without too much effort. For example, an amino group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, such as physiological/pharmaceutically acceptable Carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present disclosure. Such salt is safe and effective when used in mammals, and has due biological activity.
  • the term "therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • pharmaceutically acceptable refers to these compounds, materials, compositions and/or dosage forms, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic reaction or Other problems or complications have a reasonable benefit/risk ratio and are effective for the intended use.
  • the preparation method of medicinal salt includes the following steps:
  • the compound of general formula (IA) is subjected to acidic conditions, the amino protecting group is removed to obtain the compound of general formula (I),
  • R w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl
  • G 1 , G 2 , Q, Z, Y, R 0 , R 1 and n are as defined in the general formula (I).
  • the preparation method of the mixture form or its pharmaceutically acceptable salt includes the following steps:
  • R w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl
  • Z, Y, R 0 , R 1 , R 4 and n are as defined in the general formula (II).
  • the preparation method of the mixture form or its pharmaceutically acceptable salt includes the following steps:
  • the compound of general formula (IIIA) is subjected to acidic conditions, the amino protecting group is removed to obtain the compound of general formula (III);
  • R w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl
  • the preparation method of medicinal salt includes the following steps:
  • R w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl
  • the preparation method of the mixture form or its pharmaceutically acceptable salt includes the following steps:
  • the compound of general formula (VA) is subjected to acidic conditions, the amino protecting group is removed to obtain the compound of general formula (V),
  • R w is an amino protecting group; preferably (trimethylsilyl)ethoxymethyl
  • R m is an amino protecting group; preferably tert-butoxycarbonyl
  • R 1 , R 4 , R 6 , R 9 and n are as defined in the general formula (V).
  • the reagents that provide acidic conditions in the above synthesis scheme include but are not limited to 1,4-dioxane solution of trifluoroacetic acid, hydrochloric acid, hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid , P-toluenesulfonic acid, Me 3 SiCl and TMSOTf; preferably trifluoroacetic acid.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, Dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide and mixtures thereof.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four Methylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methylsilane
  • Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid-mass spectrometer manufactured by Agilent, MS model: 6110/6120 Quadrupole MS
  • water ACQuity UPLC-QD/SQD manufactured by Agilent, MS model: waters ACQuity Qda Detector/waters SQ Detector
  • THERMO Ultimate 3000-Q Exactive manufactured by THERMO, MS model: THERMO Q Exactive.
  • HPLC High performance liquid chromatography analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.
  • HPLC preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.
  • CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the thin layer chromatography separation and purification product is 0.4mm. ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.
  • reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the microwave reaction uses the CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC).
  • the developing reagent used in the reaction, the eluent system of column chromatography used in the purification of the compound and the developing reagent system of thin-layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethyl can also be added Basic or acidic reagents such as amine and acetic acid are used for adjustment.
  • Boc is tert-butoxycarbonyl
  • SEM is (trimethylsilyl)ethoxymethyl
  • HPLC analysis retention time 12.3 minutes, purity: 99.9% (column: X-Bridge, Prep30*150mm; 5um; mobile phase: A-water (10mM ammonium bicarbonate), B-acetonitrile; gradient ratio: A 20% -45%).
  • HPLC analysis retention time 13.9 minutes, purity: 96.2% (column: X-Bridge, Prep30*150mm; 5um; mobile phase: A-water (10mM ammonium bicarbonate), B-acetonitrile; gradient ratio: A 20% -45%).
  • the residue is purified by liquid preparation (Instrument model: Gilson 281 Column: X-Bridge, Prep 30*150mm; 5um; C18 mobile phase: A -Water (13mM trifluoroacetic acid) B-acetonitrile flow rate: 30mL/min column temperature: room temperature), sodium bicarbonate neutralized, extracted with dichloromethane, dried and concentrated to obtain the title compound 2P (2.50g), total yield : 68%.
  • liquid preparation Instrument model: Gilson 281 Column: X-Bridge, Prep 30*150mm; 5um; C18 mobile phase: A -Water (13mM trifluoroacetic acid) B-acetonitrile flow rate: 30mL/min column temperature: room temperature), sodium bicarbonate neutralized, extracted with dichloromethane, dried and concentrated to obtain the title compound 2P (2.50g), total yield : 68%.
  • reaction solution was diluted with dichloromethane (100 mL), washed with sodium bicarbonate, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography with eluent system C to obtain the title compound 3b (1.15g), yield: 66%.
  • HPLC analysis retention time 10.04 minutes, purity: 91% (column: X-Bridge, Prep 30*150mm; 5um; mobile phase: A-water (13mM trifluoroacetic acid), B-acetonitrile; flow rate: 30mL/min; Gradient ratio: B 16%-31%).
  • HPLC analysis retention time 11.49 minutes, purity: 95% (column: X-Bridge, Prep 30*150mm; 5um; A-water (13mM trifluoroacetic acid), B-acetonitrile; flow rate: 30mL/min, gradient ratio : B 16%-31%).
  • HPLC analysis retention time 13.27 minutes, purity: 91% (column: X-Bridge, Prep 30*150mm; 5um; mobile phase: A-water (13mM trifluoroacetic acid), B-acetonitrile; flow rate: 30mL/min; Gradient ratio: B 15%-30%).
  • HPLC analysis retention time 14.73 minutes, purity: 95% (column: X-Bridge, Prep 30*150mm; 5um; A-water (13mM trifluoroacetic acid), B-acetonitrile; flow rate: 30mL/min; gradient ratio : A 15%-30%).
  • the compound with long retention time is 425mg, yield: 43%; the compound with short retention time is 379mg, yield: 39% (LC-MS analysis: Column: ACQUITY UPLC BEHC18 1.7um 2.1*50mm; mobile phase: A- Water (v/v 1 ⁇ formic acid), B-acetonitrile (v/v 1 ⁇ formic acid), gradient ratio: B 10%-95%, total time 3.5 minutes.
  • the shorter retention time is 1.70 minutes, and the longer retention time Bit is 1.74 minutes).
  • the compound 6-f1 or 6-f2 (410 mg, 0.92 mmol) obtained in the fifth step with a retention time of 1.74 minutes (410 mg, 0.92 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (1.03 ml, 7.37 mmol) and 4-diethylamine were added.
  • Methylaminopyridine (112 mg, 0.92 mmol) and di-tert-butyl dicarbonate (805 mg, 3.69 mmol) were reacted at room temperature overnight. After concentration, a crude yellow liquid (502 mg) was obtained, and the product was directly used in the next reaction without purification.
  • HPLC analysis retention time 17.7 minutes, purity: 98.2% (column: X-Bridge, Prep30*150mm; 5um; mobile phase: A-water (v/v 1 ⁇ trifluoroacetic acid), B-acetonitrile; gradient ratio : A 90%-72%).
  • AKT1 Invitrogen, P2999
  • AKT2 Invitrogen, PV3184
  • AKT3 Invitrogen, PV3185
  • DMSO KinEASE-STK S3 kit
  • the 5 ⁇ buffer in the kit was diluted to 1 ⁇ buffer, and DTT (Sigma, 43816-10ML) and MgCl 2 were added to make the buffer contain 1 mM DTT and 5 mM MgCl 2 .
  • the compound was diluted 20 times with 1 ⁇ buffer for use.
  • the conditions of the AKT1 enzyme reaction are: the final concentration of enzyme is 2nM, the final concentration of ATP is 10 ⁇ M, and the final concentration of S3-biotin is 2 ⁇ M.
  • the conditions of the AKT2 enzyme reaction are: the final concentration of enzyme is 5nM, the final concentration of ATP is 10 ⁇ M, and the final concentration of S3-biotin is 2 ⁇ M.
  • the conditions of the AKT3 enzyme reaction are: the final concentration of enzyme is 0.4 nM, the final concentration of ATP is 45 ⁇ M, and the final concentration of S3-biotin is 2 ⁇ M.
  • the inhibitory activity of the compounds of the present disclosure on the AKT1/AKT2/AKT3 enzyme can be determined by the above test, and the measured IC 50 value is shown in Table 1.
  • Table 1 Compound IC50 value for the disclosure AKT1 / AKT2 / AKT3 inhibition of the IC.
  • the compound of the present disclosure has a good inhibitory effect on AKT1/AKT2/AKT3 enzymes.

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Abstract

L'invention concerne un dérivé tétracyclique fusionné tel que représenté dans la formule générale (I), son procédé de préparation, une composition pharmaceutique contenant le dérivé et son utilisation comme AKT1/2/3 (AKT pan) inhibiteur et dans la préparation de médicaments pour le traitement et/ou la prévention de tumeurs.
PCT/CN2020/136846 2019-12-17 2020-12-16 Dérivé tétracyclique fusionné, son procédé de préparation et son utilisation médicale WO2021121276A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012106448A1 (fr) * 2011-02-02 2012-08-09 Biocryst Pharmaceuticals, Inc. Composés hétérocycliques comme inhibiteurs de janus kinase
WO2015119712A1 (fr) * 2014-02-06 2015-08-13 Abbvie Inc. Inhibiteurs tétracycliques de la kinase cdk9
CN105026403A (zh) * 2013-03-12 2015-11-04 艾伯维公司 四环布罗莫结构域抑制剂

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012106448A1 (fr) * 2011-02-02 2012-08-09 Biocryst Pharmaceuticals, Inc. Composés hétérocycliques comme inhibiteurs de janus kinase
CN105026403A (zh) * 2013-03-12 2015-11-04 艾伯维公司 四环布罗莫结构域抑制剂
WO2015119712A1 (fr) * 2014-02-06 2015-08-13 Abbvie Inc. Inhibiteurs tétracycliques de la kinase cdk9

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