WO2023109540A1 - Composé hétérocyclique ayant une activité inhibitrice de kinase akt, son procédé de préparation et son utilisation médicale - Google Patents

Composé hétérocyclique ayant une activité inhibitrice de kinase akt, son procédé de préparation et son utilisation médicale Download PDF

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WO2023109540A1
WO2023109540A1 PCT/CN2022/136451 CN2022136451W WO2023109540A1 WO 2023109540 A1 WO2023109540 A1 WO 2023109540A1 CN 2022136451 W CN2022136451 W CN 2022136451W WO 2023109540 A1 WO2023109540 A1 WO 2023109540A1
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cycloalkyl
alkyl
alkenyl
membered
aryl
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PCT/CN2022/136451
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Chinese (zh)
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闫旭
陈振华
刘国标
蔡绪灿
尚飞
杜佩金
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中国医药研究开发中心有限公司
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Priority to CN202280050761.0A priority Critical patent/CN117677614A/zh
Publication of WO2023109540A1 publication Critical patent/WO2023109540A1/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
    • A61K31/495—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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the technical field of medicine, and relates to a pyrimidine heterocyclic compound, a preparation method thereof, a pharmaceutical composition containing the same, and its use as an AKT kinase inhibitor for treating abnormal cell growth such as cancer.
  • AKT also known as protein kinase B (PKB)
  • PKA protein kinase B
  • AKT is an important member of the PI3K/Akt/mTOR signaling pathway. It affects biological processes such as development, glucose homeostasis, tumor growth and metastasis by regulating many downstream effector molecules. Over-activation of PI3K/AKT pathway exists in more than 50% of tumors, such as breast cancer, prostate cancer, pancreatic cancer, etc. Given AKT's role as a key signaling hub for tumor survival, efforts have been made for many years to develop drugs that target the AKT kinase.
  • AKT is divided into three subtypes, AKT1, AKT2, and AKT3.
  • AKT1 and AKT2 are distributed throughout the body, while AKT3 is mainly expressed in some organs such as the brain, breast, heart, and kidney (Masure et al., Eur J Biochem, 1999:265(1), 353-360; Yang et al., J Biol Chem, 2003:278(34), 32124-32131).
  • the three subtypes all belong to the AGC kinase family, and the homology of the kinase domain reaches more than 85% (Hanks et al., Faseb J, 1995:9(8), 576-596).
  • AKT ATP-binding kinase domain
  • CAT ATP-binding kinase domain
  • carboxy-terminal domain Kumar et al., Oncogene, 2005: 24(50) comprising a hydrophobic motif (HM) , 7493-7501).
  • HM hydrophobic motif
  • RTKs or G protein-coupled receptors activate PI3K, and then phosphorylate PIP2 to transform into PIP3; PIP3 binds to the PH domain, activates AKT through PDK1-mediated phosphorylation, and causes AKT to undergo a conformational change ( PH-out conformation) and translocates to the plasma membrane.
  • the PH-out conformation exposes the CAT and regulatory domains, leading to two major sites: the threonine residue of the CAT domain (Thr308 of AKT1, Thr309 of AKT2 and Thr305 of AKT3) and the serine residue of the HM domain (Chu et al.
  • PIK3CA amplification/mutation (Shimoi et al., Cancer Sci, 2018:109(8), 2558-2566), loss of PTEN (Milella et al., Front Oncol, 2015:5(24)), mutation of AKT itself (eg E17K mutation of the PH domain) (Kalinsky et al., JAMA Oncol, 2021: 7(2), 271-278), as well as hyperactivation of other RTKs lead to persistent activation of AKT signaling.
  • AKT AKT deactivation protein kinase kinase
  • PTEN PTEN
  • PP2A PHLPP
  • SHIP Shiongo et al., Cancers, 2019:11(8); Villalobos-Ayala et al., Cancers, 2020:12(12); Grzechnik et al. , Biochem Soc Trans, 2016:44(6), 1675-1682.
  • AKT kinase has been discovered more than 30 years ago, and no drug has been successfully marketed yet. Although a variety of PI3K inhibitors upstream of AKT have been approved for the treatment of tumors, both pan-PI3K inhibitors and selective PI3K subtype inhibitors have serious toxicity problems; and negative effects after inhibiting downstream mTOR The feedback mechanism will lead to the re-upregulation of pAKT levels, which in turn activates other downstream oncogenic effectors. Therefore, the development of ideal molecules that directly target AKT is expected to avoid the serious side effects caused by the inhibition of upstream PI3K, and also avoid the negative feedback mechanism caused by the inhibition of downstream mTOR.
  • the drugs can be divided into three categories: PH domain inhibitors, allosteric inhibitors and ATP competitive inhibitors.
  • the allosteric inhibitor MK-2206 is the first AKT inhibitor to enter clinical trials, and the early clinical results show good AKT signaling inhibition effect and good tolerance (Yap et al., J Clin Oncol, 2011:29(35) ,4688-4695), but due to serious side effects, it has been removed from the R&D company's pipeline.
  • ATP competitive inhibitors such as capIIIAasertib (AZD5363) and ipatasertib (GDC0068)
  • Phase III clinical trials have been conducted in HR+ and triple-negative breast cancer.
  • a recent phase III result of ipatasertib demonstrated that the combination of ipatasertib with abiraterone and prednisolone significantly improved radiographic progression-free survival in patients with PTEN-null, metastatic and castration-resistant prostate compared to placebo plus abiraterone Cancer (Sweeney et al., Lancet, 2021:398(10295), 131-142).
  • other AKT inhibitors such as afuresertib, uprosertib, and HZB0071 are also in clinical development.
  • AKT inhibitors still faces many challenges: low bioavailability, narrow therapeutic window, side effects in addition to diarrhea, rash, and hyperglycemia, because targeted inhibition of the PI3K/AKT pathway can disrupt glucose uptake in certain tissues and metabolism, leading to hyperglycemia (Fruman et al., Cell, 2017:170(4), 605-635).
  • inhibition of hepatic AKT may cause liver injury, inflammation and carcinogenesis in mice, and promote lung metastasis (Wang et al., Cancer Cell, 2016:29(4), 523-535).
  • Future research directions need to improve kinase selectivity and tolerance, and at the same time explore reasonable drug combinations to overcome the problem of PI3K/AKT inhibitor resistance.
  • the inventors designed and synthesized a series of pyrimidine compounds, which exhibit AKT1/2/3 kinase inhibitory activity, and can be developed as drugs for treating and/or preventing diseases related to AKT activity, such as cancer.
  • the object of the present invention is to provide a compound represented by general formula (I) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • Ring A is selected from C 3 -C 12 cycloalkyl, 3 to 14 membered heterocyclic group, C 6 -C 14 aryl and 6 to 14 membered heteroaryl; wherein said C 3 -C 12 cycloalkyl, 5 to 14-membered heteroaryl, C 6 -C 14 aryl, and 6 to 14-membered heteroaryl are each independently optionally substituted by one or more R 1 ;
  • L is a bond or -CH 2 -;
  • Ring B is selected from 5 to 8 membered saturated heterocyclic groups containing 1-2 nitrogen atoms; the heterocyclic group is optionally substituted by one or more R 3 ;
  • G is selected from hydrogen, phenyl, 5-6 membered heteroaryl, wherein the phenyl, 5-6 membered heteroaryl is optionally substituted by one or more R 4 ;
  • Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl, heteroaryl, said alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano radical, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more groups are substituted; or,
  • Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl, heteroaryl, said alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano , hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or multiple groups substituted; or,
  • Each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, Aryl, heteroaryl, said alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano radical, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl One or more groups are substituted; or,
  • Each R is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, -S(O) p R a , -NR a R b , -OR a , -C(O)R a , -C(O)NR a R b , -S(O) p NR a R b , cycloalkyl, heterocyclyl, aryl, heteroaryl, the alkyl, Alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl , alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl
  • R a and R b are each independently selected from hydrogen, halogen, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl are optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy One or more groups of radical, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,
  • R a and R b and their connected nitrogen atoms together form a nitrogen-containing heterocyclic group, and the nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, Ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more groups;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1 or 2.
  • Each R 1 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (II) or their stereoisomers, tautomers, mesomers, Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • n 0, 1, 2, 3 or 4;
  • Each R 1 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • Ring B, L, G, R 2 and n are as defined in general formula (I).
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its stereoisomers, tautomers, mesomers, racemates isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein any two R 1 form C 3 -C 6 cycloalkyl or 3 together with the atoms they are connected to to 6-membered heterocyclic group, the C 3 -C 6 cycloalkyl or 3 to 6-membered heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, Ester group, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 - Substitution by one or more groups of C 6 al
  • Ring A is optionally substituted by one or more R 1 ; each R 1 is independently selected from the group consisting of hydrogen, halogen, amino, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; preferably R 1 is selected from hydrogen and amino, more preferably R 1 is hydrogen.
  • the compound represented by general formula (I) or general formula (II) according to the present invention or its stereoisomers, tautomers, mesomers, racemates isomers, enantiomers, diastereoisomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond.
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is represented by general formula (III-1), general formula (III-2) or general formula (III-3)
  • X 1 and X 2 are each independently selected from -CH 2 -, -O-, -NH-;
  • n 1 is 0 or 1
  • n2 is 0, 1 or 2;
  • Each R c is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;
  • q is 0, 1 or 2, preferably 0 or 1, more preferably 0;
  • Ring B, G, R 2 and n are as defined in general formula (I).
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (IV-1) or (IV-2) or stereoisomers, interconversions thereof Isomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • Ring E 1 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group
  • Ring E 2 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group
  • Each R e is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;
  • t is 0, 1 or 2, preferably 0 or 1, more preferably 0;
  • Ring B, G, R 2 and n are as defined in general formula (I).
  • the single wave line represents the position connected to the carbonyl, and the double wave line represents the position connected to the pyrimidine;
  • Ring B is optionally substituted by one or more R3 ;
  • Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • R3 is hydrogen
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (IIIA), general formula (IIIB) or general formula (IIIC) or a stereoisomer thereof isomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • X 1 and X 2 are each independently selected from -CH 2 -, -O-, -NH-;
  • n 1 is 0 or 1
  • n2 is 0, 1 or 2;
  • Each R c is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;
  • q is 0, 1 or 2, preferably 0 or 1, more preferably 0;
  • Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;
  • G, R 2 and n are as defined in general formula (I).
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (IVA) or (IVB) or stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • Ring E 1 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group
  • Ring E 2 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group
  • Each R e is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;
  • t is 0, 1 or 2, preferably 0 or 1, more preferably 0;
  • Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;
  • G, R 2 and n are as defined in general formula (I).
  • Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ;
  • R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or,
  • R a and R b the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group
  • the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo
  • halogen amino, nitro, cyano, oxo
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound represented by general formula (IIID), general formula (IIIE) or general formula (IIIF) or a stereoisomer thereof isomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,
  • X 1 and X 2 are each independently selected from -CH 2 -, -O-, -NH-;
  • n 1 is 0 or 1
  • n2 is 0, 1 or 2;
  • Each R c is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;
  • q is 0, 1 or 2, preferably 0 or 1, more preferably 0;
  • Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;
  • Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ;
  • R is selected from halogen;
  • R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or,
  • R a and R b the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group, and the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo One or more groups of hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy group replacement;
  • s 0, 1 or 2;
  • R 2 and n are as defined in general formula (I).
  • the compound represented by the general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, Enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (IVC) or (IVD) or their stereoisomers, tautomers isomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Ring E 1 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group
  • Ring E 2 is C 3 -C 6 cycloalkyl or 3 to 6 membered heterocyclic group
  • Each R e is independently selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkenyl alkenyl, C 2 -C 6 alkenyl alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered hetero Cyclic group, C 6 -C 10 aryl group and 5 to 10 membered heteroaryl group;
  • t is 0, 1 or 2, preferably 0 or 1, more preferably 0;
  • Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;
  • Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ;
  • R is selected from halogen;
  • R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or,
  • R a and R b the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group, and the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo One or more groups of hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy group replacement;
  • s 0, 1 or 2;
  • R 2 and n are as defined in general formula (I).
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (V) or stereoisomers, tautomers, and mesomers thereof , racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Ring A is a 3 to 6 membered monocyclic heterocyclic group
  • Each R d is independently selected from hydrogen, halogen, amino, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl , C 1 -C 6 haloalkoxy; preferably hydrogen and amino;
  • t 0, 1 or 2;
  • Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;
  • Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ;
  • R is selected from halogen;
  • R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or,
  • R a and R b the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group, and the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo One or more groups of hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy group replacement;
  • s 0, 1 or 2;
  • R 2 and n are as defined in general formula (I).
  • the compound represented by general formula (I) according to the present invention or its stereoisomer, tautomer, mesoform, racemate, enantiomer isomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof which are compounds represented by general formula (VI) or stereoisomers, tautomers, and mesomers thereof , racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Ring A is a 3 to 6 membered monocyclic heterocyclic group
  • R d is selected from hydrogen, halogen, amino, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy; preferably hydrogen;
  • Each R 3 is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl, the C 1 - C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6 - C 10 aryl, 5 to 10 membered heteroaryl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C
  • r is 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1;
  • Each R 4 is independently selected from halogen, cyano, hydroxyl, mercapto, C 1 -C 6 alkyl, -NR a R b , -OR a , said C 1 -C 6 alkyl being optionally substituted by halogen ;
  • R is selected from halogen;
  • R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl; or,
  • R a and R b the nitrogen atoms they connect together form a 5-6 membered nitrogen-containing heterocyclic group, and the 5-6 membered nitrogen-containing heterocyclic group is optionally selected from halogen, amino, nitro, cyano, oxo One or more groups of hydroxyl, mercapto, carboxyl, ester, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy group replacement;
  • s 0, 1 or 2;
  • R 2 and n are as defined in general formula (I).
  • the general formula ((IIIA), general formula (IIIB), general formula (C), general formula (D), general formula (E), general formula (F) according to the present invention
  • general formula (D), general formula (E), general formula (F), general formula (VIC), general formula (VID), general formula (V) according to the present invention
  • the compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers , or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein each R is independently selected from hydrogen, halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, C 1 -C 6 alkyl , C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, the C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 Alkenyl, C 2 -C 6 alkynyl is optionally selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, C 1 -C 6 haloalkyl, C 1 -C One or more groups of 6 haloalkyl, C 1
  • n 0, 1, 2, preferably 1 or 2, more preferably 2.
  • the compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from hydroxyl and C 1 -C 6 alkyl.
  • the compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 2, and each R 2 is independently selected from hydroxyl and C 1 -C 6 alkyl.
  • Typical compounds of the invention include, but are not limited to, the following compounds:
  • the present invention further provides a compound represented by general formula (IIIA) or general formula (IIIB) or general formula (IIIC) or its stereoisomer, tautomer, mesomer, racemate,
  • the compound of the formula IIIAa and the compound of the formula IIIAc obtain the compound of the formula IIIAb in the presence of a catalyst under alkaline conditions; compound;
  • the compound of formula IIIAa and the compound of formula IIIBc obtain the compound of formula IIIBb in the presence of catalyst coupling reaction under basic conditions; compound;
  • the compound of formula IIIAa and the compound of formula IIICc obtain the compound of formula IIICb in the presence of catalyst coupling reaction under basic conditions; compound;
  • the catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the alkaline condition is preferably N,N-diisopropylethylamine
  • the acidic condition is preferably hydrochloric acid
  • R x is an amino protecting group, preferably Boc
  • G, R 2 , R 3 , X 1 , X 2 , R c , n, n 1 , n 2 , q, r are as defined in general formula (IIIA), (IIIB) or (IIIC).
  • the present invention further relates to a compound represented by general formula (IIID) or general formula (IIIE) or general formula (IIIF) or its stereoisomer, tautomer, mesomer, racemate,
  • the compound of formula IIIAa and the compound of formula IIIDc obtain the compound of formula IIIDb in the presence of catalyst coupling reaction under basic conditions; compound;
  • the compound of the formula IIIAa and the compound of the formula IIIEc obtain the compound of the formula IIIEb in the presence of a catalyst under alkaline conditions in the coupling reaction; the compound of the formula IIIEb removes the protecting group under acidic conditions and obtains compound;
  • the compound of the formula IIIAa and the compound of the formula IIIFc obtain the compound of the formula IIIFb in the presence of a catalyst under alkaline conditions in the coupling reaction; the compound of the formula IIIFb removes the protecting group under acidic conditions and obtains compound;
  • the catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the alkaline condition is preferably N,N-diisopropylethylamine
  • the acidic condition is preferably hydrochloric acid
  • R x is an amino protecting group, preferably Boc
  • the present invention further relates to a compound represented by general formula (IVA) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer , or a mixture thereof, or a preparation method of a pharmaceutically acceptable salt thereof, comprising the following steps:
  • the compound of the formula IIIAa and the compound of the formula IVAc obtain the compound of the formula IVAb in the presence of the catalyst in the presence of a catalyst under alkaline conditions; the compound of the formula IVAb removes the protecting group under acidic conditions to obtain compound;
  • the catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the alkaline condition is preferably N,N-diisopropylethylamine
  • the acidic condition is preferably hydrochloric acid
  • R x is an amino protecting group, preferably Boc
  • Ring E 1 , G, R 2 , R 3 , Re , n, r, t are as defined in general formula (IVA).
  • the present invention further relates to a compound represented by general formula (IVB) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a preparation method of a pharmaceutically acceptable salt thereof, comprising the following steps:
  • the compound of formula IIIAa and the compound of formula IVBc obtain the compound of formula IVBb in the presence of catalyst coupling reaction under basic conditions; compound;
  • the catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the alkaline condition is preferably N,N-diisopropylethylamine
  • the acidic condition is preferably hydrochloric acid
  • R x is an amino protecting group, preferably Boc
  • Rings E 2 , G, R 2 , R 3 , R e , n, r, and t are as defined in general formula (IVB).
  • the present invention further relates to a compound represented by general formula (IVC) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a preparation method of a pharmaceutically acceptable salt thereof, comprising the following steps:
  • the compound of formula IIIAa and the compound of formula IVCc obtain the compound of formula IVCb in the presence of catalyst coupling reaction under basic conditions; compound;
  • the catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the alkaline condition is preferably N,N-diisopropylethylamine
  • the acidic condition is preferably hydrochloric acid
  • R x is an amino protecting group, preferably Boc
  • Rings E 1 , R 2 , R 3 , R 4 , Re , n, r, s, t are as defined in general formula (IVC).
  • the present invention further relates to a compound represented by general formula (IVD) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer , or a mixture thereof, or a preparation method of a pharmaceutically acceptable salt thereof, comprising the following steps:
  • the compound of the formula IIIAa and the compound of the formula IVDc obtain the compound of the formula IVDb in the presence of a catalyst under alkaline conditions; the compound of the formula IVDb removes the protecting group under acidic conditions to obtain compound;
  • the catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the alkaline condition is preferably N,N-diisopropylethylamine
  • the acidic condition is preferably hydrochloric acid
  • R x is an amino protecting group, preferably Boc
  • Rings E 2 , R 2 , R 3 , R 4 , Re , n, r, s, t are as defined in general formula (IVD).
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it in the preparation of a medicament for inhibiting AKT1/2/3.
  • the present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, in the preparation of a medicament for preventing and/or treating a disease associated with AKT1/2/3 kinase activity, said disease being preferably cancer, particularly associated with A cancer characterized by amplification or overexpression of AKT1/2/3, preferably ovarian cancer, breast cancer, prostate cancer, glioma, glioblastoma, gastric 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 myelo
  • the present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used as an AKT1/2/3 inhibitor.
  • the present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, for use in a medicament for the treatment and/or prevention of diseases associated with AKT1/2/3 kinase activity, preferably Cancer, in particular cancer characterized by amplification or overexpression of AKT1/2/3, preferably ovarian cancer, breast cancer, prostate cancer, glioma, glioblastoma, gastric 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, endometrium Carcinoma, head and neck tumor
  • the present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it, which is used as a medicine, especially a medicine for preventing and/or treating diseases related to AKT1/2/3 kinase activity, and treating and/or preventing diseases associated with Use in medicine of a disease associated with AKT1/2/3 kinase activity, preferably cancer, in particular cancer characterized by amplification or overexpression of AKT1/2/3, preferably ovarian cancer, breast cancer Carcinoma, 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, neuroblastom
  • the present invention also relates to a method for inhibiting AKT1/2/3, which comprises administering an effective amount of the compound according to the present invention or its stereoisomer, tautomer, endo rotamers, racemates, enantiomers, diastereoisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them.
  • the present invention also relates to a method for inhibiting cancer cell proliferation, inhibiting cancer cell invasion or inducing cancer cell apoptosis, which comprises administering an effective amount of the compound according to the present invention or its stereoisomer to a subject in need , tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present invention also relates to a method for preventing and/or treating diseases associated with AKT1/2/3 kinase activity, which comprises administering to a subject in need thereof an effective amount of a compound according to the present invention or a stereoisomer thereof isomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising it,
  • the disease is preferably cancer, especially a cancer characterized by amplification or overexpression of AKT1/2/3, the cancer is preferably ovarian cancer, breast cancer, prostate cancer, glioma, glioma, gastric 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
  • Compounds according to the present invention or their stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers, or mixtures thereof, or A pharmaceutically acceptable salt or a pharmaceutical composition comprising the same may be administered simultaneously, separately or sequentially with another anticancer therapeutic agent or method of anticancer treatment.
  • Alkyl means a saturated aliphatic hydrocarbon group including straight and branched chain groups having the indicated number of carbon atoms.
  • the alkyl group usually contains 1-20 carbon atoms (C 1 -C 20 alkyl), preferably 1 to 12 carbon atoms (C 1 -C 12 alkyl), more preferably 1 to 8 carbon atoms (C 1 -C 8 alkyl) or 1 to 6 carbon atoms (C 1 -C 6 alkyl) or 1 to 4 carbon atoms (C 1 -C 4 alkyl).
  • Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropane base, 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 base, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment.
  • an alkyl group is optionally substituted with one or more substituents, preferably 1-3 substituents.
  • Optionally substituted alkyl groups described herein may be substituted with one or more substituents, which are independently selected unless otherwise stated. To the extent such substitution is chemically significant, the total number of substituents can be equal to the total number of hydrogen atoms on the alkyl group.
  • Optionally substituted alkyl typically contains 1 to 6 optional substituents, sometimes 1 to 5 optional substituents, preferably 1 to 4 optional substituents, or more preferably 1 to 3 optional substituents Substituents.
  • an alkyl group may be substituted by one or more (up to the total number of hydrogen atoms present on the alkyl group) halo groups.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Alkenyl usually contains 2 to 20 carbon atoms (C 2 -C 20 alkenyl), preferably 2 to 12 carbon atoms (C 2 -C 12 alkenyl), more preferably 2 to 8 carbon atoms (C 2 -C 8 alkenyl) or 2 to 6 carbon atoms (C 2 -C 6 alkenyl) or 2 to 4 carbon atoms (C 2 -C 4 alkenyl).
  • alkenyl include ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, hetero Cyclosulfanyl.
  • alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • the alkynyl group usually contains 2 to 20 carbon atoms (C 2 -C 20 alkynyl), preferably 2 to 12 carbon atoms (C 2 -C 12 alkynyl), more preferably 2 to 8 carbon atoms (C 2 -C 8 alkynyl) or 2 to 6 carbon atoms (C 2 -C 6 alkynyl) or 2 to 4 carbon atoms (C 2 -C 4 alkynyl).
  • Non-limiting examples of alkynyl include ethynyl, propynyl, butynyl, and the like.
  • Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, cycloalkylthio, hetero Cyclosulfanyl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms.
  • monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene base, cyclooctyl, etc.
  • Multicyclic cycloalkyls include spiro, fused and bridged cycloalkyls.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The ⁇ -electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated ⁇ -electron systems. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, Benzocycloheptyl, etc.
  • Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, haloalkane radical, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl Oxy group, cycloalkylthio group, heterocyclylthio group, oxo group, carboxyl group or carboxylate group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuryl , Dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 6 to 10 yuan.
  • the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclyls include:
  • fused heterocyclyl 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, and one or more rings may contain one or more double bond, but none of the rings has a fully conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring
  • the atom is carbon.
  • it is 6 to 14 yuan, more preferably 6 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclic groups include:
  • bridged heterocyclyl refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond.
  • it is 6 to 14 yuan, more preferably 6 to 10 yuan.
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkane radical, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl Oxy group, cycloalkylthio group, heterocyclylthio group, oxo group, carboxyl group or carboxylate group.
  • the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkane radical, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl,
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated pi-electron system, such as benzene and naphthyl, more preferably phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkane Oxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyloxy, Cycloalkylthio, heterocyclylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; e.g. imidazolyl, furyl, thienyl, thiazolyl, pyrazole Base, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkane radical, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl Oxy group, cycloalkylthio group, heterocyclylthio group, carboxyl group or carboxylate group.
  • the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkane radical, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano,
  • alkoxy refers to -O-(alkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, haloalkane radical, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl Oxy group, cycloalkylthio group, heterocyclylthio group, carboxyl group or carboxylate group.
  • haloalkyl refers to an alkyl group substituted with one or more halo, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy group is as defined above.
  • alkylthio refers to -S-(alkyl), wherein alkyl is as defined above.
  • alkylamino refers to -NH-(alkyl), -N(alkyl) 2 -, -NH-(cycloalkyl) or -N-(cycloalkyl) 2 , wherein alkyl and cycloalkyl is defined as above.
  • cycloalkyloxy refers to -O-(cycloalkyl), wherein cycloalkyl is as defined above.
  • Non-limiting examples of cycloalkyloxy include: cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • cycloalkylthio refers to -S-(cycloalkyl), wherein cycloalkyl is as defined above.
  • heterocyclyloxy refers to -O-(heterocyclyl), wherein heterocyclyl is as defined above.
  • heterocyclylthio refers to -S-(heterocyclyl), wherein heterocyclyl is as defined above.
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • mercapto refers to -SH.
  • esters or “carboxylate” refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl refers to compounds containing the group -C(O)R, where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • amino-protecting group is used to protect the amino group with a group that can be easily removed in order to keep the amino group unchanged when other parts of the molecule react.
  • Non-limiting examples include tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.
  • the amino protecting group is preferably tert-butoxycarbonyl.
  • heterocyclyl optionally substituted with alkyl means that an alkyl group may but need not be present, and the description includes both cases where the heterocyclyl is substituted by an alkyl and cases where the heterocyclyl is not substituted by an alkyl.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients .
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • pharmaceutically acceptable salt and “pharmaceutically acceptable salt” can be used interchangeably and refer to the salts of the compounds of the present invention, which are safe and effective when used in mammals, and have due biological activity.
  • Cancer refers to any malignant and/or invasive growth or tumor (caused by abnormal cell growth). Cancers include solid tumors named for the type of cells that form them, cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Cancers of the blood include, but are not limited to, leukemias, lymphomas, and myelomas. Cancer also includes primary cancer that started in a specific part of the body, metastatic cancer that has spread from where it started to other parts of the body, recurrence from the original primary cancer after remission, and second primary cancer (This is a new primary cancer in a person with a history of previous cancer of a different type than the new primary cancer).
  • the cancer may be selected from breast cancer, ovarian cancer, prostate cancer, bladder cancer, uterine cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, and gastric cancer.
  • the cancer is characterized by amplification or overexpression of AKT1/2/3.
  • Stereoisomers described herein may include cis and trans isomers, optical isomers such as (R) and (S) enantiomers of the compounds of the invention (including compounds exhibiting more than one isomeric type) Isomers, diastereoisomers, geometric isomers, rotamers, atropisomers, conformers and tautomers; and mixtures thereof (such as racemates and asymmetric enantiomer pair).
  • optical isomers such as (R) and (S) enantiomers of the compounds of the invention (including compounds exhibiting more than one isomeric type) Isomers, diastereoisomers, geometric isomers, rotamers, atropisomers, conformers and tautomers; and mixtures thereof (such as racemates and asymmetric enantiomer pair).
  • the compounds of the present invention may exhibit tautomerism and structural isomerism.
  • compounds may exist in several tautomeric forms, including enol and imine forms and keto and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of the present invention.
  • Tautomers exist as a mixture of tautomeric sets in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention includes all tautomers of the provided compounds.
  • enantiomeric purity of the compounds described herein can be described in terms of enantiomeric excess (ee), which means that a sample contains one enantiomer in a greater amount than the other Degree.
  • ee enantiomeric excess
  • the ee of a racemic mixture is 0%, while the ee of a single, completely pure enantiomer is 100%.
  • diastereomeric purity can be described in terms of diastereomeric excess (de).
  • the compounds of the present invention can form pharmaceutically acceptable base addition salts or acid addition salts with bases or acids.
  • the base includes inorganic bases and organic bases.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc.
  • Acceptable inorganic bases include aluminum hydroxide, hydroxide Calcium, Potassium Hydroxide, Sodium Carbonate and Sodium Hydroxide etc.
  • the acid includes inorganic acid and organic acid, acceptable inorganic acid includes hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and the like.
  • Acceptable organic acids include acetic acid, trifluoroacetic acid, formic acid, ascorbic acid, and the like.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir.
  • Oral compositions can be prepared according to any method known in the art for the preparation of 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 palatable medicinal preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc.
  • These tablets may be uncoated or may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over an extended period of time.
  • water-soluble taste-masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time-extending materials such as ethylcellulose, cellulose acetate butyrate may be used.
  • Hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or in which the active ingredient is admixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil may also be used.
  • Soft gelatin capsules provide an oral formulation.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and acacia; dispersing or wetting agents, which may be natural
  • the resulting phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecanylethyleneoxycetate Heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with fatty acids and hexitols Condensation products of anhydride-derived partial esters, such as polyethylene oxide sorb
  • Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweeteners.
  • preservatives such as ethyl or n-propylparaben
  • coloring agents such as ethyl or n-propylparaben
  • flavoring agents such as sucrose, saccharin, or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents as mentioned above may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives for admixture. Suitable dispersing or wetting agents and suspending agents are mentioned above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of antioxidants such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or mixtures thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation of said partial esters with ethylene oxide Products such as polyethylene oxide sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, coloring agents and antioxidants.
  • the pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then treated in a mixture of water and glycerol to form a microemulsion.
  • the injectable solution or microemulsion can be injected into the patient's bloodstream by local bolus injection.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used.
  • the pharmaceutical composition of the present invention may be in the form of sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • sterile fixed oils are conveniently employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are prepared as injectables.
  • 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 patient's age, the patient's body weight, the patient's health status, the patient's behavior, the patient's Diet, administration time, administration method, excretion rate, drug combination, etc.
  • the optimal treatment method such as the treatment mode, the daily dosage of the compound of the general formula or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.
  • the present invention may contain the compound represented by the general formula and its pharmaceutically acceptable salt, hydrate or solvate as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare a composition, and prepared into clinically acceptable dosage form.
  • the derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like.
  • the compound of the present invention can be used as the only active ingredient, and can also be used in combination with other drugs for treating diseases related to AKT kinase activity. Combination therapy is achieved by the simultaneous, separate or sequential administration of the individual therapeutic components.
  • the present invention adopts the following synthetic scheme to prepare the compound of the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.
  • the compound of formula IIIAa and the compound of formula IIIDc obtain the compound of formula IIIDb in the presence of catalyst coupling reaction under basic conditions; compound;
  • the catalyst is preferably benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • the alkaline condition is preferably N,N-diisopropylethylamine
  • the acidic condition is preferably hydrochloric acid.
  • Step 1 In the presence of activation such as pivaloyl chloride, compound a is condensed with a chiral auxiliary such as compound b to obtain compound c;
  • Step 2 In the presence of a catalyst such as 4-dimethylaminopyridine, compound d is reacted with a suitable compound such as tert-butyl dicarbonate to obtain amino-protected compound e;
  • a catalyst such as 4-dimethylaminopyridine
  • Step 3 reducing compound e using a reducing agent such as diisobutylaluminum hydride to obtain compound f;
  • Step 4 In the presence of a catalyst such as p-toluenesulfonic acid, compound f is reacted with methanol to obtain compound g;
  • a catalyst such as p-toluenesulfonic acid
  • Step 5 Compound g is condensed with compound c in the presence of a suitable Lewis acid such as titanium tetrachloride and a weak base such as N,N-diisopropylethylamine to give compound h, preferably at low temperature such as -78 °C to 0 °C to obtain acceptable diastereoselectivity in the reaction;
  • a suitable Lewis acid such as titanium tetrachloride
  • a weak base such as N,N-diisopropylethylamine
  • Step 6 Compound h is hydrolyzed in the presence of a base such as lithium hydroxide and a hydrolytic chiral auxiliary such as hydrogen peroxide to obtain a compound of formula IIIBc.
  • a base such as lithium hydroxide
  • a hydrolytic chiral auxiliary such as hydrogen peroxide
  • Compound Ik is prepared from hydroxypyrimidine Ij under standard conditions (eg, phosphorus oxychloride); compound Ik is reacted with the desired piperazine to give compound Il; compound Il is hydrolyzed with a base such as lithium hydroxide to give compound Im; Compound Im is reacted with benzyl bromide in the presence of a base such as cesium carbonate to give compound In; compound In is reacted with carbon monoxide to give compound Io; compound Io is cyclized to give compound Ip; benzyl is removed using palladium on carbon and an acid such as formic acid oxycarbonyl to provide compound Iq; asymmetric reduction of compound Iq using a chiral catalyst in the presence of a reducing agent such as formic acid affords Ir; Enantiomers; hydrolysis affords Compound It; compound It is then deprotected to afford Compound Iu.
  • a base such as lithium hydroxide to give compound Im
  • Compound Im is reacted with benzy
  • R x is an amino protecting group, preferably Boc
  • Figure 1 is the tumor growth curves in mice of each group in Test Example 4.
  • the compounds of the present invention are prepared utilizing convenient starting materials and general preparative procedures.
  • the present invention gives typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. But unless otherwise specified, other reaction conditions can also be adopted. Optimum conditions may vary with specific reactants or solvents used, but in general, reaction optimization steps and conditions can be identified.
  • protecting groups may be used in the present invention to protect certain functional groups from unnecessary reactions.
  • Suitable protecting groups for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art.
  • Protecting Groups in Organic Preparations by T.W. Greene and G.M. Wuts (3rd Edition, Wiley, New York, 1999 and citations in the book) describes in detail the protection or deprotection of a large number of protecting groups.
  • the separation and purification of compounds and intermediates takes appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin-layer chromatography, preparative high-performance liquid chromatography or a combination of the above methods.
  • For its specific usage method please refer to the examples described in the present invention.
  • other similar separation and purification means can also be used. They can be characterized using conventional methods, including physical constants and spectral data.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined by LC (Waters 2695)/MS (Quattro Premier xE) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector).
  • Preparative high performance liquid chromatography uses lc6000 high performance liquid chromatography (manufacturer: Innovation Tongheng). Chromatographic column is DaisogelC18 10 ⁇ m 100A (30mm ⁇ 250mm), mobile phase: acetonitrile/water.
  • the thin-layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate.
  • the specification of the silica gel plate used for thin-layer chromatography (TLC) is 0.20mm-0.25mm, and the specification used for the preparation of thin-layer chromatography separation and purification products is 0.5mm.
  • the known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Wanghua Mall, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Yinuokai, Anaiji Chemical, Shanghai Biide and other companies.
  • the reactions can all be carried out under a nitrogen atmosphere.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Reaction solvents organic solvents or inert solvents are each expressed as that the solvent used does not participate in the reaction under the described reaction conditions, including such as benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, Dichloromethane, ether, methanol, nitrogen-methylpyrrolidinone (NMP), pyridine, etc.
  • the solution refers to an aqueous solution.
  • the chemical reactions described in the present invention are generally carried out under normal pressure.
  • the reaction temperature is between -78°C and 200°C.
  • the reaction time and conditions are, for example, between -78°C and 200°C under one atmospheric pressure, and the reaction is completed within about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction process in the embodiment adopts thin layer chromatography (TLC), and the system of developing agent used in the reaction has: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, C: acetone, The volume ratio of the solvent is adjusted according to the polarity of the compound.
  • TLC thin layer chromatography
  • the eluent system of the column chromatography that purifies compound adopts and the developer system of thin-layer chromatography include: A: dichloromethane and methanol system, B: sherwood oil and ethyl acetate system, the volume ratio of solvent is according to the compound It can be adjusted according to the polarity, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and trifluoroacetic acid.
  • Step 9 4-((5R,7R)-5-Methyl-7-(pivaloyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piper Preparation of tert-butylazine-1-carboxylate (1i)
  • Step 10 4-((5R,7R)-7-Hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylic acid Preparation of tert-butyl ester (1j)
  • Methyl 2-(diethoxyphosphoryl)acetate (32.5 g, 0.130 mol) was dissolved in anhydrous tetrahydrofuran (80 mL), and sodium hydride (3.71 g, 0.130 mol) was slowly added in batches under an ice bath, React at room temperature for 1 hour. Cyclopentanone (10.0 g, 0.120 mol) was then added and stirred at room temperature for 4 hours.
  • Step 16 Preparation of tert-butyl 3-hydroxy-2-azaspiro[4.4]nonane-2-carboxylate (1p)
  • tert-butyl 3-oxo-2-azaspiro[4.4]nonane-2-carboxylate (1.50g, 6.27mmol) and THF (23.0mL) were added to the reaction flask, cooled to -78 °C, DIBAL-H (10mL, 10.0mmol) was added dropwise, after the drop was completed, it was kept at -78°C for 30 minutes.
  • Step 17 Preparation of tert-butyl 3-methoxy-2-azaspiro[4.4]nonane-2-carboxylate (1q)
  • Step 19 (S)-3-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of tert-butyl -oxoethyl)-2-azaspiro[4.4]nonan-2-carboxylate (1s)
  • Step 20 (S)-2-((S)-2-(tert-butoxycarbonyl)-2-azaspiro[4.4]non-3-yl)-2-(4-chlorophenyl)acetic acid (1t ) preparation
  • Step 21 (S)-3-((S)-1-(4-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2-azaspiro[4.4]nonan-2-carboxylic acid tert-butyl ester
  • Step 22 (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-2-azaspiro[4.4]non-3-yl)ethan-1-one (1)
  • tert-butyl 8-oxo-2-oxa-7-azaspiro[4.4]nonane-7-carboxylate (1.10 g, 4.56 mmol) and THF (20.0 mL) were added to the reaction flask , cooled to -78°C, added DIBAL-H (10mL, 10.0mmol) dropwise, and kept at -78°C for 30 minutes after dropping.
  • tert-butyl 8-hydroxy-2-oxa-7-azaspiro[4.4]nonane-7-carboxylate 600 mg, 2.47 mmol
  • methanol (12 mL) and p-toluenesulfonic acid monohydrate 52.0 mg, 0.270mmol
  • the reaction system was poured into saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the residue was diluted with dichloromethane to prepare a 29 wt% solution, which was directly used in the next step.
  • Step 7 (8S)-8-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-2-oxa-7-azaspiro[4.4]nonane-7-carboxylate tert-butyl ester (2g)
  • Step 8 (2S)-2-((8S)-7-(tert-butoxycarbonyl)-2-oxa-7-azaspiro[4.4]non-8-yl)-2-(4-chlorobenzene Base) Preparation of acetic acid (2h)
  • Step 9 (8S)-8-((S)-1-(4-chlorophenyl)-2-(4-(((5R,7R)-7-hydroxy-5-methyl-6,7- Dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2-oxa-7-azaspiro[4.4]nonane- Preparation of tert-butyl 7-carboxylate (2i)
  • Step 10 (2S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane And [d] pyrimidin-4-yl)piperazin-1-yl)-2-((8S)-2-oxygen-7-azaspiro[4.4]non-8-yl)ethan-1-one ( 2) Preparation
  • tert-butyl 3-azabicyclo[3.1.0]hexane-3-carboxylate (10.2g, 50.0mmol) and ethyl acetate (250ml) were added to the reaction flask, and ruthenium dioxide- Hydrate (2.66g, 20.0mmol) and sodium periodate (53.5g, 250mmol) in aqueous solution (200ml), stirred for 12 hours.
  • the title compound as colorless oil, yield: 51.7%.
  • tert-butyl 2-hydroxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (6.66g, 32.3mmol) and methanol (70mL) were added to the reaction flask, and Toluenesulfonic acid (430mg, 2.26mmol), stirred for 2 hours.
  • reaction solution was concentrated to dryness, added with saturated sodium bicarbonate solution and ethyl acetate for extraction, the organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 5.63g
  • the title compound as a yellow oil was diluted with dichloromethane (20 mL) and used directly in the next step.
  • Step 5 (1S,2S)-2-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl) Preparation of -2-oxoethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (3e)
  • compound 1r (8.87g, 27.0mmol) and dichloromethane (90mL) were added to the reaction flask, the temperature was lowered to -78°C, titanium tetrachloride (5.12g, 27.0mmol) was added dropwise, and after 30 minutes of insulation DIPEA (4.74g, 36.8mmol) was added dropwise, and tert-butyl 2-methoxy-3-azabicyclo[3.1.0]hexane-3-carboxylate (5.21g, 24.5mmol) was added dropwise after incubation for 30 minutes A dichloromethane solution (18 mL) was incubated for 30 minutes and then naturally rose to room temperature for 1.5 hours.
  • Step 8 (2S)-2-(((2S)-3-Azabicyclo[3.1.0]hex-2-yl)-2-(4-chlorophenyl)-1-(4-((5R ,7R)-7-Hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)ethan-1-one (3) preparation of
  • reaction solution was concentrated to dryness, diluted with dichloromethane, adjusted to pH 7-8 with DIPEA, concentrated under reduced pressure, and the residue was separated and purified by preparative high-performance liquid chromatography (column model: Daisogei 30mm*250mm , C18, 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), 57.0 mg of the title compound was obtained as a white solid, and the yield was 61.2%.
  • methyl 3-cyanopropionate (7.91 g, 70.0 mmol) and tetrahydrofuran (200 mL) were added to the reaction flask, and tetraisopropyl titanate (3.98 g, 14.0 mmol) was added.
  • the temperature was lowered to below 10°C, under nitrogen atmosphere, ethylmagnesium bromide (3.0M, 51.4mL, 154mmol) was slowly added, after the addition was completed, the temperature was slowly raised to room temperature, and the reaction was stirred for 12 hours.
  • reaction solution was concentrated to dryness, added with saturated sodium bicarbonate solution and ethyl acetate for extraction, the organic phase was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 7.96g
  • the title compound as a brown oil was diluted with dichloromethane (20 mL) and used directly in the next step.
  • Step 5 (S)-5-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-4-azaspiro[2.4]heptane-4-carboxylic acid tert-butyl ester (4e)
  • Step 8 (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-4-azaspiro[2.4]hept-5-yl)ethan-1-one (4)
  • reaction solution was concentrated to dryness, diluted with dichloromethane, adjusted to pH 7-8 with DIPEA, concentrated under reduced pressure, and the residue was separated by preparative high-performance liquid chromatography (column model: Daisogei 30mm*250mm, C18 , 10um, 100A, mobile phase: acetonitrile/water, gradient: 30%-80%), 34.0 mg of the title compound was obtained as a white solid, and the yield was 32.3%.
  • tert-butyl 1-oxo-2-azaspiro[4.5]decane-2-carboxylate 338mg, crude product
  • THF 23.0mL
  • DIBAL-H 2mL, 2.0mmol
  • tert-butyl 1-hydroxy-2-azaspiro[4.5]decane-2-carboxylate methanol (20mL)
  • p-toluenesulfonic acid monohydrate 52.0mg, 0.270mmol
  • the reaction system was poured into saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the residue was diluted with dichloromethane to prepare a 29 wt% solution, which was directly used in the next step.
  • Step 4 (R)-1-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (5d)
  • Step 5 (S)-2-((R)-2-(tert-butoxycarbonyl)-2-azaspiro[4.5]dec-1-yl)-2-(4-chlorophenyl)acetic acid (5e ) preparation
  • Step 7 (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-2-azaspiro[4.5]dec-1-yl)ethan-1-one (5)
  • methyl cyclopentanecarboxylate (1.02 g, 8.00 mmol), THF (20 mL) were added into the reaction flask. Cool down to -78°C, add LDA (4.4mL, 8.80mmol) dropwise, and stir for 1 hour. At -78°C, add bromoacetonitrile (1.14g, 9.60mmol) dropwise.
  • tert-butyl 1-oxo-2-azaspiro[4.4]nonan-2-carboxylate (460 mg, 1.92 mmol) and THF (10.0 mL) were added to the reaction flask at room temperature. Cool down to -78°C, add DIBAL-H (2.9mL, 2.88mmol) dropwise, and stir at -78°C for 30 minutes. After the reaction was completed, the reaction was quenched with saturated aqueous sodium acetate (5 mL), warmed to room temperature, added saturated aqueous ammonium chloride (5 mL) and ethyl acetate (10 mL) and stirred for 10 minutes, filtered, and the aqueous phase was extracted with ethyl acetate.
  • Step 6 (R)-1-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-2-azaspiro[4.4]nonan-2-carboxylate tert-butyl ester (6f)
  • Step 7 (S)-2-((R)-2-(tert-butoxycarbonyl)-2-azaspiro[4.4]non-1-yl)-2-(4-chlorophenyl)acetic acid (6g ) preparation
  • Step 8 (R)-1-((S)-1-(4-chlorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-di Hydrogen-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2-azaspiro[4.4]nonan-2-carboxylic acid tert-butyl ester
  • Step 9 (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-2-azaspiro[4.4]non-1-yl)ethan-1-one (6)
  • dimethyl cyclopropane-1,1-dicarboxylate (10.0g, 63.3mmol) and THF (150mL) were added to the reaction flask, and lithium tris(tert-butoxy)aluminum hydride (35.4g , 139.2mmol), after the addition, the temperature was raised to 60°C for overnight reaction.
  • Step 2 Preparation of methyl 1-((p-toluenesulfonyloxy)methyl)cyclopropane-1-carboxylate (7b)
  • methyl 1-(hydroxymethyl)cyclopropane-1-carboxylate 5.0 g, 38.4 mmol
  • DCM 100 mL
  • TEA 7.76 g, 76.8 mmol
  • DMAP 468 mg, 3.84 mmol
  • TMSCN trimethyl Cyanosilane
  • TBAF tetrabutylammonium fluoride
  • tert-butyl 4-oxo-5-azaspiro[2.4]heptane-5-carboxylate 1.0 g, 4.74 mmol
  • THF 23.0 mL
  • DIBAL-H 10 mL, 10.0 mmol
  • tert-butyl 4-hydroxy-5-azaspiro[2.4]heptane-5-carboxylate 822mg, 3.86mmol
  • methanol (20mL) and p-toluenesulfonic acid monohydrate 36.6mg, 0.19mmol
  • the reaction system was poured into saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the residue was diluted with dichloromethane to prepare a 29 wt% solution, which was directly used in the next step.
  • Step 8 (R)-4-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (7h)
  • Step 9 (S)-2-((R)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptan-4-yl)-2-(4-chlorophenyl)acetic acid ( 7i)
  • Step 11 (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-5-azaspiro[2.4]heptane-4-yl)ethan-1-one (7)
  • Example 8 (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta Preparation of alkano[d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-6-azaspiro[3.4]oct-5-yl)ethan-1-one (8)
  • Methyl 1-(hydroxymethyl)cyclobutane-1-carboxylate (7.5 g, 52.0 mmol), DCM (100 mL), TEA (7.76 g, 76.8 mmol), DMAP (468 mg, 3.84 mmol) were mixed at room temperature Added to the reaction flask in turn, added p-toluenesulfonyl chloride (9.9 g, 52.0 mmol) in batches, and stirred overnight at room temperature.
  • methyl 1-((p-toluenesulfonyloxy)methyl)cyclobutane-1-carboxylate (11.0 g, 36.9 mmol) and THF (100 mL) were added to the reaction flask, and TMSCN ( 10.9g, 110.7mmol) and 1M TBAF in THF (110.7mL, 110.7mmol), stirred overnight at room temperature.
  • 6-azaspiro[3.4]octan-5-one (1.0g, 8.0mmol) was added into dichloromethane (25mL), followed by the addition of di-tert-butyl dicarbonate (3.7g, 16.8mmol) , triethylamine (3.4g, 33.6mmol) and 4-dimethylaminopyridine (68.3mg, 0.56mmol), stirred at room temperature for 2 hours.
  • Step 8 Preparation of tert-butyl 5-methoxy-6-azaspiro[3.4]octane-6-carboxylate (8h)
  • tert-butyl 5-hydroxy-6-azaspiro[3.4]octane-6-carboxylate 822mg, 3.62mmol
  • methanol 20mL
  • p-toluenesulfonic acid monohydrate 36.6mg, 0.19mmol
  • the reaction system was poured into a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and the residue was diluted with dichloromethane to obtain a 29 wt% solution, which was directly used in the next step.
  • Step 9 (R)-5-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (8i)
  • Step 10 (S)-2-((R)-6-(tert-butoxycarbonyl)-6-azaspiro[3.4]octan-5-yl)-2-(4-chlorophenyl)acetic acid ( 8j) Preparation
  • Step 12 (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((R)-6-azaspiro[3.4]oct-5-yl)ethan-1-one (8)
  • tert-Butyl 6-oxo-5-azaspiro[2.4]heptane-5-carboxylate (1.4 g, 6.63 mmol) and THF (30 mL) were added to the reaction flask at room temperature. Cool down to -78°C, add DIBAL-H (10 mL, 10.0 mmol) dropwise, and stir at -78°C for 30 minutes.
  • Step 7 (S)-6-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (9g)
  • Step 8 (S)-2-((S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptan-6-yl)-2-(4-chlorophenyl)acetic acid ( 9h)
  • Step 10 (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-5-azaspiro[2.4]hept-6-yl)ethan-1-one (9)
  • 6-azaspiro[3.4]octan-7-one (1.1g, 8.79mmol) was added into dichloromethane (50mL), followed by di-tert-butyl dicarbonate (2.88g, 13.2mmol) , triethylamine (TEA) (2.67g, 26.4mmol) and 4-dimethylaminopyridine (DMAP) (53.7mg, 0.44mmol), stirred at room temperature for 2 hours.
  • TEA triethylamine
  • DMAP 4-dimethylaminopyridine
  • tert-butyl 7-oxo-6-azaspiro[3.4]octane-6-carboxylate 1.2 g, 5.33 mmol
  • THF 24 mL
  • DIBAL-H 10 mL, 10.0 mmol
  • Step 7 (S)-7-((S)-2-((R)-4-Benzyl-2-oxooxazolidin-3-yl)-1-(4-chlorophenyl)-2 Preparation of -oxoethyl)-6-azaspiro[3.4]octane-6-carboxylic acid tert-butyl ester (10g)
  • Step 8 (S)-2-((S)-6-(tert-butoxycarbonyl)-6-azaspiro[3.4]octan-7-yl)-2-(4-chlorophenyl)acetic acid ( 10h)
  • Step 10 (S)-2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopentane Preparation of [d]pyrimidin-4-yl)piperazin-1-yl)-2-((S)-6-azaspiro[3.4]oct-7-yl)ethan-1-one (10)
  • Step 5 2-(4-Chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d] Preparation of pyrimidin-4-yl)piperazin-1-yl)-3-(3-nitrooxetan-3-yl)propan-1-one (11e)
  • Step 6 3-(3-Aminoxetan-3-yl)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl Preparation of -6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one (11)
  • Test Example 1 Inhibitory activity of compounds of the present invention on AKT1/AKT2/AKT3 kinases
  • the HTRF method was used to detect the inhibition of the activity of the compound on AKT kinase.
  • AKT1, AKT2, and AKT3 were purchased from Thermo Company, and the article numbers were P2999, PV3184, and PV3185, respectively.
  • the HTRF KinEASE-STK S3 kit was from Cisbio, Cat. No. 62ST3PEB.
  • Other reagents ATP solution (Sigma, R0441), MgCl 2 (Sigma, 7786-30-3), DMSO (Sigma, D2650-100ML), Ipatasertib (MCE, HY-15186).
  • Experimental process first dilute 5 ⁇ kinase buffer solution to prepare 1 ⁇ experimental working solution, and the final concentrations of MgCl 2 and DTT are 5mM and 1mM respectively.
  • the compound was diluted to 4 concentration points from the highest concentration point according to the 27-fold dilution method, and transferred to the Echo plate (Labcyte, LP0200).
  • Compounds were transferred to a 384-well plate (Greiner, 784075) with Echo, making the compounds into a 3-fold ratio dilution matrix with 11 concentration points.
  • IC50 values of the compounds of the present invention for the inhibition of AKT1, AKT2 and AKT3 kinases are shown in Table 1 below.
  • Table 1 The compounds of the present invention inhibit the IC50 values of AKT1, AKT2 and AKT3 kinases
  • Test Example 2 Inhibitory effect of compounds of the present invention on prostate cancer cells
  • the inhibitory level of the compound of the present invention on prostate cancer Lncap cells was detected by CTG method.
  • LNCaP cells (ATCC, CRL-1740) were cultured in RPMI-1640 medium (Gibco, C11875500BT), adding 10% FBS (Gibco, 10099141) and double antibodies (1% penicillin and streptomycin, Gibco, 15140122) . After the cells grew to a confluence of 70-80%, they were digested with trypsin substitute Tryple TM express enzyme (Invitrogen, 12604021) for 8 minutes. Cell suspension was prepared with RPMI-1640 culture medium supplemented with 10% FBS, counted, and the cell density was adjusted to 1.25 ⁇ 10 4 /ml.
  • the cell suspension was added to a 384-well plate, 40 ⁇ l per well, that is, 500 LNCaP cells per well.
  • Compound preparation starting from 10 mM, the compound was serially diluted 3 times in 100% DMSO with 10 concentration gradients. Then intermediate dilution was performed with medium containing 10% FBS, and 1 ⁇ l of the compound was added to 199 ⁇ l of medium, and diluted 200 times. The initial concentration of the experiment was 10 ⁇ M, and 10 ⁇ l of the compound diluted in the middle of the medium was added to the cells of the 384-well plate, 2 duplicate wells, a total of 50 ⁇ l of the reaction system, and the final concentration of DMSO was 0.1%.
  • IC 50 values of the compounds of the present invention for the inhibition of LNCaP cells are shown in Table 2 below.
  • Test example 3 mouse pharmacokinetic experiment of the compound of the present invention
  • the experimental animals were male ICR mice aged 7-8 weeks, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and raised in an SPF environment with a temperature of 20-26°C, a daily temperature difference of no more than 4°C, and a relative humidity of 40-70°C. %RH, 12h/12h alternate lighting every day.
  • the experimental animals went through an adaptation period of 3-5 days, and the animals administered orally were fasted overnight (>12h) one day before the experiment, without water.
  • the compound solution preparation process is as follows: dissolve the compound in DMSO first, and prepare a 10 mg/mL stock solution; take 100 ⁇ L of the stock solution, dilute it to 5 mL with 20% HP- ⁇ -CD, and obtain a concentration of 0.2 mg/mL for intravenous administration.
  • Drug solution take 100 ⁇ L of the stock solution, add solvent to make it up to 5 mL, vortex to disperse evenly, and obtain an intragastric administration solution with a compound concentration of 1 mg/mL.
  • Body weight was weighed before administration, and 0.1mL blood samples were collected through the ophthalmic venous plexus and added to heparin sodium anticoagulant tubes to prevent coagulation.
  • Each test compound was administered intravenously to 6 rats, and 6 rats were given oral administration, and food was given 2 hours after administration.
  • the sample collection time points are: gavage group: before administration and 15min, 30min, 1h, 2h, 4h, 8h after administration; intravenous group: before administration and after administration 5min, 15min, 30min, 1h, 2h, 4h , 8h.
  • Animal blood collection was divided into two parts, and cross-time point blood collection was adopted, and a maximum of 5 blood collection points were set for one mouse.
  • F% (AUC po x dose iv )/(AUC iv x dose po ) x 100%.
  • mice The pharmacokinetic parameters of the compounds of the present invention on mice are shown in Table 3 below.
  • Test Example 4 Pharmacodynamic experiments of compounds of the present invention on mouse prostate cancer model
  • mice aged 4-5 weeks were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and were raised in SPF environment. After 4-5 days of adaptive feeding, they were used to construct tumor models.
  • Cultivate human prostate cancer cell PC-3 (ATCC, CRL-1435; culture medium F12K+10% FBS), collect cells by centrifugation, prepare cell suspension with normal saline, mix with matrigel (Corning, Cat. No. 354234) at a ratio of 1:1 Mix well, and use a pre-cooled syringe to inoculate subcutaneously on the right forelimb of nude mice, with an inoculation volume of 100 ⁇ L for each animal, and inoculate 1 ⁇ 10 8 cells.
  • control group vehicle: 3% DMSO+97% (20% HP- ⁇ -CD)
  • compound 3 low dose group 25mg/kg, QD
  • compound 3 high dose group 50mg/kg, QD
  • compound 4 low dose group 25mg/kg, QD
  • compound 4 high dose group 50mg/kg, QD
  • TGI tumor growth inhibition rate
  • Table 4 shows the tumor volume and tumor growth inhibition rate of the animals after 21 days of treatment
  • Figure 1 shows the tumor growth curves in the mice of each group.
  • Table 4 The tumor volume and tumor growth inhibition rate of animals after treatment for 21 days

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Abstract

L'invention concerne un composé hétérocyclique ayant une activité inhibitrice de kinase AKT, son procédé de préparation et son utilisation médicale. En particulier, l'invention concerne un composé représenté par la formule générale (I), son procédé de préparation, une composition pharmaceutique le contenant, et son utilisation en tant qu'inhibiteur de kinase AKT dans un médicament pour la prévention et/ou le traitement d'une croissance cellulaire anormale telle que le cancer. Les définitions des groupes dans la formule générale (I) sont les mêmes que celles de la description.
PCT/CN2022/136451 2021-12-17 2022-12-05 Composé hétérocyclique ayant une activité inhibitrice de kinase akt, son procédé de préparation et son utilisation médicale WO2023109540A1 (fr)

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