WO2022017371A1 - 具有磷脂酰肌醇3-激酶δ和γ的双重抑制剂活性的杂环化合物及其医药用途 - Google Patents

具有磷脂酰肌醇3-激酶δ和γ的双重抑制剂活性的杂环化合物及其医药用途 Download PDF

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WO2022017371A1
WO2022017371A1 PCT/CN2021/107320 CN2021107320W WO2022017371A1 WO 2022017371 A1 WO2022017371 A1 WO 2022017371A1 CN 2021107320 W CN2021107320 W CN 2021107320W WO 2022017371 A1 WO2022017371 A1 WO 2022017371A1
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alkyl
aryl
cycloalkyl
membered
heteroaryl
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PCT/CN2021/107320
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French (fr)
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陈振华
刘国标
闫旭
陈士柱
杜佩金
殷惠军
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中国医药研究开发中心有限公司
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Priority to CN202180004871.9A priority Critical patent/CN114258393A/zh
Publication of WO2022017371A1 publication Critical patent/WO2022017371A1/zh

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention belongs to the technical field of medicine, and in particular relates to a heterocyclic compound, a preparation method thereof and a pharmaceutical composition containing the same, and its functions as phosphatidylinositol 3-kinase ⁇ (PI3K ⁇ ) and phosphatidylinositol 3-kinase ⁇ ( Use of a dual inhibitor of PI3K ⁇ ) in the prevention and/or treatment of respiratory diseases, particularly asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, more particularly asthma and chronic obstructive pulmonary disease.
  • respiratory diseases particularly asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, more particularly asthma and chronic obstructive pulmonary disease.
  • Phosphatidylinositol-3-kinase is a class of kinases located in the cytoplasm and using phosphatidylinositol as a substrate. It can recognize signals from receptor tyrosine kinase (RTK), G-protein coupled receptor (GPCR) and Src-like protein-coupled tyrosine kinase receptors.
  • RTK receptor tyrosine kinase
  • GPCR G-protein coupled receptor
  • Src-like protein-coupled tyrosine kinase receptors Src-like protein-coupled tyrosine kinase receptors.
  • PIP2 phosphatidylinositol-3-phosphate
  • PIP3 phosphatidylinositol-3,4-bisphosphate
  • PIP3 phosphatidylinositol-3,4,5-triphosphate
  • PIP2 and PIP3 are important second messengers in cells, which can bind to a variety of target proteins in cells, such as Akt, to transmit and amplify the signal step by step through the kinase cascade reaction, and finally regulate cell proliferation, differentiation, metabolism, A series of activities such as apoptosis (Huang et al., Science, 2007, 318(5857), 1744-1748).
  • Type I PI3Ks can be classified into three categories: I, II, and III based on their structure and their substrate selectivity.
  • Type I PI3K can be divided into two subtypes, IA and IB, among which type IA PI3K can receive signals from multiple upstream, such as RTK and GPCR, etc.; type IB PI3K mainly accepts signals transmitted by GPCR (Vanhaesebroeck et al., J Mo Med, 2016, 94, 5-11).
  • Type IA PI3Ks consist of a catalytic subunit p110 and a regulatory subunit p85 or its splice variants.
  • the p110 catalytic subunit consists of five domains: the p85 regulatory subunit binding domain (p85BD), a domain composed of ⁇ -helix- ⁇ folds, which binds to the regulatory subunit; the Ras binding domain (Ras binding domain).
  • p85BD p85 regulatory subunit binding domain
  • Ras binding domain Ras binding domain
  • Ras BD Ras BD
  • C2 domain composed of two 4-chain antiparallel ⁇ sheets, is the main site for binding to lipid membranes
  • Helical region composed of whole ⁇ -helix, whose role is unknown
  • kinase domain kinase domain, KD
  • KD kinase domain
  • the p85 regulatory subunit is composed of five domains: a domain that binds to the p110 catalytic subunit (inter Src-homology 2domain, iSH2) and the SRC homology domain on both sides-N-terminal SRC homology domain (N-terminal SRC homology domain).
  • Src-homology 2 domain, nSH2) and C-terminal SRC homology domain C-terminal Src-homology 2 domain, cSH2
  • Src-homology 3 domain, SH3 N-terminal third SRC homology domain
  • BC Homeodomain BCR homology domain, BH
  • the splice variants p55 ⁇ /p55 ⁇ and p50 ⁇ of the p85 domain consist of only three domains, iSH2, nSH2 and cSH2.
  • the nSH2, iSH2 and cSH2 domains can interact with the five domains of the catalytic subunit to inhibit catalytic activity (Zhang et al., Mol Cell, 2011, 41(5), 567-78).
  • class IA PI3Ks can be further divided into PI3K ⁇ , PI3K ⁇ , PI3K ⁇ , PI3K ⁇ 4.
  • the four catalytic subunits p110 ⁇ , p110 ⁇ , p110 ⁇ and p110 are encoded by four genes (PIK3CA, IK3CB, PIK3CD, PI3KCG), respectively.
  • the regulatory subunit can bind to receptors on the membrane, recruit PI3K to the vicinity of the cell membrane and modulate the catalytic activity of the p110 subunit.
  • the regulatory subunit p85 ⁇ (and its splice variants p55 ⁇ and p50 ⁇ ), p85 ⁇ and p55 ⁇ 3 genes are encoded respectively.
  • These lipid kinases can participate in downstream signal activation and cell function regulation in the form of synthetic second messengers.
  • synthetic membrane-anchored PIP3 binds to PH domain-containing signaling proteins AKT and PDK1 (phosphoinositide-dependent kinase-1) in cells, prompting PDK1 to phosphorylate Ser308 of AKT protein, leading to AKT activation.
  • Activated AKT regulates cellular function by phosphorylating downstream factors such as various enzymes, kinases and transcription factors (Yuan et al., Oncogene, 2008, 27(41), 5497-5510).
  • Class II PI3Ks include PI3K-C2 ⁇ , PI3K-C2 ⁇ , a-dPI3K-C2 ⁇ .
  • PI3K-C2 ⁇ and PI3K-C2 ⁇ the two most well-characterized isoforms of PIP3, appear to contribute to PIP3 vesicle production, but they are difficult to study due to the lack of selective inhibitors.
  • Class III PI3Ks include two members, Vps15 and Vps34, which are involved in vesicle trafficking, TLR signaling, and autophagy through the production of PIP3 (Margaria et al., Biomolecules, 2019, 9(3), 104).
  • PTEN phosphatase and tensin homolog
  • Src homology 2 domain-containing inositol 59-phosphatase also inhibits PI3K signaling, mainly in hematopoietic cells, including macrophages (Backers et al., Adv Enzyme Regul, 2003, 43, 15-28 ).
  • PI3K ⁇ and ⁇ are widely expressed in many tissues and control fundamental processes such as cell proliferation, and genetic deletion of either isoform is lethal in the embryo (Vanhaesebroeck et al., Blood, 2005, 106, 1432-1440).
  • PI3K ⁇ and ⁇ are more restricted in cellular distribution, are mainly expressed in leukocytes and mediate inflammatory responses, and mice lacking their genes not only survive but also have reduced inflammatory responses (Hannigan et al., Proc Natl Acad Sci U SA, 2002, 99, 3603-3608; Hirsch et al, Science, 2000, 287, 1049-1053; Yum et al, J Immunol, 2001, 167, 6601-6608).
  • PI3K/AKT/mTOR pathway plays a crucial role in the occurrence and development of tumors.
  • PI3K and PTEN have a high mutation rate in clinical tumor patients, and PI3K can be used as the target for tumor drug development.
  • Previous studies have shown that PI3K ⁇ and PI3K ⁇ are potential targets for the treatment of blood diseases.
  • the development of Idelalisib has achieved remarkable success.
  • the drug has shown significant efficacy in the treatment of chronic lymphocytic leukemia and non-Hodgkin lymphoma, and has now been approved for clinical use. used (Furman et al, N Engl J Med, 2014, 370, 997-1007; Miller et al, Clin Cancer Res, 2015, 21, 1525-1529).
  • PI3K inhibitors can also be used to enhance anti-tumor immune responses.
  • a range of mouse cancer models including melanoma, thymoma, lung, breast and pancreatic cancer
  • inhibition of PI3K ⁇ attenuated Treg function and tumor infiltration while leaving cytotoxic T cell responses relatively unimpaired, thereby enhancing Antitumor immunity (Doisne et al, Cell Rep, 2015, 10, 702-710).
  • the use of the PI3K ⁇ inhibitors TG100-115 and AS605240 both reduced tumor growth and metastasis in melanoma, lung, pancreatic and breast cancer models.
  • PI3K ⁇ signaling is required for the recruitment of myeloid cells to the tumor microenvironment through integrin ⁇ 4 ⁇ 1-mediated adhesion in response to growth factors and chemokines.
  • inhibition of p110 ⁇ signaling is effective in reducing systemic tumor-associated inflammation and angiogenesis without affecting systemic numbers of myeloid cells (Schmid et al., Cancer Cell, 2011, 19, 715-727).
  • PI3K is involved in rheumatoid arthritis, allergy, asthma, chronic obstructive pulmonary disease (COPD) and multiple sclerosis by activating factors such as inflammation, corticosteroid resistance and cellular senescence. plays a key role in a variety of diseases (Marwick et al, Ther Adv Respir Dis, 2010, 4, 19-34; Hirsch et al, Pharmacol Ther, 2008, 118, 192-205; Marone et al, Biochim Biophys Acta, 2008, 1784, 159-185; Rommel et al, Nat Rev Immunol, 2007, 7, 191-201; Ruckle et al, Nat Rev Drug Discov, 2006, 5, 903-91).
  • Asthma is defined by the Global Initiative for Asthma as a chronic inflammatory disease of the airways involving a variety of cells and cellular components. Chronic inflammation is associated with airway responsiveness that causes recurrent episodes of wheezing, shortness of breath, chest tightness, and coughing. These episodes are usually associated with widespread but variable airflow obstruction in the lungs, which often resolves spontaneously or with treatment. Asthma is the most common chronic disease among children and also affects millions of adults.
  • COPD is defined as a common preventable and treatable disease characterized by persistent respiratory symptoms and airflow limitation, usually caused by airway and/or alveolar abnormalities caused by significant exposure to noxious particles or gases of.
  • the chronic airflow limitation characteristic of COPD is caused by a mixture of small airway disease (eg, obstructive bronchiolitis) and lung parenchyma destruction (emphysema), the relative contribution of which varies from person to person.
  • Chronic inflammation can cause structural changes, narrowing of the small airways, and destruction of the lung parenchyma.
  • Small airway loss promotes airflow limitation and mucociliary dysfunction, which are characteristic features of the disease.
  • COPD patients may become prone to frequent exacerbations, leading to patient anxiety, worsening health status, decreased lung function, and increased mortality.
  • PI3K ⁇ plays a key role in mast cell degranulation following IgE receptor cross-linking, which can be blocked by the PI3K ⁇ selective inhibitor IC87114 (Ali et al., J Immunol, 2008, 180, 2538- 2544; Kim et al, Trends Immunol, 2008, 29, 493-501). Intratracheal administration of IC87114 inhibits allergic responses, Th2 cytokines and AHR in a mouse model of asthma (Lee et al., 2006a).
  • PI3K ⁇ inhibitors inhibit allergic responses, an effect mediated by inhibition of endoplasmic reticulum stress, which is increased in asthma and leads to NF-kB activation (Lee et al. Thorax, 2016, 71:52-63).
  • PI3K may also play a role in increasing contractility of canine airway smooth muscle (Halayko et al, Am J Respir Cell Mol Biol, 2004, 31, 266–275) and in promoting the proliferation of airway smooth muscle (growth factors such as TGF-b) effect (Goldsmith et al., Am J Respir Cell Mol Biol, 2006, 34, 247-254).
  • PI3K activation is also important in COPD, with significantly increased total PI3K activity expressed as p-Akt and increased expression of PI3K ⁇ isoforms in the peripheral lung and macrophages of COPD patients (Marwick et al., Am J Respir Crit Care Med, 2009 , 179, 542-548; To et al., Am J Respir Crit Care Med, 2010, 182, 897-904).
  • Oxidative stress increases p-Akt in peripheral blood monocytes and alveolar macrophages in vitro, which can be prevented by PI3K ⁇ but not PI3K ⁇ inhibitors (Marwick et al, J Allergy Clin Immunol, 2010, 125 , 1146–1153).
  • PI3K ⁇ knockout mice exhibit reduced neutrophil migration and activation, and impaired T lymphocyte and macrophage function (Medina-Tato et al., Immunology, 2007, 121, 448-461). In addition, studies have shown that PI3K ⁇ is a key signaling pathway mediating neutrophil re-aggregation into the lung after chemokine instillation (Thomas et al., Eur J Immunol, 2015, 35, 1283–1291).
  • PI3K ⁇ is also involved in glucocorticoid resistance after oxidative stress, which is mediated by reducing histone deacetylase-2 (HDAC2), and PI3K ⁇ inhibitors may reverse glucocorticoid resistance in COPD patients by increasing the expression of HDAC2 .
  • HDAC2 histone deacetylase-2
  • S6-kinase S6K
  • S6K p70 ribosomal S6 kinase
  • PI3K activation also drives cellular senescence and accelerated aging in COPD lungs by activating mTOR, which plays a key role in accelerated aging (Johnson et al., Nature, 2013, 493, 338-345). This leads to a decrease in the key anti-aging molecule sirtuin-1 in the lungs of COPD patients (Rajendrasozhan et al., Am J Respir Crit Care Med, 2008, 177, 861-870).
  • the same PI3K-mTOR pathway may also contribute to COPD-related complications such as ischemic heart disease, type 2 diabetes, osteoporosis, chronic kidney disease and dementia (Barnes et al., Eur Respir J, 2015, 45, 790-806).
  • PI3K ⁇ and ⁇ play critical roles in mediating inflammatory cell functions such as leukocyte migration and activation and mast cell degranulation
  • blocking these isoforms may also be an effective strategy for the treatment of rheumatoid arthritis.
  • inhibitors that specifically target the delta and gamma isoforms are expected to impair the progression of the immune response encountered in airway inflammation and rheumatoid arthritis (William et al., Chemistry & Biology, 17: 123-134, 2010; and Thompson et al., Chemistry & Biology, 17: 101-102, 2010).
  • PI3K pathway inhibitors have great potential in the treatment of severe asthma and chronic obstructive pulmonary disease, so it is necessary to develop novel dual inhibitors of PI3K ⁇ and PI3K ⁇ to provide more clinical drug options for patients with respiratory diseases.
  • PI3K ⁇ phosphatidylinositol 3-kinase delta
  • PI3K ⁇ phosphatidylinositol 3-kinase gamma
  • PI3K ⁇ phosphatidylinositol 3-kinase gamma
  • the object of the present invention is to provide a compound represented by the general formula (I) or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Its pharmaceutically acceptable salts:
  • X is O, S or NH
  • Y is N or CH
  • a 1 , A 2 , A 3 , A 4 and A 5 are each independently selected from N or CH;
  • R 1 are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - C(O)R a , -O(O)CR a , -C(O)OR a , -C(O)NR a R b , -NR a R b , -NR a C(O)R b , - S(O) p R a , -S(O) p NR a R b , -NR a S(O) p NR a R b and -NR a S(O) p R b , wherein the alkyl, alkane Oxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, oxo
  • R 2 is selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy;
  • R 3 is selected from -C(O)R a , -C(O)NR a R b , -S(O) p NR a R b , -S(O) p R a , -P(O)(R a ) 2 , -S(NR a )(O)R b , -NR a S(O) p R b -, -NR a S(O) p NR a R b , halogen, cycloalkyl, heterocyclyl, Aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxygen Substituted with one or more groups of substituted, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkyn
  • R 4 is selected from alkyl or cycloalkyl, wherein said alkyl or cycloalkyl group optionally further substituted selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl or heterocyclic group One or more groups are substituted;
  • R 5 is selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl or haloalkoxy;
  • R 6 is selected from hydrogen, halogen, alkyl or haloalkyl
  • R a and R b are each independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkenyl, alkyne group, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy substituted with one or more groups of alkenyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; or,
  • R a and R b are formed with the nitrogen atom they are attached form a nitrogen-containing group or a nitrogen-containing aromatic heterocyclic group, the nitrogen-containing heterocyclic group or nitrogen-containing aryl group optionally further substituted selected from halogen, amino, nitro , cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl One or more groups of radicals are substituted;
  • n 0, 1, 2 or 3;
  • p 0, 1 or 2.
  • X is O or S
  • a 1 -A 5 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n are as defined in general formula (I).
  • a 1 , A 2 , A 3 , A 4 and A 5 are N, and the rest are CH;
  • one or two of A 1 , A 2 , A 3 , A 4 and A 5 are N, and the rest are CH;
  • one of A 1 , A 2 , A 3 , A 4 and A 5 is N and the rest are CH.
  • the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or Its mixture form, or its pharmaceutically acceptable salt it is the compound represented by general formula (III) or its meso, racemate, enantiomer, diastereomer, or its mixture form, or a pharmaceutically acceptable salt thereof,
  • X is O or S
  • a 1 , A 2 , A 3 and A 4 are N, and the rest are CH;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in general formula (I).
  • a 1 , A 2 , A 3 and A 4 are N, and the rest are CH;
  • one or two of A 1 , A 2 , A 3 and A 4 are N, and the rest are CH;
  • one of A 1 , A 2 , A 3 and A 4 is N, and the rest are CH;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the general formula (I).
  • a 1 is N, and A 2 , A 3 , and A 4 are CH; or,
  • a 2 is N, and A 1 , A 3 , and A 4 are CH; or,
  • a 4 is N, and A 1 , A 2 , and A 3 are CH; or,
  • a 1 and A 3 are N, and A 2 and A 4 are CH; or,
  • a 1 and A 2 are N, and A 3 and A 4 are CH.
  • the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or Its mixture form, or its pharmaceutically acceptable salt it is the compound represented by general formula (V) or its meso, racemate, enantiomer, diastereomer, or its mixture form, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in claim 1 .
  • R 4 is selected from C 1 -C 6 alkyl, said C 1 -C 6 alkyl optionally further selected from C 3 -C 10 cycloalkyl, or 3 to 10-membered heterocyclic group with one or more groups substituted; preferably substituted by one or more groups selected from C 3 -C 8 cycloalkyl or 3 to 8 membered heterocyclyl; further preferably substituted by cyclopropyl.
  • R 1 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 10 aryl, 5 to 10-membered heteroaryl, -NR a R b , -NR a C(O) R b and -NR a S(O) p R b , wherein said C 1 -C 6 alkyl, C 1 -C 6 alkane alkoxy, C 3 -C 10 cycloalkyl group 3 to 10-membered heterocyclic group, C 6 -C 10 aryl, 5 to 10 membered heteroaryl group optionally further substituted selected from halogen, amino, nitro, cyano , one of oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, al
  • R a and R b are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C 10 -membered aryl, and 5- to 10-membered heterocyclyl Aryl, wherein the C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 3 to 10 membered heterocyclyl, C 6 -C 10 aryl and 5 to 10 membered heteroaryl groups are optionally further Selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, hetero One or more groups of aryl groups are substituted; the C 3 -C 10 cycloalkyl, 3- to 10-membered heterocyclyl, C 6 -C
  • R a and R b together with the nitrogen atom to which they are attached form a 5- to 7-membered, preferably 5- to 6-membered, nitrogen-containing heterocyclyl, or a 5- to 10-, preferably 5- to 6-membered, nitrogen-containing heteroaryl group
  • Heterocyclyl or nitrogen-containing heteroaryl is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy substituted with one or more groups of alkenyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • R 1 is selected from a 3- to 10-membered heterocyclic group, preferably a 5- to 7-membered monoheterocyclic group, a 5- to 7-membered spiro heterocyclic group or a 5- to 7-membered fused heterocyclic group, a C 6 -C 10 aryl group, a 5- to 7-membered heterocyclic group 10-membered heteroaryl, preferably 5- to 6-membered heteroaryl, more preferably 5-membered heteroaryl;
  • heterocyclyl, aryl, heteroaryl is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, haloalkyl, alkoxy substituted with one or more groups of radicals, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
  • R 1 is selected from
  • R 1 is selected from -NR a R b , -NR a C(O) R b and -NR a S(O) p R b ;
  • R a is selected from hydrogen or C 1 -C 6 alkyl
  • R b is selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, preferably C 3 -C 6 cycloalkyl.
  • R 3 is selected from -C(O)R a , -C(O)NR a R b , -S(O) p NR a R b , -S(O) p R a , -P(O)(R a ) 2 , -S(NR a )(O)R b , -NR a S(O) p R b -, halogen, C 6 -C 10 aryl and 5- to 10-membered heteroaryl, wherein the C 6 -C 10 aryl or 5 to 10 membered heteroaryl optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, haloalkyl, alkoxy substituted with one or more groups of radicals, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, hetero
  • R a and R b are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 10 -membered aryl, and 5- to 10-membered heterocyclyl aryl, wherein said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3 to 8-membered heterocyclic group, C 6 -C 10 aryl group or 5 to 10 membered heteroaryl group is optionally further Selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, hetero One or more groups of aryl groups are substituted; or,
  • R a and R b together with the nitrogen atom to which they are attached form a 3- to 8-membered nitrogen-containing heterocyclic group or a 5- to 6-membered nitrogen-containing heteroaryl group, which is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more group substitutions of cyclic, aryl, and heteroaryl;
  • p 1 or 2.
  • R 3 is selected from -S(O) p R a , -S(O) p NR a R b , -NR a S(O) p R b -, -C(O)R a , -C(O)NR a R b , -P(O)(R a ) 2 ;
  • R a is selected from hydrogen, C 1 -C 6 alkyl
  • R b is selected from hydrogen, C 1 -C 6 alkyl; or,
  • R a and R b together with the nitrogen atom to which they are attached form a 3- to 8-membered nitrogen-containing heterocyclic group optionally further selected from halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy group substituted with one or more groups;
  • the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or Its mixture form, or its pharmaceutically acceptable salt it is the compound represented by general formula (VI) or its meso, racemate, enantiomer, diastereomer, or its mixture form, or a pharmaceutically acceptable salt thereof
  • L is selected from -C(O)-, -S(O) p- , -P(O)(R a )-, -S(NR a )(O)-, -NR a S(O) p R b -;
  • R a is selected from hydrogen, C 1 -C 6 alkyl
  • R b is selected from C 1 -C 6 alkyl
  • R 7 is selected from -NR c R d ;
  • R c and R d are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3- to 8-membered heterocyclyl, C 6 -C 10 -membered aryl, and 5- to 10-membered heterocyclyl aryl, wherein said C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3 to 8-membered heterocyclic group, C 6 -C 10 aryl group or 5 to 10 membered heteroaryl group is optionally further Selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxyl, ester, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, hetero One or more groups of aryl groups are substituted; or,
  • R c and R d together with the nitrogen atom to which they are attached form a 3- to 8-membered nitrogen-containing heterocyclic group or a 5- to 6-membered nitrogen-containing heteroaryl group, which is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto, carboxyl, ester, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, hetero One or more group substitutions of cyclic, aryl, and heteroaryl;
  • R c and R d are each independently selected from hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3- to 8-membered heterocyclyl, or
  • R c and R d together with the nitrogen atom to which they are attached form a 3- to 8-membered nitrogen-containing heterocyclic group optionally further selected from halogen, hydroxy, C 1 -C 6 alkyl, C 1 One or more groups of -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy;
  • p 1 or 2.
  • R 7 is selected from Optionally further substituted selected from halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl group, a C 1 -C 6 haloalkoxy or more groups group replacement;
  • R 7 is further preferred
  • R 2 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy; preferably hydrogen.
  • R 5 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl or C 1 -C 6 haloalkoxy; preferably hydrogen.
  • R 6 is selected from hydrogen, halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; preferably C 1 -C 6 alkyl.
  • Typical compounds of the present invention include, but are not limited to:
  • the present invention further provides a compound represented by the general formula (III) or a meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof
  • the preparation method of salt it comprises the following steps:
  • the solvent is preferably a polar aprotic solvent such as DMF;
  • the heating conditions are preferably in the range of 75°C-100°C;
  • the ligand is preferably a sterically hindered trialkylphosphine, such as tri-tert-butylphosphine;
  • the base is preferably an alkali metal carbonate, such as cesium carbonate;
  • the catalyst is preferably a transition metal, such as palladium;
  • a 1 -A 4 , X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are as defined in general formula (III).
  • the present invention further provides a compound represented by the general formula (IV) or a meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof
  • the preparation method of salt it comprises the following steps:
  • the solvent is preferably a polar aprotic solvent such as DMF;
  • the heating conditions are preferably in the range of 75°C-100°C;
  • the ligand is preferably a sterically hindered trialkylphosphine, such as tri-tert-butylphosphine;
  • the base is preferably an alkali metal carbonate, such as cesium carbonate;
  • the catalyst is preferably a transition metal, such as palladium;
  • a 1 -A 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are as defined in general formula (IV).
  • the present invention further provides a compound represented by general formula (V) or a meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof
  • the preparation method of salt it comprises the following steps:
  • the solvent is preferably a polar aprotic solvent such as DMF;
  • the heating conditions are preferably in the range of 75°C-100°C;
  • the ligand is preferably a sterically hindered trialkylphosphine, such as tri-tert-butylphosphine;
  • the base is preferably an alkali metal carbonate, such as cesium carbonate;
  • the catalyst is preferably a transition metal, such as palladium;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are as defined in general formula (V).
  • the present invention further provides a compound represented by the general formula (VI) or a meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof
  • the preparation method of salt it comprises the following steps:
  • the solvent is preferably a polar aprotic solvent such as DMF;
  • the heating conditions are preferably in the range of 75°C-100°C;
  • the ligand is preferably a sterically hindered trialkylphosphine, such as tri-tert-butylphosphine;
  • the base is preferably an alkali metal carbonate, such as cesium carbonate;
  • the catalyst is preferably a transition metal, such as palladium;
  • R 2 , R 5 , R 6 , R 7 are as defined in general formula (VI).
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer and diastereomer body, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the present invention further relates to the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Use of its prodrug, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same in the preparation of a dual inhibitor of phosphatidylinositol 3-kinase delta (PI3Kdelta) and phosphatidylinositol 3-kinase gamma (PI3Kgamma).
  • PI3Kdelta phosphatidylinositol 3-kinase delta
  • PI3Kgamma phosphatidylinositol 3-kinase gamma
  • the present invention also relates to the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or Use of its prodrug, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing it in the preparation of a medicament for preventing and/or treating a disease associated with the activity of PI3K ⁇ and PI3K ⁇ , the disease is preferably a respiratory disease such as asthma, Chronic obstructive pulmonary disease, bronchitis, emphysema, preferably asthma and chronic obstructive pulmonary disease.
  • a respiratory disease such as asthma, Chronic obstructive pulmonary disease, bronchitis, emphysema, preferably asthma and chronic obstructive pulmonary disease.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer and diastereomer body, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, in combination with another active agent selected from the group consisting of glucocorticoid receptor agonists (steroidal or non-steroidal body), selective beta2 adrenergic receptor agonists, antimuscarinic agents, p38 antagonists, xanthine derivatives, and PDE4 antagonists.
  • glucocorticoid receptor agonists steroidal or non-steroidal body
  • selective beta2 adrenergic receptor agonists selective beta2 adrenergic receptor agonists
  • antimuscarinic agents p38 antagonists
  • xanthine derivatives and PDE4 antagonists.
  • the present invention also relates to the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or A prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for simultaneous, separate or sequential use with another active agent in the manufacture of a medicament for the prevention and/or treatment of a disease associated with the activity of PI3K ⁇ and PI3K ⁇ use; the disease is preferably a respiratory disease, such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, preferably asthma and chronic obstructive pulmonary disease; wherein the other active agent is selected from glucocorticoid receptor agonists (steroidal or non-steroidal), selective beta2 adrenergic receptor agonists, antimuscarinic agents, p38 antagonists, xanthine derivatives, and PDE4 antagonists.
  • the present invention also relates to the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or A prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, for use as a dual inhibitor of phosphatidylinositol 3-kinase delta (PI3Kdelta) and phosphatidylinositol 3-kinase gamma (PI3Kgamma).
  • PI3Kdelta phosphatidylinositol 3-kinase delta
  • PI3Kgamma phosphatidylinositol 3-kinase gamma
  • the present invention also relates to the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or A prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, for use as a medicament for the prevention and/or treatment of diseases associated with the activity of PI3K ⁇ and PI3K ⁇ , preferably respiratory diseases such as asthma , chronic obstructive pulmonary disease, bronchitis, emphysema, preferably asthma and chronic obstructive pulmonary disease.
  • diseases associated with the activity of PI3K ⁇ and PI3K ⁇ preferably respiratory diseases such as asthma , chronic obstructive pulmonary disease, bronchitis, emphysema, preferably asthma and chronic obstructive pulmonary disease.
  • the present invention also relates to the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or a mixture thereof, or A prodrug thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, for simultaneous, separate or sequential use with another active agent to prevent and/or treat diseases associated with the activity of PI3K ⁇ and PI3K ⁇ , preferably Respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis and emphysema, preferably asthma and chronic obstructive pulmonary disease, the further active agent is selected from glucocorticoid receptor agonists (steroidal or non-steroidal body), selective beta2 adrenergic receptor agonists, antimuscarinic agents, p38 antagonists, xanthine derivatives, and PDE4 antagonists.
  • glucocorticoid receptor agonists steroidal or non-steroidal body
  • the present invention also relates to a method of inhibiting phosphatidylinositol 3-kinase delta (PI3Kdelta) and phosphatidylinositol 3-kinase gamma (PI3Kgamma) comprising administering to a subject in need thereof an inhibitory effective amount according to the present invention
  • PI3Kdelta phosphatidylinositol 3-kinase delta
  • PI3Kgamma phosphatidylinositol 3-kinase gamma
  • the present invention also relates to a method of preventing and/or treating diseases associated with the activity of PI3K ⁇ and PI3K ⁇ , preferably respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, preferably asthma and chronic obstructive pulmonary disease , which comprises administering to a subject in need a prophylactically or therapeutically effective amount of the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.
  • respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, preferably asthma and chronic obstructive pulmonary disease
  • respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema,
  • the present invention also relates to a method of preventing and/or treating diseases associated with the activity of PI3K ⁇ and PI3K ⁇ , preferably respiratory diseases such as asthma, chronic obstructive pulmonary disease, bronchitis, emphysema, preferably asthma and chronic obstructive pulmonary disease , which comprises administering to a subject in need simultaneously, separately or sequentially a prophylactically or therapeutically effective amount of the compound represented by the general formula (I) according to the present invention or its mesoform, racemate, pair Enantiomers, diastereomers, or mixtures thereof, or prodrugs thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, and another active agent selected from From glucocorticoid receptor agonists (steroidal or non-steroidal), selective beta2 adrenergic receptor agonists, antimuscarinic agents, p38 antagonists, xanthine derivatives, and PDE4 antagonists.
  • respiratory diseases such as asthma,
  • the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable base addition salt or acid addition salt with a base or an acid.
  • the bases include 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 acids include inorganic acids and organic acids, and acceptable inorganic acids include 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.
  • compositions containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs.
  • Oral compositions may be prepared according to any method known in the art for the preparation of pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweetening, flavoring, coloring and preservative agents, to provide pleasing and palatable medicinal preparations.
  • Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate 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 they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.
  • water soluble taste masking materials such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or time prolonging materials such as ethyl cellulose, cellulose acetate butyrate can be used.
  • Hard gelatin capsules are also available wherein the active ingredient is in admixture with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
  • Soft gelatin capsules provide an oral preparation.
  • Aqueous suspensions contain the active substances 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 the condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or the condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecaethyleneoxycetyl Wax alcohols (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
  • the aqueous suspensions may also contain one or more preservatives such as ethyl or n-propyl paraben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.
  • preservatives such as ethyl or n-propyl paraben
  • coloring agents such as ethyl or n-propyl paraben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • Oily suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol.
  • the aforementioned sweetening and flavoring agents may be added to provide a palatable preparation.
  • These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water may provide the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives for mixing. Suitable dispersing or wetting agents and suspending agents are those mentioned above. Other excipients such as sweetening, flavouring and colouring agents may also be added. These compositions are preserved by the addition of antioxidants such as ascorbic acid.
  • the pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive or peanut 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 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 can be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • the pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions.
  • the 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 an oily phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then processed into a mixture of water and glycerol to form a microemulsion.
  • Injections or microemulsions can be injected into a 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 present invention. To maintain this constant concentration, a continuous intravenous drug delivery device can be used.
  • compositions of the present invention may be in the form of sterile injectable aqueous or oily suspensions 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 may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as 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 can also be used in the preparation of injectables.
  • the compounds of the present invention may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
  • the dosage of a drug to be administered depends on a variety of factors, including but not limited to the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the condition of the patient, the diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.
  • the optimal treatment modality such as the mode of treatment, the daily dosage of the compound of the general formula, or the type of pharmaceutically acceptable salt can be verified according to conventional treatment regimens.
  • the present invention can contain the compound represented by the general formula (I), and a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and Prepared in a 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 compounds of the present invention can be used as the sole active ingredient or in combination with other drugs for the treatment of diseases associated with tyrosine kinase activity. Combination therapy is accomplished by the simultaneous, separate or sequential administration of the individual therapeutic components.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms atom of the alkyl group.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkanes group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl, etc.
  • Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, eg, ethynyl, propynyl, butynyl, and the like.
  • Alkynyl groups can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms carbon atoms, more preferably 3 to 8 carbon atoms, most preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • spirocycloalkyl refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated ⁇ 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, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups.
  • spirocycloalkyl More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds, but none of the rings have a fully conjugated pi electron system. 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 fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings have complete Conjugated pi electron system. 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, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring linked to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 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) heteroatoms, excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; and most preferably contains 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • spiroheterocyclyl refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-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 monospiroheterocyclyl group.
  • Non-limiting examples of spiroheterocyclyl 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 of the rings may contain one or more Double bonds, but none of the rings have a fully conjugated pi-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), the remaining rings Atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • fused heterocyclyl groups include:
  • bridged heterocyclyl refers to a 5- to 14-membered, polycyclic heterocyclyl group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a complete common A pi-electron system of a yoke in which 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 atoms are carbon.
  • m is an integer from 0 to 2
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl groups include:
  • heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein 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 substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 10 membered, such as benzene base and naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, 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; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridine azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferred pyrazolyl or thiazolyl.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl
  • Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2.
  • thiol refers to -SH.
  • esters refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl refers to compounds containing a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.
  • sulfonyl refers to compounds containing the R group -S (O) 2, wherein R is alkyl as defined above, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • sulfinyl refers to compounds containing a -S(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.
  • phosphoryl refers to compounds containing a -P(O)RR' group, wherein R and R' are alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl as defined above.
  • Optional or “optionally” means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance occurs or instances where it does not.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • “Pharmaceutically acceptable salts” refer to salts of the compounds of the present invention, which are safe and effective when used in mammals, and possess the desired biological activity.
  • the present invention adopts the following synthetic scheme to prepare the compound of general formula (III) of the present invention.
  • Step 1 In a solvent, under heating conditions, in the presence of a base, in the presence of a ligand and a catalyst, compound (Ia) is reacted with R 1 H to obtain compound (Ib); this reaction promotes the nucleophilic aromatic
  • the solvent is typically a polar aprotic solvent, such as 1,4-dioxane; the heating conditions are typically performed at 80°C, and the heating can be performed by conventional or microwave means, and
  • a pressurized system may be used to enable the reaction to operate above the boiling point of the solvent; suitable ligands such as bidentate trisubstituted phosphines, such as xantphos; suitable bases such as alkali metal carbonates, such as cesium carbonate; suitable catalysts such as transition metals such as palladium;
  • Step 2 In a solvent, under heating conditions, in the presence of a base, in the presence of a ligand and a catalyst, compound (Ib) is reacted with compound (Ih) to obtain compound (Ic); this reaction is in the halogen of the compound.
  • the solvent is typically a polar aprotic solvent, such as DMF;
  • the heating conditions are typically at 125 ° C, heating can be carried out by conventional or microwave means, and advantageously can use additive Pressurize the system to enable the reaction to operate above the boiling point of the solvent;
  • suitable ligands such as bidentate trisubstituted phosphines such as Ruphos, suitable bases such as alkali metal carbonates such as sodium carbonate;
  • suitable catalysts such as transition metals such as palladium;
  • Step 3 Compound (Id) is reacted with benzyl mercaptan to obtain compound (Ie) in a solvent under heating in the presence of a base; a suitable solvent such as 1,4-dioxane; a suitable base Such as sodium alkoxide, such as sodium tert-butoxide; the heating conditions are typically 80°C;
  • Step 4 In a solvent, compound (Ie) is reacted with sulfonyl chloride to obtain compound (If);
  • a suitable solvent can be a mixed solvent, such as a mixture of water and acetonitrile containing acetic acid; the reaction temperature can be between -5°C and ambient temperature between;
  • Step 5 Compound (Ie) is reacted with compound HNR a R b in a solvent in the presence of a base to obtain compound (Ig); a suitable solvent such as dichloromethane; the base is typically an organic base such as triethyl amines or inorganic bases such as cesium carbonate; the reaction temperature can be between ambient temperature and 40°C);
  • Step 6 In a solvent, under heating conditions, in the presence of a base, in the presence of a ligand and a catalyst, compound (Ie) is reacted with compound (Ig) to obtain the compound of general formula (III); the reaction is in Under conditions that promote the activation of the aryl bromide and its reaction with the activated double bond (Heck reaction); the solvent is typically a polar aprotic solvent such as DMF; the heating conditions are typically at 75°C-100°C Within the range, heating can be carried out by conventional or microwave means, and advantageously a pressurized system can be used to enable the reaction to be run above the boiling point of the solvent; suitable ligands such as sterically hindered trialkylphosphines such as tri-tert-butyl Phosphine; suitable bases such as alkali metal carbonates, eg cesium carbonate; suitable catalysts such as transition metals, eg palladium;
  • suitable ligands such as sterically hindered trialkylpho
  • Hal is halogen
  • a 1 -A 4 , X, R 1 , R 2 , R 4 , R 5 , R 6 , R a , R b are as defined in general formula (III).
  • the compounds of the present invention are prepared using convenient starting materials and general preparative procedures.
  • the present invention gives typical or tendentious reaction conditions, such as reaction temperature, time, solvent, pressure, molar ratio of reactants. But unless otherwise specified, other reaction conditions can also be adopted. Optimal conditions may vary with the specific reactants or solvent used, but in general, reaction optimization procedures and conditions can be determined.
  • protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions.
  • Suitable protecting groups for various functional groups and conditions for their protection or deprotection are well known to those skilled in the art.
  • Protecting Groups in Organic Preparation by T.W. Greene and G.M. Wuts (3rd ed., Wiley, New York, 1999 and citations therein) describes in detail the protection or deprotection of a large number of protecting groups.
  • Separation and purification of compounds and intermediates can take appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer plate chromatography, preparative high performance liquid chromatography or a combination of the above methods.
  • the specific use method can refer to the examples described in the present invention. Of course, other similar separation and purification means may also be employed. It can be characterized using conventional methods including physical constants and spectral data.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the MS was measured using an LC (Waters 2695)/MS (Quattro Premier xE) mass spectrometer (manufacturer: Waters) (Photodiode Array Detector).
  • Preparative liquid chromatography was performed using an lc6000 high performance liquid chromatograph (manufacturer: Chuangxin Tongheng).
  • the chromatographic column is Daisogel C18 10 ⁇ m 100A (30mm ⁇ 250mm), mobile phase: acetonitrile/water.
  • the known starting materials of the present invention can be synthesized by adopting or according to methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Shanghai Inokay, Anaiji Chemical, Shanghai Bide and other companies.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Reaction solvent organic solvent or inert solvent are each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform , dichloromethane, ether, methanol, nitrogen-methylpyrrole ketone (NMP), pyridine, etc.
  • solvent organic solvent or inert solvent
  • solvent used that does not participate in the reaction under the described reaction conditions including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform , dichloromethane, ether, methanol, nitrogen-methylpyrrole ketone (NMP), pyridine, etc.
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • NMP nitrogen-methylpyrrole ketone
  • pyridine
  • 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 at one atmosphere, and complete in about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. There is no special description in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), and the systems of the developing solvent used in the reaction are: A: dichloromethane and methanol system, B: petroleum ether 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 for column chromatography and the developing solvent system for thin layer chromatography used for purifying the compound include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, and the volume ratio of the solvent is based on the compound Different polarities can be adjusted, and a small amount of basic or acidic reagents such as triethylamine and trifluoroacetic acid can also be added for adjustment.
  • ⁇ M micromolar
  • Boc tert-butoxycarbonyl
  • DIPEA Diisopropylethylamine
  • IC 50 concentration that inhibits 50% of the activity
  • NBS N-bromosuccinimide
  • nM nanomoles
  • PE petroleum ether
  • Ruphos 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl
  • t-buxphos methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1' - Biphenyl-2-yl)palladium(II)
  • TBS- tert-butyldimethylsilyl
  • Xantphos 4,5-bisdiphenylphosphine-9,9-dimethylxanthene.
  • Step 1 Preparation of methyl 4-bromo-2-(bromomethyl)-6-chlorobenzoate (1a).
  • Step 2 Preparation of (S)-5-bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (1b).
  • Step 3 Preparation of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylthio)isoindolin-1-one (1c).
  • Step 4 Preparation of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one (1d).
  • Step 1 Preparation of 1-(6-bromopyridin-2-yl)pyrrolidin-2-one (2a).
  • Step 2 Preparation of 1-(6-((4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (2b).
  • Step 1 Preparation of 4-bromo-N-(4-bromopyridin-2-yl)butanamide (3a).
  • Step 2 Preparation of 1-(4-bromopyridin-2-yl)pyrrolidin-2-one (3b).
  • Step 3 Preparation of 1-(4-((4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (3c).
  • Step 2 (S)-N-(5-(2-(1-Cyclopropylethyl)-7-(methylsulfonyl)-1-oxo)isoindolin-5-yl)- Preparation of 4-methylthiazol-2-yl)acetamide (4b).
  • Step 3 (S)-5-(2-Amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindoline- Preparation of 1-keto (4c).
  • Step 1 Preparation of (S)-7-(benzylthio)-5-bromo-2-(1-cyclopropylethyl)isoindolin-1-one (5a).
  • Step 2 Preparation of (S)-6-bromo-2-(1-cyclopropylethyl)-3-oxoisoindoline-4-sulfonyl chloride (5b).
  • Step 3 (S)-7-(azetidin-1-ylsulfonyl)-5-bromo-2-(1-cyclopropylethyl)isoindolin-1-one (5c) preparation.
  • Step 1 Preparation of N-(6-bromopyridin-2-yl)cyclopropanesulfonamide (6a).
  • Step 2 Preparation of N-(6-bromopyridin-2-yl)cyclopropanemethylsulfonamide (6b).
  • N-(6-bromopyridin-2-yl)cyclopropanesulfonamide 275 mg, 1.00 mmol
  • THF 10 mL
  • NaH 120 mg, 3.00 mmol
  • the reaction was stirred at 40 °C for 12 hours.
  • Step 1 Preparation of 4-bromo-2-iodo-6-methylbenzoic acid (7a).
  • Step 2 Preparation of methyl 4-bromo-2-iodo-6-methylbenzoate (7b).
  • Step 3 Preparation of methyl 4-bromo-2-(bromomethyl)-6-iodobenzoate (7c).
  • Step 4 Preparation of (S)-5-bromo-2-(1-cyclopropylethyl)-7-iodoisoindolin-1-one (7d).
  • Step 5 Preparation of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(thiazol-2-yl)isoindolin-1-one (7e).
  • Step 1 (S)-2-(1-Cyclopropylethyl)-5-(4-methyl-2-((2-(2-oxopyrrolidin-1-yl)pyridin-4-yl) ) Preparation of amino)thiazol-5-yl)-7-(methylsulfonyl)isoindolin-1-one (1).
  • Step 1 (S)-7-Chloro-2-(1-cyclopropylethyl)-5-(4-methyl-2-((6-(2-oxopyrrolidin-1-yl)pyridine) Preparation of -2-yl)amino)thiazol-5-yl)isoindolin-1-one (2).
  • Step 1 (S)-2-(1-Cyclopropylethyl)-5-(4-methyl-2-((6-(2-oxopyrrolidin-1-yl)pyrazine-2- Preparation of (3).
  • the preparation method was the same as that of Example 1, except that 1-(6-((4-methyloxazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (according to the procedure of Preparation Example 2) was used.
  • 2 Prepared by replacing 4-methylthiazol-2-amine with 4-methyloxazol-2-amine) instead of 1-(4-((4-methylthiazol-2-yl)amino)pyridine-2- yl)pyrrolidin-2-one (3c) to give the title compound.
  • the preparation method was the same as that of Example 1, except that (S)-7-(azetidin-1-ylsulfonyl)-5-bromo-2-(1-cyclopropylethyl)isoindoline was used -1-one (5c) in place of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one (1d), and with 1-(6-((4-Methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (2b) in place of 1-(4-((4-methylthiazol-2- yl)amino)pyridin-2-yl)pyrrolidin-2-one (3c) to give the title compound.
  • the preparation method was the same as that of Example 3, except that 1-(2-bromopyridin-2-yl)pyrrolidin-2-one (prepared according to steps 1 and 2 of Preparation Example 3, 4-bromopyridin-2-amine was used Substitute 2-bromopyridin-4-amine) in place of 1-(6-bromo-pyrazin-2-yl)pyrrolidin-2-one to give the title compound.
  • the preparation method was the same as in Example 3, except that N-(6-bromopyridin-2-yl)cyclopropanesulfonamide (6a) was used instead of 1-(6-bromo-pyrazin-2-yl)pyrrolidin-2-one , the title compound was obtained.
  • the preparation method was the same as that of Example 3, except that 6-bromo-1H-pyrrolo[2,3-b]pyridine was used instead of 1-(6-bromo-pyrazin-2-yl)pyrrolidin-2-one to prepare The title compound was obtained.
  • the preparation method was the same as that of Example 3, except that 2-(6-bromopyridin-2-yl)oxazole (prepared according to Step 1 of Preparation Example 2, substituting oxazole for pyrrolidin-2-one) was used instead of 1- (6-Bromo-pyrazin-2-yl)pyrrolidin-2-one to give the title compound.
  • the preparation method was the same as that of Example 3, except that 1-(2-chloropyrimidin-4-yl)pyrrolidin-2-one (prepared according to Step 1 of Preparation Example 2) was used, and 2,6-dibromopyridine was replaced by 2 -chloro-4-bromopyrimidine) in place of 1-(6-bromo-pyrazin-2-yl)pyrrolidin-2-one to give the title compound.
  • the preparation method was the same as in Example 3, except that 1 was replaced with N-(6-bromopyridin-2-yl)methanesulfonamide (prepared according to Step 1 of Preparation Example 6, replacing cyclopropylsulfonyl chloride with methanesulfonyl chloride) -(6-Bromo-pyrazin-2-yl)pyrrolidin-2-one to prepare the title compound.
  • the preparation method was the same as in Example 3, except that 2-bromo-6-(1H-imidazol-1-yl)pyridine (prepared according to Step 1 of Preparation Example 2, replacing pyrrolidin-2-one with imidazole) was used in place of 1 -(6-Bromo-pyrazin-2-yl)pyrrolidin-2-one to give the title compound.
  • Step 1 (S)-N-(5-(2-(1-Cyclopropylethyl)-7-(methylsulfonamido)-1-isoindolin-5-yl)-4-methyl Preparation of thiazol-2-yl)acetamide (13a).
  • Step 2 (S)-N-(6-(2-Amino-4-methylthiazol-5-yl)-2-(1-cyclopropylethyl)-3-isoindolin-4-yl ) preparation of methanesulfonamide (13b).
  • Step 3 (S)-N-(2-(1-Cyclopropylethyl)-6-(4-methyl-2-((6-(2-oxopyrrolidin-1-yl)pyridine- Preparation of 2-yl)amino)thiazol-5-yl)-3-isoindolin-4-yl)methanesulfonamide (13).
  • the preparation method was the same as that of Example 2, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-(thiazol-2-yl)isoindolin-1-one (7e ) in place of (S)-5-bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (1b) to give the title compound.
  • the preparation method was the same as in Example 3, except that N-(6-bromopyridin-2-yl)cyclopropanemethylsulfonamide (6b) was used instead of 1-(6-bromo-pyrazin-2-yl)pyrrolidine-2 - ketone to give the title compound.
  • the preparation method is the same as that of Example 3, except that 4-(6-bromopyridin-2-yl)-4-azaspiro[2.4]heptan-5-one (prepared according to step 1 of Preparation Example 2, 2 , 6-dibromopyridine was replaced by 5-oxo-4-azaspiro[2.4]heptane) in place of 1-(6-bromo-pyrazin-2-yl)pyrrolidin-2-one to give the title compound .
  • the preparation method was the same as that of Example 3, except that 2-(6-bromopyridin-2-yl)thiazole (prepared according to Step 1 of Preparation Example 2, replacing 2,6-dibromopyridine with thiazole) was used instead of 1-( 6-Bromo-pyrazin-2-yl)pyrrolidin-2-one to give the title compound.
  • Example 18 2-((S)-1-Cyclopropylethyl)-5-(4-methyl-2-((6-(2-oxo-3-azabicyclo[3.1.0] Preparation of hex-3-yl)pyridin-2-yl)amino)thiazol-5-yl)-7-(methylsulfonyl)isoindolin-1-one (18)
  • the preparation method was the same as that of Example 3, except that 4-(6-bromopyridin-2-yl)-azabicyclo[3.1.0]hexan-5-one (prepared according to Step 1 of Preparation Example 2, 2, Substituting 6-dibromopyridine with azabicyclo[3.1.0]hex-5-one) instead of 1-(6-bromo-pyrazin-2-yl)pyrrolidin-2-one afforded the title compound.
  • Step 1 Preparation of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(dimethylphosphoryl)isoindolin-1-one (19a).
  • Step 2 (S)-2-(1-Cyclopropylethyl)-7-(dimethylphosphoryl)-5-(4-methyl-2-((6-(2-oxopyrrolidine) Preparation of -1-yl)pyridin-2-yl)amino)thiazolazol-5-yl)isoindolin-1-one (19).
  • the preparation method was the same as that of Example 2, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-(dimethylphosphoryl)isoindolin-1-one was used instead of ( S)-5-Bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (1b) to give the title compound.
  • Step 1 (S)-N-(5-(7-(azetidin-1-ylsulfonyl)-2-(1-cyclopropylethyl)-1-oxyisoindoline- Preparation of 5-yl)-4-methylthiazol-2-yl)acetamide (20a).
  • step 2 of Preparative Example 4 Same as step 2 of Preparative Example 4, except with (S)-7-(azetidin-1-ylsulfonyl)-5-bromo-2-(1-cyclopropylethyl)isoindole Lin-1-one (5c) in place of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one (1d), prepared The title compound was obtained.
  • Step 2 (S)-5-(2-Amino-4-methylthiazol-5-yl)-7-(azetidin-1-ylsulfonyl)-2-(1-cyclopropylethyl) base) preparation of isoindolin-1-one (20b).
  • Step 3 (S)-5-(2-((6-(1H-imidazol-1-yl)pyridin-2-yl)amino)-4-methyl-thiazol-5-yl)-7-(nitrogen Preparation of cyclobutan-1-ylsulfonyl)-2-(1-cyclopropylethyl)isoindolin-1-one (20).
  • Step 1 (S)-5-Bromo-2-(1-cyclopropylethyl)-7-((3-hydroxyazetidin-1-yl)sulfonyl)isoindoline-1- Preparation of ketone (21a).
  • Step 2 (S)-2-(1-Cyclopropylethyl)-7-((3-hydroxyazetidin-1-yl)sulfonyl)-5-(4-methyl-2- Preparation of ((6-(2-oxopyrrolidin-1-yl)pyridin-2-yl)amino)thiazolyl-5yl)isoindolin-1-one (21).
  • the preparation method was the same as in Example 1, except that 1-(6-((4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (2b) was used instead of 1-(4 -((4-Methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (3c), and (S)-5-bromo-2-(1-cyclopropylethyl) yl)-7-((3-hydroxyazetidin-1-yl)sulfonyl)isoindolin-1-one (21a) instead of (S)-5-bromo-2-(1-cyclopropane) ethyl)-7-(methylsulfonyl)isoindolin-1-one (1d) to give the title compound.
  • the preparation method was the same as that of Example 2, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-(pyrrolidin-1-ylsulfonyl)isoindoline-1- Ketone (prepared according to Preparative Example 5, substituting pyrrolidine for azetidine in step 3) in place of (S)-5-bromo-7-chloro-2-(1-cyclopropylethyl)isoindole olin-1-one (1b) to give the title compound.
  • the preparation method was the same as in Example 1, except that 1-(6-((4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (2b) was used instead of 1-(4 -((4-Methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (3c), and 5-bromo-2-((S)-1-cyclopropylethyl base)-7-((3-hydroxypyrrolidin-1-yl)sulfonyl)isoindolin-1-one (prepared according to Preparation Example 5, substituting azetidine in step 3 with 3-hydroxyl pyrrolidine) in place of (S)-5-bromo-2-(1-cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one (1d) to give the title compound.
  • the preparation method was the same as in Example 1, except that 1-(6-((4-methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (2b) was used instead of 1-(4 -((4-Methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (3c), and (S)-5-bromo-2-(1-cyclopropylethyl) (S)-5-bromo- 2-(1-Cyclopropylethyl)-7-(methylsulfonyl)isoindolin-1-one (1d) to give the title compound.
  • Example 25 (S)-2-(1-Cyclopropylethyl)-7-((3,3-difluoroazetidin-1-yl)sulfonyl)-5-(4-methyl) Preparation of yl-2-((6-(2-oxopyrrolidin-1-yl)pyridin-2-yl)amino)thiazol-5-yl)isoindolin-1-one (25)
  • the preparation method was the same as that of Example 2, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-((3,3-difluoroazetidin-1-yl) was used (S)-5- Bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (1d) to give the title compound.
  • the preparation method was the same as that of Example 2, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-((3-fluoro-3-methylazetidine-1 was used -yl)sulfonyl)isoindolin-1-one (prepared according to Preparation Example 5, substituting 3-fluoro-3-methylazetidine for azetidine in step 3) in place of (S )-5-bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (1d) to give the title compound.
  • the preparation method was the same as that of Example 2, except that (S)-7-((2-oxa-6-azaspiro[3.3]hept-6-yl)sulfonyl)-5-bromo-2-(1 -Cyclopropylethyl)isoindolin-1-one (prepared according to Preparation Example 5, replacing the azetidine of step 3 with 2-oxa-6-azaspiro[3.3]heptane) Substituting (S)-5-bromo-7-chloro-2-(1-cyclopropylethyl)isoindolin-1-one (1d), the title compound was prepared.
  • Example 28 (S)-2-(1-Cyclopropylethyl)-7-((3-methoxyazetidin-1-yl)sulfonyl)-5-(4-methyl) - Preparation of 2-((6-(2-oxopyrrolidin-1-yl)pyridin-2-yl)amino)thiazol-5-yl)isoindolin-1-one (28)
  • the preparation method was the same as that of Example 2, except that (S)-5-bromo-2-(1-cyclopropylethyl)-7-((3-methoxyazetidin-1-yl) was used Sulfonyl)isoindolin-1-one (prepared according to Preparation Example 5, substituting azetidine from step 3 for 3-methoxyazetidine) instead of (S)-5-bromo- 7-Chloro-2-(1-cyclopropylethyl)isoindolin-1-one (1d) to give the title compound.
  • Test Example 1 Inhibitory activity of the compounds of the present invention on PI3K
  • Phosphoinositide 3-kinase is a family of related signaling enzymes that can phosphorylate the hydroxyl group at position 3 of the inositol ring of phosphatidylcyclohexanol, which is involved in cell survival, growth, and metabolism. and regulation of various functions such as blood glucose homeostasis. Its activity can be measured using commercial kinase assay kits. In this implementation, the ADP-Glo TM detection kit purchased from Promega was used to detect the activity of recombinant human PI3K by compounds.
  • PI3K ⁇ (Invitrogen Life Technology Co., Ltd., PV4788): The stock solution was diluted to 625 ng/mL with 1X assay buffer, ie the working concentration was 250 ng/mL.
  • PI3K ⁇ (Invitrogen Biotechnology Co., Ltd., PV5374): The stock solution was diluted to 625 ng/mL with 1X assay buffer, i.e., the working concentration was 250 ng/mL.
  • PI3K ⁇ (Invitrogen Biotechnology Co., Ltd., PV4786): The stock solution was diluted to 3.75 ⁇ g/mL with 1X assay buffer, i.e., the working concentration was 1.5 ⁇ g/mL.
  • PI3K ⁇ (Invitrogen Biotechnology Co., Ltd., PV6451): The stock solution was diluted to 625 ng/mL with 1X assay buffer, i.e., the working concentration was 250 ng/mL.
  • PIP:3PS PIP:3PS stock solution (Promega, V1701) was diluted to 0.02 mg/mL with 2.5X lipid buffer.
  • ATP ATP stock solution (Promega, V915B) was diluted to 20 [mu]M with 2.5X lipid buffer.
  • the PIP:3PS and ATP solutions were then mixed in equal proportions, ie their working concentrations were 0.01 mg/mL and 10 ⁇ M, respectively.
  • test compound working solution The test compound was dissolved in DMSO into a stock solution with an initial concentration of 100 ⁇ M, and was diluted with DMSO as a diluent in a 3-fold gradient, with a total of 10 concentrations. Each concentration solution was again diluted 20-fold with 1X assay buffer.
  • PI3K kinase working solution 2.5X PI3K kinase working solution was added to a 384-well plate (PerkinElmer, 6008280) using a pipette, 2 ⁇ L/well. 1 [mu]L of compound solutions at various concentrations were then added to each well. At the same time, 1% DMSO was set up as a negative control, and 100 ⁇ M of a known PI3K inhibitor (GSK2126458 (Selleck, S2658) was set up as a positive control. The 384-well plate was placed on a microplate shaker (Qilin Bell, QB-9002). Shake for 30s to fully mix the solution in the well, and incubate the reaction at 25°C for 15 minutes.
  • a microplate shaker Qilin Bell, QB-9002
  • the inhibition rate is calculated according to the following formula:
  • This test example provides in vitro enzymatic activity data for compounds 1-28 of the invention against various PI3K isoforms.
  • the data collected in Table 1, which provides insight into the activity of compounds in inhibiting PI3K alpha, beta, gamma, and delta activity, can be obtained using the methods previously described. These compounds are generally selective for PI3K ⁇ and ⁇ over PI3K ⁇ and PI3K ⁇ .
  • Test Example 2 Cytologically selective inhibitory activity of the compounds of the present invention on PI3K ⁇ , PI3K ⁇ and PI3K ⁇
  • IGF1 protein-directed AKT phosphorylation in C2C12 mouse myoblasts is mediated only by p110 ⁇ . Based on this, it can be used to evaluate the specific inhibitory behavior of compounds on PI3K ⁇ (Won Jun Lee, Molecules and Cells, 2009, 28(5), 495-499).
  • C2C12 cells (American Type Culture Collection, CRL-1772 TM ) was cultured in DMEM medium (Gibco, 11995-073) containing 10% fetal bovine serum (Invitrogen, 10099141) and penicillin and streptomycin (Gibco, 15140-122). To begin testing, C2C12 cells were seeded into 384-well plates (PerkinElmer, 6007680) at a density of 30,000 cells/well using a multichannel pipette (Thermo Fisher Scientific, Inc., 836-4049).
  • the cells were incubated at 37°C in a 5% CO 2 wet incubator (Thermo Fisher Scientific Co., Ltd., BBD6220) for 2 hours. Then, using a sonic pipette (Labcyte, Echo 550), different concentrations of compounds (starting at 30 ⁇ M, 3-fold serial dilution, a total of 10 concentrations) were added to the culture plate, 30 nL/well, and incubated in the above-mentioned culture. Continue to incubate for 30 minutes under conditions.
  • IGF-1 200 ng/mL, R&D Systems, 291-G1-200
  • 2X Lysis Buffer provided by the kit (AlphaLISA SureFire Ultra p-AKT1/2/3 (Thr 308) kit, PerkinElmer, ALSU-PAKT-A500) was added to each well, and the cell culture plates were Shake on a horizontal shaker for 10 minutes.
  • Raw264.7 cells (American Type Culture Collection, TIB-71 TM ) was cultured in RPMI 1640 medium (Invitrogen, A10491-01) containing 10% fetal bovine serum (Invitrogen, 10099141) and penicillin and streptomycin (Gibco, 15140-122).
  • RPMI 1640 medium Invitrogen, A10491-01
  • 10% fetal bovine serum Invitrogen, 10099141
  • Penicillin and streptomycin (Gibco, 15140-122).
  • 384-well plates PerkinElmer, 6007680
  • a density of 30,000 cells/well using a multichannel pipette (Thermo Fisher Scientific, Inc., 836-4049).
  • the cells were incubated at 37°C in a 5% CO 2 wet incubator (Thermo Fisher Scientific Co., Ltd., BBD6220) for 2 hours. Then, using a sonic pipette (Labcyte, Echo 550), different concentrations of compounds (the initial concentration was 1000 nM, 3-fold serial dilution, a total of 10 concentrations) were added to the culture plate, 30 nL/well, and incubated in the above-mentioned culture. Continue to incubate for 30 minutes under conditions.
  • B-cell receptor signaling by anti-human IgM stimulation of Raji cells is only regulated by PI3K ⁇ , so it can be used to assess the specific inhibitory behavior of compounds on PI3K ⁇ (Liu et al., Oncotarget, 2016, 7(33):53515 ).
  • Raji cells American Type Culture Collection, CCL-86 TM
  • RPMI 1640 medium Invitrogen, A10491-01
  • fetal bovine serum Invitrogen, 10099141
  • penicillin and streptomycin Gibco, 15140-122
  • Raji cells were seeded into 384-well plates (PerkinElmer, 6007680) at a density of 60,000 cells/well using a multichannel pipette (Thermo Fisher Scientific, Inc., 836-4049). After centrifugation at 500 rpm for 30 s, place in a 37 °C, 5% CO 2 wet incubator for 2 h.
  • Test Example 3 Pharmacokinetic evaluation of the compounds of the present invention in SD rats
  • Example 5 Accurately weigh 4 mg of each of the compounds of Example 5, Example 12, Example 15, Example 18, Example 26, Example 27 and Example 28, respectively, and place them in a 15 mL centrifuge tube, add 400 ⁇ L of DMSO to fully shake to make the test sample. Completely dissolve, then add 4 mL of PBS buffered saline solution and 3.6 mL of PEG400, and mix thoroughly until the compound is completely dissolved. At this time, the test sample is a solution with a concentration of 0.5 mg/mL.
  • the oral administration dose of the test substance was 3 mg/kg, and the intravenous dose was 1 mg/kg.
  • Blood samples were collected at 0.00, 0.083, 0.25, 0.50, 1.00, 2.00, 4.00, 6.00 and 8.00 h after administration, respectively.
  • Animals were under inhalation anesthesia (Isoflurane, Hebei Yipin Pharmaceutical Co., Ltd., C002151205), anesthesia parameters: flow rate: 1.0L/min, oxygen pressure: 0.1MPa, solubility: 4.5%, anesthesia time: 3 minutes.
  • Orbital blood was collected after anesthesia, and the blood volume of each animal was 500 ⁇ L at each time point.
  • the blood was collected into a numbered single-use anticoagulant tube (the anticoagulant was heparin sodium, 0.5 mg/tube), and the blood was shaken and mixed. Centrifuge at 3500rpm for 10 minutes, take the upper plasma, transfer it to a 1.5mL centrifuge tube, and store it in a -80°C refrigerator until testing. Take 50 ⁇ L of plasma sample into a 1.5 mL centrifuge tube, add 400 ⁇ L of acetonitrile working solution containing 5 ng/mL verapamil hydrochloride (internal standard), vortex for 1 minute to mix well, and centrifuge at 10,000 rpm for 10 minutes.
  • the anticoagulant was heparin sodium, 0.5 mg/tube
  • Absolute bioavailability F (AUC PO ⁇ D IV )/(AUC IV ⁇ D PO ) ⁇ 100% (AUC is the area under the plasma concentration-time curve, D is the dose, PO is the intragastric administration, IV for intravenous administration).
  • the compounds of the present invention have good pharmacokinetic properties in vivo after intravenous administration to SD rats, and have no absorption or low bioavailability after oral administration.

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Abstract

式（I）所示的杂环化合物、其制备方法、含有其的药物组合物，以及其作为磷脂酰肌醇3-激酶δ（PI3Kδ）和磷脂酰肌醇3-激酶γ（PI3Kγ）双重抑制剂，在预防和/或治疗呼吸系统疾病，特别是哮喘、慢性阻塞性肺病、支气管炎、肺气肿中的用途。

Description

具有磷脂酰肌醇3-激酶δ和γ的双重抑制剂活性的杂环化合物及其医药用途 技术领域
本发明属于医药技术领域，具体涉及一种杂环化合物、其制备方法及含有其的药物组合物，以及其作为磷脂酰肌醇3-激酶δ(PI3Kδ)和磷脂酰肌醇3-激酶γ(PI3Kγ)双重抑制剂，在预防和/或治疗呼吸系统疾病，特别是哮喘、慢性阻塞性肺病、支气管炎、肺气肿，更特别是哮喘和慢性阻塞性肺病中的用途。
背景技术
磷脂酰肌醇3-激酶(phosphatidylinositol-3 kinase，PI3K)是一类位于细胞质中以磷脂酰肌醇作为底物的激酶。它可以识别来自受体酪氨酸激酶(receptor tyrosine kinase，RTK)、G蛋白偶联受体(G-protein coupled receptor，GPCR)和Src样蛋白偶联酪氨酸激酶受体传递的信号，磷酸化磷脂酰肌醇3'位的羟基，产生磷脂酰肌醇-3-磷酸(phosphatidylinositol-3-phosphate，PIP)、磷脂酰肌醇-3,4-二磷酸(phosphatidylinositol-3,4-biphosphate，PIP2)和磷脂酰肌醇-3,4,5-三磷酸(phosphatidylinositol-3,4,5-triphosphate，PIP3)。PIP2和PIP3是细胞内重要的第二信使，可与细胞内的多种靶蛋白，如与Akt结合，通过激酶级联反应将信号逐级传递并放大，最终调节细胞的增殖、分化、代谢、凋亡等一系列活动(Huang等人，Science，2007，318(5857)，1744-1748)。
基于结构及对底物的选择性不同，PI3K可分为I、II、III三类。I型PI3K又可分为IA和IB两个亚型，其中IA型PI3K可接受来自多个上游的信号，如RTK和GPCR等；IB型的PI3K主要接受GPCR传递的信号(Vanhaesebroeck等人，J Mo Med，2016，94，5-11)。IA型的PI3K由一个催化亚基p110和一个调节亚基p85或其剪切变体组成。p110催化亚基由5个结构域组成：p85调节亚基结合结构域(p85binding domain，P85BD)，由α螺旋-β折叠组成的结构域，与调节亚基结合；Ras结合结构域(Ras binding domain，Ras BD)，由α螺旋-β折叠组成的结构域，与Ras蛋白结合；C2结构域，由2个4条链的反平行β片层构成，是与脂质膜结合的主要位点；螺旋区，由全α螺旋组成，作用未知；激酶催化结构域(kinase domain，KD)，由两个亚结构域组成，每个亚结构域均是由α螺旋-β折叠组成的超二级结构，KD是PI3Ks发挥催化作用的核心区域，与ATP及脂质底物结合(Huang等人，Science，2007，318(5857)，1744-1748)。p85调节亚基由5个结构域组成：与p110催化亚基结合的结构域(inter Src-homology 2domain，iSH2)及两侧的SRC同源结构域-N端SRC同源结构域(N-terminal Src-homology 2 domain，nSH2)和C端SRC同源结构域(C-terminal Src-homology 2 domain，cSH2)，N端的第三个SRC同源结构域(Src-homology 3 domain，SH3)和BC同源结构域(BCR homology domain，BH)。p85结构域的剪接变体p55α/p55γ和p50α仅由iSH2、 nSH2和cSH2三个结构域组成。nSH2、iSH2和cSH2结构域可与催化亚基的5个结构域作用，起到抑制催化活性的效果(Zhang等人，Mol Cell，2011，41(5)，567-78)。
根据催化亚基的不同，又可将IA类PI3Ks分为PI3Kα、PI3Kβ、PI3Kγ、PI3Kδ4类。在哺乳动物体内，4种催化亚基p110α、p110β、p110δ和p110分别由4个基因(PIK3CA、IK3CB、PIK3CD、PI3KCG)进行编码。调节亚基可与膜上的受体结合，募集PI3K至细胞膜附近并调节p110亚基的催化活性。调节亚基p85α(及其剪接变体p55α和p50α)、p85β和p55γ3个基因(PIK3R1、PIK3R2、PIK3R3)分别编码。这些脂质激酶可以合成第二信使的形式参与下游信号活化及细胞功能调控。例如合成膜锚定的PIP3，PIP3与细胞内含有PH结构域的信号蛋白AKT和PDK1(phosphoinositide dependent kinase-1)结合，促使PDK1磷酸化AKT蛋白的Ser308导致AKT活化。活化的AKT通过磷酸化多种酶、激酶和转录因子等下游因子，进而调节细胞的功能(Yuan等人，Oncogene，2008，27(41)，5497-5510)。
目前针对I型PI3K的科学研究最多，对其了解也更加透彻。相比之下关于第II类和第III类PI3K功能的信息相对较少。II类PI3K包括PI3K-C2α、PI3K-C2β、a-dPI3K-C2γ。PI3K-C2α和PI3K-C2γ是PIP3最具特征性的两种异构体，它们似乎有助于PIP3的囊泡生成，但由于缺乏选择性抑制剂，很难对它们进行研究。III类PI3K包括Vps15和Vps34两个成员，它们通过PIP3的产生参与囊泡运输、TLR信号转导和自噬(Margaria等人，Biomolecules，2019，9(3)，104)。PI3K通路受磷酸酶的严格调控，特别是磷酸酯酶与张力蛋白同源物(Phosphatase and tensin homolog，PTEN)，它是主要的内源性PI3K抑制剂，可以使PIP3去磷酸化形成PIP2，从而关闭PI3K的激活(Carracedo等人，Oncogene，2008，27，5527-5541.；Worby等人，Annu Rev Biochem，2004，83，641-669；Worby等人，Pharmacol Ther，2004，156，59-68)。PTEN是一种肿瘤抑制因子，缺失常见于肺癌等癌症中，但目前已被认为是炎症和细胞增殖的重要调节因子。含有Src同源2结构域的肌醇59-磷酸酶(SHIP)也抑制PI3K信号转导，主要存在于造血细胞，包括巨噬细胞(Backers等人，Adv Enzyme Regul，2003，43，15-28)。
在IA类PI3K的四种亚型中，PI3Kα和β在许多组织中广泛表达，并控制细胞增殖等基本过程，在胚胎上任何一种异构体的基因缺失都是致命的(Vanhaesebroeck等人，Blood，2005，106，1432-1440)。相比之下，PI3Kγ和δ在细胞分布更受限，主要表达于白细胞之中并介导炎症反应，其基因缺失的小鼠不仅存活，而且炎症反应降低(Hannigan等人，Proc Natl Acad Sci U S A，2002，99，3603-3608；Hirsch等人，Science，2000，287，1049-1053；Yum等人，J Immunol，2001，167，6601-6608)。
PI3K/AKT/mTOR通路在肿瘤的发生发展中起着至关重要的作用，临床肿瘤患者中PI3K和PTEN具有较高的突变比例，可以以PI3K为靶点进行肿瘤类药物开 发。以往研究表明PI3Kδ和PI3Kγ是治疗血液病的潜在靶点，Idelalisib的开发取得了显著的成功，该药物在治疗慢性淋巴细胞白血病和非霍奇金淋巴瘤方面显示出显著的疗效，现已获准临床使用(Furman等人，N Engl J Med，2014，370，997-1007；Miller等人，Clin Cancer Res，2015，21，1525-1529)。除了靶向PI3K途径直接抑制肿瘤细胞生长外，PI3K抑制剂还可用于提高抗肿瘤免疫反应。在包括黑色素瘤、胸腺瘤、肺癌、乳腺癌和胰腺癌在内的一系列小鼠癌症模型中，抑制PI3Kδ可减弱Treg功能和肿瘤浸润，同时使细胞毒性T细胞反应相对未受损害，从而增强抗肿瘤免疫力(Doisne等人，Cell Rep，2015，10，702-710)。在黑色素瘤、肺癌、胰腺癌和乳腺癌模型中，使用PI3Kγ抑制剂TG100-115和AS605240均可以减少肿瘤的生长和转移。PI3Kγ信号是髓系细胞在生长因子和趋化因子的作用下，通过整合素α4β1介导的黏附向肿瘤微环境募集所必需的。因此，抑制p110γ信号在减少全身肿瘤相关炎症和血管生成方面是有效的，而不影响髓系细胞的全身性数量(Schmid等人，Cancer Cell，2011，19，715-727)。
此外越来越多的证据表明，PI3K通过激活炎症、皮质类固醇抵抗和细胞衰老等因素在包括类风湿性关节炎、过敏、哮喘、慢性阻塞性肺病(chronic obstructive pulmonary disease，COPD)和多发性硬化多种疾病中发挥关键作用(Marwick等人，Ther Adv Respir Dis，2010，4，19-34；Hirsch等人，Pharmacol Ther，2008，118，192-205；Marone等人，Biochim Biophys Acta，2008，1784，159-185；Rommel等人，Nat Rev Immunol，2007，7，191-201；Ruckle等人，Nat Rev Drug Discov，2006，5，903-91)。在其中尤其以包含哮喘和COPD的研究更为引人关注。全球哮喘防治创议对哮喘的定义为一种由多种细胞和细胞组分参与的气道慢性炎症性疾病。慢性炎症与引起反复发作的喘鸣、呼吸急促、胸闷和咳嗽的气道反应性有关。这些发作通常与肺内广泛但不一的气流阻塞有关，这种气流阻塞常常自行缓解或经治疗缓解。哮喘是儿童当中最常见的慢性疾病，并且也影响到数百万成年人。而COPD则被定义为一种常见的可预防和治疗的疾病，以持续性呼吸系统症状和气流受限为特征，其通常由显著暴露于有害颗粒或气体引起的气道和/或肺泡异常导致的。COPD的长期气流受限特征是由小气道疾病(如阻塞性毛细支气管炎)和肺实质破坏(肺气肿)混合导致的，这两种因素的相对促进作用因人而异。慢性炎症可引起结构改变、小气道狭窄及肺实质破坏。小气道丢失可促进气流受限和黏液纤毛功能障碍，而后者是该病的特征性表现。随着疾病的发展，COPD患者可能会变得易于频繁恶化，导致患者焦虑、健康状况恶化、肺功能衰退并且死亡率增加。目前关于哮喘和COPD的一线疗法包含长效β激动剂、长效毒蕈碱拮抗剂和吸入皮质类固醇等。然而，这些药物减少与疾病相关联的症状及恶化而不是靶向其分子和细胞基础。因此，仍需进一步改进治疗措施。
研究表明，非选择性PI3K抑制剂LY294002吸入给药可抑制致敏小鼠对变应原的过敏性炎症反应，降低嗜酸性粒细胞、Th2细胞因子和气道高反应性(AHR) (Duan等人，2005，5，495-502)。对调节亚单位p85的显性-负性抑制剂也得到了类似的结果，表明IA类PI3K参与其中，并可能决定从Th1细胞因子到Th2细胞因子的转换(Myou等人，J Exp Med，2003，198，1573-1582)。更具体地说，PI3Kδ在IgE受体交联后的肥大细胞脱颗粒中起关键作用，这种作用可被PI3Kδ选择性抑制剂IC87114阻断(Ali等人，J Immunol，2008，180，2538-2544；Kim等人，Trends Immunol，2008，29，493-501)。在哮喘小鼠模型中，气管内给药IC87114可抑制过敏反应、Th2细胞因子和AHR(Lee等人，2006a)。在烟曲霉的小鼠过敏性炎症模型中，PI3Kδ抑制剂抑制过敏反应，这一作用是通过抑制内质网应激介导的，内质网应激在哮喘中增加，并导致NF-kB激活(Lee等人，Thorax，2016，71:52-63)。PI3K还可能在增加犬气道平滑肌的收缩性(Halayko等人，Am J Respir Cell Mol Biol，2004，31，266–275)和促进气道平滑肌的增殖(如TGF-b等生长因子)方面发挥作用(Goldsmith等人，Am J Respir Cell Mol Biol，2006，34，247-254)。PI3K激活在COPD中也很重要，COPD患者外周肺和巨噬细胞中以p-Akt表示的总PI3K活性显著增加，并且PI3Kδ亚型的表达增加(Marwick等人，Am J Respir Crit Care Med，2009，179，542-548；To等人，Am J Respir Crit Care Med，2010，182，897-904)。在体外氧化应激增加外周血单核细胞和肺泡巨噬细胞中的p-Akt，这可以被PI3Kδ抑制剂阻止，但不能被PI3Kγ抑制剂阻止(Marwick等人，J Allergy Clin Immunol，2010，125，1146–1153)。PI3Kγ基因敲除小鼠表现出中性粒细胞迁移和激活减少，T淋巴细胞和巨噬细胞功能受损(Medina-Tato等人，Immunology，2007，121，448–461)。此外，研究还表明PI3Kγ是介导趋化因子滴注后中性粒细胞重新聚集到肺中的关键信号通路(Thomas等人，Eur J Immunol，2015，35，1283–1291)。
PI3Kδ还参与氧化应激后的糖皮质激素抵抗，这是通过降低组蛋白脱乙酰化酶-2(HDAC2)介导的，PI3Kδ抑制剂可能通过增加HDAC2的表达来逆转COPD患者的糖皮质激素抵抗。用IC87114抑制PI3Kδ可以逆转小鼠对香烟烟雾暴露的皮质类固醇抗药性(To等人，Am J Respir Crit Care Med，2010，182，897-904)，并且PI3Kδ失活的小鼠在香烟烟雾暴露后不会产生皮质类固醇抗药性，而PI3Kγ失活的动物正常发展为对皮质类固醇的抗药性炎症(Marwick等人，Am J Respir Crit Care Med，2009，179，542-548)。COPD中PI3K的激活也激活了mTOR，通过p70核糖体S6激酶(S6-kinase，S6K)的磷酸化来衡量，这在COPD患者肺组织和外周血单核细胞中有所增加(Mitani等人，Am J Respir Crit Care Med，2015，193，143–153)。S6K不仅能降低HDAC2，还能激活JNK，增加c-jun，激活AP-1，从而导致皮质激素抵抗。PI3K激活还通过激活mTOR推动COPD肺中的细胞衰老和加速衰老，mTOR在加速衰老中发挥关键作用(Johnson等人，Nature，2013，493，338-345)。这会导致COPD患者肺部中关键的抗衰老分子sirtuin-1减少(Rajendrasozhan等人，Am J Respir Crit Care Med，2008，177，861-870)。同样 的PI3K-mTOR通路也可能导致与COPD相关的并发症，如缺血性心脏病、2型糖尿病、骨质疏松症、慢性肾脏疾病和痴呆(Barnes等人，Eur Respir J，2015，45，790-806)。
PI3K参与哮喘和COPD所潜在的各种细胞过程的科学证据来源于抑制剂研究及基因靶向方法。在一些COPD患者中对诸如皮质类固醇的常规疗法的抗性已被归因于PI3Kδ/γ途径的上调。另外，PI3Kδ/γ的双重抑制强烈地涉及气道及其它自身免疫性疾病的过敏及非过敏性炎症作为干预策略。因此，针对PI3Kδ/γ信号传导的抑制提供了一种旨在对抗免疫炎性反应的新手段。由于PI3Kδ和γ在介导诸如白细胞迁移和激活以及肥大细胞脱粒的炎性细胞功能中发挥关键性作用，因此阻断这些同种型同样也可以是治疗类风湿性关节炎的有效策略。鉴于这些同种型在免疫监控中确立的关键性，预期特异性地靶向δ和γ同种型的抑制剂将削弱在气道炎症和类风湿性关节炎中所遇到的免疫应答的进展(William等人，Chemistry&Biology，17：123-134，2010；和Thompson等人，Chemistry&Biology，17：101-102，2010)。
PI3K通路抑制剂在治疗严重哮喘和慢性阻塞性肺疾病方面具有极大的潜力，因此有必要开发出新颖的PI3Kδ和PI3Kγ的双重抑制剂，为呼吸系统疾病患者提供更多的临床用药选择。
发明内容
本发明人经过潜心研究，设计合成了一系列杂环化合物，其显示出抑制磷脂酰肌醇3-激酶δ(PI3Kδ)和磷脂酰肌醇3-激酶γ(PI3Kγ)的双重活性，可以被开发为治疗和/或预防与PI3Kδ和PI3Kγ的活性相关的疾病的药物，包括治疗和/或预防呼吸系统疾病，如哮喘、慢性阻塞性肺病、支气管炎、肺气肿，特别是哮喘和慢性阻塞性肺病。
因此，本发明的目的是提供一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐：
Figure PCTCN2021107320-appb-000001
其中，
X为O、S或NH；
Y为N或CH；
A 1、A 2、A 3、A 4和A 5各自独立地选自N或CH；
R 1各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷 基、烷氧基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NR aR b、-NR aC(O)R b、-S(O) pR a、-S(O) pNR aR b、-NR aS(O) pNR aR b和-NR aS(O) pR b，其中所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代；或者，
任意相邻的两个R 1与其连接的原子一起形成环烷基、杂环基、芳基或杂芳基，优选杂芳基，更优选5或6元杂芳基，所述环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代；
R 2选自氢、卤素、烷基、烷氧基、卤代烷基或卤代烷氧基；
R 3选自-C(O)R a、-C(O)NR aR b、-S(O) pNR aR b、-S(O) pR a、-P(O)(R a) 2、-S(NR a)(O)R b、-NR aS(O) pR b-、-NR aS(O) pNR aR b、卤素、环烷基、杂环基、芳基和杂芳基，其中所述环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
R 4选自烷基或环烷基，其中所述烷基或环烷基任选进一步被选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基或杂环基的一个或多个基团取代；
R 5选自氢、卤素、烷基、烷氧基、卤代烷基或卤代烷氧基；
R 6选自氢、卤素、烷基或卤代烷基；
R a和R b各自独立地选自氢、卤素、羟基、烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；或者，
R a和R b与他们连接的氮原子一起形成含氮杂环基或含氮杂芳基，所述含氮杂环基或含氮杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代；
n为0、1、2或3；
p为0、1或2。
在一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐，
Figure PCTCN2021107320-appb-000002
其中，
X为O或S；
A 1-A 5、R 1、R 2、R 3、R 4、R 5、R 6和n如通式(I)所定义。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
其中，
A 1、A 2、A 3、A 4和A 5中最多有两个为N，其余为CH；
优选地，A 1、A 2、A 3、A 4和A 5中一个或两个为N，其余为CH；
更优选，A 1、A 2、A 3、A 4和A 5之一为N，其余为CH。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
Figure PCTCN2021107320-appb-000003
其中，
X为O或S；
A 1、A 2、A 3、A 4中最多有两个为N，其余为CH；
R 1、R 2、R 3、R 4、R 5和R 6如通式(I)所定义。
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
Figure PCTCN2021107320-appb-000004
其中，
A 1、A 2、A 3、A 4中最多有两个为N，其余为CH；
优选地，A 1、A 2、A 3、A 4中一个或两个为N，其余为CH；
更优选，A 1、A 2、A 3、A 4之一为N，其余为CH；
其中，R 1、R 2、R 3、R 4、R 5和R 6如通式(I)所定义。
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)或(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
其中，
A 1为N，且A 2、A 3、A 4为CH；或者，
A 2为N，且A 1、A 3、A 4为CH；或者，
A 4为N，且A 1、A 2、A 3为CH；或者，
A 1和A 3为N，且A 2和A 4为CH；或者，
A 1和A 2为N，且A 3和A 4为CH。
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)或(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
其中，条件是当A 1为N，A 2、A 3、A 4为CH，且R 1选自
Figure PCTCN2021107320-appb-000005
R 4选自
Figure PCTCN2021107320-appb-000006
Figure PCTCN2021107320-appb-000007
时，R 3不是甲磺酰基、
Figure PCTCN2021107320-appb-000008
在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(V)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
Figure PCTCN2021107320-appb-000009
其中，R 1、R 2、R 3、R 4、R 5和R 6如权利要求1所定义。
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)、(IV)或(V)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
其中，
R 4选自C 1-C 6烷基，所述C 1-C 6烷基任选进一步被选自C 3-C 10环烷基或3至10元杂环基的一个或多个基团所取代；优选被选自C 3-C 8环烷基或3至8元杂环基的一个或多个基团所取代；进一步优选被环丙基取代。
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)、(IV)或(V)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
其中，
R 1选自卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 10环烷基、3至10元杂环基、C 6-C 10芳基、5至10元杂芳基、-NR aR b、-NR aC(O)R b和-NR aS(O) pR b，其中所述C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 10环烷基、3至10元杂环基、C 6-C 10芳基、5至10元杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代；
R a和R b各自独立地选自氢、C 1-C 6烷基、C 3-C 10环烷基、3至10元杂环基、C 6-C 10芳基和5至10元杂芳基，其中所述C 1-C 6烷基、C 3-C 10环烷基、3至10元杂环基、C 6-C 10芳基和5至10元杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；所述C 3-C 10环烷基、3至10元杂环基、C 6-C 10芳基和5至10元杂芳基优选C 3-C 8环烷基、3至6元杂环基、苯基和5至6元杂芳基；或者，
R a和R b与他们连接的氮原子一起形成含5至7元，优选5至6元氮杂环基，或5至10元，优选5至6元含氮杂芳基，所述含氮杂环基或含氮杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代。
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)、(IV)或(V)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
其中，
R 1选自3至10元杂环基，优选5至7元单杂环基、5至7元螺杂环基或5至7元稠杂环基、C 6-C 10芳基、5至10元杂芳基，优选5至6元杂芳基，更优选5元杂芳基；
其中所述杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代。
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)、(IV)或(V)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
其中，
R 1选自
Figure PCTCN2021107320-appb-000010
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)、(IV)或(V)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
R 1选自-NR aR b、-NR aC(O)R b和-NR aS(O) pR b；
R a选自氢或C 1-C 6烷基；
R b选自氢、C 1-C 6烷基、C 3-C 10环烷基优选C 3-C 6环烷基。
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)、(IV)或(V)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
其中，
R 3选自-C(O)R a、-C(O)NR aR b、-S(O) pNR aR b、-S(O) pR a、-P(O)(R a) 2、-S(NR a)(O)R b、-NR aS(O) pR b-、卤素、C 6-C 10芳基和5至10元杂芳基，其中所述C 6-C 10芳基或5至10元杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
R a和R b各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、3至8元杂环基、C 6-C 10芳基和5至10元杂芳基，其中所述C 1-C 6烷基、C 3-C 6环烷基、3至8元杂环基、C 6-C 10芳基或5至10元杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；或者，
R a和R b与他们连接的氮原子一起形成3至8元含氮杂环基或5至6元含氮杂芳基，所述含氮杂环基或含氮杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代；
p为1或2。
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)、(IV)或(V)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
R 3选自-S(O) pR a、-S(O) pNR aR b、-NR aS(O) pR b-、-C(O)R a、-C(O)NR aR b、-P(O)(R a) 2；
R a选自氢、C 1-C 6烷基；
R b选自氢、C 1-C 6烷基；或者，
R a和R b与他们连接的氮原子一起形成3至8元含氮杂环基，所述含氮杂环基任 选进一步被选自卤素、羟基、C 1-C 6烷基、C 1-C 6烷氧基的一个或多个基团取代；
p为1或2。在另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(VI)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐
Figure PCTCN2021107320-appb-000011
其中，
L选自-C(O)-、-S(O) p-、-P(O)(R a)-、-S(NR a)(O)-、-NR aS(O) pR b-；
R a选自氢、C 1-C 6烷基；
R b选自C 1-C 6烷基；
R 7选自-NR cR d；
R c和R d各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、3至8元杂环基、C 6-C 10芳基和5至10元杂芳基，其中所述C 1-C 6烷基、C 3-C 6环烷基、3至8元杂环基、C 6-C 10芳基或5至10元杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；或者，
R c和R d与他们连接的氮原子一起形成3至8元含氮杂环基或5至6元含氮杂芳基，所述含氮杂环基或含氮杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代；
优选地，
R c和R d各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、3至8元杂环基，或者
R c和R d与他们连接的氮原子一起形成3至8元含氮杂环基，所述含氮杂环基任选进一步被选自卤素、羟基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代；
p为1或2。
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)、(IV)、(V)或(VI)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
其中，
R 7选自
Figure PCTCN2021107320-appb-000012
其任选进一步被选自卤素、羟基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代；
R 7进一步优选
Figure PCTCN2021107320-appb-000013
Figure PCTCN2021107320-appb-000014
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)、(IV)、(V)或(VI)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
其中，R 2选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基或C 1-C 6卤代烷氧基；优选氢。
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)、(IV)、(V)或(VI)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
其中，R 5选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基或C 1-C 6卤代烷氧基；优选氢。
在另一个优选的实施方案中，根据本发明所述的通式(I)、(II)、(III)、(IV)、(V)或(VI)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
其中，R 6选自氢、卤素、C 1-C 6烷基、或C 1-C 6卤代烷基；优选C 1-C 6烷基。
本发明的典型化合物，包括但不限于：
Figure PCTCN2021107320-appb-000015
Figure PCTCN2021107320-appb-000016
Figure PCTCN2021107320-appb-000017
Figure PCTCN2021107320-appb-000018
Figure PCTCN2021107320-appb-000019
Figure PCTCN2021107320-appb-000020
Figure PCTCN2021107320-appb-000021
或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐。
本发明进一步提供一种通式(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：
Figure PCTCN2021107320-appb-000022
在溶剂中，在加热条件下，在碱的存在下，在配体和催化剂的存在下，将化合物(Ie)与化合物(Ig)反应得到通式(III)的化合物；
其中，所述溶剂优选为极性非质子溶剂如DMF；
所述加热条件优选在75℃-100℃的范围内；
所述配体优选空间位阻的三烷基膦，例如三叔丁基膦；
所述碱优选碱金属碳酸盐，例如碳酸铯；
所述催化剂优选过渡金属，例如钯；
其中，
A 1-A 4、X、R 1、R 2、R 3、R 4、R 5、R 6如通式(III)所定义。
本发明进一步提供一种通式(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：
Figure PCTCN2021107320-appb-000023
在溶剂中，在加热条件下，在碱的存在下，在配体和催化剂的存在下，将化合物(IVc)与化合物(Ig)反应得到通式(IV)的化合物；
其中，所述溶剂优选为极性非质子溶剂如DMF；
所述加热条件优选在75℃-100℃的范围内；
所述配体优选空间位阻的三烷基膦，例如三叔丁基膦；
所述碱优选碱金属碳酸盐，例如碳酸铯；
所述催化剂优选过渡金属，例如钯；
其中，
A 1-A 4、R 1、R 2、R 3、R 4、R 5、R 6如通式(IV)所定义。
本发明进一步提供一种通式(V)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：
Figure PCTCN2021107320-appb-000024
在溶剂中，在加热条件下，在碱的存在下，在配体和催化剂的存在下，将化合物(Vc)与化合物(Ig)反应得到通式(V)的化合物；
其中，所述溶剂优选为极性非质子溶剂如DMF；
所述加热条件优选在75℃-100℃的范围内；
所述配体优选空间位阻的三烷基膦，例如三叔丁基膦；
所述碱优选碱金属碳酸盐，例如碳酸铯；
所述催化剂优选过渡金属，例如钯；
其中，
R 1、R 2、R 3、R 4、R 5、R 6如通式(V)所定义。
本发明进一步提供一种通式(VI)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：
Figure PCTCN2021107320-appb-000025
在溶剂中，在加热条件下，在碱的存在下，在配体和催化剂的存在下，将化合物(VIc)与化合物(VIg)反应得到通式(VI)的化合物；
其中，所述溶剂优选为极性非质子溶剂如DMF；
所述加热条件优选在75℃-100℃的范围内；
所述配体优选空间位阻的三烷基膦，例如三叔丁基膦；
所述碱优选碱金属碳酸盐，例如碳酸铯；
所述催化剂优选过渡金属，例如钯；
其中，
R 2、R 5、R 6、R 7如通式(VI)所定义。
本发明还涉及一种药物组合物，其包含根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐和药学上可接受的佐剂、稀释剂或载体。
本发明进一步涉及根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐或含有其的药物组合物在制备磷脂酰肌醇3-激酶δ(PI3Kδ)和磷脂酰肌醇3-激酶γ(PI3Kγ)双重抑制剂中的用途。
本发明还涉及根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐或含有其的药物组合物在制备预防和/或治疗与PI3Kδ和PI3Kγ的活性相关的疾病的药物中的用途，所述疾病优选呼吸系统疾病，例如哮喘、慢性阻塞性肺病、支气管炎、肺气肿，优选哮喘和慢性阻塞性肺病。
本发明还涉及一种药物组合物，其包含根据本发明所述的通式(I)所示的化 合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐与另一种活性剂的组合，所述另一种活性剂选自糖皮质激素受体激动剂(甾体性或非甾体性)、选择性β2肾上腺素受体激动剂、抗毒蕈碱剂、p38拮抗剂、黄嘌呤衍生物、和PDE4拮抗剂。
本发明还涉及根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐或含有其的药物组合物与另一种活性剂同时、分开或相继使用在制备用于预防和/或治疗PI3Kδ和PI3Kγ的活性相关的疾病的药物中的用途；所述疾病优选呼吸系统疾病，例如哮喘、慢性阻塞性肺病、支气管炎、肺气肿，优选哮喘和慢性阻塞性肺病；其中所述另一种活性剂选自糖皮质激素受体激动剂(甾体性或非甾体性)、选择性β2肾上腺素受体激动剂、抗毒蕈碱剂、p38拮抗剂、黄嘌呤衍生物、和PDE4拮抗剂。
本发明还涉及根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐或含有其的药物组合物，其用作磷脂酰肌醇3-激酶δ(PI3Kδ)和磷脂酰肌醇3-激酶γ(PI3Kγ)双重抑制剂。
本发明还涉及根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐或含有其的药物组合物，其用作药物，所述药物用于预防和/或治疗与PI3Kδ和PI3Kγ的活性相关的疾病，优选呼吸系统疾病，例如哮喘、慢性阻塞性肺病、支气管炎、肺气肿，优选哮喘和慢性阻塞性肺病。
本发明还涉及根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐或含有其的药物组合物，其用于与另一种活性剂同时、分开或相继使用以预防和/或治疗与PI3Kδ和PI3Kγ的活性相关的疾病，优选呼吸系统疾病，例如哮喘、慢性阻塞性肺病、支气管炎和肺气肿，优选哮喘和慢性阻塞性肺病，所述另一种活性剂选自糖皮质激素受体激动剂(甾体性或非甾体性)、选择性β2肾上腺素受体激动剂、抗毒蕈碱剂、p38拮抗剂、黄嘌呤衍生物、和PDE4拮抗剂。
本发明还涉及一种抑制磷脂酰肌醇3-激酶δ(PI3Kδ)和磷脂酰肌醇3-激酶γ(PI3Kγ)的方法，其包括向有需要的受试者施用抑制有效量的根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐或含有其的药物组合物。
本发明还涉及一种预防和/或治疗与PI3Kδ和PI3Kγ的活性相关的疾病，优选呼吸系统疾病，例如哮喘、慢性阻塞性肺病、支气管炎、肺气肿，优选哮喘和慢性阻塞性肺病的方法，其包括向有需要的受试者施用预防或治疗有效量的根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映 异构体、或其混合物形式、或其前药、或其可药用盐或含有其的药物组合物。
本发明还涉及一种预防和/或治疗与PI3Kδ和PI3Kγ的活性相关的疾病，优选呼吸系统疾病，例如哮喘、慢性阻塞性肺病、支气管炎、肺气肿，优选哮喘和慢性阻塞性肺病的方法，其包括向有需要的受试者同时、分开或相继施用预防或治疗有效量的根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其前药、或其可药用盐或含有其的药物组合物以及另外一种活性剂，所述另一种活性剂选自糖皮质激素受体激动剂(甾体性或非甾体性)、选择性β2肾上腺素受体激动剂、抗毒蕈碱剂、p38拮抗剂、黄嘌呤衍生物、和PDE4拮抗剂。
按照本发明所属领域的常规方法，本发明通式(I)所示的化合物可以与碱或者酸生成药学上可接受的碱式加成盐或酸式加成盐。所述碱包括无机碱和有机碱，可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等，可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠等。所述酸包括无机酸和有机酸，可接受的无机酸包括盐酸、硫酸、硝酸、磷酸、氢溴酸等。可接受的有机酸包括乙酸、三氟乙酸、甲酸、抗环血酸等。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶；和润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和阿拉伯胶；分散剂或湿润剂，可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物，例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨 醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油混悬液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。
通过加入水，适用于制备水混悬液的可分散粉末和颗粒可以提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂如上所述。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂，和由脂肪酸和己糖醇酐衍生的酯或偏酯，例如山梨坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制的糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒和溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。
本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液，例如在1,3-丁二醇中制备的溶液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。
本领域技术人员熟知，药物的给药剂量依赖于多种因素，包括但并非限定于 以下因素：所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、排泄的速率、药物的组合等。另外，最佳的治疗方式如治疗的模式、通式化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
本发明可以含有通式(I)所示的化合物，及其药学上可接受的盐、水合物或溶剂化物作为活性成分，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型。本发明的衍生物可以与其他活性成分组合使用，只要它们不产生其他不利的作用，例如过敏反应等。本发明化合物可作为唯一的活性成分，也可以与其它治疗与酪氨酸激酶活性相关的疾病的药物联合使用。联合治疗通过将各个治疗组分同时、分开或相继给药来实现。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的 烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“炔基”指由至少由两个碳原子和至少一个碳-碳三键组成的如上定义的烷基，例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至10个碳原子，进一步优选包含3至8个碳原子，最优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2021107320-appb-000026
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2021107320-appb-000027
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双 环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2021107320-appb-000028
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3个是杂原子；最优选包含5至7个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选1、2、5-噁二唑基、吡喃基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2021107320-appb-000029
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选 为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2021107320-appb-000030
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2021107320-appb-000031
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2021107320-appb-000032
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2021107320-appb-000033
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、噻唑基、吡唑基或嘧啶基、噻唑基；更有选吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2021107320-appb-000034
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
术语“羟烷基”指被一个或多个羟基取代的烷基，其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”指＝O。
术语“羧基”指-C(O)OH。
术语“巯基”指-SH。
术语“酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基和环烷基如上所定义。
术语“酰基”指含有-C(O)R基团的化合物，其中R为如上定义的烷基、环烷基、杂环基、芳基、杂芳基。
术语“磺酰基”指含有-S(O) 2R基团的化合物，其中R为如上定义的烷基、环烷基、杂环基、芳基、杂芳基。
术语“亚磺酰基”指含有-S(O)R基团的化合物，其中R为如上定义的烷基、环烷基、杂环基、芳基、杂芳基。
术语“磷酰基”指含有-P(O)RR’基团的化合物，其中R和R’为如上定义的烷基、环烷基、杂环基、芳基、杂芳基。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
本发明化合物的合成方法
为了完成本发明的目的，本发明采用如下合成方案制备本发明的通式(III)化合物。
当R 3为-NR aR b时：
Figure PCTCN2021107320-appb-000035
方案1
步骤1：在溶剂中，在加热条件下，在碱的存在下，在配体和催化剂的存在下，将化合物(Ia)与R 1H反应得到化合物(Ib)；该反应在促进亲核芳族置换的条件下进行；所述溶剂典型地为极性非质子溶剂，如1,4-二氧六环；所述加热条件典型地在80℃进行，加热可以通过常规或微波方式进行，并且有利地，可以使用加压系统以使反应能够在溶剂沸点以上运行；合适的配体如二齿三取代膦，例如xantphos；合适的碱如碱金属碳酸盐，例如碳酸铯；合适的催化剂如过渡金属，例如钯；
步骤2：在溶剂中，在加热条件下，在碱的存在下，在配体和催化剂的存在下，将化合物(Ib)与化合物(Ih)反应得到化合物(Ic)；该反应在化合物的卤素被氨基基团置换的条件下进行；所述溶剂典型地为极性非质子溶剂，如DMF；所述加热条件典型地在125℃，加热可以通过常规或微波方式进行，并且有利地可以使用加压系统以使反应能够在溶剂沸点以上运行；合适的配体如二齿三取代膦，例如Ruphos，合适的碱如碱金属碳酸盐，例如碳酸钠；合适的催化剂如过渡金属，例如钯；
步骤3：在溶剂中，在加热条件下，在碱的存在下，将化合物(Id)与苄硫醇反应得到化合物(Ie)；合适的溶剂如1,4-二氧六环；合适的碱如醇钠，例如叔丁醇钠；所述加热条件典型地为80℃；
步骤4：在溶剂中，化合物(Ie)与磺酰氯反应得到化合物(If)；合适的溶剂可以为混合溶剂，例如含有乙酸的水和乙腈的混合物；该反应温度可以在-5℃与环境温度之间；
步骤5：在溶剂中，在碱的存在下，将化合物(Ie)与化合物HNR aR b反应得到化合物(Ig)；合适的溶剂例如二氯甲烷；所述碱典型地为有机碱如三乙胺或无机碱如碳酸铯；反应温度可以在环境温度与40℃之间)进行；
步骤6：在溶剂中，在加热条件下，在碱的存在下，在配体和催化剂的存在下，将化合物(Ie)与化合物(Ig)反应得到通式(III)的化合物；该反应在促进芳基溴化物活化及其与活化的双键反应(Heck反应)的条件下进行；所述溶剂典型地 为极性非质子溶剂如DMF；所述加热条件典型地在75℃-100℃的范围内，加热可以通过常规或微波方式进行，并且有利地，可以使用加压系统以使反应能够在溶剂沸点以上运行；合适的配体如空间位阻的三烷基膦，例如三叔丁基膦；合适的碱如碱金属碳酸盐，例如碳酸铯；合适的催化剂如过渡金属，例如钯；
其中，Hal为卤素；
A 1-A 4、X、R 1、R 2、R 4、R 5、R 6、R a、R b如通式(III)中所定义。
具体实施方式
进一步通过实施例来理解本发明的化合物及其制备，这些实施例说明了一些制备或使用所述化合物的方法。然而，要理解的是，这些实施例不限制本发明。现在已知的或进一步开发的本发明的变化被认为落入本文中描述的和要求保护的本发明范围之内。
本发明化合物是利用便利的起始原料和通用的制备步骤来完成制备的。本发明给出了典型的或倾向性的反应条件，诸如反应温度、时间、溶剂、压力、反应物的摩尔比。但是除非特殊说明，其他反应条件也能采纳。优化条件可能随着具体的反应物或溶剂的使用而改变，但在通常情况下，反应优化步骤和条件都能得到确定。
另外，本发明中可能用到了一些保护基团来保护某些官能团避免不必要的反应。适宜于各种官能团的保护基以及它们的保护或脱保护条件已经为本领域技术人员广泛熟知。例如T.W.Greene和G.M.Wuts的《有机制备中的保护基团》(第3版,Wiley,New York,1999和书中的引用文献)详细描述了大量的保护基团的保护或脱保护。
化合物和中间体的分离和纯化依据具体的需求采取适当的方法和步骤，例如过滤、萃取、蒸馏、结晶、柱层析、制备薄层板色谱、制备高效液相色谱或上述方法的混合使用。其具体使用方法可参阅本发明描述的实例。当然，其他类似的分离和纯化手段也是可以采用的。可以使用常规方法(包括物理常数和波谱数据)对其进行表征。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移以10 -6(ppm)的单位给出。NMR的测定是用Brukerdps 300型核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用LC(Waters 2695)/MS(Quattro Premier xE)质谱仪(生产商：沃特世)(Photodiode Array Detector)。
制备液相色谱法使用lc6000高效液相色谱仪(生产商：创新通恒)。色谱柱为DaisogelC18 10μm 100A(30mm×250mm)，流动相：乙腈/水。
薄层层析硅胶板使用青岛海洋化工GF254硅胶板，薄层色谱法(TLC)使用的硅 胶板采用的规格是0.20mm～0.25mm，制备薄层层析分离纯化产品采用的规格是0.5mm。
柱层析一般使用青岛海洋硅胶100～200目、200～300目和300～400目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自网化商城、北京偶合、Sigma、百灵威、易世明、上海书亚、上海伊诺凯、安耐吉化学、上海毕得等公司。
实施例中无特殊说明，反应能够均在氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
反应溶剂，有机溶剂或惰性溶剂各自表述为使用的该溶剂在所描述的反应条件下不参与反应，包括，如苯、甲苯、乙腈、四氢呋喃(THF)、二甲基甲酰胺(DMF)、氯仿、二氯甲烷、乙醚、甲醇、氮-甲基吡咯碄酮(NMP)、吡啶等。实施例中无特殊说明，溶液是指水溶液。
本发明中所描述的化学反应一般在常压下进行。反应温度在-78℃至200℃之间。反应时间和条件为，例如，一个大气压下，-78℃至200℃之间，大约1至24小时内完成。如果反应过夜，则反应时间一般为16小时。实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：石油醚和乙酸乙酯体系，C：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和三氟乙酸等碱性或酸性试剂进行调节。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。
缩略语
μL＝微升
μM＝微摩尔
NMR＝核磁共振
Boc＝叔丁氧基羰基
br＝宽峰
d＝双峰
δ＝化学位移
℃＝摄氏度
dd＝双双峰
DIPEA＝二异丙基乙基胺
DMAP＝4-二甲氨基吡啶
DMF＝N,N-二甲基甲酰胺
DMSO＝二甲亚砜
DCM＝二氯甲烷
EA＝乙酸乙酯
HPLC＝高效液相
Hz＝赫兹
IC 50＝抑制50％活性的浓度
J＝偶合常数(Hz)
LC-MS＝液相色谱-质普联用
m＝多重峰
M+H +＝母体化合物质量+一质子
mg＝毫克
mL＝毫升
mmol＝毫摩尔
mol＝摩尔
Ms＝甲磺酰基
MS＝质谱
MsCl＝甲基磺酰氯
m/z＝质荷比
NBS＝N-溴代琥珀酰亚胺
nM＝纳摩尔
PE＝石油醚
ppm＝每百万分
Pro＝保护基
Ruphos＝2-二环己基膦-2',6'-二异丙氧基-1,1'-联苯
s＝单峰
t＝三重峰
t-buxphos＝甲烷磺酸(2-二叔丁基膦基-2',4',6'-三异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)
TBS-＝叔丁基二甲基硅基
TEA＝三乙胺
TFA＝三氟乙酸
THF＝四氢呋喃
Xantphos＝4,5-双二苯基膦-9,9-二甲基氧杂蒽。
制备实施例1:(S)-5-溴-2-(1-环丙基乙基)-7-(甲基磺酰基)异吲哚啉-1-酮(1d)的制备
Figure PCTCN2021107320-appb-000036
步骤1：4-溴-2-(溴甲基)-6-氯苯甲酸甲酯(1a)的制备。
于室温，将4-溴-2-氯-6-甲基苯甲酸甲酯(2.61g,10.0mmol)、四氯化碳(20mL)、过氧苯甲酰(121mg,0.500mmol)、NBS(1.78g,10.0mmol)加到反应瓶中，升温至85℃搅拌反应15小时。反应结束后，加100mL水，加200mL二氯甲烷萃取，有机相用水洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到3.3g无色油的标题产物，直接用于下一步，收率：98％。
LCMS:m/z 339.90[M+H] +。
步骤2：(S)-5-溴-7-氯-2-(1-环丙基乙基)异吲哚啉-1-酮(1b)的制备。
于室温，将4-溴-2-(溴甲基)-6-氯苯甲酸甲酯(3.39g,10.0mmol)、(S)-1-环丙基乙胺(1.21g,10.0mmol)、硼酸(618mg,10mmol)、碳酸钾(4.14g,30mmol)、乙腈(20mL)加到反应瓶中，20℃搅拌反应15小时。反应结束后，抽滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝5：1)纯化，得到1.10g白色固体物的标题产物，收率：35.0％。
LCMS:m/z 314.22[M+H] +。
步骤3：(S)-5-溴-2-(1-环丙基乙基)-7-(甲硫基)异吲哚啉-1-酮(1c)的制备。
于室温，将(S)-5-溴-7-氯-2-(1-环丙基乙基)异吲哚啉-1-酮(1.10g,3.50mmol)、甲硫醇钠(0.73g,10mmol)、二氧六环(20mL)加到反应瓶中，90℃搅拌反应12小时。反应结束后，抽滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝5：1)纯化，得到0.80g黄色固体物的标题产物，收率：70.0％。
LCMS:m/z 326.22[M+H] +。
步骤4：(S)-5-溴-2-(1-环丙基乙基)-7-(甲基磺酰基)异吲哚啉-1-酮(1d)的制备。
于室温，将(S)-5-溴-2-(1-环丙基乙基)-7-(甲硫基)异吲哚啉-1-酮(0.80g,2.46mmol)、间氯过氧苯甲酸(0.846g,4.92mmol)、二氯甲烷(20mL)加到反应瓶中，20℃搅拌反应12小时。反应结束后，抽滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝1：1)纯化，得到0.40g黄色固体物的标题产物，收率：45.0％。
LCMS:m/z 358.22[M+H] +。
制备实施例2：1-(6-((4-甲基噻唑-2-基)氨基)吡啶-2-基)吡咯烷-2-酮(2b)的制备
Figure PCTCN2021107320-appb-000037
步骤1：1-(6-溴吡啶-2-基)吡咯烷-2-酮(2a)的制备。
于室温，将2,6-二溴吡啶(24.0g,100mmol)、吡咯烷-2-酮(4.25g,50.0mmol)、二氧六环(250mL)加到反应瓶中，然后加入碳酸铯(65.0g,200mmol)、Pd(OAc) 2(1.12g,5.00mmol)、Xantphos(5.78g,10.0mmol)。氮气氛下，于80℃搅拌反应6小时。反应结束后，抽滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝5：1)纯化，得到12.0g白色固体物的标题产物，收率：50.0％。
LCMS:m/z 241.19[M+H] +。
步骤2：1-(6-((4-甲基噻唑-2-基)氨基)吡啶-2-基)吡咯烷-2-酮(2b)的制备。
于室温，将1-(6-溴吡啶-2-基)吡咯烷-2-酮(2.40g,10mmol)、4-甲基噻唑-2-胺(1.14g,10.0mmol)、甲苯(15.0mL)DMF(1.00mL)加到反应瓶中，然后加入碳酸铯(6.50g,20.0mmol)、Pd(OAc) 2(112mg,0.50mmol)、Xantphos(578mg,1.00mmol)，于115℃搅拌反应5小时。反应结束后，抽滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝1：1)纯化，得到1.30g白色固体物的标题产物，收率：50.0％。
LCMS:m/z 275.19[M+H] +。
制备实施例3：1-(4-((4-甲基噻唑-2-基)氨基)吡啶-2-基)吡咯烷-2-酮(3c)的制 备
Figure PCTCN2021107320-appb-000038
步骤1：4-溴-N-(4-溴吡啶-2-基)丁酰胺(3a)的制备。
于-10℃，将4-溴吡啶-2-胺(5.02g,28.9mmol)、吡啶(3.51g,43.4mmol)、乙腈(50ml)加到反应瓶中，搅拌30分钟，缓慢滴入4-溴丁酰氯(6.50g,34.7mmol)，保持该温度搅拌2小时，缓慢升温至15℃，继续搅拌反应12小时。反应结束后，减压浓缩，得到7.22g棕色固体物的标题产物，直接用于下一步。
LCMS:m/z 322.91[M+H] +。
步骤2：1-(4-溴吡啶-2-基)吡咯烷-2-酮(3b)的制备。
于室温，将4-溴-N-(4-溴吡啶-2-基)丁酰胺(7.22g,28.9mmol)、碳酸铯(10.3g,31.8mmol)、DMF(50mL)加到反应瓶中，60℃搅拌反应15小时。反应结束后，向反应液中加入乙酸乙酯和水萃取，有机层减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝3：1)纯化，得到3.31g黄色固体物的标题产物，收率：35.6％。
LCMS:m/z 240.99[M+H] +。
步骤3：1-(4-((4-甲基噻唑-2-基)氨基)吡啶-2-基)吡咯烷-2-酮(3c)的制备。
于室温，将1-(4-溴吡啶-2-基)吡咯烷-2-酮(1.02g,4.21mmol)、4-甲基噻唑-2-胺(479mg,4.21mmol)、甲苯(45mL)、DMF(3mL)加到反应瓶中，然后加入碳酸铯(2.73g,8.42mmol)、Pd(OAc) 2(48.4mg,0.21mmol)、Xantphos(243mg,0.42mmol)，于115℃搅拌反应5小时。反应结束后，抽滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝1：1)纯化，得到620mg黄色固体物的标题产物，收率：53.7％。
LCMS:m/z 275.09[M+H] +。
制备实施例4：(S)-5-(2-氨基-4-甲基噻唑-5-基)-2-(1-环丙基乙基)-7-(甲基磺酰 基)异吲哚啉-1-酮(4c)的制备
Figure PCTCN2021107320-appb-000039
步骤1：N-(4-甲基噻唑-2-基)乙酰胺(4a)的制备。
于0℃，将4-甲基噻唑-2-胺(1.02g,8.78mmol)、乙酰氯(892mg,10.6mmol)、DCM(10ml)加到反应瓶中，搅拌20分钟，然后加入三乙胺(2.71g,26.4mmol)，搅拌1小时，缓慢升温至15℃，搅拌反应4小时。反应结束后，减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：二氯甲烷：甲醇＝20：1)纯化，得到413mg褐色固体物的标题产物，收率：30.2％。
LCMS:m/z 157.04[M+H] +。
步骤2：(S)-N-(5-(2-(1-环丙基乙基)-7-(甲基磺酰基)-1-氧代基)异吲哚啉-5-基)-4-甲基噻唑-2-基)乙酰胺(4b)的制备。
于室温，将(S)-5-溴-2-(1-环丙基乙基)-7-(甲基磺酰基)异吲哚啉-1-酮(1d)(1.02g,2.86mmol)、N-(4-甲基噻唑-2-基)乙酰胺(437mg,2.86mmol)、碳酸铯(437mg,2.86mmol)、Pd(OAc) 2(64.9mg,0.29mmol)、((t-bu) 3PH)BF 4(162mg,0.57mmol)、DMF(10mL)加到反应瓶中，100℃搅拌反应2小时。反应结束后，减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝2：1)纯化，得到770mg黄色固体物的标题产物，收率：62.2％。
LCMS:m/z 434.11[M+H] +。
步骤3：(S)-5-(2-氨基-4-甲基噻唑-5-基)-2-(1-环丙基乙基)-7-(甲基磺酰基)异吲哚啉-1-酮(4c)的制备。
于室温，将(S)-N-(5-(2-(1-环丙基乙基)-7-(甲基磺酰基)-1-氧代基)异吲哚啉-5-基)-4-甲基噻唑-2-基)乙酰胺(770mg,1.77mmol)、3M盐酸(20ml)、乙醇(20ml)混合，于70℃搅拌反应6小时。反应结束后，减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝1：1)纯化，得到312mg黄色固体物的标题产物，收率：45.1％。
LCMS:m/z 392.10[M+H] +。
制备实施例5：(S)-7-(氮杂环丁烷-1-基磺酰基)-5-溴-2-(1-环丙基乙基)异吲哚啉-1-酮(5c)的制备
Figure PCTCN2021107320-appb-000040
步骤1：(S)-7-(苄硫基)-5-溴-2-(1-环丙基乙基)异吲哚啉-1-酮(5a)的制备。
于室温，将(S)-5-溴-7-氯-2-(1-环丙基乙基)异吲哚啉-1-酮(313mg,1.00mmol)、苄硫醇(124mg,1.00mmol)、叔丁醇钠(96.0mg,1.00mmol)、二氧六环(8mL)加到反应瓶中，80℃搅拌反应12小时。反应结束后，向反应液中加入二氯甲烷、水萃取，有机层减压浓缩，得到561mg黄色油状物的标题产物，直接用于下一步。
LCMS:m/z 402.04[M+H] +。
步骤2：(S)-6-溴-2-(1-环丙基乙基)-3-氧代异吲哚啉-4-磺酰氯(5b)的制备。
于0℃，将(S)-7-(苄硫基)-5-溴-2-(1-环丙基乙基)异吲哚啉-1-酮(561mg,1.00mmol)、冰醋酸(1.8mL)、乙腈(8ml)、水(0.3ml)加到反应瓶中搅拌10分钟，加入磺酰氯(405mg,3.00mmol)，搅拌反应1小时，缓慢升温至15℃，继续搅拌1小时。反应结束后，减压浓缩，残余物加入二氯甲烷，依次用饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤，有机层减压浓缩，得到571mg黄色油状物的标题产物，直接用于下一步。
LCMS:m/z 377.95[M+H] +。
步骤3：(S)-7-(氮杂环丁烷-1-基磺酰基)-5-溴-2-(1-环丙基乙基)异吲哚啉-1-酮(5c)的制备。
于室温，将(S)-6-溴-2-(1-环丙基乙基)-3-氧代异吲哚啉-4-磺酰氯(571mg,1.00mmol)、氮杂环丁烷(571mg,10.0mmol)、三乙胺(202mg,2.00mmol)、DCM(8mL)加到反应瓶中，在氮气氛下，于40℃搅拌反应12小时。反应结束后，减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝1：1)纯化，得到265mg白色固体物的标题产物，收率66.05％。
LCMS:m/z 399.03[M+H] +。
制备实施例6：N-(6-溴吡啶-2-基)环丙烷甲基磺胺(6b)的制备
Figure PCTCN2021107320-appb-000041
步骤1：N-(6-溴吡啶-2-基)环丙烷磺胺(6a)的制备。
于室温，将6-溴吡啶-2-胺(1.71g,10mmol)、吡啶(20mL)、环丙基磺酰氯(1.40g,10.0mmol)加到反应瓶中,氮气氛下，于60℃搅拌反应12小时。反应结束后，抽滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝5：1)纯化，得到1.38g白色固体物的标题产物，直接用于下一步，收率：50.0％。
LCMS:m/z 276.96[M+H] +。
步骤2：N-(6-溴吡啶-2-基)环丙烷甲基磺胺(6b)的制备。
于室温，将N-(6-溴吡啶-2-基)环丙烷磺胺(275mg,1.00mmol)、THF(10mL)，NaH(120mg,3.00mmol)加到反应瓶中,滴加碘甲烷(426mg,3.00mmol)，氮气氛下，于40℃搅拌反应12小时。反应结束后，抽滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝5：1)纯化，得到125mg白色固体物的标题产物，收率：50.0％。
LCMS:m/z 291.96[M+H] +。
制备实施例7：(S)-5-溴-2-(1-环丙基乙基)-7-(噻唑-2-基)异吲哚啉-1-酮(7e)的制备
Figure PCTCN2021107320-appb-000042
Figure PCTCN2021107320-appb-000043
步骤1：4-溴-2-碘-6-甲基苯甲酸(7a)的制备。
于室温，将4-溴-2-甲基苯甲酸(8.60g,40.0mmol)、碘苯二乙酸(15.5g,48.0mmol)、DMF(200mL)加到反应瓶中，然后加入碘(12.2g,48.0mmol)、Pd(OAc) 2(448mg,2.00mmol，在氮气氛下，于100℃搅拌反应10小时。反应结束后，向反应瓶中加入100ml甲基叔丁基醚稀释，加入250ml Na 2SO 3溶液，缓慢滴入20ml浓盐酸，收集有机层，向其中加入30ml 10％的NaOH溶液，缓慢滴入浓盐酸至pH为2，收集有机层，浓缩得到11.1g砖红色油状液体的标题产物，直接用于下一步。
LCMS:m/z 340.86[M+H] +。
步骤2：4-溴-2-碘-6-甲基苯甲酸甲酯(7b)的制备。
于室温，将4-溴-2-碘-6-甲基苯甲酸(11.1g,32.7mmol)、碘甲烷(11.6g,81.8mmol)、碳酸钾(9.11g,65.4mmol)、DMF(500ml)加到反应瓶中，10℃搅拌反应12小时。反应结束后，抽滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝20：1)纯化，得到9.72g黄色油状物的标题产物，收率：86.2％。
LCMS:m/z 354.88[M+H] +。
步骤3：4-溴-2-(溴甲基)-6-碘苯甲酸甲酯(7c)的制备。
于室温，将4-溴-2-碘-6-甲基苯甲酸甲酯(3.54g,10.0mmol)、四氯化碳(30mL)、过氧苯甲酰(121mg,0.50mmol)、NBS(1.78g,10.0mmol)加到反应瓶中，升温至80℃搅拌反应15小时。反应结束后，加100mL水、200mL二氯甲烷萃取，有机相用水洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到5.12g淡黄色油状物的标题产物，直接用于下一步。
LCMS:m/z 434.78[M+H] +。
步骤4：(S)-5-溴-2-(1-环丙基乙基)-7-碘异吲哚啉-1-酮(7d)的制备。
于室温，将4-溴-2-(溴甲基)-6-碘苯甲酸甲酯(5.12g,9.50mmol)、(S)-1-环丙基乙胺(1.16g,9.50mmol)、硼酸(588mg,9.50mmol)、碳酸钾(3.94g,28.5mmol)、乙腈(30mL)加到反应瓶中，20℃搅拌反应15小时。反应结束后，抽滤，滤液 减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝10：1)纯化，得到1.91g黄色固体物的标题产物，收率：49.6％。
LCMS:m/z 405.92[M+H] +。
步骤5：(S)-5-溴-2-(1-环丙基乙基)-7-(噻唑-2-基)异吲哚啉-1-酮(7e)的制备。
于室温，将(S)-5-溴-2-(1-环丙基乙基)-7-碘异吲哚啉-1-酮(405mg,1.00mmol)、2-(三丁基锡烷基)噻唑(374mg,1.00mmol)、二氧六环(5mL)加到反应瓶中，然后加入碳酸钾(276mg,2.00mmol)、Pd(PPh 3) 4(58.4mg,0.05mmol)，80℃搅拌反应12小时。反应结束后，减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝5：1)纯化，得到132mg黄色固体物的标题产物，收率：36.5％。
LCMS:m/z 363.01[M+H] +。
实施例1：(S)-2-(1-环丙基乙基)-5-(4-甲基-2-((2-(2-氧代吡咯烷-1-基)吡啶-4-基)氨基)噻唑-5-基)-7-(甲基磺酰基)异吲哚啉-1-酮(1)的制备
Figure PCTCN2021107320-appb-000044
步骤1：(S)-2-(1-环丙基乙基)-5-(4-甲基-2-((2-(2-氧代吡咯烷-1-基)吡啶-4-基)氨基)噻唑-5-基)-7-(甲基磺酰基)异吲哚啉-1-酮(1)的制备。
于室温，将1-(4-((4-甲基噻唑-2-基)氨基)吡啶-2-基)吡咯烷-2-酮(3c)(138mg,0.50mmol)、(S)-5-溴-2-(1-环丙基乙基)-7-(甲基磺酰基)异吲哚啉-1-酮(1d)(179mg,0.50mmol)、DMF(1mL)加到反应瓶中，然后加入碳酸铯(325mg,1.00mmol)、Pd-118(CAS:95408-45-0)(10.4mg,0.02mmol)，80℃搅拌反应2小时。反应结束后，减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得37.1mg黄色固体状标题化合物，收率13.5％。
LCMS:m/z 552.17[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ10.95(s,1H),8.48(s,1H),8.23-8.22(d,1H),8.03-7.98(d,2H),7.65-7.63(d,1H),4.71(s,1H),4.02-3.97(t,2H),3.64-3.60(s,4H), 2.61-2.56(t,2H),2.50-2.46(s,3H),2.08-2.01(t,2H),1.32-1.14(t,5H),0.62-0.57(s,1H),0.44-0.42(m,2H),0.28-0.26(m,1H)。
实施例2：(S)-7-氯-2-(1-环丙基乙基)-5-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噻唑-5-基)异吲哚啉-1-酮(2)的制备
Figure PCTCN2021107320-appb-000045
步骤1：(S)-7-氯-2-(1-环丙基乙基)-5-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噻唑-5-基)异吲哚啉-1-酮(2)的制备。
于室温，将(S)-5-溴-7-氯-2-(1-环丙基乙基)异吲哚啉-1-酮(1b)(30.0mg,0.100mmol)、1-(6-((4-甲基噻唑-2-基)氨基)吡啶-2-基)吡咯烷-2-酮(2b)(32.0mg,0.100mmol)、DMF(1.00mL)加到反应瓶中，然后加入碳酸铯(65.0mg,0.200mmol)、Pd(OAc) 2(2.24mg,0.010mmol)、((t-bu) 3PH)BF 4(5.80mg,0.02mmol)，100℃搅拌反应2小时。反应结束后，减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得5.90mg黄色固体状标题化合物，收率11.6％。
LCMS:m/z 508.15[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.49(s,1H),7.85(s,1H),7.82(s,1H),7.62(s,1H),7.49(t,1H),6.78(d,1H),4.58(s,2H),4.23(t,2H),3.60(t,1H),2.60(t,2H),2.46(s,3H),2.11(s,2H),1.32(d,3H),1.10-1.22(m,1H),0.59-0.63(m,1H),0.40-0.47(m,2H),0.25-0.33(m,1H)。
实施例3：(S)-2-(1-环丙基乙基)-5-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡嗪-2-基)氨基)噻唑-5-基)-7-(甲基磺酰基)异吲哚啉-1-酮(3)的制备
Figure PCTCN2021107320-appb-000046
步骤1：(S)-2-(1-环丙基乙基)-5-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡嗪-2-基)氨基)噻唑-5-基)-7-(甲基磺酰基)异吲哚啉-1-酮(3)的制备。
于室温，将1-(6-溴-吡嗪-2-基)吡咯烷-2-酮(60.2mg,0.25mmol)(根据制备实施例2步骤1制备，将2,6-二溴吡啶替换为2,6-二溴吡嗪)、(S)-5-(2-氨基-4-甲基噻唑-5-基)-2-(1-环丙基乙基)-7-(甲基磺酰基)异吲哚啉-1-酮(4c)(88.9mg,0.23mmol)、碳酸钠(79.5mg,0.75mmol)、Ruphos(35.0mg,0.075mmol)、Ruphos Pd G2(58.3mg,0.075mmol)、DMF(5mL)加到反应瓶中，125℃搅拌反应3小时。反应结束后，减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得52.2mg黄色固体状标题化合物，收率41.1％。
LCMS:m/z 552.17[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ11.95(s,1H),9.05(s,1H),8.14(s,1H),8.06-8.04(d,2H),4.71(s,2H),4.20-4.17(t,2H),3.66-3.62(s,4H),2.60-2.50(t,2H),2.46(s,3H),2.15-2.11(m,2H),1.33-1.31(d,3H),1.16(m,1H),0.58(m,1H),0.42(m,2H),0.27(m,1H)。
实施例4：(S)-2-(1-环丙基乙基)-5-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噁唑-5-基)-7-(甲基磺酰基)异吲哚啉-1-酮(4)的制备
Figure PCTCN2021107320-appb-000047
与实施例1的制备方法相同，除了用1-(6-((4-甲基噁唑-2-基)氨基)吡啶-2-基)吡咯烷-2-酮(根据制备实施例2步骤2制备，将4-甲基噻唑-2-胺替换为4-甲基噁 唑-2-胺)代替1-(4-((4-甲基噻唑-2-基)氨基)吡啶-2-基)吡咯烷-2-酮(3c)，制得标题化合物。
LCMS:m/z 536.65[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ10.96(s,1H),8.21(s,1H),8.07(s,1H),7.95(d,1H),7.85(t,1H),7.68(d,1H),4.75(s,2H),4.05(t,2H),3.64(s,4H),2.60(t,2H),2.49(s,3H),2.02(s,2H),1.20(d,3H),1.18-1.20(m,1H),0.59-0.63(m,1H),0.44(m,2H),0.30(m,1H)。
实施例5：(S)-7-(氮杂环丁烷-1-基磺酰基)-2-(1-环丙基乙基)-5-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噻唑-5-基)异吲哚啉-1-酮(5)的制备
Figure PCTCN2021107320-appb-000048
与实施例1的制备方法相同，除了用(S)-7-(氮杂环丁烷-1-基磺酰基)-5-溴-2-(1-环丙基乙基)异吲哚啉-1-酮(5c)代替(S)-5-溴-2-(1-环丙基乙基)-7-(甲基磺酰基)异吲哚啉-1-酮(1d)，以及用1-(6-((4-甲基噻唑-2-基)氨基)吡啶-2-基)吡咯烷-2-酮(2b)代替1-(4-((4-甲基噻唑-2-基)氨基)吡啶-2-基)吡咯烷-2-酮(3c)，制得标题化合物。
LCMS:m/z 593.19[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.53(s,1H),7.98-7.95(d,2H),7.87-7.85(d,1H),7.74-7.70(t,1H),6.78-6.76(d,1H),4.66(s,2H),4.24-4.22(t,2H),3.92(t,4H),3.60(t,1H),2.57(t,2H),2.51-2.50(d,3H),2.07-1.99(t,4H),1.31-1.29(d,3H),0.85(s,1H),0.58(s,1H),0.42(m,2H),0.27(m,1H)。
实施例6：(S)-2-(1-环丙基乙基)-5-(4-甲基-2-((4-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噻唑-5-基)-7-(甲基磺酰基)异吲哚啉-1-酮(6)的制备
Figure PCTCN2021107320-appb-000049
Figure PCTCN2021107320-appb-000050
与实施例3的制备方法相同，除了用1-(2-溴吡啶-2-基)吡咯烷-2-酮(根据制备实施例3步骤1和2制备，将4-溴吡啶-2-胺替换为2-溴吡啶-4-胺)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，制得标题化合物。
LCMS:m/z 552.17[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ11.43(s,1H),8.28-8.27(d,1H),8.02(s,2H),4.45(s,1H),7.29-7.27(m,1H),4.70(s,2H),3.83-3.66(t,2H),3.63-3.62(s,4H),2.50-2.49(t,2H),2.44(s,3H),2.09-2.05(t,2H),1.32-1.18(m,3H),1.16-1.12(t,1H),0.58(m,1H),0.40(m,2H),0.28-0.26(m,1H)。
实施例7：(S)-N-(6-((5-(2-(1-环丙基乙基)-7-(甲基磺酰基)-1-异吲哚啉-5-基)-4-甲基噻唑-2-基)氨基)吡啶-2-基)环丙烷(7)的制备
Figure PCTCN2021107320-appb-000051
与实施例3的制备方法相同，除了用N-(6-溴吡啶-2-基)环丙烷磺胺(6a)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，制得标题化合物。
LCMS:m/z 588.58[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.44(s,1H),10.44(s,1H),8.04-8.00(m,2H),7.68-7.62(m,1H),6.77-6.75(m,1H),6.67-6.65(m,1H),4.72(s,2H),3.63-3.59(m,4H),3.33(s,1H),2.50(s,3H),1.35-0.86(m,12H),0.61-0.57(m,2H),0.47-0.41(m,2H),0.28-0.26(m,1H)。
实施例8：(S)-5-(2-((1H-吡咯并[2,3-b]吡啶-6-基)氨基)-4-甲基-噻唑-5-基)-2-(1-环丙基乙基)-7-(甲基磺酰基)异吲哚啉-1-酮(8)的制备
Figure PCTCN2021107320-appb-000052
与实施例3的制备方法相同，除了用6-溴-1H-吡咯并[2,3-b]吡啶代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，制得标题化合物。
LCMS:m/z 508.14[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.58(s,1H),11.46(s,1H),8.04(s,2H),7.91-7.88(m,1H),7.21-7.19(m,1H),6.84-6.81(m,1H),6.38-6.36(m,1H),4.72(s,2H),3.63-3.59(m,4H),2.50(s,3H),1.33-1.15(m,4H),0.62-0.59(m,1H),0.46-0.39(m,2H),0.28-0.26(m,1H)。
实施例9：(S)-2-(1-环丙基乙基)-5-(4-甲基-2-((6-(噁唑-2-基)吡啶-2-基)氨基)噻唑-5-基)-7-(甲基磺酰基)异吲哚啉-1-酮(9)的制备
Figure PCTCN2021107320-appb-000053
与实施例3的制备方法相同，除了用2-(6-溴吡啶-2-基)噁唑(根据制备实施例 2步骤1制备，将吡咯烷-2-酮替换为噁唑)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，制得标题化合物。
LCMS:m/z 536.13[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.81(s,1H),8.28(s,1H),8.14-8.06(m,2H),7.94-7.89(t,1H),7.70-7.67(m,1H),7.49(s,1H),7.20-7.17(d,1H),4.74(s,2H),3.67-3.61(t,4H),2.51-2.48(m,3H),1.34-1.31(m,3H),1.23(s,1H),0.61(s,1H),0.46-0.43(t,2H),0.29-0.27(m,1H)。
实施例10：(S)-2-(1-环丙基乙基)-5-(4-甲基-2-((4-(2-氧代吡咯烷-1-基)嘧啶-2-基)氨基)噻唑-5-基)-7-(甲基磺酰基)异吲哚啉-1-酮(10)的制备
Figure PCTCN2021107320-appb-000054
与实施例3的制备方法相同，除了用1-(2-氯嘧啶-4-基)吡咯烷-2-酮(根据制备实施例2步骤1制备，将2,6-二溴吡啶替换为2-氯-4-溴嘧啶)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，制得标题化合物。
LCMS:m/z 553.17[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.85(s,1H),8.52-8.50(m,1H),8.05(s,2H),7.87-7.85(m,1H),4.72(s,2H),4.13-4.10(t,2H),3.64-3.60(s,4H),2.60(t,2H),2.45(s,3H),2.13-2.08(t,2H),1.30-1.17(m,3H),0.83(t,1H),0.46(m,1H),0.46-0.42(m,2H),0.28-0.26(m,1H)。
实施例11：(S)-N-(6-((5-(2-(1-环丙基乙基)-7-(甲基磺酰基)-1-异吲哚啉-5-基)-4-甲基噻唑-2-基)氨基)吡啶-2-基)-甲磺酰胺(11)的制备
Figure PCTCN2021107320-appb-000055
与实施例3的制备方法相同，除了用N-(6-溴吡啶-2-基)甲磺酰胺(根据制备实施例6步骤1制备，将环丙基磺酰氯替换为甲磺酰氯)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，制得标题化合物。
LCMS:m/z 562.12[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.44(s,1H),10.55(s,1H)8.055(s,1H),8.00(s,1H),7.62(m,1H),6.75-6.72(m,1H)6.57-6.55(m,1H),4.73(s,2H),3.64 3.60(m,4H),3.40(s,3H),2.46(s,3H),1.18-1.15(m,3H),1.14-1.12(t,1H),0.44-0.42(m,1H),0.42(m,2H),0.28-0.26(m,1H)。
实施例12：(S)-5-(2-((6-(1H-咪唑-1-基)吡啶-2-基)氨基)-4-甲基-噻唑-5-基)-2-(1-环丙基乙基)-7-(甲基磺酰基)异吲哚啉-1-酮(12)的制备
Figure PCTCN2021107320-appb-000056
与实施例3的制备方法相同，除了用2-溴-6-(1H-咪唑-1-基)吡啶(根据制备实施例2步骤1制备，将吡咯烷-2-酮替换为咪唑)代替1-(6-溴-吡嗪-2-基)吡咯烷-2- 酮，制得标题化合物。
LCMS:m/z 535.15[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.85(s,1H),8.61(s,1H),8.07-7.92(m,3H),7.89(m,1H),7.38(m,1H),7.15(m,1H),7.04-7.01(m,1H),4.74(s,2H),3.65(m,4H),2.45(s,3H),1.33-1.31(m,3H),1.18(t,1H),0.45-0.42(m,1H),0.42(m,2H),0.29-0.27(m,1H)。
实施例13：(S)-N-(2-(1-环丙基乙基)-6-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噻唑-5-基)-3-异吲哚啉-4-基)甲磺酰胺(13)的制备
Figure PCTCN2021107320-appb-000057
步骤1：(S)-N-(5-(2-(1-环丙基乙基)-7-(甲基磺酰氨基)-1-异吲哚啉-5-基)-4-甲基噻唑-2-基)乙酰胺(13a)的制备。
于室温，将(S)-N-(5-(7-氯-2-(1-环丙基乙基)-1-异吲哚啉-5-基)-4-甲基噻唑-2-基)乙酰胺(根据制备实施例4步骤2制备，只将原料1d替换为1b)(389mg,1.00mmol)、甲基磺酰胺(285mg,3mmol)、DMF(10.0mL)加到反应瓶中，然后加入叔丁醇钠(288mg,3mmol)、t-buxphos(84.0mg,0.200mmol)、醋酸钯(22.4mg,0.100mmol)，140℃搅拌反应7小时。反应结束后，抽滤，滤液减压浓缩，残余物通过柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝5：1)纯化，得到0.220黄色固体物的标题产物，收率：50.0％。
LCMS:m/z 449.12[M+H] +。
步骤2：(S)-N-(6-(2-氨基-4-甲基噻唑-5-基)-2-(1-环丙基乙基)-3-异吲哚啉-4-基)甲磺酰胺(13b)的制备。
于室温，将(S)-N-(5-(2-(1-环丙基乙基)-7-(甲基磺酰氨基)-1-异吲哚啉-5-基)-4- 甲基噻唑-2-基)乙酰胺(110mg,0.25mmol)、3M盐酸(20ml)、乙醇(20ml)混合，于70℃搅拌反应6小时。反应结束后，减压浓缩，得到100mg黄色固体物的标题产物，直接用于下一步，收率：95.1％。
LCMS:m/z 407.10[M+H] +。
步骤3：(S)-N-(2-(1-环丙基乙基)-6-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噻唑-5-基)-3-异吲哚啉-4-基)甲磺酰胺(13)的制备。
于室温，将1-(6-溴吡啶-2-基)吡咯烷-2-酮(60.1mg,0.25mmol)、(S)-N-(6-(2-氨基-4-甲基噻唑-5-基)-2-(1-环丙基乙基)-3-异吲哚啉-4-基)甲磺酰胺(98.56mg,0.25mmol)、DMF(2.00mL)加到反应瓶中，然后加入碳酸钠(79mg,0.750mmol)、Ruphos(35.0mg,0.075mmol)、2ndRuphos-Pd(29.0mg,0.0375mmol)，于125℃搅拌反应3小时。反应结束后，减压浓缩，残余物用制备液相色谱法分离(色谱柱型号：Daisogei 30mm*250mm，C18，10um，100A，流动相：乙腈/水，梯度：30％-80％)，得11.0mg黄色固体状标题化合物，收率8.00％。
LCMS:m/z 567.18[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.44(s,1H),7.84-7.81(m,1H),7.71-7.68(m,1H),7.45(s,1H),7.34(s,1H),6.74-6.71(m,1H),4.72(s,2H),4.22-4.18(m,2H),3.31(s,1H),3.22(s,3H),2.59-2.56(m,2H),2.40(s,3H),2.07-2.05(m,2H),1.29-1.21(m,3H),1.20-1.10(m,1H),0.61-0.57(m,1H),0.47-0.41(m,2H),0.28-0.26(m,1H)。
实施例14：(S)-2-(1-环丙基乙基)-5-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噻唑-5-基)-7-(噻唑-2-基)异吲哚啉-1-酮(14)的制备
Figure PCTCN2021107320-appb-000058
与实施例2的制备方法相同，除了用(S)-5-溴-2-(1-环丙基乙基)-7-(噻唑-2-基)异吲哚啉-1-酮(7e)代替(S)-5-溴-7-氯-2-(1-环丙基乙基)异吲哚啉-1-酮(1b)，制得标题化合物。
LCMS:m/z 557.17[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.47(s,1H),8.30(s,1H),7.98(s,1H),7.93(s,1H),7.83(t,2H),7.71(t,1H),6.78-6.75(d,1H),4.66(s,2H),4.28-4.23(t,2H),3.65-3.60(t,1H),2.62-2.57(t,2H),2.46(s,3H),2.13-2.09(t,2H),1.32-1.30(d,3H),1.17(s,1H),0.42(s,1H),0.41(s,2H),0.28-0.26(m,1H)。
实施例15：(S)-N-(6-((5-(2-(1-环丙基乙基)-7-(甲基磺酰基)-1-异吲哚啉-5-基)-4-甲基噻唑-2-基)氨基)吡啶-2-基)N-甲基环丙烷磺酰胺(15)的制备
Figure PCTCN2021107320-appb-000059
与实施例3的制备方法相同，除了用N-(6-溴吡啶-2-基)环丙烷甲基磺胺(6b)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，制得标题化合物。
LCMS:m/z 602.15[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.70(s,1H),8.04-8.00(m,2H),7.68-7.62(m,1H),7.02-6.94(m,2H),4.72(s,2H),3.63-3.59(m,4H),3.46(s,3H),2.77(s,1H),2.50(s,3H),1.65-1.00(m,9H),0.61-0.57(m,1H),0.47-0.41(m,2H),0.28-0.26(m,1H)。
实施例16：(S)-2-(1-环丙基乙基)-5-(4-甲基-2-((6-(5-氧代-4-氮杂螺[2.4]庚-4-基)吡啶-2-基)氨基)噻唑-5-基)-7-(甲基磺酰基)异吲哚啉-1-酮(16)的制备
Figure PCTCN2021107320-appb-000060
Figure PCTCN2021107320-appb-000061
与实施例3的制备方法相同，除了用4-(6-溴吡啶-2-基)-4-氮杂螺[2.4]庚烷-5-酮(根据制备实施例2步骤1制备，将2,6-二溴吡啶替换为5-氧代-4-氮杂螺[2.4]庚烷)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，制得标题化合物。
LCMS:m/z 578.18[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.59(s,1H),8.05-8.03(m,2H),7.83-7.77(t,1H),7.06-7.03(m,1H),6.84-6.81(m,1H),4.72(s,2H),3.64-3.60(s,4H),2.51(t,2H),2.45(s,3H),2.18(t,2H),1.33(s,3H),1.07(s,1H),1.03(m,2H),0.72-0.68(m,2H),0.60(s,1H),0.44-0.42(m,2H),0.28-0.27(m,1H)。
实施例17：(S)-2-(1-环丙基乙基)-5-(4-甲基-2-((6-(噻唑-2-基)吡啶-2-基)氨基)噻唑-5-基)-7-(甲基磺酰基)异吲哚啉-1-酮(17)的制备
Figure PCTCN2021107320-appb-000062
与实施例3的制备方法相同，除了用2-(6-溴吡啶-2-基)噻唑(根据制备实施例2步骤1制备，将2,6-二溴吡啶替换为噻唑)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，制得标题化合物。
LCMS:m/z 552.11[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.81(s,1H),8.28(s,1H),8.14-8.06(m,2H),7.94-7.89(t,1H),7.70-7.67(m,1H),7.49(s,1H),7.20-7.17(d,1H),4.74(s,2H),3.67-3.61(t,4H),2.51-2.48(m,3H),1.34-1.31(m,3H),1.23(s,1H),0.61(s,1H),0.46-0.43(t,2H),0.29-0.27(m,1H)。
实施例18：2-((S)-1-环丙基乙基)-5-(4-甲基-2-((6-(2-氧代-3-氮杂双环[3.1.0]己-3-基)吡啶-2-基)氨基)噻唑-5-基)-7-(甲基磺酰基)异吲哚啉-1-酮(18)的制备
Figure PCTCN2021107320-appb-000063
与实施例3的制备方法相同，除了用4-(6-溴吡啶-2-基)-氮杂双环[3.1.0]己-5-酮(根据制备实施例2步骤1制备，将2,6-二溴吡啶替换为氮杂双环[3.1.0]己-5-酮)代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，制得标题化合物。
LCMS:m/z 564.17[M+H] +。
1HNMR(300MHz,DMSO-d 6)δ11.52(s,1H),8.09-8.05(m,2H),7.70-7.68(m,2H),6.74-6.71(m,1H),4.73(s,2H),4.31(s,1H),4.18(d,1H),3.65(s,4H),2.50-2.46(m,3H),1.33-1.31(m,3H),1.23(s,4H),0.80(s,1H),0.60(s,1H),0.44(s,2H),0.29(s,1H)。
实施例19：(S)-2-(1-环丙基乙基)-7-(二甲基磷酰基)-5-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噻唑唑-5-基)异吲哚啉-1-酮(19)的制备
Figure PCTCN2021107320-appb-000064
Figure PCTCN2021107320-appb-000065
步骤1：(S)-5-溴-2-(1-环丙基乙基)-7-(二甲基磷酰基)异吲哚啉-1-酮(19a)的制备。
于室温，将(S)-5-溴-2-(1-环丙基乙基)-7-碘代异吲哚啉-1-酮(7d)(204mg,0.504mmol)、二甲基磷氧化物(1.18g,15.1mmol)、乙腈(5mL)加到反应瓶中，然后加入磷酸三钾(129mg,0.605mmol)、Pd(dppf)Cl 2(37.4mg,0.051mmol)、Xantphos(35.3mg,0.061mmol)，60℃搅拌反应12小时。反应结束后，减压浓缩，残余物通过柱层析色谱法(洗脱剂：二氯甲烷：甲醇＝20：1)纯化，得到122mg棕色固体物的标题产物，收率：68.2％。
LCMS:m/z 356.03[M+H] +。
步骤2：(S)-2-(1-环丙基乙基)-7-(二甲基磷酰基)-5-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噻唑唑-5-基)异吲哚啉-1-酮(19)的制备。
与实施例2的制备方法相同，除了用(S)-5-溴-2-(1-环丙基乙基)-7-(二甲基磷酰基)异吲哚啉-1-酮代替(S)-5-溴-7-氯-2-(1-环丙基乙基)异吲哚啉-1-酮(1b)，制得标题化合物。
LCMS:m/z 550.20[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ11.50(s,1H),8.19-8.16(m,1H),7.85(t,2H),7.74-7.70(m,1H),6.78-6.76(m,1H),4.66(s,2H),4.23-4.21(s,2H),3.60(s,1H),2.51-2.50(m,2H),2.43(s,3H),2.09(t,2H),1.86(d,4H),1.52(t,3H),1.17-1.13(m,2H),1.10(s,1H),0.59(s,1H),0.43-0.27(m,2H),0.26-0.25(m,1H)。
实施例20：(S)-5-(2-((6-(1H-咪唑-1-基)吡啶-2-基)氨基)-4-甲基-噻唑-5-基)-7-(氮杂环丁烷-1-基磺酰基)-2-(1-环丙基乙基)异吲哚啉-1-酮(20)的制备
Figure PCTCN2021107320-appb-000066
步骤1：(S)-N-(5-(7-(氮杂环丁烷-1-基磺酰基)-2-(1-环丙基乙基)-1-氧基异吲哚啉-5-基)-4-甲基噻唑-2-基)乙酰胺(20a)的制备。
与制备实施例4的步骤2相同，除了用(S)-7-(氮杂环丁烷-1-基磺酰基)-5-溴-2-(1-环丙基乙基)异吲哚啉-1-酮(5c)代替(S)-5-溴-2-(1-环丙基乙基)-7-(甲基磺酰基)异吲哚啉-1-酮(1d)，制得标题化合物。
LCMS:m/z 475.14[M+H] +。
步骤2：(S)-5-(2-氨基-4-甲基噻唑-5-基)-7-(氮杂环丁烷-1-基磺酰基)-2-(1-环丙基乙基)异吲哚啉-1-酮(20b)的制备。
将(S)-N-(5-(7-(氮杂环丁烷-1-基磺酰基)-2-(1-环丙基乙基)-1-氧基异吲哚啉-5-基)-4-甲基噻唑-2-基)乙酰胺(322mg,0.679mmol)、氢氧化锂(164mg，6.79mmol)、甲醇(10ml)、水(2ml)加到反应瓶中，60℃搅拌反应8小时。反应结束后，减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：二氯甲烷：甲醇＝20：1)纯化，得到124mg黄色固体物的标题产物，收率：42.3％。
LCMS:m/z 433.13[M+H] +。
步骤3：(S)-5-(2-((6-(1H-咪唑-1-基)吡啶-2-基)氨基)-4-甲基-噻唑-5-基)-7-(氮杂环丁烷-1-基磺酰基)-2-(1-环丙基乙基)异吲哚啉-1-酮(20)的制备。
与实施例3的制备方法相同，除了用2-溴-6-(1H-咪唑-1-基)吡啶代替1-(6-溴-吡嗪-2-基)吡咯烷-2-酮，以及用(S)-5-(2-氨基-4-甲基噻唑-5-基)-7-(氮杂环丁烷-1-基磺酰基)-2-(1-环丙基乙基)异吲哚啉-1-酮(20b)代替(S)-5-(2-氨基-4-甲基噻唑-5- 基)-2-(1-环丙基乙基)-7-(甲基磺酰基)异吲哚啉-1-酮(4c)，制得标题化合物。
LCMS:m/z 576.18[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.85(s,1H),8.62(s,1H),8.05-8.04(m,2H),7.97-7.90(m,2H),7.38-7.36(m,1H),7.15(s,1H),7.04-7.01(m,1H),4.69(s,2H),3.98-3.93(m,4H),3.65(m,1H),2.46(s,3H),2.11-2.06(m,2H),1.32-1.29(m,3H),1.23(m,1H),0.46(m,1H),0.43(m,2H),0.41(m,1H)。
实施例21：(S)-2-(1-环丙基乙基)-7-((3-羟基氮杂环丁烷-1-基)磺酰基)-5-(4-甲基-2-((6-(2-氧吡咯烷-1-基)吡啶-2-基)氨基)噻唑基-5基)异吲哚啉-1-酮(21)的制备
Figure PCTCN2021107320-appb-000067
步骤1：(S)-5-溴-2-(1-环丙基乙基)-7-((3-羟基氮杂环丁烷-1-基)磺酰基)异吲哚啉-1-酮(21a)的制备。
于室温，将(S)-6-溴-2-(1-环丙基乙基)-3-氧代异吲哚啉-4-磺酰氯(5b)(500mg,1.33mmol)、氮杂环丁烷-3-醇(1.47g,13.3mmol)、碳酸铯(865mg,2.66mmol)、DCM(5mL)加到反应瓶中，在氮气氛下，于40℃搅拌反应12小时。反应结束后，减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：石油醚：乙酸乙酯＝2：1)纯化，得到263mg白色固体物的标题产物，收率47.8％。
LCMS:m/z 415.02[M+H] +。
步骤2：(S)-2-(1-环丙基乙基)-7-((3-羟基氮杂环丁烷-1-基)磺酰基)-5-(4-甲基-2-((6-(2-氧吡咯烷-1-基)吡啶-2-基)氨基)噻唑基-5基)异吲哚啉-1-酮(21)的制备。
与实施例1的制备方法相同，除了用1-(6-((4-甲基噻唑-2-基)氨基)吡啶-2-基)吡咯烷-2-酮(2b)代替1-(4-((4-甲基噻唑-2-基)氨基)吡啶-2-基)吡咯烷-2-酮(3c)，以及用(S)-5-溴-2-(1-环丙基乙基)-7-((3-羟基氮杂环丁烷-1-基)磺酰基)异吲哚啉-1-酮(21a)代替(S)-5-溴-2-(1-环丙基乙基)-7-(甲基磺酰基)异吲哚啉-1-酮(1d)，制 得标题化合物。
LCMS:m/z 609.19[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.54(s,1H),7.99-7.95(m,2H),7.87-7.84(m,1H),7.75-7.70(m,1H),6.78-6.76(m,1H),5.72-5.70(m,1H),4.67(s,2H),4.36-4.31(m,1H),4.26-4.21(m,2H),4.11-4.05(m,2H),3.70-3.59(m,3H),2.62-2.57(m,2H),2.45(s,3H),2.11-2.06(m,2H),1.31-1.29(m,3H),1.16-1.13(m,1H),0.59(m,1H),0.44-0.38(m,2H),0.27-0.25(m,1H)。
实施例22：(S)-2-(1-环丙基乙基)-5-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噻唑-5-基)-7-(吡咯烷-1-基磺酰基)异吲哚啉-1-酮(22)的制备
Figure PCTCN2021107320-appb-000068
与实施例2的制备方法相同，除了用(S)-5-溴-2-(1-环丙基乙基)-7-(吡咯烷-1-基磺酰基)异吲哚啉-1-酮(根据制备实施例5制备，将步骤3的氮杂环丁烷替换为吡咯烷)代替(S)-5-溴-7-氯-2-(1-环丙基乙基)异吲哚啉-1-酮(1b)，制得标题化合物。
LCMS:m/z 607.21[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.55(s,1H),7.95-7.93(m,2H),7.87-7.84(m,1H),7.75-7.70(m,1H),6.78-6.76(m,1H),4.64(s,2H),4.26-4.21(m,2H),3.64-3.59(m,1H),3.42-3.39(m,4H),2.62-2.57(m,2H),2.45(s,3H),2.10-2.06(m,2H),1.76(s,4H),1.30-1.28(m,3H),1.15(s,1H),0.61-0.58(m,1H),0.41-0.39(m,2H),0.26-0.24(m,1H)。
实施例23：2-((S)-1-环丙基乙基)-7-((3-羟基吡咯烷-1-基)磺酰基)-5-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噻唑-5-基)异吲哚啉-1-酮(23)的制备
Figure PCTCN2021107320-appb-000069
与实施例1的制备方法相同，除了用1-(6-((4-甲基噻唑-2-基)氨基)吡啶-2-基)吡咯烷-2-酮(2b)代替1-(4-((4-甲基噻唑-2-基)氨基)吡啶-2-基)吡咯烷-2-酮(3c)，以及用5-溴-2-((S)-1-环丙基乙基)-7-((3-羟基吡咯烷-1-基)磺酰基)异吲哚啉-1-酮(根据制备实施例5制备，将步骤3的氮杂环丁烷替换为3-羟基吡咯烷)代替(S)-5-溴-2-(1-环丙基乙基)-7-(甲基磺酰基)异吲哚啉-1-酮(1d)，制得标题化合物。
LCMS:m/z 623.20[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.85(s,1H),7.97-7.92(m,2H),7.86-7.84(m,1H),7.71(m,1H),6.77-6.75(m,1H),5.02(s,1H),4.63(s,2H),4.24(s,3H),3.60-3.58(m,5H),2.61-2.58(m,2H),2.43(s,3H),2.09(m,2H),2.06(m,2H),1.30(m,3H),1.28(m,1H),0.46(m,1H),0.40(m,2H),0.21(m,1H)。
实施例24：(S)-7-(氮(S)-2-(1-环丙基乙基)-5-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噻唑-5-基)-7-(吗啉磺酰基)异吲哚啉-1-酮(24)的制备
Figure PCTCN2021107320-appb-000070
Figure PCTCN2021107320-appb-000071
与实施例1的制备方法相同，除了用1-(6-((4-甲基噻唑-2-基)氨基)吡啶-2-基)吡咯烷-2-酮(2b)代替1-(4-((4-甲基噻唑-2-基)氨基)吡啶-2-基)吡咯烷-2-酮(3c)，以及用(S)-5-溴-2-(1-环丙基乙基)-7-(吗啉磺酰基)异吲哚啉-1-酮(根据制备实施例5制备，将步骤3的氮杂环丁烷替换为吗啉)代替(S)-5-溴-2-(1-环丙基乙基)-7-(甲基磺酰基)异吲哚啉-1-酮(1d)，制得标题化合物。
LCMS:m/z 623.20[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.55(s,1H),7.98(s,2H),7.87-7.84(m,1H),7.75-7.70(m,1H),6.78-6.76(m,1H),4.66(s,2H),4.27-4.22(m,2H),3.64-3.62(m,1H),3.59-3.54(m,4H),3.25(s,4H),2.62-2.57(m,2H),2.45(s,3H),2.11-2.06(m,2H),1.31-1.29(m,3H),1.23(m,1H),0.58(m,1H),0.42-0.39(m,2H),0.27-0.25(m,1H)。
实施例25：(S)-2-(1-环丙基乙基)-7-((3,3-二氟氮杂环丁烷-1-基)磺酰基)-5-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噻唑-5-基)异吲哚啉-1-酮(25)的制备
Figure PCTCN2021107320-appb-000072
与实施例2的制备方法相同，除了用(S)-5-溴-2-(1-环丙基乙基)-7-((3,3-二氟氮杂环丁烷-1-基)磺酰基)异吲哚啉-1-酮(根据制备实施例5制备，将步骤3的氮杂 环丁烷替换为3,3-二氟氮杂环丁烷)代替(S)-5-溴-7-氯-2-(1-环丙基乙基)异吲哚啉-1-酮(1d)，制得标题化合物。
LCMS:m/z 629.17[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.55(s,1H),8.00-7.98(m,2H),7.86-7.83(m,1H),7.74-7.71(m,1H),6.77-6.74(m,1H),4.68(s,2H),4.57-4.48(m,4H),4.25-4.20(m,2H),3.61(m,1H),2.61-2.55(m,2H),2.44(s,3H),2.11-2.04(m,2H),1.30-1.28(m,3H),1.22(m,1H),0.61-0.58(m,1H),0.41-0.40(m,2H),0.26-0.24(m,1H)。
实施例26：(S)-2-(1-环丙基乙基)-7-(((3-氟-3-甲基氮杂环丁烷-1-基)磺酰基)-5-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噻唑-5-基)异吲哚啉-1-酮(26)的制备
Figure PCTCN2021107320-appb-000073
与实施例2的制备方法相同，除了用(S)-5-溴-2-(1-环丙基乙基)-7-((3-氟-3-甲基氮杂环丁烷-1-基)磺酰基)异吲哚啉-1-酮(根据制备实施例5制备，将步骤3的氮杂环丁烷替换为3-氟-3-甲基氮杂环丁烷)代替(S)-5-溴-7-氯-2-(1-环丙基乙基)异吲哚啉-1-酮(1d)，制得标题化合物。
LCMS:m/z 625.20[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.55(s,1H),7.98-7.95(m,2H),7.85-7.82(m,1H),7.73-7.70(m,1H),6.76-6.73(m,1H),4.66(s,2H),4.24-4.19(m,2H),4.14-4.05(m,4H),3.65-3.62(m,1H),2.60-2.55(m,2H),2.43(s,3H),2.09-2.04(m,2H),1.53-1.45(m,3H),1.29-1.27(m,3H),1.13(m,1H),0.51-0.48(m,1H),0.39-0.37(m,2H),0.14-0.12(m,1H)。
实施例27：(S)-7-((2-氧杂-6-氮杂螺[3.3]庚-6-基)磺酰基)-2-(1-环丙基乙基)-5-(4- 甲基-2-((6-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噻唑-5-基)异吲哚啉-1-酮(27)的制备
Figure PCTCN2021107320-appb-000074
与实施例2的制备方法相同，除了用(S)-7-((2-氧杂-6-氮杂螺[3.3]庚-6-基)磺酰基)-5-溴-2-(1-环丙基乙基)异吲哚啉-1-酮(根据制备实施例5制备，将步骤3的氮杂环丁烷替换为2-氧杂-6-氮杂螺[3.3]庚烷)代替(S)-5-溴-7-氯-2-(1-环丙基乙基)异吲哚啉-1-酮(1d)，制得标题化合物。
LCMS:m/z 635.20[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.54(s,1H),7.95-7.92(m,2H),7.85-7.83(m,1H),7.73-7.68(m,1H),6.76-6.74(m,1H),4.64(s,2H),4.55(s,4H),4.25-4.20(m,2H),4.14(s,4H),3.60(m,1H),2.61-2.56(m,2H),2.43(s,3H),2.11-2.06(m,2H),1.29-1.21(m,3H),1.15(m,1H),0.57(m,1H),0.40-0.38(m,2H),0.26-0.24(m,1H)。
实施例28：(S)-2-(1-环丙基乙基)-7-((3-甲氧基氮杂环丁烷-1-基)磺酰基)-5-(4-甲基-2-((6-(2-氧代吡咯烷-1-基)吡啶-2-基)氨基)噻唑-5-基)异吲哚啉-1-酮(28)的制备
Figure PCTCN2021107320-appb-000075
Figure PCTCN2021107320-appb-000076
与实施例2的制备方法相同，除了用(S)-5-溴-2-(1-环丙基乙基)-7-((3-甲氧基氮杂环丁烷-1-基)磺酰基)异吲哚啉-1-酮(根据制备实施例5制备，将步骤3的氮杂环丁烷替换为3-甲氧基氮杂环丁烷)代替(S)-5-溴-7-氯-2-(1-环丙基乙基)异吲哚啉-1-酮(1d)，制得标题化合物。
LCMS:m/z 623.20[M+H] +。
1H NMR(300MHz,DMSO-d 6)δ11.56(s,1H),7.99-7.96(m,2H),7.87-7.84(m,1H),7.75-7.70(m,1H),6.78-6.75(m,1H),4.67(s,2H),4.24(s,2H),4.11(s,3H),3.78(s,2H),3.61(s,1H),3.12(s,3H),2.59-2.57(m,2H),2.45(s,3H),2.08(s,2H),1.31-1.29(m,3H),1.15(s,1H),0.59(s,1H),0.41(s,2H),0.25(s,1H)。
生物学测试
试验例1：本发明化合物对PI3K的抑制活性
磷酸肌醇3-激酶(PI3K)是由细胞内能够磷酸化磷脂酰环己六醇的肌醇环3号位置羟基基团的相关信号传导酶组成的一个家族，其参与细胞存活、生长、代谢和血糖稳态等多种功能的调控。可利用商业化激酶检测试剂盒对其活性进行测定。本实施采用购自于普洛麦格公司的ADP-Glo TM检测试剂盒进行化合物对重组人PI3K活性的检测。
(1)溶液制备
①配制1X实验缓冲液，其中包含50mM HEPES(西格玛奥德里奇公司，H3375)PH7.5，3mM MgCl 2(西格玛奥德里奇公司，M1028)，1mM EGTA(西格玛奥德里奇公司，E3889)，0.03％CHAPS(西格玛奥德里奇公司，C9426)，100mM NaCl(西格玛奥德里奇公司，S5886)，2mM DTT(Merk，CB233155)。
②配制2.5X脂质缓冲液，其中包含62.5mM HEPES PH7.5，1.25mM EGTA。
③配制2.5X PI3K激酶工作溶液：
PI3Kα(英杰生命技术有限公司，PV4788)：利用1X实验缓冲液将储备液稀释至625ng/mL，即工作浓度为250ng/mL。
PI3Kβ(英杰生命技术有限公司，PV5374)：利用1X实验缓冲液将储备液稀释至625ng/mL，即工作浓度为250ng/mL。
PI3Kγ(英杰生命技术有限公司，PV4786)：利用1X实验缓冲液将储备液稀 释至3.75μg/mL，即工作浓度为1.5μg/mL。
PI3Kδ(英杰生命技术有限公司，PV6451)：利用1X实验缓冲液将储备液稀释至625ng/mL，即工作浓度为250ng/mL。
④2.5X基质工作液：
PIP:3PS：利用2.5X脂质缓冲液将PIP:3PS储备液(普洛麦格公司，V1701)稀释至0.02mg/mL。
ATP：利用2.5X脂质缓冲液将ATP储备液(普洛麦格公司，V915B)稀释至20μM。
随后将PIP：3PS及ATP溶液等比例混合，即它们的工作浓度分别为0.01mg/mL和10μM。
⑤测试化合物工作液制备：测试化合物利用DMSO溶解为初始浓度为100μM的储备液，并利用DMSO为稀释液以3倍梯度进行稀释，共10个浓度。各浓度溶液再次利用1X实验缓冲液进行20倍稀释。
(2)活性筛选
利用移液器将2.5X PI3K激酶工作溶液加入到384孔板(珀金埃尔默公司，6008280)中，2μL/孔。随后向各孔中加入1μL不同浓度的化合物溶液。同时设立1％DMSO作为阴性对照，100μM已知PI3K抑制剂(GSK2126458(Selleck公司，S2658)作为阳性对照。将384孔板置于微孔板摇床(其林贝尔公司，QB-9002)上振摇30s使孔内溶液充分混合，并将反应物于25℃孵育15分钟。孵育结束后，向各孔中加入2μL 2.5X基质工作液，密封384孔板后于25℃孵育60分钟。反应结束后，向各孔中加入5μL ADP-Glo试剂(普洛麦格公司，V9102)，密封384孔板后于25℃继续孵育40分钟。随后向各孔加入10μL激酶检测试剂，将384孔板密封，于25℃孵育40分钟。利用多功能酶标仪(珀金埃尔默公司，Envision 2104)进行数据获取。
其中抑制率按以下公式进行计算：
Figure PCTCN2021107320-appb-000077
所获得数据利用软件(GraphPad软件公司，GraphPad prism 6.0)进行统计分析，以化合物的浓度Log值为横坐标，抑制率％为纵坐标，采用非线性拟合(剂量响应-变化斜率)计算IC 50值。结果如下表1所示。
表1 本发明化合物对各种PI3K的抑制IC 50值
Figure PCTCN2021107320-appb-000078
Figure PCTCN2021107320-appb-000079
本试验例提供了本发明化合物1-28对各种PI3K同种型的体外酶学活性数据。使用前面描述的方法可以获得表1中收集的数据，该表提供了对化合物在抑制PI3Kα、β、γ和δ活性中的活性的了解。相对于PI3Kα和PI3Kβ，这些化合物一般对PI3Kδ和γ具有选择性。
试验例2：本发明化合物对PI3Kα、PI3Kγ和PI3Kδ的细胞学选择性抑制活性
(1)PI3Kα选择性抑制测试
C2C12小鼠肌母细胞中由IGF1蛋白引导的AKT磷酸化仅由p110α介导。基于此，可以用于评估化合物对于PI3Kα的特异性抑制行为(Won Jun Lee，Molecules and Cells，2009，28(5)，495-499)。
具体实施方案如下：将C2C12细胞(美国典型培养物保藏中心，
Figure PCTCN2021107320-appb-000080
CRL-1772 TM)培养于含有10％胎牛血清(Invitrogen，10099141)以及青霉素和链 霉素(Gibco公司，15140-122)的DMEM培养基(Gibco，11995-073)中。开始测试时，利用多道移液器(赛默飞世尔科技有限公司，836-4049)将C2C12细胞以30,000细胞/孔的密度接种至384孔板(珀金埃尔默公司，6007680)。500转/分钟离心30秒后置于37℃，5％CO 2湿式培养箱(赛默飞世尔科技有限公司，BBD6220)中孵育2小时。随后利用声波移液器(Labcyte公司，Echo 550)将不同浓度的化合物(起始终浓度为30μM，3倍梯度稀释，共计10个浓度)加入到培养板之中，30nL/孔，并在上述培养条件下继续孵育30分钟。随后向各孔中加入2μL 4倍浓度的IGF-1(200ng/mL，R&D Systems公司，291-G1-200)，500转/分钟离心30秒后置于37℃，5％CO 2湿式培养箱中孵育20分钟。随后向各孔加入试剂盒(AlphaLISA SureFire Ultra p-AKT1/2/3(Thr 308)试剂盒，珀金埃尔默公司，ALSU-PAKT-A500)所提供2X裂解液2μL，并将细胞培养板置于水平摇床上振摇10分钟。向各孔中加入5μL试剂盒所提供的受体混合液，1000转/分钟离心1分钟，接着加入5μL试剂盒所提供的供体混合液，1000转/分钟离心1分钟。将细胞培养板移至25℃环境避光孵育2小时。利用多功能酶标仪(珀金埃尔默公司，Envision 2104)读取AlphaLISA信号数据。
(2)PI3Kγ选择性抑制测试
RAW264.7小鼠巨噬细胞中由C5a引导的AKT磷酸化仅由p110γ介导。基于此，可以用于评估化合物对于PI3Kγ的特异性抑制行为(Montserrat Camps等人，Nature Medicine，2005，11(9)，936-943)。
具体实施方案如下：将Raw264.7细胞(美国典型培养物保藏中心，
Figure PCTCN2021107320-appb-000081
TIB-71 TM)培养于含有10％胎牛血清(Invitrogen，10099141)以及青霉素和链霉素(Gibco公司，15140-122)的RPMI 1640培养基(Invitrogen，A10491-01)中。开始测试时，利用多道移液器(赛默飞世尔科技有限公司，836-4049)将Raw264.7细胞以30000细胞/孔的密度接种至384孔板(珀金埃尔默公司，6007680)。500转/分钟离心30秒后置于37℃，5％CO 2湿式培养箱(赛默飞世尔科技有限公司，BBD6220)中孵育2小时。随后利用声波移液器(Labcyte公司，Echo 550)将不同浓度的化合物(起始终浓度为1000nM，3倍梯度稀释，共计10个浓度)加入到培养板之中，30nL/孔，并在上述培养条件下继续孵育30分钟。随后向各孔中加入2μL 4倍浓度的C5a(320ng/mL，西格玛奥德里奇公司，204902)，500转/分钟离心30秒后置于37℃，5％CO 2湿式培养箱中孵育5分钟。随后向各孔加入试剂盒(AlphaLISA SureFire Ultra p-AKT1/2/3(Thr 308)试剂盒，珀金埃尔默公司，ALSU-PAKT-A500)所提供2X裂解液2μL，并将细胞培养板置于水平摇床上振摇10分钟。向各孔中加入5μL试剂盒所提供的受体混合液，1000转/分钟离心1分钟，接着加入5μL试剂盒所提供的供体混合液，1000转/分钟离心1分钟。将细胞培养板移至25℃环境避光孵育2小时。利用多功能酶标仪(珀金埃尔默公司，Envision 2104)读取AlphaLISA信号数据。
(3)PI3Kδ选择性抑制测试
利用抗人IgM刺激Raji细胞所造成的B细胞受体的信号传导仅受PI3Kδ所调控，因此可以用于评估化合物对于PI3Kδ的特异抑制行为(Liu等人，Oncotarget，2016，7(33):53515)。
具体实施方案如下：将Raji细胞(美国典型培养物保藏中心，
Figure PCTCN2021107320-appb-000082
CCL-86 TM)培养于含有10％胎牛血清(Invitrogen，10099141)以及青霉素和链霉素(Gibco，15140-122)的RPMI 1640培养基(Invitrogen，A10491-01)中。开始测试时，利用多道移液器(赛默飞世尔科技有限公司，836-4049)将Raji细胞以60000细胞/孔的密度接种至384孔板(珀金埃尔默公司，6007680)。500转/分钟离心30秒后置于37℃，5％CO 2湿式培养箱中孵育2小时。随后利用声波移液器(Labcyte公司，Echo 550)将不同浓度的化合物(起始终浓度为1000nM，3倍梯度稀释，共计10个浓度)加入到培养板之中，30nL/孔，并在上述培养条件下继续孵育30分钟。随后向各孔中加入2μL4倍浓度的山羊抗人IgM(12μg/mL，杰克逊免疫研究实验有限公司，109-006-129)，500转/分钟离心30秒后置于37℃，5％CO 2湿式培养箱中孵育10分钟。随后向各孔加入试剂盒(AlphaLISA SureFire Ultra p-AKT1/2/3(PS 473)试剂盒，珀金埃尔默公司，ALSU-PAKT-B500)所提供2X裂解液2μL，并将细胞培养板置于水平摇床上振摇10分钟。向各孔中加入5μL试剂盒所提供的受体混合液，1000转/分钟离心1分钟，接着加入5μL试剂盒所提供的供体混合液，1000转/分钟离心1分钟。将细胞培养板移至25℃环境避光孵育2小时。利用多功能酶标仪(珀金埃尔默公司，Envision 2104)读取AlphaLISA信号数据。
所获得数据利用软件(GraphPad软件公司，GraphPad prism 6.0)进行统计分析，以化合物的浓度Log值为横坐标，抑制率％为纵坐标，采用非线性拟合(剂量响应-变化斜率)计算IC 50值。化合物针对不同亚型PI3K细胞水平抑制结果如下表2所示。
表2 本发明化合物对不同亚型PI3K细胞的抑制IC 50值
Figure PCTCN2021107320-appb-000083
Figure PCTCN2021107320-appb-000084
数据结果表明本发明化合物在细胞水平具有特异性抑制PI3Kγ/δ的能力。
试验例3：本发明化合物在SD大鼠体内药代动力学评价
分别精确称取实施例5、实施例12、实施例15、实施例18、实施例26、实施例27和实施例28化合物各4mg置于15mL离心管中，加入400μL DMSO充分震荡使供试品完全溶解，随后加入4mL PBS缓冲盐溶液以及3.6mL PEG400，充分混匀至化合物完全溶解状态，此时供试品为浓度0.5mg/mL的溶液。
雄性SD大鼠(北京维通利华实验动物中心)，6-8周龄，饲养环境：温湿度：温度20～26℃，相对湿度40～70％RH；换气次数：≥15次/小时；动物照度：15-20Lx。适应性饲养3天后，于实验前禁食过夜。给药前称重体重，尾部编号。按表3所列方式进行给药。
表3 动物试验方案表
Figure PCTCN2021107320-appb-000085
Figure PCTCN2021107320-appb-000086
受试物的灌胃给药剂量为3mg/kg，静脉给药剂量为1mg/kg。分别于给药后0.00、0.083、0.25、0.50、1.00、2.00、4.00、6.00和8.00h进行血液样本采集。动物采用吸入麻醉(异氟烷，河北一品制药有限公司，C002151205)，麻醉参数：流速：1.0L/min，氧气压力：0.1MPa，溶度：4.5％，麻醉用时：3分钟。麻醉后眼眶采血，每只动物每个时间点采血量为500μL，将血液收集至已编号的一次性使用抗凝管(抗凝剂为肝素钠，0.5mg/管)中，摇晃混匀。3500rpm离心，离心10分钟，取上层血浆，转移至1.5mL离心管之中，冻存到-80℃冰箱内直至测试。取血浆样品50μL于1.5mL离心管中，加入400μL含有5ng/mL盐酸维拉帕米(内标)的乙腈工作液，涡旋1分钟充分混匀，10000rpm离心10分钟。移取上清液0.2mL，用0.22μM有机膜(AS081320-T，Agela Technologies)过滤后，加入进样小瓶中，经LC/MS(Waters，Waters UPLC I Class、TQ-S micro)分析得出血药浓度，并通过DAS软件3.3.0分析药代动力学参数。
按下列公式计算绝对生物利用度：
绝对生物利用度F＝(AUC PO×D IV)/(AUC IV×D PO)×100％(AUC为血药浓度-时间曲线下面积，D为给药剂量，PO为灌胃给药，IV为静脉注射给药)。
本发明化合物给药后药代动力学试验数据见表4。
表4 本发明化合物在SD大鼠体内药代动力学参数
Figure PCTCN2021107320-appb-000087
Figure PCTCN2021107320-appb-000088
本发明化合物静脉给予SD大鼠后有较好的体内药代动力学性质，口服给药无吸收或生物利用度较小。

Claims (26)

  1. 一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐：
    Figure PCTCN2021107320-appb-100001
    其中，
    X为O、S或NH；
    Y为N或CH；
    A 1、A 2、A 3、A 4和A 5各自独立地选自N或CH；
    R 1各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-C(O)R a、-O(O)CR a、-C(O)OR a、-C(O)NR aR b、-NR aR b、-NR aC(O)R b、-S(O) pR a、-S(O) pNR aR b、-NR aS(O) pNR aR b和-NR aS(O) pR b，其中所述烷基、烷氧基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代；
    任意相邻的两个R 1与其连接的原子一起形成环烷基、杂环基、芳基或杂芳基，优选杂芳基，更优选5或6元杂芳基，所述环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代；
    R 2选自氢、卤素、烷基、烷氧基、卤代烷基或卤代烷氧基；
    R 3选自-C(O)R a、-C(O)NR aR b、-S(O) pNR aR b、-S(O) pR a、-P(O)(R a) 2、-S(NR a)(O)R b、-NR aS(O) pR b-、-NR aS(O) pNR aR b、卤素、环烷基、杂环基、芳基和杂芳基，其中所述环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    R 4选自烷基或环烷基，其中所述烷基或环烷基任选进一步被选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基、环烷基或杂环基的一个或多个基团取代；
    R 5选自氢、卤素、烷基、烷氧基、卤代烷基或卤代烷氧基；
    R 6选自氢、卤素、烷基或卤代烷基；
    R a和R b各自独立地选自氢、卤素、羟基、烷基、烯基、炔基、环烷基、杂环 基、芳基和杂芳基，其中所述烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；或者，
    R a和R b与他们连接的氮原子一起形成含氮杂环基或含氮杂芳基，所述含氮杂环基或含氮杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代；
    n为0、1、2或3；
    p为0、1或2。
  2. 根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    Figure PCTCN2021107320-appb-100002
    其中，
    X为O或S
    A 1-A 5、R 1、R 2、R 3、R 4、R 5、R 6和n如权利要求1所定义。
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    其中，
    A 1、A 2、A 3、A 4和A 5中最多有两个为N，其余为CH；
    优选地，A 1、A 2、A 3、A 4和A 5中一个或两个为N，其余为CH；
    更优选，A 1、A 2、A 3、A 4和A 5之一为N，其余为CH。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    Figure PCTCN2021107320-appb-100003
    其中，
    X为O或S；
    A 1、A 2、A 3、A 4中最多有两个为N，其余为CH；
    R 1、R 2、R 3、R 4、R 5和R 6如权利要求1所定义。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IV)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    Figure PCTCN2021107320-appb-100004
    其中，
    A 1、A 2、A 3、A 4中最多有两个为N，其余为CH；
    优选地，A 1、A 2、A 3、A 4中一个或两个为N，其余为CH；
    更优选，A 1、A 2、A 3、A 4之一为N，其余为CH；
    其中，R 1、R 2、R 3、R 4、R 5和R 6如权利要求1所定义。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    A 1为N，且A 2、A 3、A 4为CH；或者，
    A 2为N，且A 1、A 3、A 4为CH；或者，
    A 4为N，且A 1、A 2、A 3为CH；或者，
    A 1和A 3为N，且A 2和A 4为CH；或者，
    A 1和A 2为N，且A 3和A 4为CH。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    其中，条件是当A 1为N，A 2、A 3、A 4为CH，且R 1选自
    Figure PCTCN2021107320-appb-100005
    R 4选自
    Figure PCTCN2021107320-appb-100006
    Figure PCTCN2021107320-appb-100007
    时，R 3不是甲磺酰基、
    Figure PCTCN2021107320-appb-100008
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(V)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    Figure PCTCN2021107320-appb-100009
    其中，R 1、R 2、R 3、R 4、R 5和R 6如权利要求1所定义。
  9. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    R 4选自C 1-C 6烷基，所述C 1-C 6烷基任选进一步被选自C 3-C 10环烷基或3至10元杂环基的一个或多个基团所取代；优选被选自C 3-C 8环烷基或3至8元杂环基的一个或多个基团所取代；进一步优选被环丙基取代。
  10. 根据权利要求1至9中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    R 1选自卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 10环烷基、3至10元杂环基、C 6-C 10芳基、5至10元杂芳基、-NR aR b、-NR aC(O)R b和-NR aS(O) pR b，其中所述C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 10环烷基、3至10元杂环基、C 6-C 10芳基、5至10元杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代；
    R a和R b各自独立地选自氢、C 1-C 6烷基、C 3-C 10环烷基、3至10元杂环基、C 6-C 10芳基和5至10元杂芳基，其中所述C 1-C 6烷基、C 3-C 10环烷基、3至10元杂环基、C 6-C 10芳基和5至10元杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；所述C 3-C 10环烷基、3至10元杂环基、C 6-C 10芳基和5 至10元杂芳基优选C 3-C 8环烷基、3至6元杂环基、苯基和5至6元杂芳基；或者，
    R a和R b与他们连接的氮原子一起形成含5至7元，优选5至6元氮杂环基，或5至10元，优选5至6元含氮杂芳基，所述含氮杂环基或含氮杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代。
  11. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    R 1选自3至10元杂环基，优选5至7元单杂环基、5至7元螺杂环基或5至7元稠杂环基、C 6-C 10芳基、5至10元杂芳基，优选5至6元杂芳基，更优选5元杂芳基；
    其中所述杂环基、芳基、杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代。
  12. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    R 1选自
    Figure PCTCN2021107320-appb-100010
  13. 根据权利要求1至10中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    R 1选自-NR aR b、-NR aC(O)R b和-NR aS(O) pR b；
    R a选自氢或C 1-C 6烷基；
    R b选自氢、C 1-C 6烷基、C 3-C 10环烷基优选C 3-C 6环烷基。
  14. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
    R 3选自-C(O)R a、-C(O)NR aR b、-S(O) pNR aR b、-S(O) pR a、-P(O)(R a) 2、-S(NR a)(O)R b、-NR aS(O) pR b-、卤素、C 6-C 10芳基和5至10元杂芳基，其中所述C 6-C 10芳基或5至10元杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    R a和R b各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、3至8元杂环基、C 6-C 10芳基和5至10元杂芳基，其中所述C 1-C 6烷基、C 3-C 6环烷基、3至8元杂环基、C 6-C 10 芳基或5至10元杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；或者，
    R a和R b与他们连接的氮原子一起形成3至8元含氮杂环基或5至6元含氮杂芳基，所述含氮杂环基或含氮杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代；p为1或2；
    优选地，
    R 3选自-S(O) pR a、-S(O) pNR aR b、-NR aS(O) pR b-、-C(O)R a、-C(O)NR aR b、-P(O)(R a) 2；
    R a选自氢、C 1-C 6烷基；
    R b选自氢、C 1-C 6烷基；或者，
    R a和R b与他们连接的氮原子一起形成3至8元含氮杂环基，所述含氮杂环基任选进一步被选自卤素、羟基、C 1-C 6烷基、C 1-C 6烷氧基的一个或多个基团取代；p为1或2。
  15. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(VI)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐
    Figure PCTCN2021107320-appb-100011
    其中，
    L选自-C(O)-、-S(O) p-、-P(O)(R a)-、-S(NR a)(O)-、-NR aS(O) pR b-；
    R a选自氢、C 1-C 6烷基；
    R b选自C 1-C 6烷基；
    R 7选自-NR cR d；
    R c和R d各自独立地选自氢、C 1-C 6烷基、C 3-C 6环烷基、3至8元杂环基、C 6-C 10芳基和5至10元杂芳基，其中所述C 1-C 6烷基、C 3-C 6环烷基、3至8元杂环基、C 6-C 10芳基或5至10元杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；或者，
    R c和R d与他们连接的氮原子一起形成3至8元含氮杂环基或5至6元含氮杂芳基，所述含氮杂环基或含氮杂芳基任选进一步被选自卤素、氨基、硝基、氰基、氧代 基、羟基、巯基、羧基、酯基、烷基、烷氧基、卤代烷基、卤代烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基的一个或多个基团取代；
    优选地，
    R c和R d与他们连接的氮原子一起形成3至8元含氮杂环基，所述含氮杂环基任选进一步被选自卤素、羟基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代；
    p为1或2。
  16. 根据权利要求1至15中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    其中，
    R 7选自
    Figure PCTCN2021107320-appb-100012
    其任选进一步被选自卤素、羟基、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基、C 1-C 6卤代烷氧基的一个或多个基团取代；
    R 7进一步优选
    Figure PCTCN2021107320-appb-100013
    Figure PCTCN2021107320-appb-100014
  17. 根据权利要求1至16中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    其中，R 2选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基或C 1-C 6卤代烷氧基；优选氢。
  18. 根据权利要求1至17中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    其中，R 5选自氢、卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6卤代烷基或C 1-C 6卤代烷氧基；优选氢。
  19. 根据权利要求1至17中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
    其中，R 6选自氢、卤素、C 1-C 6烷基、或C 1-C 6卤代烷基；优选C 1-C 6烷基。
  20. 根据权利要求1至19中任一项所述通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中所述化合物选自：
    Figure PCTCN2021107320-appb-100015
    Figure PCTCN2021107320-appb-100016
  21. 一种通式(III)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：
    Figure PCTCN2021107320-appb-100017
    在溶剂中，在加热条件下，在碱的存在下，在配体和催化剂的存在下，将化合物(Ic)与化合物(Ig)反应得到通式(III)的化合物；
    其中，所述溶剂优选为极性非质子溶剂如DMF；
    所述加热条件优选在75℃-100℃的范围内；
    所述配体优选空间位阻的三烷基膦，例如三叔丁基膦；
    所述碱优选碱金属碳酸盐，例如碳酸铯；
    所述催化剂优选过渡金属，例如钯；
    其中，
    A 1-A 4、X、R 1、R 2、R 3、R 4、R 5、R 6如权利要求4所定义。
  22. 一种药物组合物，其包含根据权利要求1至20中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐和药学上可接受的佐剂、稀释剂或载体。
  23. 根据权利要求1至20中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或根据权利要求22所述的药物组合物在制备磷脂酰肌醇3-激酶δ(PI3Kδ)和磷脂酰肌醇3-激酶γ(PI3Kγ)双重抑制剂中的用途。
  24. 根据权利要求1至20中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或根据权利要求22所述的药物组合物在制备预防和/或治疗与PI3Kδ和PI3Kγ的活性相关的疾病的药物中的用途，所述疾病优选呼吸系统疾病，例如哮喘、慢性阻塞性肺病、支气管炎、肺气肿，优选哮喘和慢性阻塞性肺病。
  25. 一种药物组合物，其包含根据权利要求1至20中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐与另一种活性剂的组合，所述另一种活性剂选自糖皮质激素受体激动剂(甾体性或非甾体性)、选择性β2肾上腺素受体激动剂、抗毒蕈碱剂、p38拮抗剂、黄嘌呤衍生物、和PDE4拮抗剂。
  26. 根据权利要求1至20中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或根据权利要求21所述的药物组合物与另一种活性剂同时、分开或相继使用在制备用于预防和/或治疗PI3Kδ和PI3Kγ的活性相关的疾病的药物中的用途；所述疾病优选呼吸系统疾病，例如哮喘、慢性阻塞性肺病、支气管炎、肺气肿，优选哮喘和慢性阻塞性肺病；其中所述另一种活性剂选自糖皮质激素受体激动剂(甾体性或非甾体性)、选择性β2肾上腺素受体激动剂、抗毒蕈碱剂、p38拮抗剂、黄嘌呤衍生物、和PDE4拮抗剂。
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