WO2024099478A1 - 可吸入型芳环并噻嗪及类似物、含其的药物组合物及其在抗炎、抗肿瘤中的应用 - Google Patents

可吸入型芳环并噻嗪及类似物、含其的药物组合物及其在抗炎、抗肿瘤中的应用 Download PDF

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WO2024099478A1
WO2024099478A1 PCT/CN2024/071470 CN2024071470W WO2024099478A1 WO 2024099478 A1 WO2024099478 A1 WO 2024099478A1 CN 2024071470 W CN2024071470 W CN 2024071470W WO 2024099478 A1 WO2024099478 A1 WO 2024099478A1
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ring
amino
alkyl
cyano
dioxide
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French (fr)
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盛荣
楼金芳
危俊
冯恩光
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杭州百诚医药科技股份有限公司
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    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medical technology, and in particular to an inhalable aromatic ring thiazine and its structural analogs, a pharmaceutical composition containing the same, and applications thereof in anti-inflammatory and anti-tumor drugs.
  • Phosphatidylinositol 3-kinase (PI3K) as the starting point of the PI3K-AKT-mTOR signaling pathway, strictly regulates the level of the key second messenger phosphatidylinositol-3,4,5-triphosphate (PIP3) in cells, thereby mediating related cell physiological processes such as growth, proliferation, metabolism, chemotaxis and survival.
  • PIP3K can be divided into three major categories: I, II, and III, among which type I PI3K has been studied most in depth (Curr. Med. Chem. 2013, 20, 2991).
  • Type I PI3K can be further divided into two categories: IA (PI3K ⁇ , ⁇ and ⁇ ) and IB (PI3K ⁇ ) according to its regulatory subunits.
  • IA type PI3K mediates signal transduction of receptor tyrosine kinases, while PI3K ⁇ is mainly activated by GPCR.
  • PI3K ⁇ and ⁇ are widely distributed in various tissues and organs. PI3K ⁇ and ⁇ are mainly expressed in immune-related cells and play an important role in blood tumors, inflammation and autoimmune diseases. Therefore, for more than a decade, PI3K ⁇ has been an important target for the treatment of blood cancer-related diseases (Oncogene 2008, 27, 5511).
  • Chinese invention patent CN107033145B discloses a benzothiazine or benzothiadiazine PI3K ⁇ selective inhibitor, wherein the ring B in the general formula a is selected from a monocyclic aromatic heterocyclic group or a fused bicyclic ring substituted with 1-2 Re, and the corresponding representative molecules are SI-11 and SI-19; from Examples 12 and 13 of the specification of CN107033145B, it can be seen that the compounds (especially the representative molecules SI-11 and SI-19) show excellent proliferation inhibition activity in the B lymphocyte leukemia cell line SU-DHL-6, and show extremely high selectivity for the subtypes of PI3K ⁇ .
  • the structural formulas of the general formula a and the representative molecules SI-11 and SI-19 in patent CN107033145B are as follows:
  • PI3K ⁇ mutations are closely related to the occurrence and development of inflammatory diseases, and inhibition of PI3K ⁇ is effective in treating respiratory inflammation, arthritis and other diseases.
  • activated PI3K ⁇ can mediate the occurrence and development of Th2 asthma and hormone-resistant asthma through related signal nodes such as hypoxia-inducible factor (HIF-1 ⁇ )-vascular endothelial growth factor (VEGF), mitochondrial reactive oxygen species (mtROS) and histone deacetylase 2 (HDAC2). Therefore, PI3K ⁇ inhibitors have significant therapeutic effects on Th2 asthma and hormone-resistant asthma (Acta pharmacol. Sin. 2015, 36, 1170).
  • HIF-1 ⁇ hypoxia-inducible factor
  • mtROS mitochondrial reactive oxygen species
  • HDAC2 histone deacetylase 2
  • GSK's Nemiralisib (GSK2269557) has completed Phase I clinical trials for severe asthma and Phase II clinical trials for chronic obstructive pulmonary disease (COPD) (J.Med.Chem.2015,58,7381); its analog GSK-2292767 has also completed Phase I clinical studies for the treatment of asthma (Pulm.Pharmacol.Ther.2017,46,69).
  • COPD chronic obstructive pulmonary disease
  • CN102459253B protects the two molecules GSK2269557 and GSK2292767
  • CN109715623A discloses the AZD8154 molecule
  • CN102712645B protects the RV1729 molecule
  • CN105229007B protects the RV16153 molecule.
  • Control drugs refer to drugs that need to be used daily for a long time, which mainly maintain clinical control of asthma through anti-inflammatory effects
  • reliever drugs refer to drugs used on demand, which mainly relieve asthma symptoms by quickly relieving bronchospasm.
  • Inhalers are currently important therapeutic drugs for respiratory diseases such as asthma and COPD, including inhaled glucocorticoids, such as fluticasone, budesonide, mometasone, etc.; inhaled ⁇ 2 receptor agonists, such as salbutamol, terbutaline, etc.
  • inhaled drugs have the advantages of high targeting, small dose and low side effects; in addition, in addition to high activity and high selectivity for the target, the pharmacokinetic properties of inhaled drugs are also different from those of conventional oral and intravenous drugs. It has special requirements: that is, the drug has sufficient retention time in the lungs, and at the same time, the drug has a high plasma clearance rate in the blood to ensure rapid metabolism after absorption into the blood through the lungs, that is, low intravenous exposure and low oral bioavailability are required.
  • S-I-19 has a certain oral bioavailability and a certain exposure amount after intravenous injection. Therefore, it is easy to cause systemic exposure after inhalation, resulting in corresponding toxicity, which is consistent with the results of the preliminary pharmacodynamic experiment of S-I-19 administered by inhalation to mice.
  • the technical problem to be solved by the present invention is to provide a PI3K ⁇ selective inhibitor with a new structure, using an aromatic ring thiazine compound as a skeleton molecule, which is used for inhalation administration to treat respiratory diseases such as asthma and COPD.
  • the present invention provides a PI3K ⁇ selective inhibitor, which is a compound represented by general formula I or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from a benzene ring, a pyridine ring, a thiophene ring or a furan ring substituted with at least one R1 ;
  • R1 is selected from hydrogen, halogen, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 monoalkylamino, C1-6 dialkylamino or cyano;
  • Ring B is selected from a benzene ring, a pyridine ring, a pyrazine ring, a pyridazine ring, a pyrimidine ring, a thiazole ring, and a pyrazole ring substituted with at least one R 2 , and R 2 is selected from one or more of hydrogen, halogen, C 2-6 alkynyl, C 2-6 alkenyl, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 1-6 monoalkylamino, C 1-6 dialkylamino, amino, cyano, hydroxyl, carboxyl, carbonyl, and keto;
  • R 3 , R 4 and R 5 are each independently selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-8 cycloalkyl, amino, cyano, C 1-6 monoalkylamino or C 1-6 dialkylamino.
  • the present invention also provides a PI3K ⁇ selective inhibitor, which is a compound represented by general formula a or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from a benzene ring, a pyridine ring, a thiophene ring, or a furan ring substituted with at least one R1 ;
  • R1 is selected from hydrogen, a C1-6 alkyl group, a C1-6 fluorinated alkyl group, a C1-6 alkoxy group, a C1-6 fluorinated alkoxy group, a C1-6 monoalkylamino group, a C1-6 dialkylamino group, a halogen group, or a cyano group;
  • Ring B is selected from a benzene ring, a pyridine ring, a pyrazine ring, a pyridazine ring, a pyrimidine ring, a thiazole ring, and a pyrazole ring substituted with at least one R 2 ;
  • R 2 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 monoalkylamino, C 1-6 dialkylamino, cyano, or carboxyl;
  • R 3 is selected from halogen, amino, C 1-6 monoalkylamino, C 1-6 dialkylamino, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 fluorinated alkyl.
  • R1 is selected from the following heterocyclic rings substituted with:
  • R 1 is selected from hydrogen, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, cyano, and ethynyl.
  • ring B is selected from a benzene ring, a pyridine ring, a pyrazine ring, a pyridazine ring, a pyrimidine ring, a thiazole ring, and a pyrazole ring substituted with R2 ; and R2 is hydrogen, methyl, ethyl, fluorine, chlorine, bromine, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, methylamino, dimethylamino, diethylamino, cyano, and carboxyl.
  • R 3 is amino, methyl, ethyl, cyclopropyl, fluorine, chlorine, bromine, trifluoromethyl, difluoromethyl, 2.2.2-trifluoroethyl.
  • the present invention also provides a PI3K ⁇ selective inhibitor, which is a compound represented by general formula II or a pharmaceutically acceptable salt thereof:
  • R1 is selected from halogen, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C1-6 monoalkylamino, C1-6 dialkylamino or cyano
  • R2 is selected from hydrogen, halogen, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, C1-6 monoalkylamino, C1-6 dialkylamino , amino, cyano, hydroxyl, carboxyl , carbonyl or keto
  • R3, R4 and R5 are each independently selected from C1-6 alkyl , halogenated C1-6 alkyl , amino, cyano, C1-6 monoalkylamino or C1-6 dialkylamino.
  • the present invention also provides a PI3K ⁇ selective inhibitor, which is a compound represented by the general formula III or a pharmaceutically acceptable salt thereof:
  • any one of X, Y, M, and N is N, and the other three are C;
  • R1 is selected from hydrogen, halogen, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy or halogenated C1-6 alkoxy;
  • R2 is selected from hydrogen, halogen, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, C1-6 monoalkylamino, C1-6 dialkylamino, amino, cyano, hydroxyl, carboxyl, carbonyl or keto;
  • R3 , R4 , and R5 are each independently selected from methyl, amino or cyano.
  • the present invention also provides a PI3K ⁇ selective inhibitor, which is a compound represented by general formula IV or a pharmaceutically acceptable salt thereof:
  • any one of A, B, and Q is S or O, and the other two are C;
  • R1 is selected from hydrogen, halogen, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy or halogenated C1-6 alkoxy; and when A is S or O, R1 connected to A is hydrogen;
  • R2 is selected from hydrogen, halogen, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, C1-6 monoalkylamino, C1-6 dialkylamino, amino, cyano, hydroxyl, carboxyl, carbonyl or keto;
  • R3 , R4 , and R5 are each independently selected from methyl, amino or cyano.
  • the present invention also provides a PI3K ⁇ selective inhibitor selected from the following characteristic compounds numbered 1 to 66 or their isomers or pharmaceutically acceptable salts or prodrugs:
  • the "compounds” described in the present invention include but are not limited to the following forms of compounds: free base, stereoisomers, geometric isomers, tautomers, isotopes, pharmaceutically acceptable salts, solvates, hydrates, prodrugs (esters or phosphates), etc.
  • the "compounds" of the present invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included, such as enantiomers and diastereomers.
  • the compounds of the present invention containing asymmetric carbon atoms can be isolated in optically pure form or racemic form. Optically pure forms can be obtained by resolution of racemic mixtures, synthesis using chiral starting materials or chiral reagents.
  • the "pharmaceutically acceptable salts" of the present invention refer to salts of the compounds of the present invention, which are prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, magnesium salts, ammonium or organic ammonia.
  • alkali metal salts alkaline earth metal salts, other metal salts, inorganic base salts, organic base salts, inorganic acid salts, lower alkane sulfonates, aryl sulfonates, organic acid salts, amino acid salts, etc.
  • compounds provided by the present invention also exist in prodrug form.
  • Prodrugs of compounds described herein easily undergo chemical changes under physiological conditions to be converted into compounds of the present invention.
  • prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • C 1-6 alkyl refers to a straight or branched alkane containing 1 to 6 carbon atoms.
  • alkyl used in the present invention include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl and tert-butyl.
  • Alkyl also includes substituted alkyl. The alkyl may be optionally substituted one or more times by halogen or hydroxy.
  • C 1-6 fluorinated alkyl refers to an alkyl group containing a fluorine atom, wherein alkyl is as defined above.
  • Examples of “C 1-6 fluorinated alkyl” used herein include, but are not limited to, trifluoromethyl, difluoromethyl, 2.2.2-trifluoroethyl.
  • C 1-6 fluorinated alkyl also includes C 1-6 substituted fluorinated alkyl. The C 1-6 substituted fluorinated alkyl may be optionally substituted one or more times with halogen.
  • C 1-6 alkoxy refers to an -O-alkyl group, wherein alkyl is as defined above.
  • alkoxy as used herein include but are not limited to The term “alkoxy” refers to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
  • Alkoxy also includes substituted alkoxy. Alkoxy may be optionally substituted one or more times by halogen.
  • C 1-6 fluorine-containing alkoxy refers to an -O-alkyl group containing a fluorine atom, wherein alkyl is as defined above.
  • Examples of "C 1-6 fluorine-containing alkoxy” used herein include, but are not limited to, trifluoromethoxy and difluoromethoxy.
  • C 1-6 monoalkylamino refers to an amino group substituted with a C 1-6 monoalkyl group, wherein the alkyl group is as defined above.
  • Examples of "C 1-6 monoalkylamino” as used herein include, but are not limited to, methylamino, ethylamino, propylamino, cyclopropylamino, isopropylamino.
  • C 1-6 dialkylamino refers to an amino group substituted with two C 1-6 alkyl groups, wherein the alkyl group is as defined above.
  • Examples of “C 1-6 dialkylamino” as used herein include, but are not limited to, dimethylamino, diethylamino, aziridine, azetidine, azopentyl, and azidine.
  • cycloalkyl refers to a saturated carbon ring of 3-8 ring atoms.
  • Examples of “cycloalkyl” used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound as described above or a pharmaceutically acceptable salt thereof as an active ingredient, and at least one or more pharmaceutically acceptable carriers.
  • the "pharmaceutical composition” of the present invention refers to a preparation of one or more compounds of the present invention or their salts and a carrier generally accepted in the art for delivering biologically active compounds to an organism (e.g., human).
  • the purpose of the pharmaceutical composition is to facilitate administration and delivery to an organism.
  • the pharmaceutical composition provided by the present invention adopts an inhalable drug delivery method.
  • the "inhalable type" of the present invention means that such compounds can be administered through the airway and lungs so that they are absorbed by the lung epithelial cells or respiratory mucosa and directly enter the blood circulation.
  • “Inhalable type” indicates that it can be administered by inhalation but is not limited to inhalation administration. It is still suitable for administration routes such as oral (including buccal or sublingual administration), rectal administration, topical administration (including buccal, sublingual or transdermal administration), vaginal administration or parenteral administration (including subcutaneous injection, intramuscular injection, intravenous injection or intradermal injection).
  • These preparations can be prepared by any method known in the field of pharmacy. For example, by mixing the active ingredient with a carrier or excipient.
  • the present invention also provides a method for preparing the aforementioned compound or pharmaceutical composition for use in preventing or treating diseases associated with PI3K ⁇ kinase activity.
  • the aforementioned medicament is used for preventing or treating allergic diseases and inflammatory diseases; in particular, it plays a role in preventing or treating asthma, COPD and autoimmune diseases associated with PI3K ⁇ deficiency by delivery via inhalation administration.
  • the aforementioned allergic diseases and inflammatory diseases are selected from asthma of any type or cause, including but not limited to intrinsic asthma, exogenous asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma, Th2 asthma and non-Th2 asthma, wheezing infant syndrome, acute lung injury, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, adult-onset/acute respiratory distress syndrome and other respiratory diseases; and autoimmune diseases such as rheumatoid arthritis, osteoarthritis, lupus erythematosus, psoriasis, atopic dermatitis, multiple sclerosis and the like.
  • inflammatory or obstructive airway diseases to which the present invention is applicable are selected from pneumoconiosis of any type or cause, including but not limited to asbestosis, fume contusion, siderosis, hair pneumoconiosis and byssinosis.
  • the aforementioned medicine is used to prevent or treat lung tumors.
  • the aforementioned lung tumors include, but are not limited to, non-small cell lung cancer, small cell lung cancer, etc.
  • the present invention has the following beneficial effects:
  • the inventor team of the present application unexpectedly discovered through creative research that the introduction of an amino group at the 2-position of the pyrimidine group of S-I-19 (i.e., forming a trisubstitution on the pyrimidine ring) resulted in a significant change in the pharmacokinetic properties of the resulting target molecule, a significant increase in plasma clearance, and a significant decrease in oral bioavailability, which meets the oral pharmacokinetic requirements for inhaled medication.
  • the compounds provided by the present invention all have PI3K ⁇ inhibitory effects, and most of the compounds have significant inhibitory effects on PI3K ⁇ with high selectivity.
  • some compounds can be well retained in the lungs after inhalation delivery, have better inhalation pharmacokinetic properties, and can be used as inhaled drugs for preventing or treating respiratory diseases such as asthma and COPD.
  • FIG1 shows the oral pharmacokinetic properties of the compounds provided by the present invention.
  • FIG2 shows the inhalation pharmacokinetic properties of the compounds provided by the present invention.
  • FIG. 3 shows the changes in body weight of Balb/C mice after administration of OVA to induce acute asthma.
  • FIG. 4 shows the total number of cells in bronchoalveolar lavage fluid (BALF) after administration of OVA to induce acute asthma in Balb/C mice.
  • BALF bronchoalveolar lavage fluid
  • FIG. 5 shows the results of Wright staining of bronchoalveolar lavage fluid after administration of OVA to induce acute asthma in Balb/C mice.
  • FIG. 6 shows the results of the lung function test after administration of OVA to induce acute asthma in Balb/C mice.
  • the present invention also provides a method for preparing the above compound, but is not limited to the following method:
  • 2-Bromo-6-fluoroaniline (A1, 1.9 g) was added dropwise to 7.0 mL of 10 M HCl solution at 0 °C, and a large amount of white solid precipitated. Subsequently, at this temperature, a 40% sodium nitrite aqueous solution was added dropwise until the solution was clear to obtain a yellow diazonium salt solution. 9.0 mL of concentrated hydrochloric acid and 0.25 g of CuSO 4 ⁇ 5H 2 O were placed in a 250 mL round-bottom flask. Under an ice bath, a 35% NaHSO 3 aqueous solution and the above diazonium salt solution were added dropwise at the same time.
  • Step 3 Preparation of (S)-2-(1-(8-fluoro-1,1-dioxide-2-phenyl-2H-benzo[e][1,2]thiazin-3-yl)ethyl)isoindoline-1,3-dione (A4):
  • Step 4 Preparation of (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5):
  • Step 5 Preparation of (S)-2,4-diamino-6-((1-(8-fluoro-1,1-dioxide-2-phenyl-2H-benzo[e][1,2]thiazine-3-)ethyl)amino)pyrimidine-5-cyano:
  • Example 3 The synthesis of the compound of Example 3 was accomplished by using a procedure similar to that described in Example 2. 2-amino-4-methyl-5-cyano-6-chloropyrimidine was replaced with 2-amino-4-ethyl-5-cyano-6-chloropyrimidine to give a white solid in 61% yield.
  • Example 4 The synthesis of the compound of Example 4 was accomplished by using a procedure similar to that described in Example 2. 2-amino-4-methyl-5-cyano-6-chloropyrimidine was replaced with 2-amino-4-cyclopropyl-5-cyano-6-chloropyrimidine to give a white solid in a yield of 41%.
  • Example 5 The synthesis of the compound of Example 5 was accomplished by using a procedure similar to that described in Example 2. 2-amino-4-methyl-5-cyano-6-chloropyrimidine was replaced with 2-amino-4-trifluoromethyl-5-cyano-6-chloropyrimidine to give a white solid in 78% yield.
  • Example 6 The synthesis of Example 6 was accomplished by using a procedure similar to that described in Example 2. 2-amino-4-methyl-5-cyano-6-chloropyrimidine was replaced with 2-amino-4-(2,2,2-trifluoroethyl)-5-cyano-6-chloropyrimidine to give a white solid in 65% yield.
  • Example 7 The synthesis of Example 7 was accomplished by using a procedure similar to that described in Example 2. 2-amino-4-methyl-5-cyano-6-chloropyrimidine was replaced with 2-amino-4-difluoromethyl-5-cyano-6-chloropyrimidine to give a white solid in 69% yield.
  • Example 8 The synthesis of the compound of Example 8 was accomplished by using a procedure similar to that described in Example 1. 2,4-diamino-5-cyano-6-chloropyrimidine was replaced with 2-amino-4-methylamino-5-cyano-6-chloropyrimidine to obtain a white solid in a yield of 45%.
  • Example 9 The synthesis of Example 9 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-8-fluoro-2-(pyridin-3-yl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (B5) to give a white solid in 66% yield.
  • Example 10 The synthesis of Example 10 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-8-fluoro-2-(pyrazin-4-yl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (C5) to give a white solid in 56% yield.
  • Example 11 The synthesis of Example 11 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-8-fluoro-2-(pyrazin-4-yl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (C5) to give a white solid in 66% yield.
  • Example 12 The synthesis of Example 12 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-8-fluoro-2-(pyridazin-2-yl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (D5) to give a white solid in 46% yield.
  • Example 13 The synthesis of Example 13 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-8-fluoro-2-(pyridazin-2-yl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (D5) to give a white solid in 76% yield.
  • Example 14 The synthesis of Example 14 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-8-fluoro-2-(pyrimidin-5-yl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (E5) to give a white solid in 36% yield.
  • Example 15 The synthesis of Example 15 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-8-fluoro-2-(pyrimidin-5-yl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (E5) to give a white solid in 66% yield.
  • Example 16 The synthesis of Example 16 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-8-fluoro-2-(thiazol-5-yl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (F5) to give a white solid in 56% yield.
  • Example 17 The synthesis of Example 17 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-8-fluoro-2-(thiazol-5-yl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (F5) to give a white solid in 73% yield.
  • Example 18 The synthesis of Example 18 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-8-fluoro-2-(1H-pyrazol-4-yl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (G5) to give a white solid in 46% yield.
  • Example 19 The synthesis of Example 19 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-8-fluoro-2-(4-fluorophenyl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (H5) to give a white solid in 79% yield.
  • Example 20 The synthesis of Example 20 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-8-fluoro-2-(3-methylphenyl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (I5) to give a white solid in 76% yield.
  • Example 21 The synthesis of Example 21 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-8-fluoro-2-(3-methoxyphenyl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (J5) to give a white solid in 74% yield.
  • Example 22 The synthesis of Example 22 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-8-fluoro-2-(3-methylaminophenyl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (K5) to give a white solid in 26% yield.
  • Example 23 The synthesis of Example 23 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-8-fluoro-2-(3-dimethylaminophenyl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (L5) to give a white solid in 56% yield.
  • Example 24 The synthesis of Example 24 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-8-fluoro-2-(3-cyanophenyl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (M5) to give a white solid in 81% yield.
  • Example 25 The synthesis of the compound of Example 25 was completed by using steps similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-8-fluoro-2-(3-carboxymethyl ester phenyl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (N5) to obtain a white solid; then, the above product was dissolved in a mixed solvent of tetrahydrofuran (1 mL) and water (1 mL), and lithium hydroxide monohydrate (2 equiv.) was added and reacted at 60°C for two hours.
  • Example 26 The synthesis of Example 26 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-8-methyl-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (O5) to give a white solid in 66% yield.
  • Example 27 The synthesis of Example 27 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-8-trifluoromethyl-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (P5) to give a white solid in 75% yield.
  • Example 28 The synthesis of Example 28 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-8-methoxy-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (Q5) to give a white solid in 76% yield.
  • Example 29 The synthesis of Example 29 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-8-trifluoromethoxy-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (R5) to give a white solid in 76% yield.
  • Example 30 The synthesis of the compound of Example 30 was completed by using a procedure similar to that described in Example 2.
  • (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-8-chloro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (S5) to obtain a white solid; then, the above product was dissolved in tetrahydrofuran (1 mL), DIPEA (5 equiv.) and methylamine hydrochloride (2 equiv.) were added, and the reaction was carried out at 100° C. for 24 hours. After the reaction was completed, the solvent was dried by spin drying, and a white solid product was obtained by column chromatography, with a total yield of 36% for two steps.
  • Example 31 The synthesis of Example 31 was accomplished by using procedures similar to those described in Example 30. Methylamine hydrochloride was replaced with dimethylamine hydrochloride to give a white solid in 76% yield.
  • Example 32 The synthesis of Example 32 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-8-cyano-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (T5) to give a white solid in 56% yield.
  • Example 33 The synthesis of Example 33 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-8-cyano-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (T5) to give a white solid in 77% yield.
  • Example 34 The synthesis of Example 34 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-8-ethynyl-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (U5) to give a white solid in 77% yield.
  • Example 35 The synthesis of Example 35 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-8-chloro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (S5) to give a white solid in 35% yield.
  • Example 36 The compound of Example 36 is the intermediate in Example 30. White solid, yield 75%.
  • Example 37 The synthesis of Example 37 was accomplished by using procedures similar to those described in Example 30. 2-amino-4-methyl-5-cyano-6-chloropyrimidine was replaced with 2-amino-4-ethyl-5-cyano-6-chloropyrimidine to give a white solid in 75% yield.
  • Example 38 The synthesis of Example 38 was accomplished by using procedures similar to those described in Example 30. 2-amino-4-methyl-5-cyano-6-chloropyrimidine was replaced with 2-amino-4-trifluoromethyl-5-cyano-6-chloropyrimidine to give a white solid in 78% yield.
  • Example 39 The synthesis of Example 39 was accomplished by using procedures similar to those described in Example 38. (S)-3-(1-aminoethyl)-8-chloro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (S5) was replaced by (S)-3-(1-aminoethyl)-8-chloro-2-(1H-pyrazol-4-yl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (V5) to give a white solid in 54% yield.
  • Example 40 The synthesis of Example 40 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-8-chloro-2-(1H-pyrazol-4-yl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (V5) to give a white solid in 29% yield.
  • Example 41 The synthesis of Example 41 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-8-chloro-2-(4-fluorophenyl)-2H-benzo[e][1,2]thiazine-1,1-dioxide (W5) to give a white solid in 69% yield.
  • Example 42 The synthesis of Example 42 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-2-phenyl-2H-thiophene[2,3-e][1,2]thiazine-1,1-dioxide (X5) to give a white solid in 37% yield.
  • Example 43 The synthesis of Example 43 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-2-phenyl-2H-thiophene[2,3-e][1,2]thiazine-1,1-dioxide (X5) to give a white solid in 77% yield.
  • Example 44 The synthesis of Example 44 was accomplished by using procedures similar to those described in Example 43. 2-amino-4-methyl-5-cyano-6-chloropyrimidine was replaced with 2-amino-4-ethyl-5-cyano-6-chloropyrimidine to give a white solid in 74% yield.
  • Example 45 The synthesis of Example 45 was accomplished by using procedures similar to those described in Example 43. 2-amino-4-methyl-5-cyano-6-chloropyrimidine was replaced with 2-amino-4-trifluoromethyl-5-cyano-6-chloropyrimidine to give a white solid in 73% yield.
  • Example 46 The synthesis of Example 46 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-2-(3-pyridyl)-2H-thiophene[2,3-e][1,2]thiazine-1,1-dioxide (Y5) to give a white solid in 71% yield.
  • Example 47 The synthesis of Example 47 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-2-(1H-pyrazol-4-yl)-2H-thiophene[2,3-e][1,2]thiazine-1,1-dioxide (Z5) to give a white solid in 37% yield.
  • Example 48 The synthesis of Example 48 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-2-phenyl-2H-thiophene[3,2-e][1,2]thiazine-1,1-dioxide (AA5) to give a white solid in 57% yield.
  • Example 49 The synthesis of Example 49 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-2-phenyl-2H-thiophene[3,2-e][1,2]thiazine-1,1-dioxide (AA5) to give a white solid in 77% yield.
  • Example 50 The synthesis of Example 50 was accomplished by using procedures similar to those described in Example 2.
  • (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-2-(1H-pyrazol-4-yl)-2H-thiophene[3,2-e][1,2]thiazine-1,1-dioxide Dioxide (AB5) was obtained as a white solid with a yield of 19%.
  • Example 51 The synthesis of Example 51 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-2-phenyl-2H-furano[2,3-e][1,2]thiazine-1,1-dioxide (AC5) to give a white solid in 38% yield.
  • Example 52 The synthesis of Example 52 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-2-phenyl-2H-furano[2,3-e][1,2]thiazine-1,1-dioxide (AC5) to give a white solid in 77% yield.
  • Example 53 The synthesis of Example 53 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-2-(1H-pyrazol-4-yl)-2H-furano[2,3-e][1,2]thiazine-1,1-dioxide (AD5) to give a white solid in 37% yield.
  • Example 54 The synthesis of Example 54 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-2-phenyl-2H-furano[3,2-e][1,2]thiazine-1,1-dioxide (AE5) to give a white solid in 37% yield.
  • Example 55 The synthesis of Example 55 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-2-phenyl-2H-furano[3,2-e][1,2]thiazine-1,1-dioxide (AE5) to give a white solid in 77% yield.
  • Example 56 The synthesis of Example 56 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-2-(1H-pyrazol-4-yl)-2H-furano[3,2-e][1,2]thiazine-1,1-dioxide (AF5) to give a white solid in 37% yield.
  • Example 57 The synthesis of Example 57 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-2-phenyl-2H-pyrido[2,3-e][1,2]thiazine-1,1-dioxide (AG5) to give a white solid in 57% yield.
  • Example 58 The synthesis of Example 58 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-2-phenyl-2H-pyrido[2,3-e][1,2]thiazine-1,1-dioxide (AG5) to give a white solid in 75% yield.
  • Example 59 The synthesis of Example 59 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-2-(1H-pyrazol-4-yl)-2H-pyrido[2,3-e][1,2]thiazine-1,1-dioxide (AH5) to give a white solid in 47% yield.
  • Example 60 The synthesis of Example 60 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-2-phenyl-2H-pyrido[3,4-e][1,2]thiazine-1,1-dioxide (AI5) to give a white solid in 37% yield.
  • Example 61 The synthesis of Example 61 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-2-phenyl-2H-pyrido[3,4-e][1,2]thiazine-1,1-dioxide (AI5) to give a white solid in 75% yield.
  • Example 62 The synthesis of Example 62 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-2-(1H-pyrazol-4-yl)-2H-pyrido[3,4-e][1,2]thiazine-1,1-dioxide (AJ5) to give a white solid in 67% yield.
  • Example 63 The synthesis of Example 63 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-2-phenyl-2H-pyrido[4,3-e][1,2]thiazine-1,1-dioxide (AK5) to give a white solid in 79% yield.
  • Example 64 The synthesis of Example 64 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-2-phenyl-2H-pyrido[4,3-e][1,2]thiazine-1,1-dioxide (AK5) to give a white solid in 75% yield.
  • Example 65 The synthesis of Example 65 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-2-(1H-pyrazol-4-yl)-2H-pyrido[4,3-e][1,2]thiazine-1,1-dioxide (AL5) to give a white solid in 47% yield.
  • Example 66 The synthesis of Example 66 was accomplished by using procedures similar to those described in Example 1. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-2-phenyl-2H-pyrido[3,2-e][1,2]thiazine-1,1-dioxide (AM5) to give a white solid in 43% yield.
  • Example 67 The synthesis of Example 67 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced by (S)-3-(1-aminoethyl)-2-phenyl-2H-pyrido[3,2-e][1,2]thiazine-1,1-dioxide (AM5) to give a white solid in 75% yield.
  • Example 68 The synthesis of Example 68 was accomplished by using procedures similar to those described in Example 2. (S)-3-(1-aminoethyl)-8-fluoro-2-phenyl-2H-benzo[e][1,2]thiazine-1,1-dioxide (A5) was replaced with (S)-3-(1-aminoethyl)-2-(1H-pyrazol-4-yl)-2H-pyrido[3,2-e][1,2]thiazine-1,1-dioxide (AN5) to give a white solid in 37% yield.
  • Example 69 PI3K ⁇ inhibitory activity of the compounds of the present invention (aromatic ring thiazine)
  • idelalisib was used as a positive control and ADP-Glo Luminescent Assay was used to evaluate the PI3K ⁇ inhibitory activity of the above 68 aromatic ring thiazine derivatives.
  • Other compounds of the present invention have similar beneficial effects to the compounds listed below, but this should not be interpreted as the compounds of the present invention having only the following beneficial effects.
  • test compound was dissolved in 100% DMSO to a 10 mM stock solution and stored in a nitrogen cabinet away from light.
  • test compound concentration gradient The test compound concentration is 1000nM, 5-fold dilution, 6 concentrations, single-well test. Gradient dilutions are made into 6 different concentrations of 100-fold final concentration in a 384-well plate. Use Echo to transfer 50nL to the compound well of the 384-well plate; add 50nL of DMSO to the negative control well and the positive control well, respectively.
  • RLU is the chemiluminescence value of the sample
  • Mean (NC) is the mean ratio of the negative control wells
  • Mean (PC) is the mean ratio of the positive control wells.
  • the log value of the concentration was used as the X-axis and the percentage inhibition rate was used as the Y-axis.
  • the log (inhibitor) vs. response-Variable slope of the analysis software GraphPad Prism 5 was used to fit the dose-effect curve to obtain the IC 50 value of each compound on the enzyme activity.
  • PI3K ⁇ inhibitory activity and tumor cell proliferation inhibitory activity of aromatic ring thiazine compounds ⁇ Note: ⁇ ++++ indicates activity ⁇ 10nM, +++ indicates activity 10-200nM, ++ indicates activity 200-500nM, + indicates activity >500nM.
  • Example 70 Inhibitory activity of preferred compounds of the present invention against Class I PI3Ks
  • the present invention conducted activity tests on different subtypes of Class I PI3Ks on some highly active compounds and found that they had good selectivity for PI3K ⁇ . The results are shown in Table 3.
  • the present invention conducted oral pharmacokinetic property tests on SD rats for some highly active compounds (such as compound 36), and the results are shown in Figure 33.
  • Example 72 Pharmacokinetic properties of some compounds of the present invention after oral/intravenous administration (p.o. 10 mg/kg, i.v. 0 mg/kg)
  • Compounds with poor oral absorption characteristics and F values ⁇ 5% include: compounds 1, 2, 6, 7, 10, 18, 24, 26, 35, 36, 39, 40, 42, 43, 44, 48, 49, 50, 51, 52, 56, 57, 66, 67.
  • the compounds that are rapidly eliminated after intravenous injection with T1/2 ⁇ 0.6h include: compounds 1, 2, 3, 5, 7, 12, 24, 26, 35, 36, 39, 40, 41, 42, 43, 44, 46, 48, 50, 51, 52, 56, 57, 62, 66, 67.
  • Healthy male SD rats weighing 190 to 220 g were randomly divided into 6 groups, 3 rats in each group, and intratracheally administered with a microsprayer under isoflurane anesthesia at a dose of 60 ⁇ g/kg.
  • the lung tissue was perfused and homogenized at 0.2 h, 1 h, and 2 h after administration, and the drug concentration was detected. The plasma drug concentration at each time point was also detected. The results are shown in Table 4 and Figure 2.
  • compound 36 has excellent inhalation pharmacokinetic properties and is suitable for inhalation administration.
  • Example 74 Pharmacodynamics experiment of acute asthma model induced by OVA in Balb/C mice
  • 1 Sensitization solution weigh 1 mg OVA in a 50 mL EP tube, dissolve it with 20 mL PBS to prepare an OVA solution with a concentration of 50 ⁇ g/mL; weigh 1 g Al(OH) 3 in a 15 mL EP tube, add 10 mL PBS to prepare an Al(OH) 3 suspension with a concentration of 10%, and shake vigorously until completely dissolved; mix the above two solutions thoroughly (1:1), leave them at room temperature for 1 hour; centrifuge at 1500 r/min for 5 minutes, and discard the supernatant; finally, make up to 7 mL with double distilled water.
  • nebulizer solution 150mg OVA + 10mL PBS, ready for use.
  • mice After one week of adaptive feeding, female Balb/C mice weighing 18-22g were randomly divided into 3 groups: normal group (control), model group (model), compound 36 group, and BUD group, with 4 mice in each group. Mice in each group were ear-tagged and housed in separate cages. During the experiment, mice had free access to water and sufficient feed.
  • OVA sensitization The mice in the model group, compound 36 group, and BUD group were intraperitoneally injected with 0.2 mL of sensitization solution on day 1 and day 7. The mice in the control group were intraperitoneally injected with 0.2 mL of PBS buffer.
  • OVA stimulation Under isoflurane anesthesia (Abbott Laboratories), 1.5% OVA aerosol solution was administered by micro-nebulizer for 7 consecutive days from day 14 to day 21 to stimulate asthma.
  • the control group was treated with PBS buffer instead of OVA solution for aerosol inhalation.
  • the drug administration group was administered by micro-nebulizer one hour before 1.5% OVA aerosolization for a total of 7 days, and the mice were weighed every day.
  • mice in each group ate normally and had no abnormal behavior.
  • the model group showed different degrees of irritability, incontinence, cyanosis of the mouth and nose, etc. Since pulmonary inhalation administration requires anesthesia, some mice still did not wake up during the nebulization stimulation, and their breathing was seen to be rapid during the stimulation.
  • mice Observation of general indicators: Observe the morphological changes of mice before and after administration, and whether they have symptoms such as difficulty breathing and shortness of breath.
  • bronchoalveolar lavage fluid (BALF): After killing the mice, cut the neck skin, separate the neck trachea, make a small "T"-shaped incision in the lower part of the trachea, use a silicone hose to intubate the trachea, and ligate the trachea.
  • Counting and staining of inflammatory cells in BALF Centrifuge the collected BALF at 1500 rpm/min for 5 min, discard the supernatant, add 1 mL PBS to resuspend the cells, and take 20 ⁇ L to count the total number of inflammatory cells on a cell counter. Apply the perfusion fluid on a glass slide, and stain it with Wright-Giemsa staining solution after drying to observe the proportion of inflammatory cells.
  • the total number of cells in the bronchoalveolar lavage fluid (BALF) of the model group mice increased significantly, which were 0.728 ⁇ 0.204 ⁇ 10 6 and 8.367 ⁇ 1.646 ⁇ 10 6 , respectively.
  • BALF bronchoalveolar lavage fluid
  • BALF bronchoalveolar lavage fluid
  • compound 36 inhibited the total number of cells in BALF better than budesonide (BUD), which were 1.575 ⁇ 0.337 ⁇ 10 6 and 2.304 ⁇ 0.747 ⁇ 10 6 , respectively.
  • compound 36 can significantly alleviate the asthma phenotype symptoms, and its effect is slightly better than budesonide (BUD).

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Abstract

PI3Kδ选择性抑制剂及其游离碱、同分异构体、溶剂化物、及药学上可接受的盐等结构形式，具有显著的PI3Kδ拮抗活性，部分化合物经药代动力学研究表明具有高血浆清除率和低口服生物利用度，适合作为吸入型药物开发用于预防或治疗与PI3Kδ激酶活性异常表达相关的疾病，尤其是哮喘、COPD等呼吸系统疾病。

Description

可吸入型芳环并噻嗪及类似物、含其的药物组合物及其在抗炎、抗肿瘤中的应用
本申请引用申请号为202211400330.0、申请日为2022年11月09日、发明名称为“可吸入型芳环并噻嗪及类似物、含其的药物组合物及其在抗炎、抗肿瘤中的应用”的中国专利申请作为优先权。
技术领域
本发明涉及医药技术领域，具体涉及一种可吸入型芳环并噻嗪以及其结构类似物、含其的药物组合物及其在抗炎、抗肿瘤药物中的应用。
背景技术
磷脂酰肌醇3-激酶(PI3K)，作为PI3K-AKT-mTOR信号通路的起始点，其严格调控着细胞内关键第二信使磷脂酰肌醇-3,4,5-三磷酸酯(PIP3)的水平，从而介导相关的细胞生理过程，如生长，增殖，代谢，趋化和存活。PI3K可分为I,II,III三大类，其中对I型PI3K的研究最为深入(Curr.Med.Chem.2013,20,2991)。I型PI3K又可根据其调节亚基的不同而细分为IA(PI3Kα,β和δ)和IB(PI3Kγ)两类。IA类PI3K介导受体酪氨酸激酶的信号转导，而PI3Kγ主要通过GPCR激活。PI3Kα和β广泛分布于多种组织器官。PI3Kδ、γ主要表达于免疫相关细胞中，在血液肿瘤、炎症和自身免疫性疾病中发挥重要作用。因此十余年间，PI3Kδ一直作为治疗血液肿瘤相关疾病的重要靶标(Oncogene 2008,27,5511)。
例如，中国发明专利CN107033145B公开了一种苯并噻嗪类或苯并噻二嗪类PI3Kδ选择性抑制剂，其通式a中的环B选自被1-2个Re取代的单环芳杂基或稠合双环，对应的代表分子为S-I-11和S-I-19；从CN107033145B说明书的实施例12和实施例13可知，该类化合物(尤其是代表分子S-I-11和S-I-19)在B淋巴细胞白血病细胞株SU-DHL-6显示出优良的增殖抑制活性，且对PI3Kδ的亚型表现出极高的选择性。专利CN107033145B中的通式a、代表分子S-I-11和S-I-19的结构式见下：
进一步研究表明，上述通式a所示化合物尤其是S-I-11等代表分子，其口服生物利用度良好，具有开发成口服抗肿瘤药物的潜力。
此外，有研究表明PI3Kδ的突变还与炎症相关疾病的发生发展密切相关，抑制PI3Kδ对治疗呼吸系统炎症、关节炎等疾病有效。尤其在哮喘和COPD等呼吸系统疾病中，活化的PI3Kδ可以通过低氧诱导因子(HIF-1α)-血管内皮生长因子(VEGF)、线粒体活性氧(mtROS)和组蛋白去乙酰化酶2(HDAC2)等相关信号节点，介导Th2型哮喘及激素抵抗型哮喘的发生发展，因此PI3Kδ抑制剂对Th2型哮喘及激素抵抗型哮喘具有显著的疗效(Acta pharmacol.Sin.2015,36,1170)。
当前，已经有吸入型PI3Kδ抑制剂分子进入临床试验，例如GSK公司的Nemiralisib(即GSK2269557)已完成重症哮喘的I期和慢性阻塞性肺病(COPD)II期临床试验(J.Med.Chem.2015,58,7381)；其类似物GSK-2292767也完成了哮喘治疗的I期临床研究(Pulm.Pharmacol.Ther.2017,46,69)。
另外，除GSK公司的吸入型PI3Kδ抑制剂进入临床研究外，还有一些吸入型PI3Kδ/γ双重抑制剂(如RV-1729,RV-6153和AZD8154)也已经进入临床I期研究，用于哮喘和COPD的治疗(J.Med.Chem.2018,61,9551，J.Med.Chem.2021,64,8053)；目前处于临床研究阶段的吸入型PI3Kδ抑制剂，其结构式公开见下：
上述处于临床研究阶段的吸入型PI3Kδ抑制剂，其化合物专利分别为：CN102459253B保护了GSK2269557和GSK2292767这2个分子，CN109715623A公开了AZD8154分子，CN102712645B保护了RV1729分子，CN105229007B保护了RV16153分子。
众所周知，治疗哮喘等呼吸系统疾病的药物可以分为控制药物和缓解药物，控制药物是指需要长期每天使用的药物，主要通过抗炎作用使哮喘维持临床控制；缓解药物是指按需使用的药物，主要通过迅速解除支气管痉挛从而缓解哮喘症状。吸入剂作为当前哮喘、COPD等呼吸系统疾病的重要治疗药物，包括吸入型糖皮质激素，如氟替卡松、布地奈德、莫米松等；吸入用β2受体激动剂，如沙丁胺醇、特布他林等。上述吸入型药物具有靶向性高、剂量小、副作用低的优点；此外，吸入型药物除了对靶点的高活性、高选择性以外，其药代动力学特性也和常规的口服、静注药物不同，它具有特殊的要求：即药物在肺部具有足够的保留时间，同时，药物在血液中具有高的血浆清除率，以确保通过肺部吸收入血后迅速代谢，即要求静注暴露量低、口服生物利用度低。
经检索，目前尚未有上市的吸入型PI3Kδ抑制剂，鉴于现有的PI3Kδ抑制剂在临床研究阶段的哮喘治疗效果，申请人尝试对前期研究发现的代表性分子S-I-19进行吸入给药的可行性探索研究。
在鸡卵清蛋白(OVA)诱导的Balb/C小鼠过敏性哮喘模型上开展吸入的药效学预实验，发现与模型组相比，2.5mg/Kg吸入给药S-I-19不能明显降低小鼠肺泡灌洗液(BALF)中总细胞数，模型组为(7.82±1.23)×106，实验组为(7.21±1.54)×106，而且动物显示出一定的体重减轻，提示该分子具有一定的毒性。也就是说，预实验的结果表明：具有显著抗肿瘤活性的代表分子S-I-19不适合用于吸入给药治疗哮喘。
进一步测试S-I-19在大鼠中的口服和静注给药的药代动力学，测试数据见表1：
表1.单次口服和静脉注射给药S-I-19后的主要药代动力学测试结果
从表1中可见，S-I-19具有一定的口服生物利用度，且静注后有一定的暴露量，因此在吸入后易引起全身暴露，从而导致相应的毒性，这与对小鼠吸入给药S-I-19的药效学预实验的结果相匹配。
综上所述，如何对具有显著抗肿瘤活性的代表分子S-I-19进行结构改造，开发出一类在保持或提升 PI3Kδ抑制活性的同时，增加血浆清除率、降低口服生物利用度的PI3Kδ抑制剂，以期达到吸入用药的要求，作为预防或治疗哮喘、COPD等呼吸系统疾病的潜力药物开发，是本领域技术人员急需解决的技术难题。
发明内容
本发明要解决的技术问题在于，提供一种全新结构的PI3Kδ选择性抑制剂，以芳环并噻嗪类化合物作为骨架分子，用于吸入给药以治疗哮喘、COPD等呼吸系统疾病。
为解决上述技术问题，本发明提供的技术方案具体如下：
本发明提供了一种PI3Kδ选择性抑制剂，为通式Ⅰ所示的化合物或其药学可接受的盐：
式中：环A选自至少被一个R1取代的苯环、吡啶环、噻吩环或呋喃环；R1选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6单烷基胺基、C1-6二烷基胺基或氰基；
环B选自至少被一个R2取代的苯环、吡啶环、吡嗪环、哒嗪环、嘧啶环、噻唑环、吡唑环，R2选自氢、卤素、C2-6炔基、C2-6烯基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6单烷基胺基、C1-6二烷基胺基、氨基、氰基、羟基、羧基、羰基、酮基中的一种或几种；
R3、R4、R5各自独立的选自卤素、C1-6烷基、卤代C1-6烷基、C3-8环烷基、氨基、氰基、C1-6单烷基胺基或C1-6二烷基胺基。
本发明还提供了一种PI3Kδ选择性抑制剂，为通式a所示的化合物或其药学可接受的盐：
式中：环A选自至少被一个R1取代的苯环、吡啶环、噻吩环、呋喃环；R1选自氢、C1-6烷基、C1-6含氟烷基、C1-6烷氧基、C1-6含氟烷氧基、C1-6单烷基胺基、C1-6二烷基胺基、卤素或氰基；
环B选自至少被一个R2取代的苯环、吡啶环、吡嗪环、哒嗪环、嘧啶环、噻唑环、吡唑环；R2选自氢、卤素、C1-6烷基、C1-6烷氧基、C1-6单烷基胺基、C1-6二烷基胺基、氰基或羧基；
R3选自卤素、氨基、C1-6单烷基胺基、C1-6二烷基胺基、C1-6烷基、C3-8环烷基、C1-6含氟烷基。
优选的，上述通式Ⅰ或通式a中，选自R1取代的以下杂环：
优选的，上述的通式Ⅰ或通式a中，R1选自氢、甲基、乙基、氟、氯、溴、三氟甲基、二氟甲基、甲氧基、三氟甲氧基、二氟甲氧基、氰基、乙炔基。
优选的，上述的通式Ⅰ或通式a中，环B选自R2取代的苯环、吡啶环、吡嗪环、哒嗪环、嘧啶环、噻唑环、吡唑环；R2为氢、甲基、乙基、氟、氯、溴、三氟甲基、二氟甲基、甲氧基、三氟甲氧基、二氟甲氧基、甲胺基、二甲胺基、二乙胺基、氰基、羧基。
优选的，上述的通式Ⅰ或通式a中，R3为氨基、甲基、乙基、环丙基、氟、氯、溴、三氟甲基、二氟甲基、2.2.2-三氟乙基。
本发明还提供了一种PI3Kδ选择性抑制剂，为通式Ⅱ所示的化合物或其药学可接受的盐：
式中：R1选自卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6单烷基胺基、C1-6二烷基胺基或氰基；R2选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6单烷基胺基、C1-6二烷基胺基、氨基、氰基、羟基、羧基、羰基或酮基；R3、R4、R5各自独立的选自C1-6烷基、卤代C1-6烷基、氨基、氰基、C1-6单烷基胺基或C1-6二烷基胺基。
本发明还提供了一种PI3Kδ选择性抑制剂，为通式Ⅲ所示的化合物或其药学可接受的盐：
式中：X、Y、M、N中的任意一个为N，其余三个为C；R1选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基或卤代C1-6烷氧基；R2选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6单烷基胺基、C1-6二烷基胺基、氨基、氰基、羟基、羧基、羰基或酮基；R3、R4、R5各自独立的选自甲基、氨基或氰基。
本发明还提供了一种PI3Kδ选择性抑制剂，为通式Ⅳ所示的化合物或其药学可接受的盐：
式中：A、B、Q中的任意一个为S或O，其余二个为C；R1选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基或卤代C1-6烷氧基；且当A为S或O时，与A连接的R1为氢；R2选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6单烷基胺基、C1-6二烷基胺基、氨基、氰基、羟基、羧基、羰基或酮基；R3、R4、R5各自独立的选自甲基、氨基或氰基。
进一步，本发明还提供了一种PI3Kδ选择性抑制剂，选自化合物编号为1～66的如下特征化合物或其异构体或其药学可接受的盐或者前药：



【术语说明】
本发明所述的“化合物”，包括但不限于化合物的如下情形：游离碱、立体异构体、几何异构体、互变异构体、同位素、药学上可接受的盐、溶剂化物、水合物、前药(酯或磷酸酯)等形式。
本发明所述的“化合物”，可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本发明中含有不对称碳原子的化合物，可以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以通过外消旋混合物拆分、使用手性原料或手性试剂合成的方法获得。
本发明所述的“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式，获得碱加成盐。药学上可接受的碱加成盐，包括但不限于钠、钾、钙、镁盐、铵或有机氨。例如：碱金属盐、碱土金属盐、其他金属盐、无机碱盐、有机碱盐、无机酸盐、低级烷磺酸盐、芳基磺酸盐、有机酸盐、氨基酸盐等。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
含有前述通式结构的化合物，本文中所用的术语具有如下含义：
术语“卤素”，指氟、氯、溴或碘。
术语“C1-6烷基”，除非指明不同数目的原子，是指包含1-6个碳原子的直链或支链的烷烃。本发明所用“烷基”的实例包括但不限于甲基、乙基、正丙基、正丁基、正戊基、异丁基、异丙基和叔丁基。“烷基”还包括取代烷基。所述烷基可任选被卤素或羟基一次或多次取代。
术语“C1-6含氟烷基”，是指含有氟原子的烷基基团，其中烷基如上所定义。本文所用“C1-6含氟烷基”的实例包括但不限于三氟甲基、二氟甲基、2.2.2-三氟乙基。“C1-6含氟烷基”还包括C1-6取代含氟烷基。C1-6取代含氟烷基可任选被卤素取代一次或多次。
术语“C1-6烷氧基”，是指-O-烷基基团，其中烷基如上所定义。本文所用“烷氧基”的实例包括但不 限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基和叔丁氧基。“烷氧基”还包括取代烷氧基。烷氧基可任选被卤素取代一次或多次。
术语“C1-6含氟烷氧基”，是指含有氟原子的-O-烷基基团，其中烷基如上所定义。本文所用“C1-6含氟烷氧基”的实例包括但不限于三氟甲氧基、二氟甲氧基。
术语“C1-6单烷基胺基”，是指C1-6单烷基取代的氨基，其中烷基如上所定义。本文所用“C1-6单烷基胺基”的实例包括但不限于甲胺基、乙氨基、丙氨基、环丙基氨基、异丙基氨基。
术语“C1-6双烷基胺基”，是指两个C1-6烷基取代的氨基，其中烷基如上所定义。本文所用“C1-6双烷基胺基”的实例包括但不限于二甲胺基、二乙氨基、氮杂环丙烷基、氮杂环丁烷基、氮杂环戊烷基、氮杂环己烷基。
术语“环烷基”，是指3-8个环原子的饱和的碳环，本文所用“环烷基”的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
本发明还提供了一种药物组合物，包含至少一种如前所述的化合物或其药学上可接受的盐作为活性成份，以及至少一种或多种药学上可接受的载体。
本发明所述的“药物组合物”，指一种或多种本发明的化合物或其盐与在本领域中通常接受的用于将生物活性化合物输送至有机体(例如人)的载体的制剂。药物组合物的目的是有利于对有机体给药输送。
特别的，本发明提供的药物组合物，采用可吸入型的药物递送方式。
本发明所述的“可吸入型”，是指该类化合物可以通过气道、肺部给药使其通过肺上皮细胞或呼吸道黏膜吸收，直接进入血液循环。“可吸入型”表明其可以进行吸入给药但不局限于吸入给药，其仍然适用于如口服(包括含服或舌下给药)、直肠给药、局部给药(包括含服、舌下给药或经皮给药)、阴道给药或胃肠外给药(包括皮下注射、肌内注射、静脉注射或皮内注射)等给药途径。这些制剂可由药剂学领域中已知的任何方法制备。例如通过将活性成分与载体或赋形剂混在一起的方法。
本发明还提供了一种制备如前所述的化合物或药物组合物在预防或治疗与PI3Kδ激酶活性相关的疾病中的用途。
优选的，前述的药物用于预防或治疗过敏性疾病和炎性疾病；特别是通过吸入给药的递送方式在预防或治疗哮喘、COPD以及PI3Kδ缺陷相关的自身免疫性疾病的治疗中发挥作用。
更优选的，前述的过敏性疾病和炎性疾病选自任何类型或起因的哮喘，包括但不限于内源性哮喘、外源性哮喘、轻度哮喘、中度哮喘、重度哮喘、支气管炎性哮喘、运动型哮喘、职业性哮喘、Th2型哮喘和非Th2型哮喘、喘鸣婴儿综合征、急性肺损伤、慢性阻塞性肺病、慢性支气管炎、肺气肿、成人型/急性呼吸窘迫综合征等呼吸系统疾病；以及类风湿性关节炎、骨关节炎、红斑狼疮、牛皮癣、过敏性皮炎、多发性硬化症等自身免疫性疾病。
特别的，本发明适用的其他炎症或阻塞性气道疾病，选自任何类型或起因的尘肺，包括但不限于石棉肺、烟尘肺、铁尘肺、毛尘肺和棉尘肺等。
优选的，前述的药物用于预防或治疗肺部肿瘤。
更优选的，前述的肺部肿瘤，包括但不限于非小细胞肺癌、小细胞肺癌等。
与现有技术相比，本发明有益效果如下：
本申请的发明人团队经过创造性研究意外的发现，在S-I-19的嘧啶基团的2-位引入氨基(即嘧啶环上形成三取代)，得到的目标分子的药代特性产生明显变化，血浆清除率明显增加，口服生物利用度显著降低，符合吸入用药的口服药代动力学要求。
综上，本发明提供的化合物均具有PI3Kδ抑制作用，大部分化合物高选择性的对PI3Kδ有显著的抑制作用。并且，经吸入方式递送，部分化合物能较好的保留在肺部，具有较佳的吸入药代动力学特性，可作为预防或治疗哮喘、COPD等呼吸系统疾病的吸入型药物。
附图说明
图1为本发明提供化合物的口服药代动力学性质。
图2为本发明提供化合物的吸入药代动力学性质。
图3为OVA诱导Balb/C小鼠急性哮喘给药后的体重变化情况。
图4为OVA诱导Balb/C小鼠急性哮喘给药后的支气管肺泡灌洗液(BALF)细胞总数。
图5为OVA诱导Balb/C小鼠急性哮喘给药后的支气管肺泡灌洗液瑞氏染色结果。
图6为OVA诱导Balb/C小鼠急性哮喘给药后的肺功能检测实验结果。
具体实施方式
下面包含的特定实施例是为了举例说明，不应被理解为对本发明范围的限制。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
本发明还提供了上述化合物的制备方法，但不仅限于以下方法：
实施例1：(S)-2,4-二氨基-6-((1-(8-氟-1,1-二氧化物-2-苯基-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)嘧啶-5-氰基(1)的合成
步骤1:中间体2-溴-6-氟苯磺酰氯(A2)的制备：
将2-溴-6-氟苯胺(A1,1.9g)于0℃逐滴滴加至7.0mL 10M的HCl溶液中，析出大量白色固体。随后在该温度下，滴加质量分数为40％的亚硝酸钠水溶液直至溶液澄清，得到黄色的重氮盐溶液。9.0mL浓盐酸和0.25g CuSO4·5H2O置于250mL圆底烧瓶中。冰浴下，同时滴加质量分数为35％的NaHSO3水溶液和上述重氮盐溶液，加毕继续搅拌30min，监测反应。原料消失后，加入二氯甲烷萃取，合并有机层，干燥，旋干溶剂，得黄色油状液体，无需纯化直接进行下一步反应，收率83％。
步骤2:2-溴-6-氟-N-苯基苯磺酰胺(A3)的制备：
将2-溴-6-氟苯磺酰氯(A2,6.7g,20.5mmol)溶于20mL的DCM中，加入8mL无水吡啶，0℃逐滴滴加苯胺(1.9mL,20.5mmol)，室温搅拌30min。反应结束后旋干DCM,将反应液倒入20mL的2N盐酸中，析出红色固体。抽滤，水洗，得红色固体产物，无需纯化，直接进行下一步反应，收率98％。
ESI-MS:m/z＝330[M+H]+。
1H NMR(500MHz,DMSO-d6)δ10.86(s,1H),7.68(d,J＝8.0Hz,1H),7.53(td,J＝8.5,5.5Hz,1H),7.47-7.42(m,1H),7.27-7.24(m,2H),7.14-7.12(m,2H),7.05-7.01(m,1H)。
步骤3:(S)-2-(1-(8-氟-1,1-二氧化物-2-苯基-2H-苯并[e][1,2]噻嗪-3-基)乙基)异吲哚啉-1,3-二酮(A4)的制备：
将中间体(A3,7.4g,16.5mmol)、手性炔胺(5.0g,24.8mmol)和Pd(PPh3)2Cl(5mol％)置于干燥的封管中，N2置换3次，正压下加入DIPEA和50mL DMF(49.5mmol)，90℃搅拌过夜。原料消失后，旋干溶剂得黑色油状物，经快速柱层析(PE/EA＝12:1)得淡黄色固体，收率：71％。
ESI-MS:m/z＝449[M+H]+。
1H NMR(500MHz,CDCl3)δ7.80-7.81(m,2H),7.72-7.70(m,2H),7.59-7.55(m,1H),7.32-7.28(m,4H),7.17-7.14(m,1H),7.07-7.05(m,3H),4.99-4.95(q,J＝7.0Hz,1H),1.82(d,J＝7.5Hz,3H)。
步骤4:(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)的制备：
中间体A4和水合肼(85％,2.6mL,43.2mmol,2.0equiv.)加入100mL EtOH中、充分冷却，N2置换3次，80℃搅拌反应2h。反应完全后，充分冷却，析出大量白色絮状沉淀，抽滤，滤液浓缩得白色固体。向其中加入EtOH，冷却，抽滤，滤液继续浓缩后加入乙酸乙酯，冷却，抽滤，滤液旋干得黄色油状粗产物A5，无需纯化，直接进行下一步反应。收率85％；ESI-MS:m/z＝319[M+H]+。
步骤5：(S)-2,4-二氨基-6-((1-(8-氟-1,1-二氧化物-2-苯基-2H-苯并[e][1,2]噻嗪-3-)乙基)氨基)嘧啶-5-氰基的制备：
氮气氛围下，将中间体A5(56.0mg,0.17mmol)、2,4-二氨基-5-氰基-6-氯嘧啶(31.6mg,0.18mmol)、无水氟化钾(19.7mg,0.34mmol)、DIPEA(118.0μL,0.68mmol)和DMSO(2.0mL)依次加入干燥的单口瓶中，回流反应24h。反应结束后，加入大量的水，乙酸乙酯萃取，合并有机层，饱和食盐水洗涤，无水Na2SO4干燥，减压浓缩得黄色油状物，经快速柱层析得白色固体，收率39％。
ESI-MS:m/z＝452[M+H]+。
1H NMR(500MHz,CDCl3)δ7.57-7.53(m,1H),7.38-7.37(m,3H),7.24-7.23(m,3H),7.17(t,J＝9.0Hz,1H),6.70(s,1H),5.33(brs,2H),5.28(d,J＝7.5Hz,1H),4.94(brs,2H),4.79-4.74(m,1H),1.49(d,J＝7.0Hz,3H)。
13C NMR(125MHz,CDCl3)δ164.4,162.7,162.0,157.4(d,J＝258.5Hz),146.0,135.8,134.8,133.6(d,J＝8.6Hz),129.1,129.0,128.6,123.9,120.6(d,J＝14.5Hz),116.3,116.1,116.0,111.3,47.9,19.9。
实施例2：(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物-2-苯基-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(2)的合成
氮气氛围下，将中间体A5(56.0mg,0.17mmol)、2-氨基-4-甲基-5-氰基-6-氯嘧啶(0.18mmol)、DIPEA(118.0μL,0.68mmol)和t-BuOH(2.0mL)依次加入干燥的封管中，100摄氏度反应24h。反应结束后，浓缩反应液，经快速柱层析得白色固体，收率73％。
ESI-MS:m/z＝451[M+H]+。
1H NMR(500MHz,DMSO-d6)δ7.74(d,J＝5.0Hz,1H),7.56(d,J＝7.5Hz,1H),7.44-7.33(m,5H),7.20(d,J＝7.0Hz,3H),6.91(s,1H),6.24(s,1H),4.73-4.71(m,1H),2.25(s,3H),1.38(d,J＝6.0Hz,3H)。
13C NMR(125MHz,DMSO-d6)δ171.4,162.8,162.1,156.7(d,J＝254.6Hz),145.7,135.6,135.4,135.0(d,J＝8.9Hz),129.7,129.3,128.8,125.1,120.0,117.5,116.2(d,J＝20.7Hz),111.0,78.9,47.3,23.2,18.8。
实施例3：(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物-2-苯基-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-乙基嘧 啶-5-氰基(3)的合成
实施例3化合物的合成通过使用类似于实施例2中所述步骤完成。将2-氨基-4-甲基-5-氰基-6-氯嘧啶替换为2-氨基-4-乙基-5-氰基-6-氯嘧啶，得白色固体，收率61％。
ESI-MS:m/z＝465[M+H]+。
实施例4:(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物-2-苯基-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-环丙基嘧啶-5-氰基(4)的合成
实施例4化合物的合成通过使用类似于实施例2中所述步骤完成。将2-氨基-4-甲基-5-氰基-6-氯嘧啶替换为2-氨基-4-环丙基-5-氰基-6-氯嘧啶，得白色固体，收率41％。
ESI-MS:m/z＝477[M+H]+。
实施例5:(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物-2-苯基-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-三氟甲基嘧啶-5-氰基(5)的合成
实施例5化合物的合成通过使用类似于实施例2中所述步骤完成。将2-氨基-4-甲基-5-氰基-6-氯嘧啶替换为2-氨基-4-三氟甲基-5-氰基-6-氯嘧啶，得白色固体，收率78％。
ESI-MS:m/z＝505[M+H]+。
实施例6:(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物-2-苯基-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-(2,2,2-三氟乙基)嘧啶-5-氰基(6)的合成
实施例6化合物的合成通过使用类似于实施例2中所述步骤完成。将2-氨基-4-甲基-5-氰基-6-氯嘧啶替换为2-氨基-4-(2,2,2-三氟乙基)-5-氰基-6-氯嘧啶，得白色固体，收率65％。
ESI-MS:m/z＝519[M+H]+。
实施例7:(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物-2-苯基-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-二氟甲基嘧啶-5-氰基(7)的合成
实施例7化合物的合成通过使用类似于实施例2中所述步骤完成。将2-氨基-4-甲基-5-氰基-6-氯嘧啶替换为2-氨基-4-二氟甲基-5-氰基-6-氯嘧啶，得白色固体，收率69％。
ESI-MS:m/z＝487[M+H]+。
实施例8:(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物-2-苯基-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲氨基嘧啶-5-氰基(8)的合成
实施例8化合物的合成通过使用类似于实施例1中所述步骤完成。将2,4-二氨基-5-氰基-6-氯嘧啶替换为2-氨基-4-甲胺基-5-氰基-6-氯嘧啶，得白色固体，收率45％。
ESI-MS:m/z＝466[M+H]+。
实施例9:(S)-2,4-二氨基-6-((1-(8-氟-1,1-二氧化物--2-(吡啶-3-基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-嘧啶-5-氰基(9)的合成
实施例9化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(吡啶-3-基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(B5)，得白色固体，收率66％。
ESI-MS:m/z＝453[M+H]+。
实施例10:(S)-2,4-二氨基-6-((1-(8-氟-1,1-二氧化物--2-(吡嗪-4-基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-嘧啶-5-氰基(10)的合成
实施例10化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(吡嗪-4-基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(C5)，得白色固体，收率56％。
ESI-MS:m/z＝454[M+H]+。
实施例11:(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物--2-(吡嗪-4-基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(11)的合成
实施例11化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(吡嗪-4-基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(C5)，得白色固体，收率66％。
ESI-MS:m/z＝453[M+H]+。
实施例12:(S)-2,4-二氨基-6-((1-(8-氟-1,1-二氧化物--2-(哒嗪-2-基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-嘧啶-5-氰基(12)的合成
实施例12化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(哒嗪-2-基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(D5)，得白色固体，收率46％。
ESI-MS:m/z＝454[M+H]+。
实施例13:(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物--2-(哒嗪-2-基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(13)的合成
实施例13化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(哒嗪-2-基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(D5)，得白色固体，收率76％。
ESI-MS:m/z＝453[M+H]+。
实施例14:(S)-2,4-二氨基-6-((1-(8-氟-1,1-二氧化物--2-(嘧啶-5-基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-嘧啶-5-氰基(14)的合成
实施例14化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(嘧啶-5-基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(E5)，得白色固体，收率36％。
ESI-MS:m/z＝454[M+H]+。
实施例15:(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物--2-(嘧啶-5-基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(15)的合成
实施例15化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(嘧啶-5-基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(E5)，得白色固体，收率66％。
ESI-MS:m/z＝453[M+H]+。
实施例16:(S)-2,4-二氨基-6-((1-(8-氟-1,1-二氧化物--2-(噻唑-5-基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-嘧啶-5-氰基(16)的合成
实施例16化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(噻唑-5-基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(F5)，得白色固体，收率56％。
ESI-MS:m/z＝459[M+H]+。
实施例17:(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物--2-(噻唑-5-基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(17)的合成
实施例17化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(噻唑-5-基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(F5)，得白色固体，收率73％。
ESI-MS:m/z＝458[M+H]+。
实施例18:(S)-2,4-二氨基-6-((1-(8-氟-1,1-二氧化物--2-(1H-吡唑-4-基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-嘧啶-5-氰基(18)的合成
实施例18化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(1H-吡唑-4-基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(G5)，得白色固体，收率46％。
ESI-MS:m/z＝442[M+H]+。
实施例19:(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物--2-(4-氟苯基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(19)的合成
实施例19化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(4-氟苯基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(H5)，得白色固体，收率79％。
ESI-MS:m/z＝469[M+H]+。
实施例20:(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物--2-(3-甲基苯基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(20)的合成
实施例20化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(3-甲基苯基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(I5)，得白色固体，收率76％。
ESI-MS:m/z＝465[M+H]+。
实施例21:(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物--2-(3-甲氧基苯基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(21)的合成
实施例21化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(3-甲氧基苯基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(J5)，得白色固体，收率74％。
ESI-MS:m/z＝481[M+H]+。
实施例22:(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物--2-(3-甲胺基苯基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(22)的合成
实施例22化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(3-甲胺基苯基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(K5)，得白色固体，收率26％。
ESI-MS:m/z＝480[M+H]+。
实施例23:(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物--2-(3-二甲胺基苯基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(23)的合成
实施例23化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(3-二甲胺基苯基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(L5)，得白色固体，收率56％。
ESI-MS:m/z＝494[M+H]+。
实施例24:(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物--2-(3-氰基苯基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(24)的合成
实施例24化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(3-氰基苯基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(M5)，得白色固体，收率81％。
ESI-MS:m/z＝476[M+H]+。
实施例25:(S)-2-氨基-4-((1-(8-氟-1,1-二氧化物--2-(3-羧基苯基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(25)的合成
实施例25化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氟-2-(3-羧甲酯苯基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(N5)，得白色固体；随后，将上述产物溶于四氢呋喃(1mL)和水(1mL)的混合溶剂中，加入一水合氢氧化锂(2equiv.)，60℃反应两个小时。反应结束后旋干大部分有机溶剂，抽滤，滤液用1.0N HCl酸化，析出大量白色固体，抽滤，滤渣干燥后得白色固体产物，两步总收率64％。
ESI-MS:m/z＝495[M+H]+。
实施例26:(S)-2-氨基-4-((1-(8-甲基-1,1-二氧化物--2-苯基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(26)的合成
实施例26化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-甲基-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(O5)，得白色固体，收率66％。
ESI-MS:m/z＝447[M+H]+。
实施例27:(S)-2-氨基-4-((1-(8-三氟甲基-1,1-二氧化物--2-苯基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(27)的合成
实施例27化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-三氟甲基-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(P5)，得白色固体，收率75％。
ESI-MS:m/z＝501[M+H]+。
实施例28:(S)-2-氨基-4-((1-(8-甲氧基-1,1-二氧化物--2-苯基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(28)的合成
实施例28化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-甲氧基-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(Q5)，得白色固体，收率76％。
ESI-MS:m/z＝463[M+H]+。
实施例29:(S)-2-氨基-4-((1-(8-三氟甲氧基-1,1-二氧化物--2-苯基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(29)的合成
实施例29化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-三氟甲氧基-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(R5)，得白色固体，收率76％。
ESI-MS:m/z＝517[M+H]+。
实施例30:(S)-2-氨基-4-((1-(8-甲胺基-1,1-二氧化物--2-苯基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(30)的合成
实施例30化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氯-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(S5)，得白色固体；随后，将上述产物溶于四氢呋喃(1mL)中，加入DIPEA(5equiv.)、甲胺盐酸盐(2equiv.)，100℃反应24个小时。反应结束后旋干溶剂，柱层析得白色固体产物，两步总收率36％。
ESI-MS:m/z＝462[M+H]+。
实施例31:(S)-2-氨基-4-((1-(8-二甲胺基-1,1-二氧化物--2-苯基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(31)的合成
实施例31化合物的合成通过使用类似于实施例30中所述步骤完成。将甲胺盐酸盐替换成二甲胺盐酸盐，得白色固体，收率76％。
ESI-MS:m/z＝476[M+H]+。
实施例32:(S)-2,4-二氨基-6-((1-(8--1,1-二氧化物-2-苯基-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)嘧啶-5-氰基(32)的合成
实施例32化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氰基-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(T5)，得白色固体，收率56％。
ESI-MS:m/z＝459[M+H]+。
实施例33:(S)-2-氨基-4-((1-(8-氰基-1,1-二氧化物--2-苯基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(33)的合成
实施例33化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氰基-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(T5)，得白色固体，收率77％。
ESI-MS:m/z＝458[M+H]+。
实施例34:(S)-2-氨基-4-((1-(8-乙炔基-1,1-二氧化物--2-苯基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(34)的合成
实施例34化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-乙炔基-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(U5)，得白色固体，收率77％。
ESI-MS:m/z＝457[M+H]+。
实施例35:(S)-2,4-二氨基-6-((1-(8-氯-1,1-二氧化物-2-苯基-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)嘧啶-5-氰基(35)的合成
实施例35化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氯-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(S5)，得白色固体，收率35％。
ESI-MS:m/z＝468[M+H]+。
1H NMR(500MHz,DMSO)δ7.67-7.56(m,5H),7.50-7.42(m,3H),7.23(d,J＝7.5Hz,2H),6.92(d,J＝8.0Hz,1H),6.83(s,1H),6.65(s,2H),4.68-4.65(m,1H),1.36(d,J＝6.5Hz,3H)。
13C NMR(125MHz,DMSO)δ165.8,163.3,163.1,146.1,135.8,135.6,133.9,130.9,129.7,129.6,129.3,128.9,128.6,128.4,117.8,110.9,60.9,47.1,19.0。
实施例36:(S)-2-氨基-4-((1-(8-氯-1,1-二氧化物-2-苯基-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(36)的合成
实施例36化合物为实施例30中的中间体。白色固体，收率75％。
ESI-MS:m/z＝467[M+H]+。
1H NMR(500MHz,DMSO)δ7.70-7.67(m,2H),7.62(dd,J＝7.5,2.0Hz,1H),7.46-7.41(m,2H),7.41-7.38(m,2H),7.20-7.18(m,2H),7.10(s,1H),6.86(s,1H),6.26(s,1H),4.73-4.67(m,1H),2.25(s,3H),1.38(d,J＝7.0Hz,3H)。
13C NMR(125MHz,DMSO)δ171.4,162.8,162.1,145.2,135.8,135.6,133.9,131.0,129.7,129.6,129.3,128.9,128.6,128.5,117.6,111.3,78.8,47.1,23.2,18.7。
实施例37:(S)-2-氨基-4-((1-(8-氯-1,1-二氧化物-2-苯基-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-乙基嘧啶-5-氰基(37)的合成
实施例37化合物的合成通过使用类似于实施例30中所述步骤完成。将2-氨基-4-甲基-5-氰基-6-氯嘧啶替换为2-氨基-4-乙基-5-氰基-6-氯嘧啶，得白色固体，收率75％。
ESI-MS:m/z＝481[M+H]+。
实施例38:(S)-2-氨基-4-((1-(8-氯-1,1-二氧化物-2-苯基-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-三氟甲基嘧啶-5-氰基(38)的合成
实施例38化合物的合成通过使用类似于实施例30中所述步骤完成。将2-氨基-4-甲基-5-氰基-6-氯嘧啶替换为2-氨基-4-三氟甲基-5-氰基-6-氯嘧啶，得白色固体，收率78％。
ESI-MS:m/z＝521[M+H]+。
实施例39:(S)-2-氨基-4-((1-(8-氯-1,1-二氧化物--2-(1H-吡唑-4-基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-三氟甲基嘧啶-5-氰基(39)的合成
实施例39化合物的合成通过使用类似于实施例38中所述步骤完成。将(S)-3-(1-氨乙基)-8-氯-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(S5)替换为(S)-3-(1-氨乙基)-8-氯-2-(1H-吡唑-4-基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(V5)，得白色固体，收率54％。
ESI-MS:m/z＝511[M+H]+。
实施例40:(S)-2,4-二氨基-6-((1-(8-氯-1,1-二氧化物-2-(1H-吡唑-4-基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)嘧啶-5-氰基(40)的合成
实施例40化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氯-2-(1H-吡唑-4-基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(V5)，得白色固体，收率29％。
ESI-MS:m/z＝458[M+H]+。
实施例41:(S)-2-氨基-4-((1-(8-氯-1,1-二氧化物--2-(4-氟苯基)-2H-苯并[e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(41)的合成
实施例41化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-8-氯-2-(4-氟苯基)-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(W5)，得白色固体，收率69％。
ESI-MS:m/z＝485[M+H]+。
实施例42:(S)-2,4-二氨基-6-((1-(1,1-二氧化物-2-苯基-2H-噻吩[2,3-e][1,2]噻嗪-3-基)乙基)氨基)嘧啶-5-氰基(42)的合成
实施例42化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-苯基-2H-噻吩[2,3-e][1,2]噻嗪-1,1-二氧化物(X5)，得白色固体，收率37％。
ESI-MS:m/z＝440[M+H]+。
实施例43:(S)-2-氨基-4-((1-(1,1-二氧化物-2-苯基-2H-噻吩[2,3-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(43)的合成
实施例43化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-苯基-2H-噻吩[2,3-e][1,2]噻嗪-1,1-二氧化物(X5)，得白色固体，收率77％。
ESI-MS:m/z＝439[M+H]+。
实施例44:(S)-2-氨基-4-((1-(1,1-二氧化物-2-苯基-2H-噻吩[2,3-e][1,2]噻嗪-3-基)乙基)氨基)-6-乙基嘧啶-5-氰基(44)的合成
实施例44化合物的合成通过使用类似于实施例43中所述步骤完成。将2-氨基-4-甲基-5-氰基-6-氯嘧啶替换为2-氨基-4-乙基-5-氰基-6-氯嘧啶，得白色固体，收率74％。
ESI-MS:m/z＝453[M+H]+。
实施例45:(S)-2-氨基-4-((1-(1,1-二氧化物-2-苯基-2H-噻吩[2,3-e][1,2]噻嗪-3-基)乙基)氨基)-6-三氟甲基嘧啶-5-氰基(45)的合成
实施例45化合物的合成通过使用类似于实施例43中所述步骤完成。将2-氨基-4-甲基-5-氰基-6-氯嘧啶替换为2-氨基-4-三氟甲基-5-氰基-6-氯嘧啶，得白色固体，收率73％。
ESI-MS:m/z＝493[M+H]+。
实施例46:(S)-2-氨基-4-((1-(1,1-二氧化物-2-(3-吡啶基)-2H-噻吩[2,3-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(46)的合成
实施例46化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-(3-吡啶基)-2H-噻吩[2,3-e][1,2]噻嗪-1,1-二氧化物(Y5)，得白色固体，收率71％。
ESI-MS:m/z＝440[M+H]+。
实施例47:(S)-2-氨基-4-((1-(1,1-二氧化物-2-(1H-吡唑-4-基)-2H-噻吩[2,3-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(47)的合成
实施例47化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-(1H-吡唑-4-基)-2H-噻吩[2,3-e][1,2]噻嗪-1,1-二氧化物(Z5)，得白色固体，收率37％。
ESI-MS:m/z＝429[M+H]+。
实施例48:(S)-2,4-二氨基-6-((1-(1,1-二氧化物-2-苯基-2H-噻吩[3,2-e][1,2]噻嗪-3-基)乙基)氨基)嘧啶-5-氰基(48)的合成
实施例48化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-苯基-2H-噻吩[3,2-e][1,2]噻嗪-1,1-二氧化物(AA5)，得白色固体，收率57％。
ESI-MS:m/z＝440[M+H]+。
实施例49:(S)-2-氨基-4-((1-(1,1-二氧化物-2-苯基-2H-噻吩[3,2-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(49)的合成
实施例49化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-苯基-2H-噻吩[3,2-e][1,2]噻嗪-1,1-二氧化物(AA5)，得白色固体，收率77％。
ESI-MS:m/z＝439[M+H]+。
1H NMR(500MHz,DMSO)δ8.00(d,J＝5.0Hz,1H),7.49(t,J＝7.5Hz,2H),7.42(dd,J＝10.5,6.0Hz,3H),7.26(d,J＝7.5Hz,2H),7.10(s,1H),6.83(s,1H),6.27(s,1H),4.70-4.67(m,1H),2.26(s,3H),1.65(d,J＝6.5Hz,3H)。
13C NMR(125MHz,DMSO)δ171.3,162.8,162.0,145.4,141.6,134.9,131.8,129.8,129.3,129.1,127.1,126.8,117.5,105.9,78.8,47.1,23.2,19.0。
实施例50:(S)-2-氨基-4-((1-(1,1-二氧化物-2-(1H-吡唑-4-基)-2H-噻吩[3,2-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(50)的合成
实施例50化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-(1H-吡唑-4-基)-2H-噻吩[3,2-e][1,2]噻嗪-1,1- 二氧化物(AB5)，得白色固体，收率19％。
ESI-MS:m/z＝429[M+H]+。
实施例51:(S)-2,4-二氨基-6-((1-(1,1-二氧化物-2-苯基-2H-呋喃[2,3-e][1,2]噻嗪-3-基)乙基)氨基)嘧啶-5-氰基(51)的合成
实施例51化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-苯基-2H-呋喃[2,3-e][1,2]噻嗪-1,1-二氧化物(AC5)，得白色固体，收率38％。
ESI-MS:m/z＝424[M+H]+。
实施例52:(S)-2-氨基-4-((1-(1,1-二氧化物-2-苯基-2H-呋喃[2,3-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(52)的合成
实施例52化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-苯基-2H-呋喃[2,3-e][1,2]噻嗪-1,1-二氧化物(AC5)，得白色固体，收率77％。
ESI-MS:m/z＝423[M+H]+。
实施例53:(S)-2-氨基-4-((1-(1,1-二氧化物-2-(1H-吡唑-4-基)-2H-呋喃[2,3-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(53)的合成
实施例53化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-(1H-吡唑-4-基)-2H-呋喃[2,3-e][1,2]噻嗪-1,1-二氧化物(AD5)，得白色固体，收率37％。
ESI-MS:m/z＝413[M+H]+。
实施例54:(S)-2,4-二氨基-6-((1-(1,1-二氧化物-2-苯基-2H-呋喃[3,2-e][1,2]噻嗪-3-基)乙基)氨基)嘧啶-5-氰基(54)的合成
实施例54化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-苯基-2H-呋喃[3,2-e][1,2]噻嗪-1,1-二氧化物(AE5)，得白色固体，收率37％。
ESI-MS:m/z＝424[M+H]+。
实施例55:(S)-2-氨基-4-((1-(1,1-二氧化物-2-苯基-2H-呋喃[3,2-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(55)的合成
实施例55化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-苯基-2H-呋喃[3,2-e][1,2]噻嗪-1,1-二氧化物(AE5)，得白色固体，收率77％。
ESI-MS:m/z＝423[M+H]+。
实施例56:(S)-2-氨基-4-((1-(1,1-二氧化物-2-(1H-吡唑-4-基)-2H-呋喃[3,2-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(56)的合成
实施例56化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-(1H-吡唑-4-基)-2H-呋喃[3,2-e][1,2]噻嗪-1,1-二氧化物(AF5)，得白色固体，收率37％。
ESI-MS:m/z＝413[M+H]+。
实施例57:(S)-2,4-二氨基-6-((1-(1,1-二氧化物-2-苯基-2H-吡啶并[2,3-e][1,2]噻嗪-3-基)乙基)氨基)嘧啶-5-氰基(57)的合成
实施例57化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-苯基-2H-吡啶并[2,3-e][1,2]噻嗪-1,1-二氧化物(AG5)，得白色固体，收率57％。
ESI-MS:m/z＝435[M+H]+。
实施例58:(S)-2-氨基-4-((1-(1,1-二氧化物-2-苯基-2H-吡啶并[2,3-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(58)的合成
实施例58化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-苯基-2H-吡啶并[2,3-e][1,2]噻嗪-1,1-二氧化物(AG5)，得白色固体，收率75％。
ESI-MS:m/z＝434[M+H]+。
1H NMR(500MHz,CDCl3)δ8.82(s,1H),8.06(d,J＝7.5Hz,1H),7.38(s,4H),7.23(s,2H),6.96(s,1H),5.54(d,J＝6.0Hz,2H),5.34(s,1H),4.83-4.80(m,1H),2.37(s,3H),1.53(d,J＝6.5Hz,3H)。
13C NMR(125MHz,CDCl3)δ171.2,161.8,153.3,150.4,148.6,135.2,131.0,129.3,129.2,128.6,128.4,122.7,116.1,112.6,81.0,60.4,48.1,22.9,19.8。
实施例59:(S)-2-氨基-4-((1-(1,1-二氧化物-2-(1H-吡唑-4-基)-2H-吡啶并[2,3-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(59)的合成
实施例59化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-(1H-吡唑-4-基)-2H-吡啶并[2,3-e][1,2]噻嗪-1,1-二氧化物(AH5)，得白色固体，收率47％。
ESI-MS:m/z＝424[M+H]+。
实施例60:(S)-2,4-二氨基-6-((1-(1,1-二氧化物-2-苯基-2H-吡啶并[3,4-e][1,2]噻嗪-3-基)乙基)氨基)嘧啶-5-氰基(60)的合成
实施例60化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-苯基-2H-吡啶并[3,4-e][1,2]噻嗪-1,1-二氧化物(AI5)，得白色固体，收率37％。
ESI-MS:m/z＝435[M+H]+。
实施例61:(S)-2-氨基-4-((1-(1,1-二氧化物-2-苯基-2H-吡啶并[3,4-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(61)的合成
实施例61化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-苯基-2H-吡啶并[3,4-e][1,2]噻嗪-1,1-二氧化物(AI5)，得白色固体，收率75％。
ESI-MS:m/z＝434[M+H]+。
实施例62:(S)-2-氨基-4-((1-(1,1-二氧化物-2-(1H-吡唑-4-基)-2H-吡啶并[3,4-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(62)的合成
实施例62化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-(1H-吡唑-4-基)-2H-吡啶并[3,4-e][1,2]噻嗪-1,1-二氧化物(AJ5)，得白色固体，收率67％。
ESI-MS:m/z＝424[M+H]+。
实施例63:(S)-2,4-二氨基-6-((1-(1,1-二氧化物-2-苯基-2H-吡啶并[4,3-e][1,2]噻嗪-3-基)乙基)氨基)嘧啶-5-氰基(63)的合成
实施例63化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-苯基-2H-吡啶并[4,3-e][1,2]噻嗪-1,1-二氧化物(AK5)，得白色固体，收率79％。
ESI-MS:m/z＝435[M+H]+。
实施例64:(S)-2-氨基-4-((1-(1,1-二氧化物-2-苯基-2H-吡啶并[4,3-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(64)的合成
实施例64化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-苯基-2H-吡啶并[4,3-e][1,2]噻嗪-1,1-二氧化物(AK5)，得白色固体，收率75％。
ESI-MS:m/z＝434[M+H]+。
实施例65：(S)-2-氨基-4-((1-(1,1-二氧化物-2-(1H-吡唑-4-基)-2H-吡啶并[4,3-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(65)的合成
实施例65化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-(1H-吡唑-4-基)-2H-吡啶并[4,3-e][1,2]噻嗪-1,1-二氧化物(AL5)，得白色固体，收率47％。
ESI-MS:m/z＝424[M+H]+。
实施例66:(S)-2,4-二氨基-6-((1-(1,1-二氧化物-2-苯基-2H-吡啶并[3,2-e][1,2]噻嗪-3-基)乙基)氨基)嘧啶-5-氰基(66)的合成
实施例66化合物的合成通过使用类似于实施例1中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-苯基-2H-吡啶并[3,2-e][1,2]噻嗪-1,1-二氧化物(AM5)，得白色固体，收率43％。
ESI-MS:m/z＝435[M+H]+。
实施例67:(S)-2-氨基-4-((1-(1,1-二氧化物-2-苯基-2H-吡啶并[3,2-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(67)的合成
实施例67化合物的合成通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-苯基-2H-吡啶并[3,2-e][1,2]噻嗪-1,1-二氧化物(AM5)，得白色固体，收率75％。
ESI-MS:m/z＝434[M+H]+。
实施例68:(S)-2-氨基-4-((1-(1,1-二氧化物-2-(1H-吡唑-4-基)-2H-吡啶并[3,2-e][1,2]噻嗪-3-基)乙基)氨基)-6-甲基嘧啶-5-氰基(68)的合成
实施例68化合物的合成，通过使用类似于实施例2中所述步骤完成。将(S)-3-(1-氨乙基)-8-氟-2-苯基-2H-苯并[e][1,2]噻嗪-1,1-二氧化物(A5)替换为(S)-3-(1-氨乙基)-2-(1H-吡唑-4-基)-2H-吡啶并[3,2-e][1,2]噻嗪-1,1-二氧化物(AN5)，得白色固体，得白色固体，收率37％。
ESI-MS:m/z＝424[M+H]+。
实施例69:本发明化合物(芳环并噻嗪类)的PI3Kδ抑制活性
本部分以idelalisib为阳性对照，采用ADP-Glo Luminescent Assay评价了上述68个芳环并噻嗪衍生物的PI3Kδ抑制活性。本发明的其他化合物与以下所列举的化合物有类似的有益效果，但不应将此理解为本发明化合物仅具有以下有益效果。
1)化合物配制
待测化合物用100％DMSO溶解为10mM储备液，于氮气柜避光存放。
2)测试过程
(1)配制1×Kinase buffer。
(2)化合物浓度梯度的配制：受试化合物测试浓度为1000nM,5倍稀释，6个浓度，单孔测试。在384孔板中梯度稀释成100倍终浓度的6个不同浓度的溶液。用Echo转移50nL到384孔板的化合物孔；阴性对照孔和阳性对照孔中分别加50nL的DMSO。
(3)用1×Kinase buffer配制2倍终浓度的激酶溶液。
(4)在化合物孔和阳性对照孔分别加2.5μL的2倍终浓度的激酶溶液；阴性对照孔中加2.5μL的1×Kinase buffer。
(5)1000rpm离心30秒，振荡混匀后室温孵育10分钟。
(6)用1×Kinase buffer配制2倍终浓度的ATP和底物PIP2的混合溶液。
(7)加入2.5μL的2倍终浓度的ATP和底物的混合溶液，起始反应。
(8)将384孔板1000rpm离心30秒，振荡混匀后室温反应120min。
(9)加入5μL ADP-Glo Reagent，1000rpm离心30秒，振荡混匀后室温孵育180分钟。
(10)加入10μL Kinase Detection Reagent，1000rpm离心30秒，振荡混匀后室温孵育30分钟。
(11)用Envision酶标仪读取发光值RLU。
3)数据分析
抑制率计算公式：
注：“RLU”为样品的化学发光值；“Mean(NC)”为阴性对照孔比值均值；“Mean(PC)”为阳性对照孔比值均值。
4)拟合量效曲线
以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对酶活性的IC50值。
表2.芳环并噻嗪类化合物的PI3Kδ抑制活性和肿瘤细胞增殖抑制活性

【注：】++++表示活性<10nM，+++表示活性10-200nM，++表示活性200-500nM，+表示活性>500nM。
由表2中的抑酶活性数据可知，超半数化合物呈现出中等到强的PI3Kδ抑制活性。具有良好的应用前景。
实施例70:本发明优选化合物对Class I PI3Ks的抑制活性
本发明对部分高活性化合物进行了Class I PI3Ks不同亚型的活性测试，发现对PI3Kδ的选择性作用良好，结果见表3。
表3.优选化合物的Class I PI3Ks抑制活性

由表3中的选择性数据可知，上述化合物均显示出良好的PI3Kδ亚型选择性。
此外需要说明的是，本发明的其他化合物也有类似的效果，不应将此理解为本发明仅表3所述的化合物对PI3Kδ良好的选择性。
实施例71:本发明优选化合物的口服药代动力学特性
本发明对部分高活性化合物(如化合物36)进行SD大鼠的口服药代动力学特性测试，结果见图33。
化合物36经SD大鼠灌胃给药10mg/kg后未在血浆中检测到血药浓度。
SD大鼠静脉注射给药1mg/kg后，药时曲线下面积AUC(0-t)为250.44μg/L*h；消除半衰期为0.47h，血浆清除率CLz/F为18.38L/h/kg。说明化合物36通过静脉给药后消除迅速。此外，化合物36显示出较大的表观分布容积，Vz/F为12.39L/kg，表明该化合物具有较强的组织亲和力。
综上实验表明，化合物36的口服药代动力学特性极差，满足吸入型化合物对口服药代动力学的要求。
实施例72:本发明部分化合物的口服/静注给药后药代动力学特性(p.o.10mg/kg,i.v.0mg/kg)
除本发明的化合物36外，还对其它部分化合物也参照实施例71的方法进行了口服/静注给药后的药代动力学特性测试，通过分析这些化合物的半衰期(T1/2)、生物利用度(F值)等药代动力学参数，归纳出化合物的共性特性，结果见下。
口服吸收特性差，F值<5％的化合物包括：化合物1,2,6,7，10,18,24,26，35,36,39,40,42,43,44,48,49,50,51,52,56,57,66,67。
静注后快速消除，T1/2<0.6h的化合物包括：化合物1,2,3,5,7，12,24,26，35,36,39,40,41,42,43,44,46,48,50,51,52,56,57,62,66,67。
实施例73:本发明化合物36的吸入药代动力学特性
将体重190至220g的健康雄性SD大鼠随机分成6组，每组3只，在异氟烷(Abbott Laboratories)麻醉下，使用微型喷雾器进行气管内给药，给药剂量为60μg/kg。分别在给药后0.2h、1h、2h对肺组织进行灌流，并对肺组织进行匀浆，检测其药物浓度。同时也检测每个时间点的血浆药物浓度。结果见表4和图2。
表4.优选化合物36吸入给药2h后的肺血浓度比
吸入药代动力学实验表明，化合物36经吸入给药后，在肺部能够较长时间的保留，给药2h后肺组织中药物浓度依然维持着很高的水平，并且给药后血浆中的药物浓度一直维持着极低的水平，肺血比为1062优于阳性药物布地奈德(肺血比＝580)；说明化合物36储存在肺部发挥药效同时，也能够避免在血浆充分暴露而导致的毒副作用。
综上可知，化合物36的吸入药代动力学性质优秀，适合吸入给药方式。
实施例74:OVA诱导Balb/C小鼠急性哮喘模型药效学实验
实验材料：
1)体重为18-22g的雌性Balb/C小鼠12只，6～8周龄，购自上海杰思捷实验动物有限公司，许可证号码：SCXK(沪)2018-004。
2)所有药物均以1:9的比例与乳糖混匀。
3)阳性对照：布地奈德(BUD)，由杭州百诚医药科技股份有限公司提供。
4)试剂的配制：
①致敏液：称取1mg OVA于50mL EP管中，用20mL PBS溶解，配制成浓度为50μg/mL的OVA溶液；称取1g Al(OH)3于15mL EP管中，加PBS 10mL，配制成浓度为10％的Al(OH)3混悬液，用力震荡至完全溶解；将上述两溶液充分混匀(1:1)，室温放置1h；1500r/min，离心5min，弃上清；最后用双蒸水定容至7mL。
②1.5％雾化液：150mg OVA+10mL PBS，现配现用。
5)实验分组：体重为18-22g雌性Balb/C小鼠适应性饲养一周后，随机分3组：正常组(control)、模型组(model)、化合物36组、BUD组，每组4只。各组小鼠打耳标标记，分笼饲养。实验过程中，小鼠自由饮水，饲料充足。
6)急性哮喘模型的建立
(1)OVA致敏：模型组、化合物36组和BUD组小鼠在第1天和第7天通过腹腔注射0.2mL的致敏液。control组小鼠经腹腔注射0.2mL PBS缓冲液。
(2)OVA激发：在异氟烷(Abbott Laboratories)麻醉下，第14至21天连续7天使用微型喷雾器给予1.5％OVA雾化液雾化吸入激发哮喘，对照组用PBS缓冲液代替OVA溶液雾化吸入。给药组在用1.5％OVA雾化前一个小时通过微型喷雾器给药，共计7天，并每天称量小鼠体重。
7)造模完成后，各组小鼠饮食正常，无异常行为。激发过程中，与control组小鼠相比，model组出现不同程度的烦躁不安、大小便失禁、口鼻发绀等现象。由于肺部吸入给药需进行麻醉，在雾化激发时仍有部分小鼠未苏醒过来，在激发时可见其呼吸急促。
8)小鼠清醒状态下肺生理学功能测定与病理学指标检测
(1)一般指标观察：观察给药前后小鼠形态学变化，是否出现呼吸困难、急促等症状。
(2)小鼠清醒状态肺功能测定：在OVA雾化攻击7天后，各组小鼠用肺功能检测系统检测清醒状态下肺功能，将小鼠置于检测装置中，稳定5min使小鼠适应环境，测定10min，并用肺功能分析软件分析肺功能数据。指标主要为吸气时间(TI)、呼气时间(TE)、呼吸频率(F)、气道阻力(Penh)等。
9)支气管肺泡灌洗液(BALF)的获取：小鼠处死后，切开颈部皮肤，分离出颈部气管后，在气管下段作一小“T”形切口，采用硅胶软管进行气管插管，结扎气管。用冷的PBS通过注射器缓慢注入肺部，每次0.5mL，重复灌洗3次，每次回收率需达到80％以上，将所有灌洗液盛入5mL离心管中。
10)BALF中炎症细胞计数和染色：将收集的BALF于1500rpm/min转速下离心5min,弃上清，加1mL PBS重悬细胞，取20μL于细胞计数仪下计算炎症细胞总数。将灌流液涂于玻片上，干后用瑞氏-吉姆萨染色液染色，观察炎症细胞占比情况。
11)统计学分析：实验所得的数据以均数±标准误(X±SEM)表示，运用SPSS 20.0统计学软件进行结果处理，运用GraphPad Prism software 6.0软件做图。P<0.05为差异有统计学意义。
12)实验结果如图3、图4、图5、图6所示。
由图3可知，连续给药7天后，BUD组小鼠体重呈下降趋势，其他组小鼠体重变化不大。实验结束时，各组无小鼠死亡。说明化合物36具有较好的安全性。
由图4可知，与control组相比，model组小鼠肺泡灌洗液(BALF)中总细胞数明显增多，分别为0.728±0.204×106和8.367±1.646×106。气管内2.5mg/kg给予药物36或布地奈德(BU)干预后，小鼠支气管肺泡灌洗液(BALF)中总细胞数显著降低。其中化合物36抑制BALF中总细胞数要优于布地奈德(BUD),分别为1.575±0.337×106和2.304±0.747×106。
由图5的瑞氏-吉姆萨染色结果可知，model组视野中可见染色的炎性细胞数要明显高于control组，给药36和布地奈德BUD后，能够明显下调炎性细胞的水平。
由图6的小鼠清醒状态下肺功能检测结果可知，与模型组相比，化合物36显示出明显的扩张支气管作用，它能够降低哮喘小鼠吸气时间，缩短呼气时间，提升呼吸间歇，增加了呼吸频率，布地奈德也显示类似效果，但是效果略低于化合物36。
综上可知，化合物36能够显著缓解哮喘表型症状，且效果稍优于布地奈德(BUD)。

Claims (12)

  1. 一种PI3Kδ选择性抑制剂，为通式Ⅰ所示的化合物或其药学可接受的盐：
    式中：环A选自至少被一个R1取代的苯环、吡啶环、噻吩环或呋喃环；所述R1选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6单烷基胺基、C1-6二烷基胺基或氰基；
    环B选自至少被一个R2取代的苯环、吡啶环、吡嗪环、哒嗪环、嘧啶环、噻唑环、吡唑环，所述R2选自氢、卤素、C2-6炔基、C2-6烯基、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6单烷基胺基、C1-6二烷基胺基、氨基、氰基、羟基、羧基、羰基、酮基中的一种或几种；
    R3、R4、R5各自独立的选自卤素、C1-6烷基、卤代C1-6烷基、C3-8环烷基、氨基、氰基、C1-6单烷基胺基或C1-6二烷基胺基。
  2. 根据权利要求1所述的PI3Kδ选择性抑制剂，其特征在于，为通式a所示的化合物或其药学可接受的盐：
    式中：环A选自至少被一个R1取代的苯环、吡啶环、噻吩环、呋喃环；所述R1选自氢、C1-6烷基、C1-6含氟烷基、C1-6烷氧基、C1-6含氟烷氧基、C1-6单烷基胺基、C1-6二烷基胺基、卤素或氰基；
    环B选自至少被一个R2取代的苯环、吡啶环、吡嗪环、哒嗪环、嘧啶环、噻唑环、吡唑环；所述R2选自氢、卤素、C1-6烷基、C1-6烷氧基、C1-6单烷基胺基、C1-6二烷基胺基、氰基或羧基；
    R3选自卤素、氨基、C1-6单烷基胺基、C1-6二烷基胺基、C1-6烷基、C3-8环烷基、C1-6含氟烷基。
  3. 根据权利要求1或2所述的PI3Kδ选择性抑制剂，其特征在于，所述的通式Ⅰ或通式a中，选自R1取代的以下杂环：
  4. 根据权利要求1或2所述的PI3Kδ选择性抑制剂，其特征在于，所述的通式Ⅰ或通式a中，
    R1选自氢、甲基、乙基、氟、氯、溴、三氟甲基、二氟甲基、甲氧基、三氟甲氧基、二氟甲氧基、氰基、乙炔基；
    环B选自R2取代的苯环、吡啶环、吡嗪环、哒嗪环、嘧啶环、噻唑环、吡唑环；R2为氢、甲基、乙基、氟、氯、溴、三氟甲基、二氟甲基、甲氧基、三氟甲氧基、二氟甲氧基、甲胺基、二甲胺基、二乙胺基、氰基、羧基；
    R3为氨基、甲基、乙基、环丙基、氟、氯、溴、三氟甲基、二氟甲基、2.2.2-三氟乙基。
  5. 根据权利要求3所述的PI3Kδ选择性抑制剂，其特征在于，为通式Ⅱ所示的化合物或其药学可接受的盐：
    式中：R1选自卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、卤代C1-6烷氧基、C1-6单烷基胺基、C1-6二烷基胺基或氰基；
    R2选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6单烷基胺基、C1-6二烷基胺基、氨基、氰基、羟基、羧基、羰基或酮基；
    R3、R4、R5各自独立的选自C1-6烷基、卤代C1-6烷基、氨基、氰基、C1-6单烷基胺基或C1-6二烷基胺基。
  6. 根据权利要求3所述的PI3Kδ选择性抑制剂，其特征在于，为通式Ⅲ所示的化合物或其药学可接受的盐：
    式中：X、Y、M、N中的任意一个为N，其余三个为C；
    R1选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基或卤代C1-6烷氧基；
    R2选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6单烷基胺基、C1-6二烷基胺基、氨基、氰基、羟基、羧基、羰基或酮基；
    R3、R4、R5各自独立的选自甲基、氨基或氰基。
  7. 根据权利要求3所述的PI3Kδ选择性抑制剂，其特征在于，为通式Ⅳ所示的化合物或其药学可接受的盐：
    式中：A、B、Q中的任意一个为S或O，其余二个为C；
    R1选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基或卤代C1-6烷氧基；且当A为S或O时，与A连接的R1为氢；
    R2选自氢、卤素、C1-6烷基、卤代C1-6烷基、C1-6烷氧基、C1-6单烷基胺基、C1-6二烷基胺基、氨基、氰基、羟基、羧基、羰基或酮基；
    R3、R4、R5各自独立的选自甲基、氨基或氰基。
  8. 一种PI3Kδ选择性抑制剂，选自如下特征化合物或其异构体或其药学可接受的盐：



  9. 一种药物组合物，包含至少一种如权1～8中任一项所述的活性组分及至少一种药学上可接受的载体或赋形剂。
  10. 一种制备如权利要求1～8中任一项所述的化合物或权9所述的药物组合物在预防或治疗与PI3Kδ激酶活性相关的疾病中的用途。
  11. 根据权利要求10所述的用途，其特征在于，所述的药物用于预防或治疗过敏性疾病和炎性疾病，以及肺部肿瘤等；特别是通过吸入给药的递送方式在预防或治疗哮喘、COPD以及PI3Kδ缺陷相关的自身免疫性疾病的治疗中发挥作用。
  12. 根据权利要求11所述的用途，其特征在于，所述的过敏性疾病和炎性疾病选自任何类型或起因的哮喘，包括但不限于内源性哮喘、外源性哮喘、轻度哮喘、中度哮喘、重度哮喘、支气管炎性哮喘、运动型哮喘、职业性哮喘、Th2型哮喘和非Th2型哮喘、喘鸣婴儿综合征、急性肺损伤、慢性阻塞性肺病、慢性支气管炎、肺气肿、成人型/急性呼吸窘迫综合征等呼吸系统疾病；以及类风湿性关节炎、骨关节炎、过敏性结膜炎、过敏性角膜炎、红斑狼疮、牛皮癣、过敏性皮炎、多发性硬化症、晚期肾病以及囊性纤维化关联的T细胞介导的炎症等自身免疫性疾病；
    所述的肺部肿瘤，包括但不限于非小细胞肺癌、小细胞肺癌等。
PCT/CN2024/071470 2022-05-19 2024-01-09 可吸入型芳环并噻嗪及类似物、含其的药物组合物及其在抗炎、抗肿瘤中的应用 WO2024099478A1 (zh)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101031569A (zh) * 2004-05-13 2007-09-05 艾科斯有限公司 作为人磷脂酰肌醇3－激酶δ抑制剂的喹唑啉酮
CN106008479A (zh) * 2015-03-06 2016-10-12 南京圣和药业股份有限公司 作为磷脂酰肌醇3-激酶δ抑制剂的取代嘧啶类化合物及其应用
CN106366085A (zh) * 2015-07-25 2017-02-01 复旦大学 异喹啉酮类化合物或其盐及其制备方法和用途
CN107033145A (zh) * 2016-02-04 2017-08-11 浙江大学 苯并噻嗪和苯并噻二嗪类化合物及制备和应用
CN117088867A (zh) * 2022-05-19 2023-11-21 杭州百诚医药科技股份有限公司 可吸入型芳环并噻嗪及类似物、含其的药物组合物及其在抗炎、抗肿瘤中的应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101031569A (zh) * 2004-05-13 2007-09-05 艾科斯有限公司 作为人磷脂酰肌醇3－激酶δ抑制剂的喹唑啉酮
CN106008479A (zh) * 2015-03-06 2016-10-12 南京圣和药业股份有限公司 作为磷脂酰肌醇3-激酶δ抑制剂的取代嘧啶类化合物及其应用
CN106366085A (zh) * 2015-07-25 2017-02-01 复旦大学 异喹啉酮类化合物或其盐及其制备方法和用途
CN107033145A (zh) * 2016-02-04 2017-08-11 浙江大学 苯并噻嗪和苯并噻二嗪类化合物及制备和应用
CN117088867A (zh) * 2022-05-19 2023-11-21 杭州百诚医药科技股份有限公司 可吸入型芳环并噻嗪及类似物、含其的药物组合物及其在抗炎、抗肿瘤中的应用

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