CN117736200A - 2- [ (6H-dibenzo [ b, d ] pyran-3-yl) oxy ] amide derivative and preparation method and application thereof - Google Patents
2- [ (6H-dibenzo [ b, d ] pyran-3-yl) oxy ] amide derivative and preparation method and application thereof Download PDFInfo
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- CN117736200A CN117736200A CN202311742705.6A CN202311742705A CN117736200A CN 117736200 A CN117736200 A CN 117736200A CN 202311742705 A CN202311742705 A CN 202311742705A CN 117736200 A CN117736200 A CN 117736200A
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- pyran
- dibenzo
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Abstract
The invention discloses a 2- [ (6H-dibenzo [ b, d)]Pyran-3-yl) oxy]Amide derivative, preparation method and application thereof, and 2- [ (6H-dibenzo [ b, d)]Pyran-3-yl) oxy]The amide derivative comprises a compound shown in a general formula (I), a stereoisomer shown in the general formula (I) or a salt thereof:wherein R is 1 The radical is any one of hydrogen atom, methyl, ethyl and benzyl; r is R 2 The group is any one of amino, substituted amino, azacyclyl, substituted azacyclyl, morpholinyl and substituted morpholinyl; r is R 3 The group is a substituted heterocyclic group or a substituted pyrimidinyl group; when said R is 2 When the radical is an amino group, R is 1 The radical is benzyl.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and relates to a 2- [ (6H-dibenzo [ b, d ] pyran-3-yl) oxy ] amide derivative, and a preparation method and application thereof.
Background
Phosphatidylinositol-3-kinase (PI 3K) belongs to the family of lipid kinases and is capable of catalyzing the phosphorylation of the hydroxyl group at the 3-position of phosphatidylinositol to produce phosphatidylinositol-3, 4, 5-triphosphate (PtdIns (3, 4, 5) P3, PIP 3). PIP3 is a second enabling agent that activates protein kinase B (AKT) or other cellular messengers, such as mammalian target of rapamycin (mTOR). The PI3K/AKT/mTOR signaling pathway is involved in regulating the growth, survival, proliferation, apoptosis and migration of cells. Thus, deregulation or mutation of the PI3K/AKT/mTOR signaling pathway may trigger cancer. PI3K kinases can be classified into three classes, class I, II and III, based on structural characteristics and substrate specificity. At present, the research on the class I PI3K is the most intensive, and the class I PI3K can be classified into IA and IB according to different regulation modes. Class IA PI3 ks contain three subtypes PI3kα, PI3kβ and PI3kδ, are heterodimers consisting of catalytic subunits p110α, p110β, p110δ and regulatory subunits p85α, p85β, p55α, p55δ and p50α. Class IB PI3 ks are heterodimers consisting of the catalytic subunit p110γ and one of the regulatory subunits p101, p87 or p 84. Pi3kδ is mainly expressed in immune cells, and participates in mediating various cell vital activities, and is a therapeutic target for hematological tumors, autoimmune diseases and inflammation. Currently approved PI3K delta inhibitors Idelalisb, duvelisib, umbralisib, leniolisb, copanlisib and Linperlisb are used to treat Chronic Lymphocytic Leukemia (CLL), recurrent Small Lymphocytic Lymphoma (SLL), recurrent Follicular Lymphoma (FL), and PI3K delta activation syndrome (APDS). PI3K delta inhibitors, which are still in clinical research stage, are Nemiralisib, zandelisib, parsaclisib, selelalisib and the like, and are used for treating hematological tumors, immune-related diseases and inflammation-related diseases. Idelalisb, duvelisb and combralisb have withdrawn some of the clinical indications due to severe adverse reactions occurring in clinical use. The PI3K delta inhibitor disclosed at present can be divided into a propeller type and a plane type according to the action mode of the PI3K delta inhibitor and a target point; the propeller type is represented by Idelalisb and the planar type is represented by Leniolisb. These inhibitors often have a double-ring structure of a six-membered ring and a six-membered ring or a six-membered ring and a five-membered ring as cores. The research of the PI3K delta inhibitor has sufficient clinical medical value and commercial value, is helpful for solving the problems of large toxic and side effects and the like of the existing inhibitor, is helpful for expanding the applicable range of the inhibitor and is helpful for expanding the core structure type of the inhibitor.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a 2- [ (6H-dibenzo [ b, d ] pyran-3-yl) oxy ] amide derivative, and a preparation method and application thereof, so that the technical problem of single core structure type of a PI3K delta inhibitor in the prior art is solved, and the technical problem of large toxic and side effects of the PI3K delta inhibitor is hopeful to be solved.
The invention is realized by the following technical scheme:
a 2- [ (6H-dibenzo [ b, d ] pyran-3-yl) oxy ] amide derivative comprising a compound represented by the general formula (I):
wherein R is 1 The radical is any one of hydrogen atom, methyl, ethyl and benzyl; r is R 2 The group is any one of amino, substituted amino, azacyclyl, substituted azacyclyl, morpholinyl and substituted morpholinyl; r is R 3 The group is a substituted heterocyclic group or a substituted pyrimidinyl group; when said R is 2 When the radical is an amino group, R is 1 The radical is benzyl.
Preferably, said R 2 The base is as follows:
any one of the above.
Preferably, said R 3 The base is as follows:
any one of the above.
A pharmaceutical composition comprising a compound of formula (I) as described above, a stereoisomer of formula (I) or a salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients; the medicinal composition is prepared into tablets, capsules, soft capsules, cream, gel, solution, injection, aerosol, spray or powder mist by adding auxiliary materials into the compounds, stereoisomers or salts thereof.
Preferably, the auxiliary materials comprise one or more of a filler, an adhesive, a disintegrating agent, a lubricant, a glidant, a flavoring agent, a colorant, a diluent, an absorbent, a wetting agent, an adhesive, a cream matrix, an emulsifying agent, a humectant, an absorption enhancer, a gel solvent, a stabilizer, a surfactant, a solubilizer, a cosolvent, a preservative, a stabilizer, an antioxidant, a pH regulator, an isotonicity regulator, a propellant, a latent solvent and a penetrating agent.
The application of the compound shown in the general formula (I), the stereoisomer shown in the general formula (I) or the salt or the medicinal composition in preparing the PI3K delta inhibitor medicine.
The application of the compound shown in the general formula (I), the stereoisomer or the salt or the medicinal composition of the general formula (I) in preparing the tumor medicaments of blood and lymphatic system; the tumors of the blood and lymphatic system comprise any one of chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, diffuse large B cell lymphoma, marginal zone lymphoma, hodgkin's lymphoma, fahrenheit macroglobulinemia, peripheral T cell lymphoma, B cell prolymphocytic leukemia, central nervous system lymphoma and multiple myeloma.
The use of a compound of formula (I), a stereoisomer of formula (I) or a salt or a pharmaceutical composition thereof, as described above, in the manufacture of a medicament for use in the treatment of an immune system disorder, including any one of PI3K delta hyperactivation syndrome, graft versus host disease, chronic graft versus host disease, rheumatoid arthritis and systemic lupus erythematosus.
The use of a compound of formula (I), a stereoisomer of formula (I) or a salt or a pharmaceutical composition thereof as described above for the manufacture of a medicament for inflammatory diseases including any one of asthma, chronic obstructive pulmonary disease, allergic rhinitis and allergic dermatitis.
The preparation method of the compound shown in the general formula (I), the stereoisomer shown in the general formula (I) or the salt thereof comprises the following steps:
s1: reacting 2, 4-dibromobenzoic acid with resorcinol to give 3-hydroxy-9-bromo-6H-dibenzo [ b, d ] pyran-6-one;
s2: reacting 3-hydroxy-9-bromo-6H-dibenzo [ b, d ] pyran-6-one with a borane tetrahydrofuran complex to give 9-bromo-6H-dibenzo [ b, d ] pyran-3-ol;
s3: reacting 9-bromo-6H-dibenzo [ b, d ] pyran-3-ol with an ester compound to obtain an ester compound of 2- [ (9-bromo-6H-dibenzo [ b, d ] pyran-3-yl) oxy ];
s4: reacting the ester compound of 2- [ (9-bromo-6H-dibenzo [ b, d ] pyran-3-yl) oxy ] with an amino compound, a substituted amino compound, an azacyclyl compound, a substituted azacyclyl compound, morpholine and a substituted morpholinyl compound, and then reacting the resulting product with a substituted heterocyclyl compound or a substituted pyrimidinyl compound to produce the compound of formula (I), a stereoisomer of formula (I) or a salt thereof.
Compared with the prior art, the invention has the following beneficial technical effects:
the invention discloses a 2- [ (6H-dibenzo [ b, d ] pyran-3-yl) oxy ] amide derivative, wherein the structures of a 6H-dibenzo [ b, d ] pyran ring, a 9-site substituted aromatic heterocycle and the like in the derivative respectively enhance interaction with a hinge region and an affinity region of a PI3K delta kinase catalytic activity region, and an amide side chain containing different structures at the 3-site interacts with non-conservative amino acids Trp760, thr750 and Met752, so that specific combination with the PI3K delta kinase is enhanced, and the derivative has better inhibitory activity on the PI3K delta kinase. The tricyclic structure is expanded as a novel inhibitor core structure, and candidate compounds are provided for exploring PI3K delta selective inhibitors with stronger activity.
Detailed Description
So that those skilled in the art can appreciate the features and effects of the present invention, a general description and definition of the terms and expressions set forth in the specification and claims follows. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, and in the event of a conflict, the present specification shall control.
The theory or mechanism described and disclosed herein, whether right or wrong, is not meant to limit the scope of the invention in any way, i.e., the present disclosure may be practiced without limitation to any particular theory or mechanism.
All features such as values, amounts, and concentrations that are defined herein in the numerical or percent ranges are for brevity and convenience only. Accordingly, the description of a numerical range or percentage range should be considered to cover and specifically disclose all possible sub-ranges and individual values (including integers and fractions) within the range.
Herein, unless otherwise indicated, "comprising," "including," "having," or similar terms encompass the meanings of "consisting of … …" and "consisting essentially of … …," e.g., "a includes a" encompasses the meanings of "a includes a and the other and" a includes a only.
In this context, not all possible combinations of the individual technical features in the individual embodiments or examples are described in order to simplify the description. Accordingly, as long as there is no contradiction between the combinations of these technical features, any combination of the technical features in the respective embodiments or examples is possible, and all possible combinations should be considered as being within the scope of the present specification.
The invention provides a 2- [ (6H-dibenzo [ b, d ] pyran-3-yl) oxy ] amide derivative, which comprises a compound shown in a general formula (I), a stereoisomer shown in the general formula (I) or a salt thereof, preferably pharmaceutically acceptable salt:
wherein R is 1 The radical is any one of hydrogen atom, methyl, ethyl and benzyl; r is R 2 The group is any one of amino, substituted amino, azacyclyl, substituted azacyclyl, morpholinyl and substituted morpholinyl; r is R 3 The group is a substituted heterocyclic group or a substituted pyrimidinyl group; when said R is 2 When the radical is an amino group, R is 1 The radical is benzyl.
Preferably, said R 2 The base is as follows:
any one of the above.
The R is 3 The base is as follows:
any one of the above.
The invention also provides a medicinal composition, which comprises a compound shown in the general formula (I), stereoisomer shown in the general formula (I) or salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients, wherein the medicinal composition is prepared into tablets, capsules, soft capsules, cream, gel, solution, injection, aerosol, spray or powder mist by adding auxiliary materials into the compound shown in the general formula (I), stereoisomer shown in the general formula (I) or salt thereof, wherein each tablet, granule or each preparation contains 10-500 mg of the compound shown in the general formula (I), stereoisomer shown in the general formula (I) or salt thereof; the added auxiliary materials comprise one or more of filling agent, adhesive, disintegrating agent, lubricant, glidant, flavoring agent, colorant, diluent, absorbent, wetting agent, adhesive, cream matrix, emulsifying agent, humectant, absorption promoter, gel solvent, stabilizer, surfactant, solubilizer, cosolvent, preservative, stabilizer, antioxidant, PH regulator, isotonic regulator, propellant, latent solvent and penetrating agent.
The invention also provides application of the compound shown in the general formula (I), the stereoisomer shown in the general formula (I) or the salt thereof in preparing a PI3K delta inhibitor drug.
The invention also provides application of the compound shown in the general formula (I), the stereoisomer shown in the general formula (I) or the salt thereof in preparing medicines for treating tumors of blood and lymphatic system, wherein the tumors of blood and lymphatic system comprise any one of chronic lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, diffuse large B cell lymphoma, fahrenheit macroglobulinemia, B cell juvenile lymphocytic leukemia, central nervous system lymphoma and multiple myeloma.
The invention also provides application of the compound shown in the general formula (I), the stereoisomer shown in the general formula (I) or the salt thereof in preparing medicines for treating immune system diseases, wherein the immune system diseases comprise any one of PI3K delta over-activation syndrome, graft-versus-host disease, chronic graft-versus-host disease, rheumatoid arthritis and systemic lupus erythematosus;
the invention also provides application of the compound shown in the general formula (I), the stereoisomer shown in the general formula (I) or the salt thereof in preparing medicines for inflammatory diseases, wherein the inflammatory diseases comprise any one of asthma, chronic obstructive pulmonary disease, allergic rhinitis and allergic dermatitis.
In addition, the invention also discloses a preparation method of the compound shown in the general formula (I) and the stereoisomer or the salt thereof shown in any one of claims 1 to 3, which comprises the following steps:
s1: reacting 2, 4-dibromobenzoic acid with resorcinol to give 3-hydroxy-9-bromo-6H-dibenzo [ b, d ] pyran-6-one;
s2: reacting 3-hydroxy-9-bromo-6H-dibenzo [ b, d ] pyran-6-one with a borane tetrahydrofuran complex to give 9-bromo-6H-dibenzo [ b, d ] pyran-3-ol;
s3: reacting 9-bromo-6H-dibenzo [ b, d ] pyran-3-ol with an ester compound to obtain an ester compound of 2- [ (9-bromo-6H-dibenzo [ b, d ] pyran-3-yl) oxy ];
s4: reacting the ester compound of 2- [ (9-bromo-6H-dibenzo [ b, d ] pyran-3-yl) oxy ] with an amino group, a substituted amino compound, an azacyclyl compound, a substituted azacyclyl compound, morpholine and a substituted morpholinyl compound, and then reacting the resulting product with a substituted heterocyclyl compound or a substituted pyrimidinyl compound to produce the compound of formula (I), a stereoisomer of formula (I) or a salt thereof.
Specifically, the ester compound may be (L/D) -methyl lactate, (R/S) -methyl 2-hydroxybutyrate, ethyl bromoacetate or (L/D) -methyl phenyllactate.
The preparation method specifically comprises the following steps:
when said R is 1 The radical is any one of hydrogen atom, methyl, ethyl and benzyl; r is R 2 The group is any one of amino, substituted amino, azacyclyl, substituted azacyclyl, morpholinyl and substituted morpholinyl; when the R3 group is any one of a substituted heterocyclic group and a substituted pyrimidine group, the method comprises the following steps:
s1: reacting 2, 4-dibromobenzoic acid with resorcinol to give 3-hydroxy-9-bromo-6H-dibenzo [ b, d ] pyran-6-one;
s2: 3-hydroxy-9-bromo-6H-dibenzo [ b, d ] pyran-6-one is subjected to reduction reaction by borane tetrahydrofuran complex to obtain 9-bromo-6H-dibenzo [ b, d ] pyran-3-phenol;
s3: when R is 1 In the presence of hydrogen, subjecting the 9-bromo-6H-dibenzo [ b, d ] obtained in step S2]The pyran-3-phenol and ethyl bromoacetate are subjected to a Williams ether synthesis reaction to prepare 2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]Ethyl acetate;
when R is 1 When the compound is methyl, ethyl or benzyl, the 9-bromo-6H-dibenzo [ b, d ] obtained in the step S2 is reacted with]The pyran-3-phenol reacts with (L/D) -methyl lactate, (R/S) -2-hydroxy methyl butyrate or (L/D) -phenyl methyl lactate by light delay to prepare (S/R) -2- [ (9-bromo-6H-dibenzo [ b, D)]Pyran-3-yl) oxy]Methyl propionate, (S/R) -2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]Butyric acid methyl ester or (S/R) -2- [ (9-bromo-6H-dibenzo [ b, d ]]Pyran-3-yl) oxy]-methyl 3-phenylpropionate;
s4: when R is 1 In the case of hydrogen, methyl or ethyl, the reaction mixture obtained in the step S3 is subjected to 2- [ (9-bromo-6H-di-n-ethyl)Benzo [ b, d]Pyran-3-yl) oxy]Ethyl acetate, (S/R) -2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]Methyl propionate or (S/R) -2- [ (9-bromo-6H-dibenzo [ b, d ]]Pyran-3-yl) oxy]Methyl butyrate is hydrolyzed and then reacts with any one of substituted amine, nitrogen heterocyclic compound, substituted nitrogen heterocyclic compound, morpholine and substituted morpholine to prepare the corresponding 2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]Acetamides, (S/R) -2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]Propionamides or (S/R) -2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]Butyramides;
when R is 1 In the case of benzyl, the reaction mixture obtained in the step S3 is (S/R) -2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]Reaction of methyl-3-phenylpropionate with a methanolic ammonia solution to give (S/R) -2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]-3-phenylpropionamide;
s5: 9-bromo-6H-dibenzo [ b, d ] with different side chains at the 3-position obtained in S4]The pyran compound and the bisboronic acid pinacol ester are reacted to obtain a compound which is directly reacted with halogenated substituted pyrimidinyl by a one-pot method to prepare a compound of a general formula (I), a stereoisomer of the general formula (I) or a salt thereof, wherein R 3 Is substituted pyrimidinyl;
when R is 3 In the case of a substituted heterocyclic group, the corresponding compound obtained in the step S4 is reacted with a substituted heterocyclic compound to obtain a compound of the formula (I), a stereoisomer of the formula (I) or a salt thereof, wherein R 3 Is a substituted heterocyclic group.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and gas chromatography-mass spectrometry (GC-MS) or high resolution mass spectrometry. NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus, or AVANCEIII-600 nuclear magnetic resonance apparatus, with deuterated dimethyl sulfoxide (DMSO-d 6) and deuterated chloroform (CDCl 3) as measurement solvents, tetramethylsilane (TMS) as internal standard, and Shimadzu GCMS-QP2010 gas chromatography-mass spectrometry apparatus as measurement solvents. The measurement of high-resolution mass spectrum uses a Simerfei Q exact Plus high-resolution mass spectrometer. The thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. Column chromatography generally uses yellow sea silica gel with 200-300 meshes as a carrier. The starting materials in the examples of the present invention are known and commercially available or may be synthesized according to methods known in the art. All reactions of the invention were carried out under continuous magnetic stirring under a dry nitrogen atmosphere, the solvent being a dry solvent, and the reaction temperature being in degrees celsius, without specific explanation.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. Further, it is understood that various changes and modifications may be made by those skilled in the art after reading the teachings of the present invention, and such equivalents are intended to fall within the scope of the claims appended hereto.
The following examples use instrumentation conventional in the art. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. The following examples used various starting materials, unless otherwise indicated, were conventional commercial products, the specifications of which are conventional in the art. In the description of the present invention and the following examples, "%" means weight percent, and "parts" means parts by weight, and ratios means weight ratio, unless otherwise specified.
A 2- [ (6H-dibenzo [ b, d ] pyran-3-yl) oxy ] amide derivative comprising a compound represented by the general formula (I):
wherein R is 1 The radical is any one of hydrogen atom, methyl, ethyl and benzyl; r is R 2 The group is any one of amino, substituted amino, azacyclyl, substituted azacyclyl, morpholinyl and substituted morpholinyl; r is R 3 The group is any one of a substituted heterocyclic group and a substituted pyrimidine group. When saidR 2 When the radical is an amino group, R is 1 The radical is benzyl.
I.e. comprising the general formula
Wherein R is 1 Is hydrogen,R 2 、R 3 Is R as above 2 、R 3 。
Table 1 shows the specific structures of the 2- [ (6H-dibenzo [ b, d ] pyran-3-yl) oxy ] amide derivatives prepared in examples 1 to 43 and the characterization results of the products. The Chinese names corresponding to the 2- [ (6H-dibenzo [ b, d ] pyran-3-yl) oxy ] amide derivatives prepared in examples 1 to 43 are shown in Table 2.
Table 1 characterization test data for the products in examples 1 to 43
Wherein, the preparation method of the 2- [ (6H-dibenzo [ b, d ] pyran-3-yl) oxy ] amide derivative in the example 1, namely (R) -4-isopropyl-3- (3- (((R) -1-morpholin-1-oxypropane-2-yl) oxy) -6H-dibenzo [ b, d ] pyran-9-yl) oxazolidin-2-ketone is as follows:
the first step: preparation of 3-hydroxy-9-bromo-6H-dibenzo [ b, d ] pyran-6-one
2, 4-dibromobenzoic acid (24.00 g,85.70 mmol), resorcinol (18.88 g,171.50 mmol) and sodium hydroxide (6.86 g,171.50 mmol) are weighed into a 250mL three-necked flask, a reflux device is added, 60mL of water is slowly added into the flask after nitrogen protection by a syringe, after heating and refluxing for 2h at 125 ℃, 36mL of 5% copper sulfate solution is slowly dripped into a reaction system, a large amount of brick red precipitate is immediately precipitated, heating and refluxing for 1h at 125 ℃ is continued, the reaction is stopped, the reaction system is cooled to room temperature and then subjected to suction filtration treatment, the filtrate is discarded, and a filter cake is collected, so that the title compound (17.50 g,70% yield) is obtained after drying.
HRMS(ESI)[M-H] - :288.9515/290.9495. 1 H NMR(600MHz,DMSO-d6)δ10.46(s,1H),8.51(s,1H),8.22(d,J＝8.3Hz,1H),8.06(d,J＝8.4Hz,1H),7.71(d,J＝8.3Hz,1H),6.83(d,J＝8.7Hz,1H),6.74(s,1H).
And a second step of: preparation of 9-bromo-6H-dibenzo [ b, d ] pyran-3-ol
3-hydroxy-9-bromo-6H-dibenzo [ b, d ] pyran-6-one (14.00 g,48.09 mmol) was weighed into a 100mL three-necked flask, tetrahydrofuran (10 mL) was added with a syringe after nitrogen protection, and was stirred until dissolved, borane tetrahydrofuran complex (120 mL) was added dropwise at room temperature, bubbles were formed during the addition and a black floccule appeared, and the system was clear, pale yellow and transparent after the addition was completed. Reflux reaction for 6h, adding water and quenching reaction. The reaction solution was extracted three times with ethyl acetate (20 mL), and the organic phase was washed with saturated NaCl solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by suction filtration, and the title compound (11.20 g, 84%) was obtained by column chromatography on silica gel as it was.
HRMS(ESI)[M-H] - :274.9721/276.9701. 1 H NMR(600MHz,DMSO-d6)δ9.84(s,1H),7.86(s,1H),7.71(d,J＝8.5Hz,1H),7.39(d,J＝8.0Hz,1H),7.18(d,J＝8.0Hz,1H),6.50(d,J＝8.5Hz,1H),6.37(s,1H),5.03(d,J＝10.9Hz,2H).
And a third step of: preparation of methyl (R) -2- [ (9-bromo-6H-dibenzo [ b, d ] pyran-3-yl) oxy ] propionate
9-bromo-6H-dibenzo [ b, d ] pyran-3-ol (3.00 g,10.80 mmol), triphenylphosphine (4.26 g,16.20 mmol) were weighed into a 100mL three-necked flask, nitrogen blanketed. Methyl L-lactate (2.25 g,21.70 mmol) and 6mL of 1, 4-dioxane were weighed into a three-necked flask by syringe and stirred at room temperature until the solid was completely dissolved. After 30min on ice, DIAD (3.20 ml,16.20 mmol) was slowly added dropwise to the three-necked flask and stirred overnight at room temperature, after about 12h TLC monitored complete reaction of starting material and stopped. The reaction solvent was evaporated to dryness under reduced pressure, extracted three times with 50mL of ethyl acetate/water, washed three times with saturated NaCl solution and the organic phases were combined, dried over anhydrous sodium sulfate and stirred, and separated by silica gel column chromatography to give the title compound (3.45 g, 88%).
HRMS(ESI)[M+Na] + :385.0044/387.0026. 1 H NMR(400MHz,DMSO-d6)δ7.94(d,J＝1.9Hz,1H),7.84(d,J＝8.7Hz,1H),7.45(dd,J＝8.1,1.9Hz,1H),7.22(d,J＝8.1Hz,1H),6.62(dd,J＝8.7,2.6Hz,1H),6.50(d,J＝2.6Hz,1H),5.07(d,J＝9.2Hz,3H),3.69(s,3H),1.51(d,J＝6.7Hz,3H).
Fourth step: preparation of (R) -2- [ (9-bromo-6H-dibenzo [ b, d ] pyran-3-yl) oxy ] -1-morpholinopropan-1-one
Weighing (R) -2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]Methyl propionate (0.50 g,1.38 mmol) was placed in a round bottom flask and then methanol (18 mL) and water (1.8 mL) were added to weigh LiOH H 2 O (0.08 g,2.05 mmol) was added to a round bottom flask, the reaction mixture was heated at 50deg.C for about 16h, TLC monitored complete hydrolysis of the starting material, HCl (1N, aq) was added to adjust pH to 4, and evaporated to residue under reduced pressure. The resulting residue was dissolved in dichloromethane (32 mL), TBTU (0.53 g,1.66 mmol) and DIPEA (0.46 mL,2.76 mmol) were added, and after stirring and activation at room temperature for 30min, morpholine (0.25 mL,2.82 mmol) was added, stirring at room temperature was continued overnight, after 24h TLC monitored complete reaction of starting materials, and the reaction was stopped. The title compound (0.48 g, 83%) was obtained by repeated extraction with dichloromethane/water, washing with saturated NaCl solution three times, mixing the organic phases, drying the organic phases over anhydrous sodium sulfate, and column chromatography on silica gel.
HRMS(ESI)[M+H] + :418.0656/420.0639. 1 H NMR(400MHz,DMSO-d6)δ7.94(d,J＝1.9Hz,1H),7.84(d,J＝8.7Hz,1H),7.44(dd,J＝8.1,1.9Hz,1H),7.21(d,J＝8.1Hz,1H),6.60(dd,J＝8.7,2.5Hz,1H),6.48(d,J＝2.5Hz,1H),5.32(q,J＝6.5Hz,1H),5.08(s,2H),3.65-3.43(m,8H),1.42(d,J＝6.5Hz,3H).
Fifth step: preparation of (R) -4-isopropyl-3- (3- (((R) -1-morpholin-1-oxypropane-2-yl) oxy) -6H-dibenzo [ b, d ] pyran-9-yl) oxazolidin-2-one
Weighing (R) -2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]-1-morpholinopropan-1-one (0.30 g,0.72 mmol), (R) -4-isopropyloxazolidin-2-one (0.19 g,1.44 mmol), anhydrous K 2 CO 3 (0.30 g,2.16 mmol) and cuprous iodide (0.03 g,0.14 mmol) were placed in a 15mL reaction tube under nitrogen. trans-N, N-dimethyl-1, 2-cyclohexanediamine (0.04 g,0.29 mmol) was measured and placed in a vial, then 2mL of toluene was added, the vial was injected into the reaction tube by syringe, then 2mL of toluene was added to wash the vial, the vial was injected into the reaction tube by syringe again, the reaction was heated and stirred at 110℃for 24 hours, after which the TLC monitored complete reaction of the starting materials and stopped. The reaction system was filtered, and after the residue was removed, a sample was taken up in silica gel column chromatography to give the title compound (0.07 g, 21%).
HRMS(ESI)[M+H] + :467.2180. 1 H NMR(400MHz,CDCl 3 )δ7.74(d,J＝2.1Hz,1H),
7.62(d,J＝8.6Hz,1H),7.23(d,J＝2.1Hz,1H),7.14(d,J＝8.2Hz,1H),6.62(dd,J＝8.6,2.6Hz,1H),6.53(d,J＝2.5Hz,1H),5.07(s,2H),4.97(q,J＝6.8Hz,1H),4.47-4.41(m,2H),4.30-4.24(m,1H),3.77-3.50(m,8H),2.18-2.11(m,1H),1.62(d,J＝6.8Hz,3H),0.92(d,J＝7.1Hz,3H),0.87(d,J＝6.8Hz,3H).
Wherein the preparation of (R) -2- ((9- (6-aminopyrimidin-4-yl) -6H-dibenzo [ b, d ] pyran-3-yl) oxy) -1-morpholinopropan-1-one in example 18 is as follows:
weighing (R) -2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]-1-morpholinopropan-1-one (0.62 g,1.50 mmol), pinacol diboronate (0.56 g,2.22 mmol), CH 3 COOK (0.44 g,4.5 mmol) and PbCl 2 (dppf) (0.22 g,0.30 mmol) in a three-necked flask, was added backThe reaction was stopped by a flow device, nitrogen protection, and TLC monitoring of complete reaction of starting materials after 20mL of 1, 4-dioxane was added by syringe and reacted at 100℃for 8 h. After the system cooled to room temperature, 6-bromo-4-aminopyrimidine (0.31 g,1.80 mmol), pbCl 2 (dppf) (0.22 g,0.30 mmol), anhydrous K 2 CO 3 (0.62 g,4.50 mmol) and water (4 mL) (1, 4-dioxane: water=5:1) were added to the reaction system, nitrogen protected, and TLC after 8h of reaction monitored complete reaction of the borate starting material, the reaction was stopped. The title compound (0.26 g, 40%) was obtained by repeated extraction with ethyl acetate/water, washing with saturated NaCl solution three times, mixing the organic phases, drying the organic phases over anhydrous sodium sulfate, and column chromatography on silica gel.
HRMS(ESI)[M+H] + :433.1883.1H NMR(400MHz,CDCl 3 )δ8.68(d,J＝1.2Hz,1H),
8.24(d,J＝1.7Hz,1H),7.83-7.75(m,2H),7.22(d,J＝7.8Hz,1H),6.85(d,J＝1.1Hz,1H),6.64(dd,J＝8.6,2.6Hz,1H),6.53(d,J＝2.6Hz,1H),5.14(s,2H),5.03(s,2H),4.98(d,J＝6.7Hz,1H),3.82-3.49(m,8H),1.63(d,J＝6.8Hz,3H).
The preparation of 1- ((2 s,6 r) -2, 6-dimethylmorpholinyl) -2- ((9- (6-aminopyrimidin-4-yl) -6H-dibenzo [ b, d ] pyran-3-yl) oxy) ethan-1-one in example 33 is as follows:
the first step: preparation of ethyl 2- ((9-bromo-6H-dibenzo [ b, d ] pyran-3-yl) oxy) acetate
The operation steps are as follows: 9-bromo-6H-dibenzo [ b, d ] pyran-3-ol (1.00 g,3.36 mmol) was weighed into a 100mL eggplant-shaped bottle, 8mL of acetone was added to dissolve, anhydrous potassium carbonate (0.93 g,6.72 mmol) and potassium iodide (0.56 g,3.36 mmol) were added sequentially, stirring was performed at room temperature for 0.5H, 745. Mu.L of ethyl bromoacetate (1.12 g,6.72 mmol) was added, heating was performed for 8H under reflux, TLC monitored complete reaction of the starting materials, and the reaction was stopped. The title compound (0.93 g, 76%) was obtained by repeated extraction with ethyl acetate/water, washing with saturated NaCl solution three times, mixing the organic phases, drying the organic phases over anhydrous sodium sulfate, and column chromatography on silica gel.
GC-MS(ESI)[M] + :362.10/364.10. 1 H NMR(400MHz,Chloroform-d)δ7.72(d,J＝2.0Hz,1H),7.58(d,J＝8.7Hz,1H),7.34(dd,J＝8.0,1.9Hz,1H),7.00(d,J＝7.8Hz,1H),6.65(dd,J＝8.6,2.6Hz,1H),6.52(d,J＝2.7Hz,1H),5.04(s,2H),4.63(s,2H),4.28(q,J＝7.1Hz,2H),1.31(t,J＝7.2Hz,3H).
And a second step of: preparation of 2- ((9-bromo-6H-dibenzo [ b, d ] pyran-3-yl) oxy) -1- ((2S, 6R) -2, 6-dimethylmorpholinyl) ethan-1-one
The procedure is referred to the fourth step in the preparation of example 1 above.
GC-MS(ESI)[M] + :431.15/433.15. 1 H NMR(400MHz,Chloroform-d)δ7.72(d,J＝1.9Hz,1H),7.58(d,J＝8.7Hz,1H),7.35(dd,J＝8.0,1.9Hz,1H),7.00(d,J＝8.0Hz,1H),6.68(dd,J＝8.6,2.6Hz,1H),6.56(d,J＝2.5Hz,1H),5.04(s,2H),4.70(d,J＝1.9Hz,2H),4.40(dt,J＝13.6,2.1Hz,1H),3.78(dt,J＝13.2,2.2Hz,1H),3.53(dddd,J＝16.5,8.8,6.2,2.5Hz,2H),2.85(dd,J＝13.1,10.6Hz,1H),2.40(dd,J＝13.2,10.7Hz,1H),1.20(t,J＝6.0Hz,6H).
And a third step of: preparation of 1- ((2S, 6R) -2, 6-dimethylmorpholinyl) -2- ((9- (6-aminopyrimidin-4-yl) -6H-dibenzo [ b, d ] pyran-3-yl) oxy) ethan-1-one
Procedure reference is made to the preparation of example 18 above.
GC-MS(ESI)[M+H] + :474.30. 1 H NMR(400MHz,Chloroform-d)δ8.68(d,J＝1.3Hz,1H),8.23(d,J＝1.4Hz,1H),7.85-7.69(m,2H),7.21(d,J＝7.9Hz,1H),6.85(d,J＝1.3Hz,1H),6.69(dd,J＝8.6,2.6Hz,1H),6.57(d,J＝2.7Hz,1H),5.14(s,2H),5.07(s,2H),4.71(d,J＝1.9Hz,2H),4.40(dt,J＝13.2,2.2Hz,1H),3.79(dt,J＝13.2,2.2Hz,1H),3.59-3.40(m,2H),2.85(dd,J＝13.1,10.6Hz,1H),2.40(dd,J＝13.2,10.7Hz,1H),1.20(dd,J＝7.5,6.2Hz,6H).
The preparation of (R) -2- ((9- (6-aminopyrimidin-4-yl) -6H-dibenzo [ b, d ] pyran-3-yl) oxy) -3-phenylpropionamide in example 42 was as follows:
the first step: preparation of methyl (R) -2- [ (9-bromo-6H-dibenzo [ b, d ] pyran-3-yl) oxy ] -3-phenylpropionate
9-bromo-6H-dibenzo [ b, d ] pyran-3-ol (1.00 g,3.60 mmol), methyl L-phenyllactate (1.30 g,7.20 mmol), triphenylphosphine (1.42 g,5.40 mmol) were weighed into a 100mL three-necked flask and blanketed with nitrogen. 6mL of 1, 4-dioxane was metered into a three-necked flask using a syringe and stirred at room temperature until the solid was completely dissolved. After 30min on ice, DIAD (1.10 ml,5.40 mmol) was slowly added dropwise to the three-necked flask and stirred overnight at room temperature, after about 12h TLC monitored complete reaction of starting material and stopped. The reaction solvent was evaporated to dryness under reduced pressure, extracted three times with 50mL of ethyl acetate/water, washed three times with saturated NaCl solution and the organic phases were combined, dried over anhydrous sodium sulfate and stirred with silica gel, and separated by silica gel column chromatography to give the title compound (1.37 g, 87%).
HRMS(ESI)[M+Na] + :461.0355. 1 H NMR(400MHz,CDCl 3 )δ7.65(d,J＝1.9Hz,1H),
7.48(d,J＝8.7Hz,1H),7.33-7.26(m,3H),7.26-7.16(m,3H),6.94(d,J＝8.1Hz,1H),6.53(dd,J＝8.6,2.5Hz,1H),6.41(d,J＝2.6Hz,1H),4.97(s,2H),4.79(dd,J＝7.4,5.5Hz,1H),3.70(s,3H),3.23-3.19(m,2H).
And a second step of: preparation of (R) -2- [ (9-bromo-6H-dibenzo [ b, d ] pyran-3-yl) oxy ] -3-phenylpropionamide
Methyl (R) -2- [ (9-bromo-6H-dibenzo [ b, d ] pyran-3-yl) oxy ] -3-phenylpropionate (0.5 g,1.14 mmol) was weighed and placed in a round bottom flask, ammonia-methanol solution (8.14 mL,7 mmol/mL) was added and reacted at room temperature for 12H, after which TLC monitored complete reaction of starting material, stopping reaction, ethyl acetate dissolution, stirring with silica gel and column chromatography on silica gel gave the title compound (0.34 g, 70%).
HRMS(ESI)[M+H] + :424.0550. 1 H NMR(400MHz.CDCl 3 )δ7.68(d,J＝1.9Hz,1H),
7.53(d,J＝8.7Hz,1H),7.33(dd,J＝8.0,1.9Hz,1H),7.29-7.26(m,3H),7.24(s,2H),6.97(d,J＝8.0Hz,1H),6.55(dd,J＝8.6,2.6Hz,1H),6.49(d.J＝2.5Hz,1H),6.16(s,1H),5.41(s,1H),5.00(s,2H),4.78(dd,J＝7.2,3.8Hz,1H),3.31(dd,J＝14.3,3.8Hz,1H),3.19(dd,J＝14.2,7.2Hz,1H).
And a third step of: preparation of (R) -2- ((9- (6-aminopyrimidin-4-yl) -6H-dibenzo [ b, d ] pyran-3-yl) oxy) -3-phenylpropionamide
Weighing (R) -2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]3-Phenylpropionamide (0.55 g,1.33 mmol), pinacol biborate (0.49 g,1.90 mmol), CH 3 COOK (0.38 g,3.90 mmol) and PbCl 2 (dppf) (0.19 g,0.26 mmol) in a three-necked flask, a reflux apparatus was added, nitrogen was used for protection, 15mL of 1, 4-dioxane was added by syringe, and after reaction at 100℃for 8 hours, TLC was monitored for complete reaction of starting materials, and the reaction was stopped. After the system cooled to room temperature, 6-bromo-4-aminopyrimidine (0.27 g,1.56 mmol), pbCl 2 (dppf) (0.19 g,0.26 mmol), anhydrous K 2 CO 3 (0.54 g,3.90 mmol) and water (3 mL) (1, 4-dioxane: water=5:1) were added to the reaction system, nitrogen protected, and after 8h of reaction, TLC monitored complete reaction of starting materials, stopping the reaction. The title compound (0.04 g, 7%) was obtained by repeated extraction with ethyl acetate/water, washing with saturated NaCl solution three times, mixing the organic phases, drying the organic phases over anhydrous sodium sulfate, and column chromatography on silica gel.
HRMS(ESI)[M+H] + :439.1773. 1 H NMR(400MHz,CDCl 3 )δ8.65(s,1H),8.20(s,1H),7.80-7.70(m,2H),7.27(s,2H),7.26-7.17(111,4H),6.82(d,J＝3.2Hz,1H),6.59-6.48(m,2H),6.20(d,J＝3.6Hz,1H),5.50(d,J＝3.7Hz,1H),5.10(s,2H),5.01(s,2H),4.79(dd,J＝7.1 3.7Hz,1H),3.36-3.17(m,2H).
TABLE 2 names of products prepared in examples 1 to 43
Wherein the preparation methods of the corresponding products of examples 2 to 17 refer to example 1; the preparation methods of the corresponding products of examples 19 to 32 and 37 to 41 refer to example 18; the preparation methods of the corresponding products of examples 34 to 36 refer to example 33; example 43 the corresponding product was prepared as described in reference to example 42.
When said R is 1 The radical is any one of hydrogen atom, methyl, ethyl and benzyl; r is R 2 The group is any one of amino, substituted amino, azacyclyl, substituted azacyclyl, morpholinyl and substituted morpholinyl; when the R3 group is any one of a substituted heterocyclic group and a substituted pyrimidine group, the method comprises the following steps:
s1: reacting 2, 4-dibromobenzoic acid with resorcinol to give 3-hydroxy-9-bromo-6H-dibenzo [ b, d ] pyran-6-one;
s2: 3-hydroxy-9-bromo-6H-dibenzo [ b, d ] pyran-6-one is subjected to reduction reaction by borane tetrahydrofuran complex to obtain 9-bromo-6H-dibenzo [ b, d ] pyran-3-phenol;
s3: when R is 1 In the presence of hydrogen, subjecting the 9-bromo-6H-dibenzo [ b, d ] obtained in step S2]The pyran-3-phenol and ethyl bromoacetate are subjected to a Williams ether synthesis reaction to prepare 2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]Ethyl acetate;
when R is 1 When the compound is methyl, ethyl or benzyl, the step S2 is carried outTo 9-bromo-6H-dibenzo [ b, d]The pyran-3-phenol reacts with (L/D) -methyl lactate, (R/S) -2-hydroxy methyl butyrate or (L/D) -phenyl methyl lactate by light delay to prepare (S/R) -2- [ (9-bromo-6H-dibenzo [ b, D)]Pyran-3-yl) oxy]Methyl propionate, (S/R) -2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]Butyric acid methyl ester or (S/R) -2- [ (9-bromo-6H-dibenzo [ b, d ]]Pyran-3-yl) oxy]-methyl 3-phenylpropionate;
s4: when R is 1 In the case of hydrogen, methyl or ethyl, subjecting the 2- [ (9-bromo-6H-dibenzo [ b, d ] obtained in step S3 to a reaction]Pyran-3-yl) oxy]Ethyl acetate, (S/R) -2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]Methyl propionate or (S/R) -2- [ (9-bromo-6H-dibenzo [ b, d ]]Pyran-3-yl) oxy]Methyl butyrate is hydrolyzed and then reacts with any one of substituted amine, nitrogen heterocyclic compound, substituted nitrogen heterocyclic compound, morpholine and substituted morpholine to prepare the corresponding 2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]Acetamides, (S/R) -2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]Propionamides or (S/R) -2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]Butyramides;
when R is 1 In the case of benzyl, the reaction mixture obtained in the step S3 is (S/R) -2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]Reaction of methyl-3-phenylpropionate with a methanolic ammonia solution to give (S/R) -2- [ (9-bromo-6H-dibenzo [ b, d)]Pyran-3-yl) oxy]-3-phenylpropionamide;
s5: 9-bromo-6H-dibenzo [ b, d ] with different side chains at the 3-position obtained in S4]The pyran compound and the bisboronic acid pinacol ester are reacted to obtain a compound which is directly reacted with halogenated substituted pyrimidinyl by a one-pot method to prepare a compound of a general formula (I), a stereoisomer of the general formula (I) or a salt thereof, wherein R 3 Is substituted pyrimidinyl;
when R is 3 In the case of a substituted heterocyclic group, the corresponding compound obtained in the step S4 is reacted with a substituted heterocyclic compound to obtain a compound of the formula (I), a stereoisomer of the formula (I) or a salt thereof, wherein R 3 Is a substituted heterocyclic group.
The results of the inhibition of PI3K delta kinase by the 2- [ (6H-dibenzo [ b, d ] pyran-3-yl) oxy ] amide derivatives prepared in examples 1-43 of the present invention are shown in Table 3, and the specific test procedures are as follows:
the purpose of the experiment is as follows: the compounds of the examples were tested for their inhibitory activity against pi3kδ kinase.
Experimental instrument: centrifuge (5430) was purchased from Eppendorf corporation, pipettor from Eppendorf corporation, and microplate reader (Envision, SN. 1050214) from Perkin Elmer corporation.
The experimental method comprises the following steps: the experiment adopts ADP-GLO lipid kinase assay method (Promega#V9102) of Promega company, lipid kinase PI3K delta is catalyzed by the presence of substrate PIP2:3PS and ATP to generate ADP, the content of ADP in the reaction is measured to characterize the activity of the lipid kinase, and the inhibition rate of the compound to single concentration of PI3K delta kinase activity, or half inhibition concentration IC is obtained 50 。
The specific experimental operation is as follows:
the kinase reaction was performed in a white 384 well plate (Perkin Elmer # 6007299) with 50nL of ddH in 1% DMSO per well 2 O diluted 100 times final concentration of compound at different concentrations, positive control wells were added with 50nL ddH containing 1% DMSO 2 O, then 2.5. Mu.L of 1 Xkinase buffer (HEPES 250mM, mgCl) was added per well 2 15mM,NaCl 250mM,BSA0.05%) diluted 2-fold final concentration of PI3K kinase solution, adding 2.5. Mu.L of 1 Xkinase buffer to the negative control wells, centrifuging at 1000rpm for 30 seconds, incubating at room temperature for 10 minutes after shaking and mixing, starting the reaction by adding 2.5. Mu.L of a 2-fold final concentration of PIP2:3PS (Promega#V1701) and ATP mixed solution prepared from 1 Xkinase buffer to all wells, centrifuging at 1000rpm for 30 seconds, and adding 5. Mu.L of ADP-Glo Reagent (containing 10mM MgCl) to each well after shaking and mixing at room temperature for 90-120 minutes 2 ) After 60 minutes at room temperature to remove the excess ATP, 10. Mu. L Kinase Detection Reagent was added to each well, and the reaction was carried out at room temperature for 20 minutes in the dark, and the chemiluminescent value was measured by an Envision microplate reader.
The experimental data processing method comprises the following steps:
the IC50 values were calculated by calculating the percent inhibition data {% inhibition = 100- [ (test compound value-negative control value ]/(positive control value-negative control value) ×100} for wells treated with compound versus positive control wells (DMSO control wells) and negative control wells (no kinase added) on the plate.
Conclusion of experiment:
the above protocol shows that the example compounds of the present invention show the biological activity in pi3kδ kinase activity assays as shown in tables 3 and 4 below.
Table 3 inhibition of PI3K delta by the products of examples 1 to 17 (%), concentration 100nmol/L,n＝3)/>
TABLE 4 IC of the products in examples 18-43 and the positive control compound against PI3K delta 50 (nmol/L)
As is clear from Table 3, the inhibitory activity of example 19, example 22, example 24 and example 31 was the strongest in the PI3K delta kinase, and the half inhibitory concentration on PI3K delta was lower than 30nmol/L, and was 29.2nmol/L, 22.9nmol/L, 29.5nmol/L and 27.1nmol/L, respectively, among the example compounds of the present invention. In the invention, 6H-dibenzo [ b, d ] pyran is taken as a mother nucleus, the 9 positions are replaced by aromatic heterocycle and other structures, the 6H-dibenzo [ b, d ] pyran respectively interacts with an affinity region and a hinge region of a PI3K delta kinase catalytic active region, the 3 positions are connected with amide side chains of different structures through oxygen, hydrophobic interaction is generated in a selective action region of PI3K delta and non-conservative amino acid Trp760, the specific combination with the PI3K delta kinase is enhanced, a compound with better inhibition activity on the PI3K delta kinase is obtained, and a candidate compound is provided for exploring a strong activity PI3K delta selective inhibitor.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted equally without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. 2- [ (6H-dibenzo [ b, d ] pyran-3-yl) oxy ] amide derivatives characterized by comprising a compound represented by the general formula (I):
wherein R is 1 The radical is any one of hydrogen atom, methyl, ethyl and benzyl; r is R 2 The group is any one of amino, substituted amino, azacyclyl, substituted azacyclyl, morpholinyl and substituted morpholinyl; r is R 3 The group is a substituted heterocyclic group or a substituted pyrimidinyl group; when said R is 2 When the radical is an amino group, R is 1 The radical is benzyl.
2. A 2- [ (6H-dibenzo [ b, d) according to claim 1]Pyran-3-yl) oxy]An amide derivative, characterized in that R 2 The base is as follows:
any one of the above.
3. A 2- [ (6H-dibenzo [ b, d) according to claim 1]Pyran-3-yl) oxy]An amide derivative, characterized in that R 3 The base is as follows:
any one of the above.
4. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 3, a stereoisomer of formula (I) or a salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients; the pharmaceutical composition is prepared into tablets, capsules, soft capsules, cream, gel, solution, injection, aerosol, spray or powder mist by adding auxiliary materials into the compounds, stereoisomers or salts thereof shown in any one of claims 1 to 3.
5. A pharmaceutical composition according to claim 4 wherein the adjuvant comprises one or more of fillers, binders, disintegrants, lubricants, glidants, flavoring agents, colorants, diluents, absorbents, wetting agents, binders, cream bases, emulsifiers, moisturizers, absorption promoters, gelling agent solvents, stabilizers, surfactants, solubilizers, co-solvents, preservatives, stabilizers, antioxidants, pH adjusters, isotonicity adjusters, propellants, latent solvents and osmotic agents.
6. Use of a compound of general formula (I), a stereoisomer of general formula (I) or a salt thereof, as defined in any one of claims 1 to 3, or a pharmaceutical composition as defined in any one of claims 4 to 5, for the preparation of a PI3K delta inhibitor medicament.
7. Use of a compound of general formula (I), a stereoisomer of general formula (I) or a salt thereof, as defined in any one of claims 1 to 3, or a pharmaceutical composition according to any one of claims 4 to 5, for the preparation of a medicament for the treatment of tumors of the blood and lymphatic systems; wherein the tumor of blood and lymphatic system comprises any one of chronic lymphocytic leukemia, small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, diffuse large B cell lymphoma, marginal zone lymphoma, hodgkin's lymphoma, fahrenheit macroglobulinemia, peripheral T cell lymphoma, B cell prolymphocytic leukemia, central nervous system lymphoma and multiple myeloma.
8. Use of a compound of general formula (I), a stereoisomer of general formula (I) or a salt thereof, according to any one of claims 1 to 3, or a pharmaceutical composition according to any one of claims 4 to 5, for the manufacture of a medicament for the treatment of an immune system disorder, wherein the immune system disorder comprises any one of PI3K delta overactive syndrome, graft versus host disease, chronic graft versus host disease, rheumatoid arthritis and systemic lupus erythematosus.
9. Use of a compound of general formula (I), a stereoisomer of general formula (I) or a salt thereof, according to any one of claims 1 to 3, or a pharmaceutical composition according to any one of claims 4 to 5, for the manufacture of a medicament for inflammatory diseases, wherein the inflammatory diseases comprise any one of asthma, chronic obstructive pulmonary disease, allergic rhinitis, and allergic dermatitis.
10. A process for producing a compound represented by the general formula (I), a stereoisomer of the general formula (I) or a salt thereof according to any one of claims 1 to 3, which comprises the steps of:
s1: reacting 2, 4-dibromobenzoic acid with resorcinol to give 3-hydroxy-9-bromo-6H-dibenzo [ b, d ] pyran-6-one;
s2: reacting 3-hydroxy-9-bromo-6H-dibenzo [ b, d ] pyran-6-one with a borane tetrahydrofuran complex to give 9-bromo-6H-dibenzo [ b, d ] pyran-3-ol;
s3: reacting 9-bromo-6H-dibenzo [ b, d ] pyran-3-ol with an ester compound to obtain an ester compound of 2- [ (9-bromo-6H-dibenzo [ b, d ] pyran-3-yl) oxy ];
s4: reacting the ester compound of 2- [ (9-bromo-6H-dibenzo [ b, d ] pyran-3-yl) oxy ] with an amino compound, a substituted amino compound, an azacyclyl compound, a substituted azacyclyl compound, morpholine and a substituted morpholinyl compound, and then reacting the resulting product with a substituted heterocyclyl compound or a substituted pyrimidinyl compound to produce the compound of formula (I), a stereoisomer of formula (I) or a salt thereof.
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