CN113968861A - Compound with PI3K delta/BTK double-target-point activity and preparation method and application thereof - Google Patents
Compound with PI3K delta/BTK double-target-point activity and preparation method and application thereof Download PDFInfo
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- CN113968861A CN113968861A CN202111304088.2A CN202111304088A CN113968861A CN 113968861 A CN113968861 A CN 113968861A CN 202111304088 A CN202111304088 A CN 202111304088A CN 113968861 A CN113968861 A CN 113968861A
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- compound
- btk
- pi3k
- lymphoma
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Abstract
The invention discloses a compound with PI3K delta/BTK double-target-point activity, a preparation method thereof and application thereof in preparing a pharmaceutical preparation for preventing or treating diseases caused by PI3K delta or BTK protein abnormality. In particular, the invention describes compounds of formula a. The main advantage of the combined use of two inhibitors according to the invention is that the synergistic effect can be achieved by complementationThe treatment effect of 1+1 is more than 2, and the double-target inhibitor can not only ensure the treatment effect of the medicament, but also reduce the risk of medicament-medicament interaction by reducing the administration dosage and further improve the safety, so that the compound with the PI3K delta/BTK double-target activity provided by the invention can be widely applied to the preparation of medicinal preparations for preventing or treating diseases caused by B cell receptor abnormality.
Description
Technical Field
The invention relates to the field of small molecule drugs, and particularly provides a compound with double target point inhibitory activity on Bruton Tyrosine Kinase (BTK) and phosphatidylinositol-3-kinase delta subtype (PI3K delta), and synthesis and application of the compound.
Background
B-cell lymphoma is a heterogeneous group of lymphoproliferative diseases, and is a malignant tumor with a relatively high degree of death, and can be divided into Hodgkin Lymphoma (HL) and non-hodgkin lymphoma (NHL). HL usually originates in lymph nodes with Reed-Sternberg tumor cells; NHL is often found in extranodal lymphoid tissues with a higher prevalence including Mantle Cell Lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), Chronic Lymphocytic Leukemia (CLL), Follicular Lymphoma (FL), marginal zone B-cell lymphoma (MZL), and the like. The current conventional treatment for B cell lymphoma is radiation, chemotherapy. In the NCCN clinical guidelines in the united states, the first-line treatment regimen for B-cell lymphomas is R-CHOP therapy, a combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. However, the toxicity associated with these therapies is poorly tolerated by elderly patients or patients who themselves have other diseases.
The pathogenesis of B cell lymphomas is closely related to the B Cell Receptor (BCR). In many B cell lymphomas, BCR is overexpressed, and the BCR signaling pathway is also overactive, resulting in inhibition of the normal differentiation and apoptosis processes of B cells and promotion of abnormal proliferation processes. Therefore, the BCR signaling pathway is crucial for the growth and survival of a variety of tumor cells, and different targeted drugs directed to this pathway can inhibit the progression of B-cell related diseases, including spleen tyrosine kinase (SYK), Bruton Tyrosine Kinase (BTK), and phosphatidylinositol-3-kinase (PI3K), among others.
PI3K is a class of lipid kinases involved in regulating physiological processes associated with tumorigenesis and development. Currently, 5 PI3K inhibitors are approved by the FDA for marketing. In 7 months 2014, the first selective PI3K δ inhibitor Idelalisib was approved by FDA for marketing, with a selectivity over 40-fold higher than other subtypes, and was mainly used for the treatment of recurrent CLL, FL, or SLL. However, Idelalisib has a black box warning with severe side effects such as hepatotoxicity, severe diarrhea, colitis, pneumonia and intestinal perforation. In view of the severe adverse effects of Idelalisib, 9 months 2017, FDA accelerated approval of the marketing of Copanlisib for the treatment of FL. Copalisib is a PI3K alpha/delta inhibitor, has similar treatment effect to Idelalisib, and has greatly improved safety. Duvelisib, approved to market in 2018 at 10 months, is a PI3K delta/gamma selective inhibitor, and the total remission rate can reach 78%. The Alpelisib is a PI3K alpha inhibitor, has high selectivity, is mainly used for treating the advanced metastatic breast cancer with PIK3CA mutation, fills the gap of poor treatment effect of a patient with the PIK3CA mutant breast cancer, and has three times of survival time compared with a placebo group. The newly approved PI3K delta/CK 1 epsilon dual target inhibitor Umbralisib was even more FDA qualified for orphan drug treatment for FL/MZL. The research on the PI3K inhibitor in the world is still very hot, but a plurality of complex mechanisms exist in the PI3K target, each subtype has own unique function, so that the inhibitors aiming at different subtypes inhibit tumors through different mechanisms, and the toxicity is also superposed. Therefore, PI3K inhibitor with high subtype selectivity has a more promising prospect in the aspect of safety.
PI3K δ is expressed only in hematopoietic cells, and studies have shown that B cell function is severely impaired in mice knockout for PI3K δ, and therefore PI3K δ is an effective target for the treatment of B cell lymphomas. Meanwhile, PI3K delta is also related to immune diseases, can regulate immune threshold and limit the immunity of endogenous microbiota, and is expected to be used for treating immune cell related diseases such as rheumatoid arthritis, multiple sclerosis, Alzheimer's disease and the like. A more attractive second generation PI3K δ inhibitor, Umbralisib, was recently marketed in the united states for MZL and FL patients who had previously received treatment. The tolerance and the safety of Umbralisib are better, and autoimmune toxicity is less. Therefore, the second generation PI3K inhibitor has higher selectivity, and reduces the side effect caused by the superimposed toxicity to a greater extent.
BTK kinases can promote cell proliferation, antibody secretion, switch-like recombination, and production of proinflammatory cytokines. At present, 5 BTK inhibitors are on the market all over the world, and clinical tests for treating pancreatic cancer, breast cancer, autoimmune diseases and the like are also in progress besides hematological tumors. Ibrutinib is the first BTK inhibitor to be successfully marketed, is approved by FDA in 2013, and still occupies the first position in BTK inhibitor sales. The acaraburtinib and zanuburtinib subsequently marketed are structurally similar to Ibrutinib, but with less off-target side effects. Orelabrutinib, which was recently approved in NMPA in China, has a higher selectivity, and clinical trials are continuing to develop more indications.
Due to the complex mechanism of the B cell signal pathway network and the existence of compensatory activation, most patients with recurrent or refractory B cell lymphoma usually cannot obtain long-term benefit from single-drug treatment and are easy to have drug resistance and side effects. The measures of combined medication or combined radiotherapy and chemotherapy are generally adopted clinically, so that the safety and the curative effect are improved. Although both PI3K and BTK inhibitors belong to the BCR signaling pathway and are directed against B-cell lymphomas, they are two relatively independent pathways, and inhibition of one kinase has little effect on activation of the other, so that the combined administration of PI3K and BTK reduces compensatory activation in the signaling pathway, and inhibits both targets at the same time at a lower drug dose, possibly with higher therapeutic effect. Clinical trials involving the combined use of PI3K and a BTK inhibitor are currently ongoing, for example, studies on the treatment of recurrent or refractory primary central nervous lymphoma (PCNSL) by combination of Copalisib and Ibrutinib have shown that a higher complete remission rate can be achieved more rapidly and the time to tumor recurrence can be significantly prolonged, which is in stage Ib/II. The synergistic administration of the PI3K inhibitor Umbralisib and the BTK inhibitor Ibrutinib to CLL/MCL tumor patients showed good tolerability.
However, differences in PK properties between different drugs (e.g., drug half-life, drug distribution, and drug-drug interactions) limit the utility of some drug combinations, and multi-component administration may also present metabolic and drug resistance issues.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a compound with PI3K delta/BTK double-target-point activity, a pharmaceutically acceptable salt thereof, a synthetic method thereof and application thereof in medicines for inhibiting B protein receptors.
The purpose of the invention is realized by the following technical scheme: a compound having dual PI3K δ/BTK target activity and pharmaceutically useful salts thereof, having the structure of formula a:
wherein R has the following structure:
the invention also provides a preparation method of the compound with PI3K delta/BTK double-target activity, which comprises the following steps:
the first step is as follows: under the action of sodium carbonate and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride, 3-iodine-1H-pyrazolo [3,4-d ] pyrimidine-4-amine and 3-fluoro-4-methoxy boric acid generate a compound with a B-1 structure in a solvent system of N-methylpyrrolidone and water;
the second step is that: adding 3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine, triphenylphosphine oxide and triphenylphosphine, adding N, N-dimethylformamide for dissolving, placing under an ice bath under the protection of nitrogen, and dropwise adding diisopropyl azodicarboxylate to obtain a compound with a B-2 structure;
the third step: intermediate B-2 was mixed with the starting N-Boc-protected alcohol, triphenylphosphine TPP was added, diisopropyl azodicarboxylate DIAD was added slowly dropwise in an ice bath, the reaction was stirred at room temperature, and the progress of the reaction was monitored by TLC. Adding water for quenching, extracting by dichloromethane, and separating by silica gel column chromatography to obtain a product C-1;
the fourth step: removing a protecting group of the obtained C-1 product in dilute hydrochloric acid to obtain C-2;
the fifth step: and carrying out condensation reaction on the intermediate C-2 and acrylic acid substituted by R5 to obtain a target product A.
The reaction equation is as follows:
wherein,
r5 is H, F or methyl;
the structural definition of R is consistent with the foregoing.
The compound with the PI3K delta/BTK double-target activity can be used alone or prepared into pharmaceutically acceptable salts by a conventional method, wherein the pharmaceutically acceptable salts are hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acetate, propionate, butyrate, oxalate, tartrate, methanesulfonate, p-toluenesulfonate, fumarate, taurate, citrate, succinate or mixed salts thereof.
The invention also provides a compound with PI3K delta/BTK double-target-point activity and an application of the compound in pharmacy, wherein the application specifically comprises the following steps: is used for preparing a pharmaceutical preparation for preventing or treating diseases caused by PI3K delta/BTK abnormality. The disease is lymphoma, including chronic lymphocytic leukemia, B cell lymphoma, mantle cell lymphoma, lymphoplasmacytic lymphoma, diffuse large B cell lymphoma, non-Hodgkin's lymphoma, follicular central lymphoma, marginal zone B cell lymphoma, or autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriasis, etc.
Compared with the prior art, the invention has the following advantages:
the main advantage of the combined application of the two inhibitors is that the therapeutic effect of 1+1 > 2 can be realized through complementary synergistic action, and the double-target inhibitor can not only ensure the therapeutic effect of the drug, but also reduce the risk of drug-drug interaction and further improve the safety by reducing the administration dosage, so that the compound with the PI3K delta/BTK double-target activity provided by the invention can be widely applied to the preparation of pharmaceutical preparations for preventing or treating diseases caused by B cell receptor abnormality.
Drawings
Fig. 1 is a graph of plasma concentration versus time for compounds CXY20, CXY23 and CXY 27.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
EXAMPLE 1N- (2- (1- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) ethyl) -4-chloro-5-fluorophenyl) acrylamide
The first step is as follows: 3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine
3-iodine-1H-pyrazolo [3,4-d ] is added into a reaction bottle in sequence]Pyrimidin-4-amine (20g,77mmol), 3-fluoro-4-methoxyboronic acid (33g,192mmol) and sodium carbonate (16g,153mmol) in a solvent of N-methylpyrrolidinone and water 5: 1: (216mL), adding 1,1' -bis-diphenylphosphino ferrocene palladium dichloride (3g, 4mmol) under the protection of nitrogen, and heating to 100 ℃ for reaction for 8 hours. Adding 2L of water into the reaction solution, heating and stirring for 30min, and performing suction filtration to obtain a black crude product. Adding N, N-dimethylformamide (400ml) into the crude product, heating to 50 ℃, pulping for 1h, cooling, and performing suction filtration to obtain a brown product with the yield of 91%.1H NMR(500MHz,DMSO)δ13.54(s,1H),8.21(s,1H),7.61–7.39(m,2H),7.33(d,J=8.6Hz,1H),6.79(s,2H),3.91(s,3H);ESI-MS:m/z=260.01[M+H]+.
The second step is that: 3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-triphenylphosphamide
Adding 3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d into a reaction bottle in sequence]Pyrimidin-4-amine (20g,77mmol), triphenylphosphine oxide (21g,77mmol) and triphenylphosphine (30g,116mmol) were dissolved in anhydrous N, N-dimethylformamide (200mL), placed in an ice bath under nitrogen protection, and diisopropyl azodicarboxylate (23mL,116mmol) was slowly added dropwise. After stirring at room temperature for 30min after dropping, ethyl acetate (400 mL. times.2) and water (400mL) were added for extraction, and the organic phases were combined, washed with saturated brine (400mL), dried over anhydrous sodium sulfate, filtered and the solvent was concentrated to give a crude product. Separating by silica gel column chromatography, and drying in a vacuum drying oven at 60 deg.C for 24 hr to obtain white powdery solid 33g with yield of 83%.1H NMR(500MHz,CDCl3)δ8.62(d,J=12.9Hz,1H),8.16(s,2H),7.86(dd,J=12.2,7.8Hz,6H),7.57(t,J=7.3Hz,3H),7.48(t,J=7.5Hz,6H),7.06(t,J=8.6Hz,1H),4.00(s,3H);ESI-MS:m/z=520.16[M+H]+.
The third step: 2-acetyl-4-chloro-5-fluorophenyl trifluoromethanesulfonate
1- (5-chloro-4-fluoro-2-hydroxyphenyl) ethan-1-one (3g,16mmol) was added to a reaction flask, dissolved in anhydrous dichloromethane (30mL), triethylamine (3mL,24mmol) was added, the reaction flask was placed in an ice bath, trifluoromethanesulfonic anhydride (3mL,21mmol) was slowly added dropwise, and after stirring at room temperature for 1h, dichloromethane (100 mL. times.2) and water (200 mL. times.2) were added theretomL), the organic phases were combined, washed with saturated brine (200mL), the organic phase was dried over anhydrous sodium sulfate, filtered and the solvent was concentrated, and the product was isolated by silica gel column chromatography to give 5g of a pale yellow liquid with a yield of 98%.1H NMR(500MHz,CDCl3)δ7.93(d,J=7.8Hz,1H),7.21(d,J=8.3Hz,1H),2.64(s,3H);ESI-MS:m/z=321.01[M+H]+.
The fourth step: 2-amino-4-fluoro-5-chloroacetophenone
Adding 2-acetyl-4-chloro-5-fluorophenyl trifluoromethanesulfonate (1g,3mmol) and diphenylimine (785 μ L,5mmol) into a reaction bottle in sequence, dissolving with toluene (8mL), adding cesium carbonate (2g,5mmol), 1 '-binaphthyl-2, 2' -bis-diphenylphosphine (291mg,0.5mmol) and tris (dibenzylideneacetone) dipalladium (286mg,0.3mmol) into a reaction tube in sequence, reacting at 80 ℃ for 8 hours under the protection of nitrogen, slowly adding a 2N hydrochloric acid solution (20mL) into the reaction solution, heating to 60 ℃ and stirring for 1 hour, filtering the reaction solution through kieselguhr, adjusting the pH of the filtrate to be 8-10, extracting, drying the organic phase with sodium sulfate hydrate, and separating by silica gel column chromatography to obtain a yellow solid with the yield of 150 mg: 27% of Si-MS, M/z is 210.04[ M + Na%]+.
The fifth step: 1- (2 ' -amino-4 ' -fluoro-5 ' -chloro-phenyl) -1-ethanol
Adding 2-amino-4-fluoro-5-chloroacetophenone (900mg,5mmol) into a reaction bottle, dissolving in anhydrous methanol (9mL), placing the reaction bottle in an ice bath, slowly adding sodium borohydride (91mg,2mmol), reacting at room temperature for 1h, adding water to quench the reaction, performing rotary evaporation to remove a methanol solvent, adding dichloromethane (150mL multiplied by 2) and water (100mL) to extract and separate, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the solvent, and purifying by silica gel column chromatography to obtain a white solid 901mg with the yield of 99%.1H NMR(500MHz,CDCl3)δ7.06(d,J=8.0Hz,1H),6.43(d,J=10.7Hz,1H),4.85(q,J=6.6Hz,1H),4.52(d,J=178.5Hz,2H),1.56(d,J=6.6Hz,3H);ESI-MS:m/z=212.04[M+Na]+.
And a sixth step: 2- (1- (tert-butyldisilyloxy)) -4-chloro-5-fluoroaniline
To a reaction flask was added 1- (2 ' -amino-4 ' -fluoro-5 ' -chloro-phenyl) -1-ethanol (900mg,5mmol) dissolved in anhydrous dichloromethane(15mL), imidazole (647mg,10mmol) and tert-butyldimethylsilyl chloride (859mg,6mmol) were added, and the mixture was reacted at room temperature for 8 hours. Dichloromethane (100 mL. times.2) and water (100mL) were added to extract and separate the layers, the organic layers were combined, washed with saturated brine (200mL), the organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated, and the product was purified by silica gel column chromatography to give 1g of a colorless transparent oil with a yield of 97%.1H NMR(400MHz,CDCl3)δ6.95(d,J=8.1Hz,1H),6.43(d,J=10.8Hz,1H),4.80(q,J=6.5Hz,1H),4.52(s,2H),1.51(d,J=6.6Hz,3H),0.92(s,9H),0.12(s,3H),0.02(s,3H);ESI-MS:m/z=304.12[M+H]+.
The seventh step: n- (2- (1- (tert-butyldisilyloxy)) ethyl) -4-chloro-5-fluorophenyl) acrylamide
N- (2- (1- (tert-butyldimethylsilyloxy)) ethyl) -4-chloro-5-fluorophenyl) acrylamide (1g,5mmol), acrylic acid (459. mu.L, 7mmol) were added to a reaction flask, and dissolved in anhydrous dichloromethane (30mL), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2g,9mmol) was added thereto, and after stirring for 30min in an ice bath, dichloromethane (100 mL. times.2) and water (100mL) were added to extract liquid separation, the organic phases were combined, washed with saturated saline (200mL), the organic layer was dried with anhydrous sodium sulfate, the solvent was concentrated, and the product was purified by silica gel column chromatography to obtain 1g of a colorless transparent oil with a yield of 74%.1H NMR(400MHz,CDCl3)δ9.77(s,1H),8.44(d,J=11.6Hz,1H),7.05(d,J=7.7Hz,1H),6.44(d,J=16.9Hz,1H),6.21(dd,J=17.0,10.3Hz,1H),5.83(d,J=10.4Hz,1H),4.89(q,J=6.6Hz,1H),1.52(d,J=6.6Hz,3H),0.93(s,9H),0.17(s,3H),0.07(s,3H);ESI-MS:m/z=358.13[M+H]+
Eighth step: n- (4-chloro-5-fluoro-2- (1-hydroxyethyl) phenyl) acrylamide
N- (2- (1- (tert-butyldisilyloxy)) ethyl) -4-chloro-5-fluorophenyl) acrylamide (1g,3mmol) was added to a reaction flask, dissolved in anhydrous tetrahydrofuran (10mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (3mL,32mmol) was added dropwise to the flask under ice bath, and the mixture was stirred at room temperature for 3 hours after completion of dropwise addition. Concentrating to remove tetrahydrofuran, adding ethyl acetate (100mL × 2) and water (100mL), extracting, separating, combining organic phases, washing with saturated saline (200mL), drying organic layer with anhydrous sodium sulfate, and concentrating the solventAnd purifying the product by silica gel column chromatography to obtain white solid 580mg with yield of 74 percent.1H NMR(400MHz,CDCl3)δ9.51(s,1H),8.28(d,J=11.4Hz,1H),7.12(d,J=7.8Hz,1H),6.38(d,J=16.1Hz,1H),6.22(dd,J=17.0,10.2Hz,1H),5.79(d,J=9.3Hz,1H),4.95(q,J=6.4Hz,1H),2.70(s,1H),1.57(d,J=6.7Hz,3H);ESI-MS:m/z=244.05[M+H]+.
The ninth step: n- (4-chloro-5-fluoro-2- (1- (3- (3-fluoro-4-methoxyphenyl) -4- ((triphenyl-15-phosphinylidene) amino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) ethyl) phenyl) acrylamide
Adding 3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d into a reaction bottle]Pyrimidine-4-triphenylphosphoramide (213mg,0.4mmol), N- (4-chloro-5-fluoro-2- (1-hydroxyethyl) phenyl) acrylamide (100mg,0.4mmol), triphenylphosphine (161mg,0.6mmol), dissolved in anhydrous tetrahydrofuran (4mL), slowly added with diisopropyl azodicarboxylate (121. mu.L, 0.6mmol) dropwise under ice bath, stirred at room temperature for 20min, quenched with appropriate amount of water, rotary evaporated to remove tetrahydrofuran, extracted with dichloromethane (100 mL. times.2) and water (100mL), combined organic phases, washed with saturated saline (200mL), dried organic layer with anhydrous sodium sulfate, concentrated solvent, purified by silica gel column chromatography to give 190mg of white solid. ESI-MS: M/z 745.19[ M + H ]]+.
The tenth step: n- (2- (1- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) ethyl) -4-chloro-5-fluorophenyl) acrylamide
Adding N- (4-chloro-5-fluoro-2- (1-hydroxyethyl) phenyl) acrylamide (190mg,0.3mmol), glacial acetic acid (2mL,0.04mmol) and water (2mL) in the same volume ratio into a reaction bottle, heating to 70 ℃, reacting for 5 hours, adding saturated sodium bicarbonate solution, neutralizing the reaction solution, adjusting the pH to be neutral, extracting and separating by dichloromethane (100mL multiplied by 2) and water (100mL), combining organic phases, washing by saturated saline (200mL), drying an organic layer by anhydrous sodium sulfate, concentrating a solvent, and purifying a product by silica gel column chromatography to obtain 90mg of white powdery solid with the yield of 72%.1H NMR(400MHz,CDCl3)δ12.07(s,1H),8.31(s,1H),7.77(d,J=10.8Hz,1H),7.42(d,J=7.5Hz,1H),7.36(d,J=11.6Hz,1H),7.31(d,J=8.5Hz,1H),7.03(t,J=8.5Hz,1H),6.68(dd,J=17.0,10.2Hz,1H),6.53(d,J=17.0Hz,1H),6.40(q,J=7.2Hz,1H),6.30(s,1H),5.96(s,1H),5.79(d,J=10.2Hz,1H),4.05(q,J=7.1Hz,1H),3.88(s,3H),1.98(d,J=4.2Hz,3H);13C NMR(101MHz,CDCl3)δ164.11,156.70,152.90,150.43,149.88,147.26,146.96,141.44,136.04,130.52,127.19,126.53,125.53,125.08,123.24,116.70,115.27,115.08,113.42,113.10,97.09,55.34,51.03,18.57;ESI-MS:m/z=485.12[M+H]+.
Example 2N- (2- (1- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) ethyl) phenyl) acrylamide
The first step is as follows: 1- (2-aminophenyl) ethanol
Reference example 1, step 5 reaction run.1H NMR(500MHz,CDCl3)δ7.11(t,J=6.7Hz,2H),6.75(t,J=7.5Hz,1H),6.70(d,J=8.2Hz,1H),4.95(q,J=6.6Hz,1H),3.18(s,3H),1.61(d,J=6.6Hz,3H).
The second step is that: 2- (1- ((tert-butyldimethylsilyl) oxy) ethyl) aniline
Reference example 1, step 6.1H NMR(400MHz,CDCl3)δ6.94(t,J=8.3Hz,1H),6.84(d,J=7.4Hz,1H),6.55(dd,J=14.2,7.6Hz,2H),4.75(q,J=6.5Hz,1H),1.41(d,J=6.6Hz,3H),0.80(d,J=13.1Hz,9H),0.14–0.09(m,3H),0.08–0.01(m,3H);ESI-MS:m/z=252.17[M+H]+.
The third step: n- (2- (1- ((tert-butyldimethylsilyl) oxy) ethyl) phenyl) acrylamide
Reference example 1, step 7 reaction run.1H NMR(500MHz,CDCl3)δ9.65(s,1H),8.42(d,J=8.1Hz,1H),7.30(d,J=2.7Hz,1H),7.02(d,J=6.1Hz,2H),6.41(d,J=18.0Hz,1H),6.23(dd,J=17.0,10.3Hz,1H),5.76(d,J=11.4Hz,1H),4.93(q,J=6.6Hz,1H),1.51(d,J=6.6Hz,3H),0.91(s,9H),0.14(s,3H),0.02(s,3H);ESI-MS:m/z=306.18[M+H]+.
The fourth step: n- (2- (1-hydroxyethyl) phenyl) acrylamide
Reference example 1 reaction procedure of step 8.1H NMR(500MHz,CDCl3)δ9.40(s,1H),8.21(d,J=7.8Hz,1H),7.30(d,J=8.4Hz,1H),7.14(d,J=7.3Hz,1H),7.08(t,J=7.4Hz,1H),6.36(d,J=16.9Hz,1H),6.25(dd,J=17.0,10.2Hz,1H),5.74(d,J=10.3Hz,1H),4.99(q,J=6.6Hz,1H),3.06(s,1H),1.57(d,J=6.7Hz,3H);ESI-MS:m/z=214.07[M+Na]+.
The fifth step: n- (2- (1- (3- (3-fluoro-4-methoxyphenyl) -4- ((triphenyl-15-phosphinylidene) amino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) ethyl) phenyl) acrylamide
Reference example 1, step 9. ESI-MS: M/z 693.25[ M + H ]]+.
And a sixth step: n- (2- (1- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) ethyl) phenyl) acrylamide
Reference example 1 reaction procedure of step 10.1H NMR(400MHz,CDCl3)δ11.73(s,1H),8.38(s,1H),7.82(d,J=7.8Hz,1H),7.50(d,J=7.6Hz,1H),7.41(d,J=11.7Hz,1H),7.34(t,J=7.6Hz,2H),7.19(t,J=7.3Hz,1H),7.07(t,J=8.3Hz,1H),6.71(dd,J=16.8,10.2Hz,1H),6.59–6.49(m,2H),5.76(d,J=10.2Hz,1H),3.92(s,3H),2.04(d,J=6.8Hz,3H);13C NMR(101MHz,CDCl3)δ165.17,157.88,153.85,150.95,148.15,147.69,142.96,136.46,131.89,130.74,129.71,127.34,126.76,125.84,125.72,124.26,116.30,116.09,114.04,98.12,56.33,52.89,19.62;ESI-MS:m/z=433.17[M+H]+.
Example 3N- (2- (1- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) ethyl) phenyl) methacrylamide
Refer to the procedure of example 2.1H NMR(400MHz,CDCl3)δ11.25(s,1H),8.40(s,1H),7.65(d,J=7.8Hz,2H),7.49–7.41(m,2H),7.39(d,J=5.9Hz,1H),7.36(s,1H),7.25–7.19(m,1H),7.08(t,J=8.3Hz,1H),6.52(d,J=6.8Hz,1H),6.29(s,1H),5.58(s,1H),4.97(dd,J=14.7,6.9Hz,1H),3.93(s,2H),2.14(s,2H),2.08(s,2H);13C NMR(101MHz,CDCl3)δ165.17,157.88,153.85,150.95,148.15,147.69,142.96,136.46,131.89,130.74,129.71,127.34,126.76,125.84,125.72,124.26,116.30,116.09,114.04,98.12,56.33,52.89,29.73,19.62;ESI-MS:m/z=447.09[M+H]+.
Example 4N- (3- (1- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) ethyl) phenyl) acrylamide
Refer to the procedure of example 2.1H NMR(400MHz,CDCl3)δ9.36(s,1H),8.13(s,1H),8.00(s,1H),7.26–7.16(m,2H),7.10(d,J=7.9Hz,1H),7.01(s,1H),6.80(d,J=7.1Hz,1H),6.34(s,2H),5.60(s,1H),5.44(q,J=6.6Hz,1H),3.92(s,3H),1.86(d,J=4.8Hz,3H);13C NMR(101MHz,CDCl3)δ177.07,164.22,159.42,158.05,155.17,153.26,149.43,141.70,139.22,135.88,131.48,129.22,127.30,126.79,126.27,121.65,119.76,117.34,113.97,100.40,59.11,56.26,22.10;ESI-MS:m/z=433.06[M+H]+.
Example 5N- (3- (1- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) ethyl) phenyl) methacrylamide
Refer to the procedure of example 2.1H NMR(400MHz,CDCl3)δ8.29(s,1H),8.05(d,J=18.0Hz,1H),7.80(s,1H),7.41(s,1H),7.23–7.03(m,2H),6.90(s,1H),5.80(s,2H),5.47(s,1H),5.43(s,1H),3.97(s,4H),2.03(s,4H),1.94(d,J=6.4Hz,3H);13C NMR(101MHz,CDCl3)δ165.17,157.88,153.85,150.95,148.15,147.69,142.96,136.46,131.89,130.74,129.71,127.34,126.76,125.84,125.72,124.26,116.30,116.09,114.04,98.12,56.33,52.89,29.73,19.62;ESI-MS:m/z=447.07[M+H]+.
Example 61- (3- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one
The first step is as follows: 3- (3- (3-fluoro-4-methoxyphenyl) -4- ((triphenyl-l 5-phosphinylidene) amino) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidine-1-carboxylic acid tert-butyl ester
Adding 3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d into a reaction bottle in sequence]Pyrimidine-4-triphenylphosphamide (2g,3mmol), N-Boc-3-hydroxypiperidine (2g,9mmol) and triphenylphosphine (2g,6mmol), and anhydrous tetrahydrofuran was added to dissolve the starting material, diisopropyl azodicarboxylate (1mL,6mmol) was slowly added dropwise under ice bath, and the mixture was stirred at room temperature for 30 min. After completion of the reaction, water was added to quench the reaction solution, tetrahydrofuran was removed by rotary evaporation, methylene chloride (200 mL. times.2) and water (200mL) were added to extract the reaction solution, the organic phases were combined, washed with saturated brine (300mL), dried over anhydrous sodium sulfate, filtered, the solvent was concentrated, and the mixture was separated by silica gel column chromatography to obtain 2g of a white solid. Yield: 94 percent. 703.16[ M + H ] M/z]+.
The second step is that: 1- (3- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one
To a reaction flask was added 3- (3- (3-fluoro-4-methoxyphenyl) -4- ((triphenyl-l 5-phosphinylidene) amino) -1H-pyrazolo [3,4-d]Pyrimidin-1-yl) piperidine-1-carboxylic acid tert-butyl ester (2g,3mmol), 4M HCl in dioxane (3mL,13mmol), was heated at 70 ℃ for 5 h. Concentrating the solvent, adding methyl tert-butyl ether, pulping, suction filtering to obtain white solid 2g, adding into a reaction bottle, simultaneously adding anhydrous dichloromethane (10mL), triethylamine (553 uL, 4mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (766mg,4mmol), slowly dropwise adding acrylic acid (180 uL, 2mmol) under ice bath, stirring at room temperature for 8h after dropwise adding, adding dichloromethane (100mL multiplied by 2) and water (100mL) for extraction, combining organic phases, washing with saturated salt water (200mL), drying with anhydrous sodium sulfate, filtering, concentratingThe solvent was condensed and the product was isolated by silica gel column chromatography to give 156mg of a white solid in 30% yield.1H NMR(400MHz,CDCl3)δ8.34(d,J=24.5Hz,1H),7.50–7.38(m,2H),7.13(t,J=8.4Hz,1H),6.69–6.52(m,1H),6.30(dd,J=16.2,11.7Hz,1H),5.79(s,2H),5.70(d,J=15.9Hz,1H),4.90(s,1H),4.86–4.52(m,1H),4.12(dd,J=61.7,13.1Hz,1H),3.97(s,3H),3.56(t,J=12.5Hz,1H),2.89(t,J=11.7Hz,1H),2.44–2.30(m,1H),2.26(s,1H),2.00(d,J=13.8Hz,1H),1.72(d,J=1.8Hz,1H);13C NMR(101MHz,CDCl3)δ165.75,157.75,155.72,155.58,153.89,151.42,148.58,143.22,128.16,127.59,124.44,116.49,116.30,113.97,98.39,56.40,50.02,45.94,42.17,25.29,23.92;ESI-MS:m/z=397.17[M+H]+.
Example 71- (3- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2-methylpropan-2-en-1-one
Refer to the procedure of example 6.1H NMR(400MHz,CDCl3)δ8.29(s,1H),7.41(dd,J=14.7,10.2Hz,2H),7.11(t,J=8.4Hz,1H),5.89(s,2H),5.15(s,1H),5.07(s,1H),4.83(s,1H),4.58(s,1H),4.09(d,J=71.0Hz,1H),3.95(s,3H),3.52(s,1H),2.97(s 1H),2.31(s,1H),2.22(d,J=9.9Hz,1H),2.00(s,1H),1.95(s,3H),1.69(s,1H);13C NMR(101MHz,CDCl3)δ171.49,157.90,155.77,153.87,151.40,148.50,143.19,140.40,126.02,124.44,116.59,116.30,115.48,113.95,98.41,56.39,53.39,45.55,41.34,26.96,20.58;ESI-MS:m/z=411.19[M+H]+.
Example 81- (3- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2-fluoroprop-2-en-1-one
Refer to the procedure of example 6.1H NMR(400MHz,CDCl3)δ8.33(s,1H),7.44(dd,J=14.7,10.2Hz,2H),7.13(t,J=8.4Hz,1H),5.99(s,1H),5.26(d,J=3.3Hz,1H),5.12(s,1H),4.98–4.85(m,1H),4.59(d,J=85.0Hz,1H),3.97(s,3H),3.89(d,J=67.5Hz,4H),3.34(d,J=95.9Hz,1H),2.76(d,J=47.2Hz,1H),2.42–2.30(m,1H),2.25(d,J=12.9Hz,1H),2.02(d,J=14.5Hz,2H),1.77(d,J=13.1Hz,1H);13C NMR(101MHz,CDCl3)δ171.24,161.59,161.29,157.84,155.60,153.88,151.41,148.65,143.36,125.86,124.42,116.48,116.29,113.97,98.40,60.44,56.39,42.56,30.26,21.10,14.21;ESI-MS:m/z=415.16[M+H]+.
Example 91- (4- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) prop-2-en-1-one
Refer to the procedure of example 6.1H NMR(400MHz,CDCl3)δ8.27(s,1H),7.34(t,J=10.7Hz,2H),7.04(t,J=8.4Hz,1H),6.59–6.47(m,1H),6.21(d,J=16.8Hz,1H),5.63(d,J=10.6Hz,1H),4.95(dd,J=9.8,5.7Hz,1H),4.74(d,J=11.5Hz,1H),4.11(d,J=12.2Hz,1H),3.88(s,3H),3.25(t,J=9.0Hz,1H),2.84(t,J=12.1Hz,1H),2.24(d,J=11.9Hz,2H),2.02(d,J=10.5Hz,2H);13C NMR(101MHz,CDCl3)δ174.77,165.51,158.00,155.67,153.85,151.36,148.48,146.57,143.03,127.74,124.43,116.44,113.99,98.46,56.38,53.85,45.01,41.25,31.77,31.07;ESI-MS:m/z=397.09[M+H]+.
Example 101- (4- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) piperidin-1-yl) -2-methylpropan-2-en-1-one
Refer to the procedure of example 6.1H NMR(400MHz,DMSO)δ8.26(s,1H),7.75(d,J=6.1Hz,1H),7.49(t,J=10.0Hz,3H),7.36(t,J=8.6Hz,1H),6.87(s,1H),5.68(s,1H),5.35(s,1H),4.78(s,1H),3.94(s,5H),2.53(s,6H),2.35(dd,J=19.1,9.3Hz,3H),1.97(s,3H),1.89(s,4H);13C NMR(101MHz,DMSO)δ168.28,158.61,155.82,154.10,153.24,150.81,147.96,142.27,140.80,126.43,125.31,119.12,116.41,116.22,114.81,97.88,56.58,54.03,45.42,28.53,27.73,19.63;ESI-MS:m/z=425.20[M+H]+.
Example 111- (3- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) prop-2-en-1-one
Refer to the procedure of example 6.1H NMR(400MHz,CDCl3)δ8.37(d,J=2.8Hz,1H),7.42(dt,J=14.3,7.1Hz,2H),7.12(t,J=8.3Hz,1H),6.43–6.41(m,1H),5.79–5.69(m,2H),5.57(dd,J=12.2,6.3Hz,1H),4.14–4.08(m,1H),3.97(s,3H),3.79(d,J=9.1Hz,1H),3.31–3.20(m,1H),2.74–2.51(m,2H);13C NMR(101MHz,CDCl3)δ164.63,157.83,155.97,154.60,153.86,151.37,148.71,143.48,128.33,128.11,124.46,116.43,113.93,98.66,56.40,55.63,50.59,31.52,29.62;ESI-MS:m/z=405.05[M+Na]+.
Example 121- (3- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) pyrrolidin-1-yl) -2-methylpropan-2-en-1-one
Refer to the procedure of example 6.1H NMR(400MHz,CDCl3)δ8.37(s,1H),7.41(t,J=16.0Hz,2H),7.13(d,J=7.8Hz,1H),5.64(d,J=27.7Hz,2H),5.18(t,J=15.2Hz,2H),3.97(s,3H),3.72(s,2H),3.28(s,1H),2.26(s,3H),1.97(d,J=15.2Hz,5H);13C NMR(101MHz,CDCl3)δ171.04,157.76,155.94,154.55,142.10,141.41,139.09,124.44,122.07,116.72,116.40,115.27,113.98,98.62,56.39,52.56,44.70,44.12,26.01,19.94;ESI-MS:m/z=397.09[M+H]+.
Example 13N- (4- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) acrylamide
Refer to the procedure of example 6.1H NMR(400MHz,DMSO)δ8.24(s,1H),7.46(t,J=9.6Hz,2H),7.34(t,J=8.5Hz,1H),6.43(dd,J=16.9,10.2Hz,1H),6.11(d,J=17.0Hz,1H),5.58(d,J=10.0Hz,1H),4.75(s,1H),3.98(s,1H),3.92(s,3H),2.51(s,4H),2.25(d,J=10.6Hz,2H),1.89(s,2H);13C NMR(101MHz,DMSO)δ164.58,158.62,155.93,153.98,153.18,150.75,147.95,142.48,132.41,126.24,125.37,116.24,114.72,97.80,56.48,54.32,44.34,28.97,27.44;ESI-MS:m/z=411.09[M+H]+.
Example 14N- (4- (4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) cyclohexyl) methacrylamide
Refer to the procedure of example 6.1H NMR(400MHz,DMSO)δ8.26(s,1H),7.75(d,J=6.1Hz,1H),7.49(t,J=10.0Hz,3H),7.36(t,J=8.6Hz,1H),6.87(s,1H),5.68(s,1H),5.35(s,1H),4.78(s,1H),3.94(s,5H),2.53(s,6H),2.35(dd,J=19.1,9.3Hz,3H),1.97(s,3H),1.89(s,4H);13C NMR(101MHz,DMSO)δ168.28,158.61,155.82,154.10,153.24,150.81,147.96,142.27,140.80,126.43,125.31,119.12,116.41,116.22,114.81,97.88,56.58,54.03,45.42,28.53,27.73,19.63;ESI-MS:m/z=425.20[M+H]+.
Example 151- (4- ((4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) piperidin-1-yl) prop-2-en-1-one
Reference toThe procedure of example 6.1H NMR(400MHz,CDCl3)δ8.36(s,1H),7.55–7.39(m,2H),7.13(t,J=8.4Hz,1H),6.56(dd,J=16.8,10.6Hz,1H),6.24(d,J=16.8Hz,1H),5.81(s,2H),5.66(d,J=10.5Hz,1H),4.67(d,J=12.5Hz,1H),4.34(d,J=7.0Hz,2H),3.97(s,3H),3.03(t,J=12.1Hz,1H),2.69–2.58(m,1H),2.34(s,2H),1.70(s,2H),1.37–1.27(m,2H);13C NMR(101MHz,CDCl3)δ165.43,157.88,156.00,154.80,151.42,148.52,143.13,127.85,127.52,124.44,116.54,114.00,98.16,56.40,51.94,45.62,41.82,36.86,30.47,29.35;ESI-MS:m/z=411.09[M+H]+.
Example 161- (2- ((4-amino-3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) methyl) pyrrolidin-1-yl) prop-2-en-1-one
Refer to the procedure of example 6.1H NMR(400MHz,CDCl3)δ8.30(d,J=8.4Hz,1H),7.42–7.30(m,2H),7.05(dd,J=17.9,8.4Hz,1H),6.61(dd,J=16.6,10.3Hz,1H),6.38–6.31(m,2H),5.74(d,J=10.4Hz,1H),5.62(dd,J=8.8,3.5Hz,1H),4.61(dd,J=15.4,5.5Hz,1H),4.36(t,J=6.6Hz,1H),3.90(d,J=3.8Hz,3H),3.43(dd,J=7.9,5.1Hz,1H),3.24(td,J=12.5,6.3Hz,1H),2.51–2.45(m,1H),2.30(t,J=6.7Hz,1H),2.20(s,2H),1.96(d,J=7.5Hz,1H);13C NMR(101MHz,CDCl3)δ163.95,163.55,156.68,155.30,155.02,129.88,128.64,127.89,127.01,126.85,123.42,115.44,113.00,97.18,55.34,46.82,43.78,34.43,26.41,22.77;ESI-MS:m/z=397.09[M+H]+.
EXAMPLE 17 preparation of the hydrochloride salt (exemplified by the Compound of example 12)
Dissolving a proper amount of the compound in ethanol, and slowly introducing HCl gas to saturation at room temperature. The mixture was cooled in an ice bath to precipitate white crystals slowly as the hydrochloride of the compound.
Example 18 kinase inhibition assay
Measurement of PI3K delta kinase inhibitory Activity
The inhibitory activity of PI3K delta kinase is detected by adopting an ADP-Glo method:
the experimental process comprises the following steps: 2.5 μ L of 2-fold final concentration kinase solution was added to each well, centrifuged at 1000rpm for 30s, shaken, mixed and incubated at room temperature for 10 min. Then, 2.5. mu.L of a mixed solution of ATP and the substrate at a final concentration 2 times that of ATP was added thereto, and the mixture was centrifuged for 30 seconds, shaken and mixed well, and then the reaction was started at room temperature. Add 5. mu.L ADP-Glo Reagent, centrifuge for 30s, mix well with shaking and incubate at room temperature for 180 min. 10 μ L of Kinase Detection Reagent was added, centrifuged, shaken and mixed well and incubated at room temperature for 30 min. And finally, reading the luminescence value RLU by using a microplate reader.
Measurement of BTK kinase inhibitory Activity
The inhibitory activity of BTK kinase was measured by the Mobility shift assay method:
the experimental process comprises the following steps: mu.L of a 2.5-fold final concentration kinase solution was added to each well, centrifuged at 1000rpm for 30s, the reaction plate was shaken and mixed, and incubated at room temperature for 10 min. mu.L of a mixture solution of ATP and substrate at 25/15 times final concentration was added, centrifuged for 30 seconds, shaken and mixed, and the reaction was started at room temperature. Add 30. mu.L of termination detection solution to stop the kinase reaction, centrifuge at 1000rpm for 30s, shake and mix. The conversion was read with a microplate reader.
Thirdly, the results are as follows:
TABLE 1 inhibitory Activity of Compounds of interest on PI3K delta and BTK kinases
(Note: NA indicates no activity examined;. indicates published activity data for positive drug, not measured)
The series of compounds have good inhibition activity on PI3K delta, wherein the highest inhibition activity can reach 9.0nM, and the highest inhibition activity on BTK can also reach 19.5nM, and the compounds CXY20, CXY23 and CXY27 have good PI3K delta/BTK kinase dual inhibition activity.
EXAMPLE 19 measurement of inhibitory Activity at cellular level
Cell inoculation: the suspension cells were spun down, resuspended in culture medium, and then counted using a cytometer. The cell suspension is diluted in the culture medium to the desired density. According to the plate map, 100 u L cells were inoculated into 96 hole culture dish. Medium only was used as background control (Min) and incubated overnight at 37 ℃.
Sample preparation: 200 Xsolutions were prepared in DMSO and the compounds were diluted to 3-fold final concentration with medium. Add 50. mu.L of sample to cells at 37 ℃ with 5% CO2And (5) incubating for 72 h.
And (4) determining the result: the plates were allowed to equilibrate to room temperature before measurement, 40. mu.L per wellThe contents were mixed on an orbital shaker for 2min to induce cell lysis. And (5) incubating at room temperature for 60min, and reading a luminescence value by a microplate reader.
The results are as follows:
TABLE 2 inhibitory Activity of Compounds of interest 20,23 and 27 on tumor cells
It can be seen that: although the inhibitory activity of compounds CXY20, CXY23 and CXY27 was lower than that of the positive drug Ibrutinib at the kinase level (about 40 times or more lower as seen from table 1), the cell inhibitory activity of this experiment was similar to that of the positive drug, or even higher. In Mino cells, compounds CXY20, 23 did not show good inhibitory activity, but compound CXY27 was slightly better than the single positive control; in both JeKo-1 and H9 cell lines, compound CXY27 exhibited superior inhibitory effects to those of the positive drug administered alone and in synergy, and its IC501.6. mu.M and 10.8. mu.M, respectively. This suggests that the dual-target inhibitor designed by us indeed has the effect of synergistically inhibiting both targets.
While CXY20 compound has a good kinase inhibitory activity, it is not remarkable in cell activity and may be caused by its poor physicochemical properties and poor membrane permeability. Therefore, we further examined the metabolism of the compound of interest in rats.
EXAMPLE 20 determination of in vivo metabolic Properties of drugs
Sprague-Dawley male rats 9, divided into 3 groups of 3 rats, fasted for more than 8h before administration. Compounds CXY20, 23 and 27 were each 10mg, and DMSO, HS15 and physiological saline were added to prepare a 1mg/mL solution. Groups 3 rats were individually gavaged with 10mg/kg compound (groups A-C). 0.2-0.25 mL of blood is taken from eye sockets 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h and 24h before administration (T0) and after administration, the blood is added into a centrifuge tube containing 20 mu L of anticoagulant EDTA-2Na, the blood plasma is obtained by centrifugation (4000rpm, 10min) within 30min, and 50 mu L of the blood plasma is stored in a refrigerator at the temperature of-20 ℃.
Sample treatment and determination methods: compounds 20,23 and 27 were formulated as 1mg/mL stock solutions and diluted in gradient to working solutions at concentrations of 1000, 500, 250, 100, 50, 25, 10, 5, 2.5ng/mL for use. mu.L of a chromatographic acetonitrile solution containing loratadine was added to 50. mu.L of the plasma sample, vortexed for 2-3min, centrifuged (14000rpm,10min), and 200. mu.L of the supernatant was taken out of the inner liner tube and all plasma samples were assayed.
Chromatographic conditions are as follows: sample introduction volume: 1 mu L of the solution; the type of the chromatographic column: poroshell 120EC-C18 (2.1X 50mm,1.9 μm); sample chamber temperature: 8 ℃; temperature of the column oven: 37 ℃; mobile phase a was water (0.1% formic acid water) and mobile phase B was acetonitrile, the flow rate was 0.4mL/min, and gradient elution was performed.
A. B, C three groups of samples are respectively prepared into a standard curve, and low, medium and high 3 concentration (the concentration of the compound is respectively 5, 100 and 500ng/mL) follow-up quality control samples are respectively prepared for detection. And finally, calculating the concentration of the drug to be detected in the plasma sample of the rat after administration according to the standard curve. Pharmacokinetic parameters were calculated using a fitting of the non-compartmental model in Phoenix WinNonlin software (version 6.3, Pharsight inc., USA).
The blood concentration of the compound to be tested in 24h after the oral administration (Dose:10mg/kg) of SD rats is detected, the blood taking time is respectively 0.25,0.5,1,2,4,6,8,12 and 24h, and pharmacokinetic parameters are calculated by Phoenix WinNonlin software, and the results are shown in Table 3:
TABLE 3 Primary pharmacokinetic parameters for Compounds CXY20, 23 and 27
(data obtained from non-identical experiments)
By measuring the plasma levels of compounds CXY20, 23 and 27 in rats, the pharmacokinetic properties associated with the absorption, distribution and elimination of these compounds can be obtained. The compounds CXY20, 23 and 27 reach C quickly within 0.25-0.33 hmaxThe peak concentration is 80.89 + -15.76, 316.51 + -138.39, 365.65 + -128.00 ng/mL respectively-1,AUC0-∞175.13 + -79.73, 393.48 + -77.98, 551.42 + -262.85 h.ng.mL respectively-1Indicating that the exposure levels of compounds 23 and 27 were generally higher than compound 20. The apparent distribution volumes of the compounds 20,23 and 27 were 675.97 + -635.07, 166.56 + -12.97, 161.03 + -135.33 L.kg-1Indicating that compound 20 is widely distributed in vivo. The half-life of the target compound is between 4 and 6 hours, and the plasma clearance rates are 64.12 +/-23.13, 26.03 +/-4.68 and 22.07 +/-12.73 L.h-1·kg-1. The pharmacokinetic parameters of the target compound all vary greatly from individual to individual.
The peak concentration of the three target compounds is quickly reached within 0.25-0.33 h, and the result is consistent with that of the positive drug Ibrutinib, which indicates that the absorption rate of the compounds is quick, thereby initiating two discussions: firstly, the time point of the absorption phase is designed to be too loose, and the sampling points of 5min and 45min are added to fit the curve of the absorption phase. ② the compound has fast absorption property, and can release medicine more stably through slow release formulation.
From the drug absorption point of view, the exposure level of compound 27 was higher and similar to the positive drug Ibrutinib. And C of Compound 20maxLower, less absorbed, and increased by changing the nature of the drug, changing the dosage form of the drug, or changing the mode of administration, etc., in view of its higher kinase and cytostatic activityTo achieve better efficacy, which will be part of our research at a later stage. From a drug elimination perspective, compound 27 eliminated more slowly than Ibrutinib. Thus, by this single dose experiment, it was initially judged that compound 27 was exposed to higher levels, eliminated at a slower rate, had a longer duration of drug action, and had potential for further development.
Claims (8)
2. the pharmaceutically acceptable salt of a compound having dual PI3K δ/BTK target activity according to claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acetate, propionate, butyrate, oxalate, tartrate, methanesulfonate, p-toluenesulfonate, fumarate, taurate, citrate, succinate, or a mixed salt thereof.
3. The method of preparing a compound having PI3K δ/BTK dual-target activity according to claim 1, comprising the steps of:
the first step is as follows: under the action of sodium carbonate and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride, 3-iodine-1H-pyrazolo [3,4-d ] pyrimidine-4-amine and 3-fluoro-4-methoxy boric acid generate a compound with a B-1 structure in a solvent system of N-methylpyrrolidone and water;
the second step is that: adding 3- (3-fluoro-4-methoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine, triphenylphosphine oxide and triphenylphosphine, adding N, N-dimethylformamide for dissolving, placing under an ice bath under the protection of nitrogen, and dropwise adding diisopropyl azodicarboxylate to obtain a compound with a B-2 structure;
the third step: mixing the intermediate B-2 with alcohol, adding triphenylphosphine TPP, dropwise adding diisopropyl azodicarboxylate under ice bath, stirring for reaction, monitoring the reaction process by TLC, adding water for quenching, extracting with dichloromethane, and separating by silica gel column chromatography to obtain a product C-1;
the fourth step: removing a protecting group of the obtained C-1 product in dilute hydrochloric acid to obtain C-2;
the fifth step: carrying out condensation reaction on the intermediate C-2 and acrylic acid substituted by R5 to obtain a compound with a structure shown in a formula A;
r5 is H, F or methyl.
4. Use of a compound having PI3K δ/BTK dual-target activity according to claim 1 for the preparation of a pharmaceutical preparation for the prevention or treatment of a disease caused by an abnormality in PI3K δ or BTK protein.
5. Use of a pharmaceutically acceptable salt of the compound having PI3K δ/BTK dual-target activity according to claim 2 in the preparation of a pharmaceutical preparation for preventing or treating a disease caused by an abnormality in PI3K δ or BTK protein.
6. The use according to claim 4 or 5, wherein the disease is lymphoma or is an autoimmune disease.
7. The use of claim 6, wherein said lymphoma is selected from the group consisting of chronic lymphocytic leukemia, B-cell lymphoma, mantle cell lymphoma, lymphoplasmacytic lymphoma, diffuse large B-cell lymphoma, non-Hodgkin's lymphoma, follicular central lymphoma, marginal zone B-cell lymphoma.
8. The use of claim 6, wherein the autoimmune disease comprises rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriasis.
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