CN115785107A - Substituted 8,9-dihydropyrimido [5,4-b ] indolizine compound, pharmaceutical composition and application thereof - Google Patents

Substituted 8,9-dihydropyrimido [5,4-b ] indolizine compound, pharmaceutical composition and application thereof Download PDF

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CN115785107A
CN115785107A CN202211613435.4A CN202211613435A CN115785107A CN 115785107 A CN115785107 A CN 115785107A CN 202211613435 A CN202211613435 A CN 202211613435A CN 115785107 A CN115785107 A CN 115785107A
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唐春雷
范为正
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Nanjing Leizheng Pharmaceutical Technology Co ltd
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Abstract

The invention discloses a substituted 8,9-dihydropyrimido [5,4-b]Indolizine compounds, pharmaceutical compositions and uses thereof, belonging to the field of chemical medicine. The invention replaces 8,9-dihydropyrimido [5,4-b]The indolizine compound and the pharmaceutically acceptable salt thereof have the structure shown in the formula (I), can be used as an Epidermal Growth Factor Receptor (EGFR) inhibitor, and can be used for preventing and/or treating cancers based on the EGFR inhibition effect.

Description

Substituted 8,9-dihydropyrimido [5,4-b ] indolizine compound, pharmaceutical composition and application thereof
Technical Field
The invention belongs to the field of chemical medicine, and relates to a substituted 8,9-dihydropyrimido [5,4-b ] indolizine compound, a pharmaceutical composition and application thereof.
Background
Lung cancer is the first killer in tumors, of which about 85% is advanced non-small cell lung cancer. Chemotherapy with platinum-based drugs has been the only option for the treatment of advanced non-small cell lung cancer (NSCLC) for a long time. This treatment increases the Overall Survival (OS) of the patient to some extent, but only 20% response rate and median survival of 8-10 months. After a certain period of chemotherapy, cancer cells develop resistance due to new mutations. Of the lung adenocarcinoma patients, approximately 15% of caucasians and 30-50% of east asians possess EGFR gene mutations. For those east asian with no history of smoking, this proportion is as high as 50-60%.
Epidermal Growth Factor Receptor (EGFR) is one of the transmembrane protein tyrosine kinases of the ErbB receptor family, which, when bound to growth factor ligands (e.g., epidermal Growth Factor (EGF)), can homodimerize with additional EGFR molecules or heterodimerize with members of another family (e.g., erbB2 (HER 2), erbB3 (HER 3) or ErbB4 (HER 4), the homodimerization and/or heterodimerization of ErbB receptors results in phosphorylation of critical tyrosine residues within cells and results in stimulation of many intracellular signaling pathways involved in cell proliferation and survival.
EGFR Tyrosine Kinase Inhibitor (TKI) is developed into a targeted drug for treating non-small cell lung cancer. Early small molecule EGFR tyrosine kinase inhibitors (EGFR-TKIs), like gefitinib and erlotinib, were used at the very beginning to treat all NSCLC patients who had received previous chemotherapy. Therefore, a series of new EGFR TKIs like Afatinib and dacomitinib have been developed greatly. However, cancer acquires resistance against gefitinib and erlotinib 6-12 months from the beginning, and the therapeutic effect becomes poor.
Therefore, this acquired resistance becomes a serious problem for the treatment of non-small cell lung cancer with highly susceptible mutant EGFR. It has been shown that about 50% of acquired resistance is due to the emergence of the drug resistant mutant EGFR protein EGFR (d 746-750/T790M) or EGFR (T790M/L858R) which has a second mutation in the EGFR gene causing the amino acid at position 790 to change from threonine to methionine. It is an important task to develop a therapeutic agent effective against non-small cell lung cancer with this drug resistant mutant EGFR.
Disclosure of Invention
The inventor discovers a novel substituted 8,9-dihydropyrimido [5,4-b ] indolizine compound in the process of researching an EGFR inhibitor, has excellent inhibitory activity on mutant EGFR and lower toxic and side effects, is expected to have good curative effect, is expected to overcome the problems of drug resistance and toxic and side effects, and has good development prospect.
The invention provides a substituted 8,9-dihydropyrimido [5,4-b ] indolizine compound or pharmaceutically acceptable salt thereof, a pharmaceutical composition and application thereof. The compound can be used as an EGFR inhibitor, and has better pharmacodynamic property and higher metabolic stability.
In one aspect, the present invention provides a compound having a structure represented by general formula (I):
Figure BDA0004001059880000021
in the formula, R 1 Selected from the group consisting of:
Figure BDA0004001059880000022
wherein R is 2 Selected from H, D, F, cl, br; r is 3 、R 4 Each independently selected from H or D; and R is 2 ，R 3 ，R 4 Not H at the same time.
In one embodiment of the invention, the compound is selected from:
Figure BDA0004001059880000023
in one embodiment of the present invention, the pharmaceutically acceptable salt is an inorganic salt or an organic salt, and the inorganic salt includes hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, ascorbate.
The invention also provides a pharmaceutical composition containing the compound with the structure shown in the general formula (I) or pharmaceutically acceptable salt thereof.
In one embodiment of the present invention, the pharmaceutical composition further comprises: a pharmaceutically acceptable carrier, excipient or diluent.
In one embodiment of the invention, the pharmaceutically acceptable carrier comprises: microspheres, nanoparticles, and liposomes.
In preparing the pharmaceutical compositions, the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention are typically mixed with a pharmaceutically acceptable carrier, excipient or diluent. Wherein, in a unit dosage form (e.g., a tablet or capsule), the compound of formula (I) or a pharmaceutically acceptable salt thereof may be present in an amount of 0.01 to 1000mg, e.g., 0.05 to 800mg, 0.1 to 500mg, 0.01 to 300mg, 0.01 to 200mg, 0.05 to 150mg, 0.05 to 50mg, etc.
The composition of the invention can be prepared into conventional pharmaceutical preparations according to conventional preparation methods. Such as tablets, pills, capsules, powders, granules, emulsions, suspensions, dispersions, solutions, tinctures, syrups, ointments, drops, suppositories, inhalants, sprays and the like.
In certain embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be formulated as solid formulations for oral administration, including, but not limited to, capsules, tablets, pills, powders, granules, and the like. In these solid dosage forms, the compound of formula (I) according to the invention or a pharmaceutically acceptable salt thereof is mixed as active ingredient with at least one conventional inert excipient (or carrier), for example with sodium citrate or dicalcium phosphate, or with one or more of the following ingredients:
(1) Fillers or solubilizers, for example, starch, lactose, sucrose, glucose, mannitol, silicic acid, and the like;
(2) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose, acacia, etc.;
(3) Humectants, such as glycerol and the like;
(4) Disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, and the like;
(5) A slow solvent such as paraffin and the like;
(6) Absorption accelerators such as quaternary ammonium compounds and the like;
(7) Wetting agents such as cetyl alcohol and glycerol monostearate and the like;
(8) Adsorbents, for example, kaolin, and the like;
(9) Lubricants, for example, talc, calcium stearate, solid polyethylene glycols, sodium lauryl sulfate, and the like, or mixtures thereof. Capsules, tablets, pills, etc. may also contain buffering agents.
In certain embodiments, the solid dosage forms, e.g., tablets, dragees, capsules, pills, and granules, can be coated or microencapsulated with coating and shell materials such as enteric coatings and other crystalline forms of materials well known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be delayed in a certain part of the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active ingredient may also be in microencapsulated form with one or more of the above excipients.
In certain embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be formulated in liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, and the like. In addition to the compounds of formula (I) or pharmaceutically acceptable salts thereof as active ingredients, the liquid dosage forms may contain inert diluents commonly employed in the art, such as water and other solvents, solubilizing agents and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide as well as oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil, sesame oil and the like or mixtures of these and the like. In addition to these inert diluents, the liquid dosage forms of the present invention may also include conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, perfuming agents and the like.
Such suspending agents include, for example, ethoxylated stearyl alcohol, polyoxyethylene sorbitol, and sorbitan, microcrystalline cellulose, agar, and the like, or mixtures of these materials.
In certain embodiments, the compounds of the present invention and pharmaceutically acceptable salts thereof may be formulated into dosage forms for parenteral injection, including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions and dispersions. Suitable carriers, diluents, solvents, excipients include water, ethanol, polyols and suitable mixtures thereof.
In certain embodiments, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be formulated in dosage forms for topical administration, including, for example, ointments, powders, suppositories, drops, sprays, inhalants and the like. The compounds of the general formula (I) according to the invention or their pharmaceutically acceptable salts as active ingredients are mixed under sterile conditions with physiologically acceptable carriers and optionally preservatives, buffers and, if desired, propellants.
The invention also provides application of the compound with the structure shown in the general formula (I) or pharmaceutically acceptable salt thereof in preparing a medicament for treating diseases mediated by EGFR activated or drug-resistant mutants in mammals, particularly human beings.
The invention also provides application of the compound with the structure shown in the general formula (I) or pharmaceutically acceptable salt thereof in preparation of anti-cancer drugs.
In certain embodiments, the cancer comprises lung cancer, breast cancer, kidney cancer, prostate cancer, pancreatic cancer, epidermal cancer.
The compounds of the invention or pharmaceutically acceptable salts thereof may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents, particularly in combination with other antineoplastic agents. Such therapeutic agents include, but are not limited to: antineoplastic drugs acting on DNA chemical structures, such as cisplatin, antineoplastic drugs affecting nucleotide synthesis, such as methotrexate, 5-fluorouracil and the like, antineoplastic drugs affecting nucleic acid transcription, such as doxorubicin, epirubicin, aclacinomycin and the like, antineoplastic drugs affecting micro-protein synthesis, such as taxol, vinorelbine and the like, aromatase inhibitors, such as aminoglutethimide, letrozole, rening and the like, cell signaling pathway inhibitors, such as epidermal growth factor receptor inhibitor Imatinib (Imatinib), gefitinib (Gefitinib), erlotinib and the like. The components to be combined may be administered simultaneously or sequentially, in a single formulation or in different formulations. Such combinations include not only combinations of one or other active agents of the compounds of the invention, but also combinations of two or more other active agents of the compounds of the invention.
In yet another aspect, the present invention provides a process for the preparation of a compound of formula (I), said process comprising:
Figure BDA0004001059880000051
and (2) adding a dichloromethane solution of the compound 2 into a dichloromethane solution containing the intermediate 1 and N, N-diisopropylethylamine at 0 ℃, stirring at room temperature for reaction, washing with water after the reaction is finished, drying, concentrating, and performing reversed-phase preparation and separation on a crude product to obtain the target compound. Wherein R is 4 Are as defined in formula (I).
ADVANTAGEOUS EFFECTS OF INVENTION
According to the present invention, there is provided a novel compound represented by the above formula (I) or a salt thereof, which is useful as an EGFR inhibitor.
The compound or the salt thereof has excellent EGFR inhibitory activity and cancer cell line growth inhibitory action. In addition, the compound of the present invention or a salt thereof has little side effect due to excellent selectivity against EGFR. Therefore, the compound designed by the invention has good development and application prospects.
Detailed Description
The technical solution of the present invention will be described in detail with reference to the following examples.
The term "disease" as used herein refers to any condition or disorder that impairs or interferes with the normal function of a cell, organ or tissue.
The term "inhibitor" as used herein refers to a compound or agent that has the ability to inhibit a biological function of a targeted protein or polypeptide, for example by inhibiting the activity or expression of the protein or polypeptide.
The term "antineoplastic agent" as used herein refers to any agent useful in the treatment of neoplastic disorders.
The term "pharmaceutically acceptable" as used herein, means a component which is, within the scope of sound medicine, suitable for use in contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. "pharmaceutically acceptable salt" refers to any non-toxic salt that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or a prodrug of a compound.
The term "effective amount" or "therapeutically effective amount" as used herein means that the amount of a compound or pharmaceutical composition described herein is sufficient to achieve the intended use, including, but not limited to, the treatment of disease. In some embodiments, the amount is detected effective to kill or inhibit cancer cell growth or spread; the size or number of tumors; or the severity level, stage and progression of the cancer. The therapeutically effective amount may vary depending on the intended application, e.g., in vitro or in vivo, the condition and severity of the disease, the age, weight, or mode of administration of the subject, etc. The term also applies to a particular response in which the dose will induce the target cell, e.g., reduce cell migration. The specific dosage will depend, for example, on the particular compound chosen, the species of the subject and their age/existing health or risk of health, the route of administration, the severity of the disease, administration in combination with other agents, the time of administration, the tissue to which it is administered, and the administration device, among other things.
In the present invention "administering" or "administering" an individual compound means providing a compound of the invention to an individual in need of treatment.
The compounds of the present invention may contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. All such isomeric forms of these compounds are expressly included in the present invention. The compounds of the invention may also exhibit multiple tautomeric forms, in which case the invention expressly includes all tautomeric forms of the compounds described herein. All such isomeric forms of such compounds are included in the present invention. All crystalline forms of the compounds described herein are expressly included in the present invention.
The following examples illustrate, but do not limit, the synthesis of the compounds of formula (I). The temperatures are given in degrees Celsius. All evaporation was performed under reduced pressure if not otherwise stated. If not otherwise stated, the reagents were purchased from commercial suppliers and used without further purification. The structure of the final products, intermediates and starting materials is confirmed by standard analytical methods, such as elemental analysis, spectroscopic characterization, e.g., MS, NMR. Abbreviations used are those conventional in the art, and some of the intermediates were purchased from Yancheng Zhengchi Biotech, inc.
The following intermediate substances are involved in the specific examples and can be synthesized by the following process routes:
preparation of (S) -6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b ] indolizine-4,8-diamine (intermediate 1)
Figure BDA0004001059880000071
The first step is as follows: preparation of tert-butyl (S) - (l- (4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pent-4-en-2-yl) carbamate (intermediate c)
Tert-butyl (S) - (l-hydroxypent-4-ene-2-yl) carbamate (3 g,14.9 mmol) and 4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidine (4.16g, 14.9 mmol) were dissolved in DME (50 mL). Triphenylphosphine (4.69g, 17.9 mmol) and diisopropyl azodicarboxylate (3.61g, 17.9 mmol) were added sequentially under ice-bath. The reaction solution was stirred for 30 minutes in an ice bath and then for 1 hour at room temperature, and after completion of the reaction, it was concentrated, diluted with ethyl acetate, and the organic phase was washed with water and dried over anhydrous sodium sulfate. Concentrating under reduced pressure. The resulting crude product was purified by silica gel column chromatography to give tert-butyl (S) - (l- (4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pent-4-lin-2-yl) carbamate (4.5 g, yield: 65%) as a pale yellow solid. ESI-MS m/z:463,465[ M + H ] +.
The second step: preparation of tert-butyl (S) - (l- (4-amino-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pent-4-en-2-yl) carbamate (intermediate d)
Tert-butyl (S) - (l- (4-chloro-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pent-4-yn-2-yl) carbamate (4.5 g, 9.74mmol) was dissolved in DME (50 mL), concentrated aqueous ammonia (20 mL) was added, and the reaction was heated to 100 ℃ in an autoclave and stirred for 8 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and water (100 mL) was added thereto and the mixture was stirred at room temperature for 4 hours. The solid was precipitated, filtered, washed with water, and dried to give tert-butyl (S) - (l- (4-amino-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pent-4-yn-2-yl) carbamate (4 g, yield: 93%) as a pale yellow solid. ESI-MS m/z:444[ 2 ], [ M + H ] +.
The third step: preparation of (S) - (l- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pent-4-lin-2-yl) carbamic acid tert-butyl ester (intermediate f)
Tert-butyl (S) - (l- (4-amino-5-iodo-7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pent-4-yn-2-yl) carbamate (4g, 9.0mmol), 3-quinolineboronic acid (1.87g, 10.8mmol), sodium carbonate (1.9g, 18mmol), tetrakis (triphenylphosphine) palladium (1.04g, 0.9mmol) were dissolved in DME (40 mL) and water (40 mL), heated to 100 ℃ under nitrogen and stirred for 6 hours. After the reaction, the mixture was cooled to room temperature, filtered, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to give tert-butyl (S) - (l- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pent-4-lin-2-yl) carbamate (3 g, yield: 75%) as a pale yellow solid. ESI-MS m/z:445[ M + H ] +.
The fourth step: preparation of (S) - (l- (4-amino-6-bromo-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pent-4-en-2-yl) carbamic acid tert-butyl ester (intermediate g)
Tert-butyl (S) - (l- (4-amino-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pent-4-lin-2-yl) carbamate (3g, 6.75mmol) was dissolved in DMF (50 mL), cooled to-15 deg.C, NBS (1.2g, 6.75mmol) was added in portions, and then stirred at-15 deg.C for 1 hour. After completion of the reaction, 10% aqueous sodium thiosulfate (50 mL) was added, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride in the organic phase, and dried over anhydrous sodium sulfate. Concentrating under reduced pressure. The resulting crude product was purified by silica gel column chromatography to give tert-butyl (S) - (l- (4-amino-6-bromo-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pent-4-en-2-yl) carbamate (2.8 g, yield: 79%) as a pale brown solid. ESI-MS m/z:523,525[ M + H ] +.
The fifth step: preparation of (S) - (4-amino-6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b ] indolizin-8-yl) carbamic acid tert-butyl ester (intermediate h)
Tert-butyl (S) - (l- (4-amino-6-bromo-5- (quinolin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-7-yl) pent-4-en-2-yl) carbamate (2.8g, 5.35mmol) was dissolved in THF (50 mL), and 4N aqueous sodium hydroxide (5 mL) and tetrakis (triphenylphosphine) palladium (612mg, 0.53mmol) were added, and the mixture was heated to 80 ℃ under nitrogen and stirred overnight. After the reaction, the mixture was cooled to room temperature, filtered, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate. Concentrating under reduced pressure. The resulting crude product was purified by reverse phase preparative to give tert-butyl (S) - (4-amino-6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b ] indolizin-8-yl) carbamate (1.5 g, yield: 63%) as a yellow solid. ESI-MS m/z [ 443 ], [ M + H ] +.
And a sixth step: preparation of (S) -6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b ] indolizine-4,8-diamine (intermediate 1)
Tert-butyl (S) - (4-amino-6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b ] indolizin-8-yl) carbamate (1.5g, 3.4 mmol) was dissolved in 4M hydrochloric acid-dioxane (20 mL) and reacted at room temperature for 5 hours, after completion of the reaction, concentrated under reduced pressure, adjusted to pH 8-9 with 2M aqueous sodium hydroxide solution, extracted with ethyl acetate, and the organic phase was dried and concentrated to give (S) -6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b ] indolizine-4,8-diamine (1 g, yield: 86%) as a pale yellow solid. ESI-MS m/z:343[ m + H ] +.
Example 1: (S) -N- (4-amino-6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b ] indolizin-8-yl) -3,3-dideuteroacrylamide
Figure BDA0004001059880000091
Mixing (S) -6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b]Indolizine-4,8-diamine (intermediate 1) (100mg, 0.29mmol) and triethylamine (35mg, 0.35mmol) were dissolved in dichloromethane (5 mL), 3,3-dideuteroacryloyl chloride (32mg, 0.35mmol) was slowly added at 0 ℃ and reacted at 0 ℃ for 1 hour. After the reaction is finished, adding water for quenching, extracting by dichloromethane, drying an organic phase by anhydrous sodium sulfate, concentrating, and obtaining (S) -N- (4-amino-6-methyl-5- (quinoline-3-yl) -8,9-dihydropyrimido [5,4-b ] by reverse phase HPLC]Indolizin-8-yl) -3,3-dideuteroacrylamide (42 mg, yield: 36%) as a pale yellow solid. ESI-MS m/z:399[ m ] +H] + .
1 H-NMR(400MHz,DMSO-d 6 ):δ8.93(s,l H),8.45(d,J＝7.2Hz,l H),8.40(s,l H),8.14(s,1H),8.10(d,J＝8.6Hz,1H),8.06(d,J＝8.4Hz,1H),7.82(t,J＝7.6Hz,1H),7.68(t,J＝7.1Hz,1H),6.26(dd,J＝17.2,9.8Hz,1H),6.16(dd,J＝17.2,2.4Hz,1H),6.01-5.67(brs,2H),4.85-4.75(m,1H),4.26(dd＝13.3,5.2Hz,1H),4.18(dd,J＝13.3,5.2Hz,1H),1.53(s,3H).
Example 2: (S) -N- (4-amino-6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b ] indolizin-8-yl) -3,3,2-trideuteroacrylamide
Figure BDA0004001059880000092
The compound of example 2 was synthesized by reference to the procedure of example 1, substituting 3,3,2-trideutero acryloyl chloride for 3,3-dideutero acryloyl chloride, to give the title compound (28.2 mg) as a pale yellow solid. ESI-MS m/z of 400[ 2 ], [ M ] +H] + .
1 H-NMR(400MHz,DMSO-d 6 ):δ8.93(s,l H),8.45(d,J＝7.1Hz,l H),8.40(s,l H),8.14(s,lH),8.10(d,J＝8.6Hz,l H),8.06(d,J＝8.1Hz,l H),7.82(t,J＝7.6Hz,l H),7.68(t,J＝7.1Hz,l H),6.26(dd,J＝17.1,9.8Hz,l H),6.02(s,2H),4.85-4.75(m,l H),4.26(dd,J＝13.2,5.1Hz,l H),4.18(dd,J＝13.2,5.1Hz,l H),1.53(s,3H).
Example 3: (S) -N- (4-amino-6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b ] indolizin-8-yl) -2-fluoroacrylamide
Figure BDA0004001059880000101
The compound of example 3 was synthesized by reference to the procedure of example 1, substituting 3,3-dideuteroacryloyl chloride with 2-fluoroacryloyl chloride, to give the title compound (22.6 mg) as a pale yellow solid.
ESI-MS m/z:415[M+H] +
1 H-NMR(400MHz,DMSO-d 6 ):δ8.86(s,l H),8.45(d,J＝7.0Hz,l H),8.40(s,l H),8.14(s,lH),8.11(d,J＝8.6Hz,l H),8.06(d,J＝8.1Hz,l H),7.81(t,J＝7.6Hz,l H),7.66(t,J＝7.5Hz,l H),6.25(dd,J＝17.1,9.8Hz,l H),6.03(s,2H),5.88-5.64(m,2H),4.87-4.79(m,l H),4.27-4.17(m,l H),1.54(s,3H).
Example 4: (S) -N- (4-amino-6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b ] indolizin-8-yl) -2-methacrylamide
Figure BDA0004001059880000102
The compound of example 4 was synthesized by reference to the procedure of example 1, substituting 3,3-dideuteroacryloyl chloride with 2-methacryloyl chloride to obtain the title compound (42.1 mg) as a pale yellow solid. ESI-MS m/z:411[ m ] +H] + .
1 H-NMR(400MHz,DMSO-d 6 ):δ8.88(s,l H),8.44(d,J＝7.0Hz,l H),8.41(s,l H),8.14(s,lH),8.11(d,J＝8.6Hz,l H),8.06(d,J＝8.1Hz,l H),7.81(t,J＝7.6Hz,l H),7.65(t,J＝7.1Hz,l H),6.24(dd,J＝17.1,9.8Hz,l H),6.03(s,2H),5.81(l H,dd,J＝5.1,1.2Hz),5.60(l H,dd,J＝9.8,2.7Hz),4.86-4.79(m,l H),4.25(dd,J＝13.2,5.1Hz,l H),4.16(dd,J＝13.2,5.1Hz,l H),2.01(s,3H),1.51(s,3H).
Example 5: (S) -N- (4-amino-6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b ] indolizin-8-yl) -2-trifluoromethylacrylamide
Figure BDA0004001059880000103
The compound of example 5 was synthesized by reference to the procedure of example 1, substituting 3,3-dideuteroacryloyl chloride with 2-trifluoromethylacryloyl chloride to obtain the title compound (22.6 mg), a light yellow solid. ESI-MS m/z:465[ 2 ] M + H] + .
1 H-NMR(400MHz,DMSO-d 6 ):δ8.93(s,l H),8.45(d,J＝7.0Hz,l H),8.40(s,l H),8.14(s,lH),8.11(d,J＝8.6Hz,l H),8.07(d,J＝8.1Hz,l H),7.82(t,J＝7.6Hz,l H),7.67(t,J＝7.1Hz,l H),6.25(dd,J＝17.1,9.8Hz,l H),6.03(s,2H),5.93-5.67(m,2H),4.92-4.84(m,l H),4.41-4.22(m,2H),1.61(s,3H).
Example 6: (S) -N- (4-amino-6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b ] indolizin-8-yl) -2-fluoro-3,3-dideuteroacrylamide
Figure BDA0004001059880000111
The compound of example 6 was synthesized by reference to the procedure of example 1, substituting 2-fluoro-3,3-dideuteroacryloyl chloride for 3,3-dideuteroacryloyl chloride, to give the title compound (15 mg) as a pale yellow solid. ESI-MS m/z:417[ 2 ] M + H] + .
1 H-NMR(400MHz,DMSO-d 6 ):δ8.86(s,l H),8.45(d,J＝7.0Hz,l H),8.40(s,l H),8.14(s,lH),8.11(d,J＝8.6Hz,l H),8.06(d,J＝8.1Hz,l H),7.86(t,J＝7.6Hz,l H),7.66(t,J＝7.5Hz,l H),6.25(dd,J＝17.1,9.8Hz,l H),6.05(s,2H),4.89-4.79(m,l H),4.28-4.17(m,l H),1.58(s,3H).
Example 7: (S) -N- (4-amino-6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b ] indolizin-8-yl) -2-methyl-3,3-dideuteroacrylamide
Figure BDA0004001059880000112
The compound of example 7 was synthesized with reference to the procedure of example 1, in which 3,3-dideuteroacryloyl chloride was replaced with 2-methyl-3,3-dideuteroacryloyl chloride, thereby obtaining the objective compound (30 mg), a light yellow solid. ESI-MS m/z:413[ deg. ] M + H ]] + .
1 H-NMR(400MHz,DMSO-d 6 ):δ8.88(s,l H),8.44(d,J＝7.0Hz,l H),8.41(s,l H),8.14(s,lH),8.11(d,J＝8.6Hz,l H),8.06(d,J＝8.1Hz,l H),7.81(t,J＝7.6Hz,l H),7.65(t,J＝7.1Hz,l H),6.24(dd,J＝17.1,9.8Hz,l H),6.03(s,2H),4.86-4.79(m,l H),4.25(dd,J＝13.2,5.1Hz,l H),4.16(dd,J＝13.2,5.1Hz,l H),2.02(s,3H),1.54(s,3H).
Example 8: (S) -N- (4-amino-6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b ] indolizin-8-yl) -propynylamine
Figure BDA0004001059880000121
Mixing (S) -6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b]Indolizine-4,8-diamine (intermediate 1) (100mg, 0.29mmol) was dissolved in THF (2 mL), propiolic acid (24mg, 0.35mmol), triethylamine (35mg, 0.35mmol) and T3P (222mg, 0.35mmol, w/w 50 in DMF) were added sequentially, and then reacted at room temperature for 3h, after completion of the reaction, concentrated under reduced pressure, and the crude product was subjected to reverse phase HPLC to give (S) -N- (4-amino-6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b ] a]Indolizin-8-yl) -propynylamine (51 mg, yield: 44%) light yellow solid. ESI-MS m/z, 395[ m + H ]] + .
1 H-NMR(400MHz,DMSO-d 6 ):δ8.97(s,l H),8.45(d,J＝7.1Hz,l H),8.40(s,l H),8.17(s,lH),8.13(d,J＝8.6Hz,l H),8.06(d,J＝8.1Hz,l H),7.83(t,J＝7.6Hz,l H),7.67(t,J＝7.1Hz,l H),6.22(dd,J＝17.1,9.8Hz,l H),6.03(s,2H),4.88-4.71(m,l H),4.27(dd,J＝13.2,5.1Hz,l H),4.18(dd,J＝13.2,5.1Hz,l H),2.82(s,1H),1.54(s,3H).
Example 9: (S, E) -N- (4-amino-6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimidine [5,4-b ] indolizin-8-yl) -4- (dimethylamino) -but-2-enamide
Figure BDA0004001059880000122
The compound of example 9 was synthesized with reference to the procedure of example 8, in which propiolic acid was replaced with trans-4-dimethylaminocrotonic acid, to thereby obtain the objective compound (16.5 mg) as a pale yellow solid. ESI-MS m/z [ 454 ] M + H] + .
1 H-NMR(400MHz,DMSO-d 6 ):δ8.92(s,l H),8.43(d,J＝7.1Hz,l H),8.40(s,l H),8.12(s,lH),8.11(d,J＝8.6Hz,l H),8.07(d,J＝8.1Hz,l H),7.81(t,J＝7.6Hz,l H),7.69(t,J＝7.1Hz,l H),6.79-6.31(m,3H),6.03(s,2H),4.85-4.75(m,l H),4.28(dd,J＝13.2,5.1Hz,l H),4.21(dd,J＝13.2,5.1Hz,l H),3.08(d,J＝7.6Hz,2H),2.76(s,6H)1.53(s,3H).
Comparative example 1:
(S) -N- (4-amino-6-methyl-5- (quinolin-3-yl) -8,9-dihydropyrimido [5,4-b ] indolizin-8-yl) acrylamide
Figure BDA0004001059880000131
The compound was synthesized according to the method disclosed in international patent WO 2015025936. ESI-MS m/z:397[ m ] +H] + .
Example 10: biological Activity assay
(1) Measurement of EGFR (T790M/L858R) kinase inhibitory Activity
Among the materials for measurement of inhibitory activity, substrate peptides and kinase proteins were obtained as follows. Kinase protein purified recombinant human EGFR (T790M/L858R) protein was purchased from Carna Biosciences, inc.
The inhibitory activity was measured as follows. (a) The compound to be tested was prepared into a 10mM stock solution in an EP tube using dimethylsulfoxide as a solvent, and stored in a freezer at-20 ℃ in the dark for future use. The mother liquor was diluted to the concentration required for the experiment and transferred to 250nL 384 well plates using Echo 550. Subsequently, a solution containing the substrate peptide (final concentration: 250 nM), magnesium chloride (final concentration: 10 mM), manganese chloride (final concentration: 10 mM), and ATP (final concentration: 1. Mu.M) in a buffer for kinase reaction was mixed with a dilution of these compounds (final concentration of DMSO at the time of kinase reaction: 2.5%). (b) A Kinase buffer (1 XKinase buffer) was prepared, and used to prepare a Kinase solution having a final concentration of 2.5 times. (c) Adding prepared kinase solution into the compound hole and the positive control hole respectively, wherein the volume of the kinase sample is 10 mu L; no Kinase solution was added to the negative control wells, and 1 XKinase buffer was added to each well in a volume of 10. Mu.L. (d) Setting the rotation speed of a centrifuge to be 1000rpm and the time to be 30 seconds, shaking and mixing the mixture by the centrifuge, and then placing a 384-hole plate at room temperature for incubation for 10 minutes. (e) A mixed solution of Kinase substrate 22 and ATP was prepared using a 1 XKinase buffer at a final concentration of 25/15 times. 10 μ L of the mixed solution was taken, transferred to a 384-well plate, and the reaction was started. (f) Setting the rotation speed of a centrifuge to be 1000rpm and the time to be 30 seconds, shaking and mixing the mixture by the centrifuge, and then placing a 384-hole plate at room temperature for incubation for 30 minutes. (g) The termination test solution was added to a 384-well plate, and 30. Mu.L of the solution was added to each well, to terminate the kinase reaction. (h) Setting the rotation speed of a centrifuge as 1000rpm and the time as 30 seconds, oscillating and mixing uniformly, and measuring the conversion rate of the sample by using a Caliper EZ Reader. Formula for calculating inhibition ratio of compound:
Figure BDA0004001059880000132
finally, the obtained reaction inhibition (%) at each concentration was plotted for each compound, and IC was determined using XLfit curve fitting software (IDBS) 50 Value (nM), which is the concentration of compound at which phosphorylation of EGFR (T790M/L858R) is 50% inhibited.
(2) Measurement of EGFR (d 746-750/T790M) kinase inhibitory Activity
The inhibitory activity of the compounds of the invention against EGFR (d 746-750/T790M) kinase activity was measured.
Materials, measurementsThe methods and data analysis methods were essentially the same as those described above with respect to "measuring EGFR (T790M/L858R) kinase inhibitory activity", except that purified recombinant human EGFR (d 746-750/T790M) protein was used as the kinase protein, and the measurement was performed using a final ATP concentration of 1.5. Mu.M. Finally, the IC of each compound with respect to EGFR (d 746-750/T790M) was determined by data analysis 50 Values (nM).
(3) Measurement of EGFR (L858R) kinase inhibitory Activity
The inhibitory activity of the compounds of the invention against EGFR (L858R) kinase activity was measured.
The materials, measurement methods and data analysis methods were substantially the same as those shown above in connection with "measuring EGFR (T790M/L858R) kinase inhibitory activity", except that purified recombinant human EGFR (L858R) protein was used as the kinase protein, and measurement was performed using ATP at a final concentration of 4. Mu.M. Finally, the IC of each compound with respect to EGFR (L858R) was determined by data analysis 50 Values (nM).
(4) Measurement of EGFR (d 746-750) kinase inhibitory Activity
Measuring the inhibitory activity of the compounds of the invention against EGFR (d 746-750) kinase activity.
The materials, measurement methods and data analysis methods were substantially the same as those shown above for "measuring EGFR (T790M/L858R) kinase inhibitory activity", except that purified recombinant human EGFR (d 746-750) protein was used as the kinase protein, measurement was performed using ATP at a final concentration of 5. Mu.M, and incubation for the kinase reaction was performed for 90 minutes. Finally, the IC of each compound with respect to EGFR (d 746-750) was determined by data analysis 50 Values (nM).
(5) Measurement of EGFR (WT) kinase inhibitory Activity
Measuring the inhibitory activity of the compounds of the invention against EGFR (WT) kinase activity.
The materials, measurement methods and data analysis methods were substantially the same as those shown above for "measuring EGFR (T790M/L858R) kinase inhibitory Activity", except that the cytoplasmic domain of human EGFR (WT) fused N-terminally to FLAG tag was expressed in insect Sf9 cells by using a baculovirus expression system, and thenThe kinase protein prepared by purifying it with anti-FLAG antibody agarose was used as the kinase protein, with a final concentration of substrate peptide of 500nM and ATP of 4.7 μ M. Finally, the IC of each compound with respect to EGFR (WT) was determined by data analysis 50 Values (nM).
TABLE 1 IC of the activity assay of the examples of the invention and of the reference compounds 50 Data (nM)
Figure BDA0004001059880000141
Figure BDA0004001059880000151
The results show that the compound of the invention shows good inhibitory activity against EGFR (T790M/L858R), EGFR (d 746-750:/T790M), EGFR (L858R) and EGFR (d 746-750), has small inhibitory activity against EGFR (WT), and realizes selective inhibition.
Example 11: biological Activity assay
Test of growth inhibitory activity against cell lines expressing wild type and mutant EGFR (in vitro). 1) Preparation of complete culture medium: adding 10mL fetal calf serum and 1mL penicillin/streptomycin solution into 89mL IMDM basal medium to prepare cell culture solution, and storing in a refrigerator at 4 ℃ for later use. 2) Preparation of test compound: accurately weighing the mass of the compound to be detected by an analytical balance, adding DMSO solution to prepare 2mg/mL mother liquor, and storing the mother liquor in a refrigerator at 4 ℃ for later use. 3) The EGFR (T790M/L858R) -expressing human non-small cell lung cancer cell line NCI-H1975, the EGFR (d 746-750) -expressing human non-small cell lung cancer cell line HCC827, and the EGFR (WT) -expressing human epithelial-like cancer cell line a431 were each suspended in the ATCC recommended complete growth medium in an incubator (5% carbon dioxide, temperature: standing at 37 deg.C for 4 hr, subculturing by half liquid exchange method, and maintaining cell culture density at 1 × 10 5 ～1×10 6 cells mL -1 . The cells after passage were kept at 37 ℃ with 5% CO 2 The cultivation is continued in the incubator. 4) Paving a plate and adding medicine: centrifuging the cells,Removing supernatant, adding new culture medium, counting according to 1.5 × 10 5 cells mL -1 The seeding density of (a) was seeded in 96-well plates. The test compound was diluted with medium to different concentrations, 9 concentrations, 3 replicates, and there were both blank control (cells and medium added, no drug added) and positive control (cells and medium added, comparative compound added). Test compounds of different concentrations were added to the corresponding wells and incubated in an incubator for 72h. 5) Determination of OD value: add 10. Mu.L of CCK-8 solution to blank, positive control and drug-affected wells (drug group) and continue in CO 2 Culturing in an incubator for 4h. After shaking the plate (4 min), the OD at 450nm in each well was measured with a microplate reader. 6) GI (GI tract) 50 Calculation of the value: calculating the inhibition rate under different concentrations by adopting GraphPad Prism 5 software, fitting a corresponding function according to an inhibition rate curve, and calculating GI 50 The value is obtained.
Figure BDA0004001059880000152
Wherein, the OD value T of the drug group refers to the absorbance of the hole containing the cells when the exposure time of the drug is T; the OD value T0 of the drug group is the absorbance of the wells containing cells at a drug exposure time of 0; the blank control group OD value T refers to the absorbance of the hole containing the cells when the administration concentration is 0 and the exposure time is T; the OD value T0 of the blank control group means the absorbance of the wells containing cells at the time of exposure at 0 and 0 administration concentration.
TABLE 2 GI of examples of the invention and reference compound activity assays 50 Data (nM)
EGFR class EGFR(T790M/L858R) EGFR(d746-750) EGFR(WT)
Cells NCI-H1975 HCC827 A431
Example 1 53 13 1760
Example 2 61 17 1850
Example 3 42 10 1830
Example 4 125 31 1920
Example 5 130 42 2100
Example 6 45 12 1770
Example 7 132 38 2150
Example 8 56 17 1880
Example 9 37 11 1610
Comparative example 1 83 21 1900
The results show that the compounds of the invention show strong growth inhibitory effects not only against cells expressing EGFR (d 746-750), but also against cells expressing EGFR (T790M/L858R); in addition, their growth inhibitory effect against cells expressing EGFR (WT) is lower than that against the above EGFR protein.
While the invention has been illustrated by the foregoing specific embodiments, it is not to be construed as limited thereby; but rather the invention encompasses the generic aspects disclosed hereinbefore. Various modifications and embodiments can be made without departing from the spirit and scope of the invention.

Claims (10)

1. A compound having the structure shown in formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0004001059870000011
in the formula, R 1 Selected from:
Figure FDA0004001059870000012
wherein R is 2 Selected from H, D, F, cl, br; r 3 、R 4 Each independently selected from H or D; and R is 2 ，R 3 ，R 4 Not H at the same time.
2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of:
Figure FDA0004001059870000013
3. the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is an inorganic salt or an organic salt, and the inorganic salt includes hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, bisulfate, nitrate, phosphate, and acid phosphate; the organic salt is selected from formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, salicylate, p-toluenesulfonate, ascorbate.
4. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.
5. The pharmaceutical composition of claim 4, further comprising: a pharmaceutically acceptable carrier, excipient or diluent.
6. The pharmaceutical composition of claim 4, wherein the pharmaceutically acceptable carrier comprises: microspheres, nanoparticles, and liposomes.
7. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is in the form of a pharmaceutical composition comprising: tablets, pills, capsules, powders, granules, emulsions, suspensions, dispersions, solutions, tinctures, syrups, ointments, drops, suppositories, inhalants, sprays, injections.
8. Use of a compound of formula (I) as defined in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease mediated by an EGFR-activating or drug-resistant mutant in a mammal, particularly a human.
9. Use of a compound of formula (I) as defined in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the manufacture of an anti-cancer medicament.
10. The use of claim 9, wherein cancer comprises: lung cancer, breast cancer, kidney cancer, prostate cancer, pancreatic cancer, and epidermal cancer.
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CN104136438A (en) * 2012-02-23 2014-11-05 大鹏药品工业株式会社 Quinolylpyrrolopyrimidyl fused-ring compound or salt thereof
CN105073752A (en) * 2013-02-22 2015-11-18 大鹏药品工业株式会社 Method for producing tricyclic compound, and tricyclic compound capable of being produced by said production method
CN105683195A (en) * 2013-08-22 2016-06-15 大鹏药品工业株式会社 Novel quinoline-substituted compound
CN110191711A (en) * 2016-10-31 2019-08-30 大鹏药品工业株式会社 The selective depressant of extron 20 insertion mutation type EGFR
CN111465397A (en) * 2017-09-01 2020-07-28 大鹏药品工业株式会社 Selective inhibitors of exon 18 and/or exon 21 mutant EGFR

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Publication number Priority date Publication date Assignee Title
CN104136438A (en) * 2012-02-23 2014-11-05 大鹏药品工业株式会社 Quinolylpyrrolopyrimidyl fused-ring compound or salt thereof
CN105073752A (en) * 2013-02-22 2015-11-18 大鹏药品工业株式会社 Method for producing tricyclic compound, and tricyclic compound capable of being produced by said production method
CN105683195A (en) * 2013-08-22 2016-06-15 大鹏药品工业株式会社 Novel quinoline-substituted compound
CN110191711A (en) * 2016-10-31 2019-08-30 大鹏药品工业株式会社 The selective depressant of extron 20 insertion mutation type EGFR
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