CN114057724A - BTK inhibitor - Google Patents
BTK inhibitor Download PDFInfo
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- CN114057724A CN114057724A CN202010743104.7A CN202010743104A CN114057724A CN 114057724 A CN114057724 A CN 114057724A CN 202010743104 A CN202010743104 A CN 202010743104A CN 114057724 A CN114057724 A CN 114057724A
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Abstract
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a BTK inhibitor; the invention aims to analyze the structural characteristics of the marketed drug ibrutinib, and combines the newly reported structure-activity relationship, the difference of the substituent R1 at the N2 position of piperidine-2, 6-diketone has little influence on the activity of Btk enzyme, and R1 faces to a hydrophilic pocket of the enzyme, and different hydrophilic groups are introduced to adjust the physicochemical properties of the compound. The spatial orientation of the substituent R2 at position N9 towards the gatekeeper region of the kinase and interaction with specific residues in the Tec family varies among the amino acid residues interacting with the gatekeeper regions of different kinases: it is expected to design and synthesize compounds with higher cytotoxicity, exert anticancer effect and have pharmaceutical potential. The cytotoxicity experiment shows that the compound has stronger in-vitro inhibition effect on various cancer cells.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a novel 3-amino-2, 7-dihydropyrano [4,3-c ] pyrazole-4, 6-diketone BTK inhibitor, and a preparation method and application thereof.
Background
Tumors are a common and frequently encountered disease that seriously threatens human health, and are caused by abnormal proliferation of cells in the human body. Lung cancer, digestive tract tumor and liver cancer are the most common tumors in men, accounting for over 70% of all cases (lung cancer 23%, stomach cancer 15.2%, liver cancer 13.57%, esophageal cancer 10.46%, colorectal cancer 9.39%), while breast cancer, lung cancer, digestive tract tumor and liver cancer are the most common tumors in women accounting for over 60% of all cases (breast cancer 16.97%, lung cancer 14.85%, colorectal cancer 9.68%, stomach cancer 8.53%, liver cancer 6.17%). With the aging of the Chinese population, the prevalence of cancer is increasing. In addition, environmental contamination has increased the prevalence of some cancers, such as lymphoma. Autoimmune diseases are diseases caused by the immune system generating immune reaction to the components of the body, causing damage.
Btk (bruton tyrosine kinase) is a cytoplasmic protein belonging to the non-receptor tyrosine kinase Tec family, which is expressed in most hematopoietic cells such as B cells, mast cells, megakaryocytes, etc., but not in T cells, NK cells, and plasma cells. BTK plays a very critical role in B cell receptor signaling pathways, and has a significant impact on B cell proliferation, differentiation, and apoptosis.
In malignant B cells, the B cell receptor signaling pathway is hyperactive, thereby inhibiting normal differentiation and apoptosis of B cells, promoting abnormal proliferation. It is known that aberrant regulation of the BCR pathway is often present in malignancies of various B cell types, such as Diffuse Large B Cell Lymphoma (DLBCL), Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL), Follicular Lymphoma (FL), fahrenheit macroglobulinemia (WM), Marginal Zone Lymphoma (MZL), B lymphoblastic leukemia (B-LBL), Burkitt Lymphoma (BL), and the like.
Since the first discovery of BTK inhibitors in 1993, drug research on BTK has not been stopped. The indications for BTK inhibitors are still expanding, and in addition to anti-tumor, the use of autoimmune diseases will be the key to push BTK inhibitors to another market segment. At present, various small molecule inhibitors of BTK are successively developed in China and show good anti-tumor effect in vivo and in vitro tests, more new BTK inhibitors are researched besides the marketed drugs Ibrutinib and ACP-196, and CT1530 and GS-4059 have already entered clinical stage II except BGB-3111 which are rapidly developed at present
Currently, tumor-targeted small molecule drugs targeting BTK targets have been developed up to generation 2, the first generation BTK inhibitor is Ibrutinib (Ibrutinib) marketed in the us in 2013 for clinical treatment of relapsed or refractory Mantle Cell Lymphoma (MCL), a BTK-targeted star drug, Ibrutinib is capable of inhibiting the growth and metastasis of malignant proliferating B cells, and Ibrutinib is the first BTK inhibitor approved by the FDA organization for marketing. In addition to being used to treat various hematological disorders, Ibrutinib is also used to treat autoimmune-related disorders including stem cell transplantation, immune resistance after transplantation, arthritis, and the like. However, the response rate of the Ibrutinib in the treatment is not one hundred percent, and the disease can relapse, and the drug has unknown primary drug resistance and acquired drug resistance. With the advent of drug marketing and clinical use, Ibrutinib began to develop resistance by different mechanisms in different patients. Acquired drug resistance is only discovered by the two target point mutations so far, and in a BCR signal pathway, the clinical drug resistance problem of the disease Ibrutinib in a BTK and Ibrutinib dose-dependent arthritis inhibition model is more and more, and a plurality of side effects are also generated.
The second-generation BTK inhibitor, namely, Acalabastinib (ACP-196), ACP-196 is called the second-generation BTK inhibitor, because the inhibition of BTK kinase target does not produce inhibition effect on other kinases. Approved by the FDA for the treatment of Mantle Cell Lymphoma (MCL) in 8 months of 2017, and a plurality of indications are in clinic at present, for example, Chronic Lymphocytic Leukemia (CLL) is in the third stage of clinic; some solid tumors such as non-small cell lung cancer, head and neck cancer, etc. are in the second stage of clinical treatment and develop very rapidly. ACP-196 is also currently clinically treated for arthritis, due to the off-target effects of Ibrutinib. Therefore, the second generation of BTK inhibitor with better selectivity starts to be applied in the stage of the stage, and has good development prospect in treating chronic diseases such as autoimmune diseases due to high selectivity and few side effects.
It is known that the selectivity of BTK inhibitors is not ideal, and besides BTK, the BTK inhibitors also inhibit other various kinases (such as ETK, EGF, BLK, FGR, HCK, YES, BRK, JAK3 and the like), so that more side effects are generated; meanwhile, the BTK binding site is mutated to cause the generation of drug resistance. Therefore, more BTK inhibitors are clinically needed for treating diseases such as tumors and the like, and simultaneously, adverse events can be overcome.
The invention designs and synthesizes a novel 3-amino-2, 7-dihydropyrano [4,3-c ]]Pyrazole-4, 6-diketone compounds, which are proved to have effect on cancer cells by in vitro experimentsHas good cytotoxicity, wherein the IC of compound TM10 on lung cancer cells50Up to 0.86 μ M, is a compound developed into a novel anticancer drug; in terms of the preparation method, the key intermediate and the target compound thereof are efficiently synthesized by a simple method.
Disclosure of Invention
The invention aims to analyze the structural characteristics of the marketed drug ibrutinib, and combines the newly reported structure-activity relationship, the difference of substituent R1 at N2 of piperidine-2, 6-diketone has little influence on the activity of Btk enzyme, and R1 faces to a hydrophilic pocket of the enzyme, and different hydrophilic groups (such as acid, amide and amine) are introduced to adjust the physicochemical properties of the compound. The spatial orientation of the substituent R2 at position N9 towards the gatekeeper region of the kinase and interaction with specific residues in the Tec family varies among the amino acid residues interacting with the gatekeeper regions of different kinases:
it is expected to design and synthesize compounds with higher cytotoxicity, exert anticancer effect and have pharmaceutical potential. The cytotoxicity experiment shows that the compound has stronger in-vitro inhibition effect on various cancer cells.
Interpretation of terms
The following sets forth definitions of various terms used to describe the present application. These definitions apply to the terms used throughout the specification and claims, unless otherwise limited in specific instances either individually or as part of a larger group.
The term "alkyl" as used herein refers to a saturated straight or branched chain hydrocarbon radical, in certain embodiments containing from 1 to 4, C, respectively1-4Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, or the like.
The term "aryl" in the present invention refers to a monocyclic or polycyclic carbocyclic ring system having one or more fused or non-fused aromatic rings, including but not limited to phenyl, naphthyl, tetrahydronaphthyl, and the like, and wherein the hydrogen atoms on the ring carbons may also be substituted with one or more substituents.
The term "halo" in the present invention refers to a group formed by replacing a hydrogen atom on a carbon atom with a halogen atom, wherein the halogen atom includes but is not limited to F, Cl, Br, I.
The term "alkoxy" in the present invention refers to an-O-alkyl group, wherein said alkyl group includes but is not limited to C1-3Alkyl and C3-6Specific examples of cycloalkyl groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and halo forms thereof.
The term "alkylamino" in the present invention refers to the group-N-alkyl, wherein said alkyl includes but is not limited to C1-3Alkyl and C3-6Specific examples of cycloalkyl groups include, but are not limited to, methylamino, ethylamino, propylamino, cyclopropylamino, cyclobutoxy, and the like. The term "cycloalkyl" in the context of the present invention is intended to mean a monovalent radical of a monocyclic or polycyclic, saturated or partially unsaturated, carbocyclic compound, C3-6Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and the hydrogen atoms on the ring carbons may also be substituted with one or more substituents.
The term "heterocycloalkyl" in the context of the present invention refers to a monocyclic or polycyclic non-aromatic ring system containing 2 to 6 ring carbon atoms and 1 to 3 ring heteroatoms selected from N, O, S.
The term "heteroaryl" in the present invention refers to an aromatic ring system containing 1 to 6 carbons and at least one heteroatom selected from N, S, O.
The term "alkylamino" according to the invention refers to the group-alkyl-NRaRbWherein alkyl includes but is not limited to C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy and C3-6Cycloalkyl radical, RaAnd RbEach independently selected from H, C1-3Alkyl or C3-6A cycloalkyl group.
The "pharmaceutically acceptable salt" as referred to herein refers to a salt of a compound of the present invention, prepared with a compound having a specific substituent as found in the present invention, and a relatively nontoxic acid or base. The present invention contains relatively basic functional groups and acid addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of an acid in neat solution or in a suitable inert solvent, and pharmaceutically acceptable acid addition salts include inorganic and organic acid salts. The inorganic acid salts include, but are not limited to: hydrochloride, nitrate, borate, hydrocyanate, hydrofluoride, hydrobromide, hydroiodide, nitrite, perhalogenate, halate, hypohalite, metaaluminate, sulfate, phosphate, nitrate; the organic acid salts include, but are not limited to: formate, acetate, propionate, butyrate, acrylate, oxalate, malonate, succinate, benzoate, phthalate, mesylate, ethanesulfonate, benzenesulfonate, phenylmethanesulfonate, p-toluenesulfonate, thioacetate, trifluoroacetate, tartrate, malate, citrate, ascorbate, salicylate, caffeic acid, fumarate, lactate, citrate, glutamate, camphorate, camphorsulfonate, and the like.
The term "solvate" as used herein refers to a form containing stoichiometric or non-stoichiometric amounts of an additive solvent selected from the group consisting of water, ethanol, isopropanol, ether, acetone, and the like.
The term "prodrug" as used herein refers to a compound that is metabolically convertible in the body to provide any of the compounds described by the formulae herein, and various forms of the drug are known in the art.
An "effective amount" as used herein refers to a dose that achieves the desired therapeutic effect in a desired subject without undue adverse effects, and the specific dose can generally be determined as desired by one of ordinary skill in the art.
"treating" as used herein refers to a method of alleviating or alleviating a disease or its complications; by preventing is meant reducing or eliminating the onset of symptoms or complications of a disease, condition, or disorder.
It is to be understood that other terms not explained above, but appearing in the present invention, are to be defined as commonly understood by one of ordinary skill in the art.
The specific technical scheme of the invention is as follows:
in a first aspect of the present invention, there is provided a hydrate, solvate, prodrug, stereoisomer or tautomer of a pyrazole-4, 6-dione compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
r is independently selected from H, halogen, aryl, heteroaryl and C1-4Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Heterocycloalkyl, aryloxy, -NR2R3(ii) a Or substituted aryl, substituted heteroaryl, substituted C3-6Cycloalkyl, substituted C2-6Heterocycloalkyl, substituted aryloxy, substituted C1-6One or more independent groups in the alkoxy group, wherein the substituent groups are selected from halogen, aryl, heteroaryl, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-4Alkyl, substituted C2-6Heterocycloalkyl, halogen substituted C2-6Heterocycloalkyl radical, C2-6One or more substituents in the heterocycloalkyl group.
R is preferably-NR2R3Aryl, heteroaryl, C1-4Alkyl radical, C2-6Heterocycloalkyl, substituted aryl, substituted heteroaryl.
R is further preferably-NR2R3Aryl, heteroaryl, substituted aryl.
R2Independently selected from H or C1-4An alkyl group; r2More preferably methyl.
R3Independently selected from H, C1-4Alkyl radical, C3-6Cycloalkyl radical, C1-3Haloalkyl, aryl, heteroaryl, and mixtures thereof,C1-6Alkoxy radical, C1-6Alkylamino, substituted C2-6Heterocycloalkyl, halogen substituted C2-6Heterocycloalkyl radical, C2-6One or more of heterocycloalkyl; r3More preferably methyl.
Z is independently selected from C1-4An alkyl or aryl group; z is preferably methyl, ethyl or benzene; z is more preferably methyl or benzene.
In a preferred embodiment of the invention, the compound of formula (I) is selected from the group consisting of:
in a second aspect of the invention, a preparation method of pyrazole-4, 6-dione compounds shown in formula (I) is provided. The compounds of the present application can be prepared using a variety of means known to those skilled in the art. The present application can be synthesized using the methods described herein and organic chemical synthesis methods or variations thereof as understood by those skilled in the art. Preferred methods include, but are not limited to, the following.
Preferably, the preparation method of the pyrazole-4, 6-dione compound shown in the formula (I) comprises the following steps:
preparation of compound 6:
general synthesis of compound 11:
preparation of compound I:
wherein R and Z are defined as for the compound of formula (I) according to the first aspect of the invention;
preferably, the preparation method of the pyrazole-4, 6-diketone compound shown in the formula (I) comprises the following reaction steps:
step 1: carrying out condensation reaction on the compound 1 in a sodium ethoxide solution to obtain a compound 2;
step 2: reacting the compound 2 with hydrazine hydrate to obtain a compound 3;
and step 3: reacting the compound 3 under an alkaline condition to obtain a compound 4;
and 4, step 4: the compound 4 is subjected to temperature-controlled reflux dehydration to generate an intermediate compound 5;
and 5: and reacting the compound 5 with 3-bromo-4-fluorobenzoic acid, EDCI and HOBt in dichloromethane to obtain a compound 6.
Step 6: reaction of compound 8 with compound 9 affords compound 10.
And 7: hydrolysis of compound 10 affords compound 11.
And 8: reacting the compound 6 with the compound 11 in an organic solvent, crystallizing, filtering and drying to obtain the target compound I. Preferably, the preparation method of the pyrazole-4, 6-dione compound shown in the formula (I) comprises the following specific reaction steps:
step 1: adding sodium ethoxide into an ethanol solvent, stirring for dissolving, adding the compound 1, heating to reflux, detecting by TLC (thin layer chromatography), controlling the temperature to crystallize after the reaction is finished, performing suction filtration, leaching a filter cake by using ethanol, and drying to obtain a crude compound 2; the crude product is recrystallized to obtain the final compound 2.
Preferably, the crystallization temperature is 15-30 ℃.
Step 2: adding the compound 2 into water, stirring for dissolving, adding hydrazine hydrate, heating to reflux, detecting by TLC, cooling to separate out solid after the reaction is finished, filtering, and drying to obtain a compound 3.
Preferably, the crystallization temperature is-10 to 5 ℃.
And step 3: and adding the compound 3 into an alkali solution, stirring for dissolving, heating to reflux, detecting by TLC (thin layer chromatography), cooling after the reaction is finished, adding hydrochloric acid to adjust the PH to 3-4, separating out a solid, filtering, and drying to obtain a compound 4.
Preferably, the alkali is sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, and more preferably sodium hydroxide.
And 4, step 4: dissolving the compound 4 in acetic anhydride, adding a condensing agent, heating to reflux, detecting by TLC, finishing the reaction,
cooling, crystallizing, filtering, leaching filter cake with methyl tert-butyl ether, and drying to obtain compound 5.
Preferably, the condensing agent is Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride [ EDCI ], 2-chloro-1, 3-dimethylimidazoline chloride (DMC), and more preferably dicyclohexylcarbodiimide (DC C).
And 5: dissolving 3-bromo-4-fluorobenzoic acid in dried dichloromethane, sequentially adding EDCI, HOBt and the compound 5, stirring at room temperature for reaction, detecting by TLC, filtering after the reaction is finished, concentrating, evaporating to dryness under reduced pressure, and separating by a column layer to obtain a compound 6.
Step 6: adding the compound 8 into dried dichloromethane, sequentially adding the compound 9 and a condensing agent, stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain a compound 10.
Preferably, the condensing agent is selected from Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride [ EDCI ], 2-chloro-1, 3-dimethylimidazoline chloride (DMC), 1-carbonylbenzotriazole (HOBt), and more preferably 1-carbonylbenzotriazole (HOBt) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride [ EDCI ].
And 7: dissolving the compound 10 in an organic solvent, dropwise adding hydrochloric acid with the concentration of 3mol/L, removing Boc groups, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain a compound 11.
Preferably, the organic solvent is ethyl acetate, dichloromethane, methanol, ethanol, wherein ethyl acetate is preferred.
And 8: dissolving the compound 6 in an organic solvent, adding the compound 11, heating until reflux reaction, finishing TLC detection reaction, cooling for crystallization, leaching a filter cake with the organic solvent, and drying to obtain a compound I.
Preferably, the organic solvent is toluene, benzene, xylene, wherein toluene is preferred.
Preferably, the crystallization temperature is-5 to 5 ℃, and preferably 0 ℃.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising: a therapeutically effective amount of a compound of formula (I) as described herein, or one or more of a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and optionally a pharmaceutically acceptable carrier, excipient, adjuvant, or diluent.
Preferably, the pharmaceutical composition can be used for treating diseases related to abnormal expression or high activity of tyrosine kinase.
Preferably, the diseases associated with abnormal expression or high tyrosine kinase activity of tyrosine kinase include, but are not limited to, abnormal cell proliferation, morphological changes, hyperkinesia, angiogenesis diseases, tumor growth, and tumor metastasis diseases.
In a preferred embodiment, the BTK inhibitor comprises an inhibiting effective amount of one or more of pyrazole-4, 6-diones of formula (I) according to the invention, or pharmaceutically acceptable salts, tautomers, optical isomers, pharmaceutically acceptable solvates thereof, and optionally a pharmaceutically acceptable carrier, excipient, adjuvant, or diluent.
The compounds of the invention can be used directly for prophylaxis and therapy or, preferably, in the form of pharmaceutical compositions. Although the active ingredients can be administered separately, they are preferably in the form of pharmaceutical preparations or compositions. Accordingly, the present invention provides a pharmaceutical formulation comprising a compound of the present invention in association with a pharmaceutically acceptable diluent, excipient or carrier (collectively referred to herein as "carrier" material). The pharmaceutical compositions of the present invention may take the form of pharmaceutical formulations as described hereinafter. The present invention therefore relates to a pharmaceutical composition comprising at least one compound of formula (I) and conventional excipients.
Exemplary compositions for oral administration include: suspending agents which may include, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancing agent, and sweetening or flavoring agents such as those known in the art; such as immediate release tablets, which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and/or lactose and/or other excipients, binders, bulking agents, disintegrants, diluents and lubricants such as those known in the art. Suitable binders include: starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Disintegrants include, but are not limited to: starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The compounds of formula (I) may also be delivered orally by sublingual and/or buccal means. Molded, compressed or lyophilized tablets are exemplary forms that may be used. Exemplary compositions include those formulated with the compounds of the present invention with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. These formulations may also include high molecular weight excipients such as cellulose (microcrystalline powdered cellulose) or polyethylene glycol (PEG). These formulations may also include excipients to aid mucosal adhesion, such as hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (SCMC), maleic anhydride copolymers (e.g., Gantrez) and agents to control release such as polyacrylic copolymers (e.g., Carbopo 1934). Lubricants, glidants, flavoring agents, coloring agents and stabilizers may also be added to facilitate preparation and use. Lubricants used in these dosage forms include: sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. For oral administration in liquid form, the oral pharmaceutical composition may be combined with any oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
The pharmaceutical formulations of the invention include those suitable for oral, parenteral [ including subcutaneous, intradermal, intramuscular, intravenous (bolus or infusion) and intraarticular ], inhalation (including fine particle powders or sprays which may be produced by means of various types of metered dose pressurised aerosols), nebuliser or inhaler, rectal, intraperitoneal and topical (including dermal, buccal, sublingual and intraocular) administration, although the most suitable route may depend, for example, on the condition and state of the recipient.
Formulations of the invention suitable for oral administration may be presented as discrete units containing a predetermined amount of the active ingredient, for example, as capsules, cachets, pills or tablets; a powder or granules; solutions or suspensions in aqueous or non-aqueous liquids, such as elixirs, tinctures, suspensions or syrups; or an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient can also be made into bolus, electuary or paste.
Tablets may be made by compression or molding with optionally one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricant, surfactant or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained or controlled release of the active ingredient therein. The compounds of the invention may be administered in a form suitable for immediate release or sustained release. Immediate release or sustained release can be achieved by using suitable pharmaceutical compositions comprising the compounds of the invention or, especially in the case of sustained release, by using devices such as subcutaneous implants or osmotic pumps. The compounds of the invention may also be administered in liposomes. Preferred unit dose formulations are those containing an effective dose (as described below) or an appropriate fraction thereof of the active ingredient.
It will be appreciated that in addition to the ingredients particularly mentioned above, the formulations of the invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavouring agents.
The formulations may be conveniently presented in unit dosage form and may be manufactured by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more additional ingredients. In general, the active ingredient is combined uniformly and intimately with liquid carriers and/or finely divided solid carriers to prepare formulations, which are then, if necessary, shaped to give the desired formulation.
The compounds of the invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, 1, 2-dipalmitoylphosphatidylcholine, phosphatidylethanolamine (cephalin), phosphatidylserine, phosphatidylinositol, diphosphatidylglycerol (cardiolipin), or phosphatidylcholine (lecithin).
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and the compositions may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Exemplary compositions for parenteral administration include: injectable solutions or suspensions which may contain, for example, suitable non-toxic parenterally acceptable diluents or solvents such as polyethylene glycol, ethanol, 1, 3-butanediol, water, ringer's solution, sodium chloride, and the like, or other suitable dispersing or wetting agents and suspending agents, including synthetic mono-or diglycerides and fatty acids, including oleic acid and Cremaphor.
Exemplary compositions for nasal, aerosol or inhalation administration include solutions in saline, which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
Formulations for rectal administration may be presented as a suppository with conventional carriers such as cocoa butter/synthetic glycerides or polyethylene glycols. These carriers are typically solid at ambient conditions, but liquefy and/or dissolve in the rectal lumen to release the drug.
Formulations for topical administration, e.g. buccal or sublingual administration, in the buccal cavity include lozenges comprising the active ingredient in a flavoured base, such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a base of gelatin and glycerol or sucrose and acacia. Exemplary compositions for topical administration include topical carriers such as Plastibase (mineral oil gelled with polyethylene).
In a fourth aspect, the present invention provides the use of a pyrazole-4, 6-dione compound of formula (I), in particular for the preparation of a tyrosine kinase inhibitor, for the non-therapeutic inhibition of tyrosine kinase activity in vitro, for the non-therapeutic inhibition of tumor cell growth in vitro or a combination thereof, for the treatment or prevention of a disease in which BTK plays a role.
In a preferred embodiment, the pyrazole-4, 6-dione compound of formula (I) is used for preparing a medicament for treating or preventing diseases in which BTK plays a role.
Preferably, the BTK-acting disease comprises cancer or an autoimmune system-related disease, in particular, the cancer includes, but is not limited to, non-small cancer lung cells, lymphoma, breast cancer, leukemia and head and neck squamous cell sarcoma, lung cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, prostate cancer, plasmacytoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, non-hodgkin's lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal stromal tumors, thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myelocytic leukemia, multiple myeloma, melanoma or mesothelioma; the autoimmune related diseases include, but are not limited to, chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus, myasthenia gravis, ulcerative colitis, pernicious anemia with chronic atrophic gastritis, goodpasture's syndrome, primary biliary cirrhosis, multiple sclerosis, acute idiopathic polyneuritis, systemic lupus erythematosus, rheumatoid arthritis, systemic vasculitis, scleroderma, pemphigus, dermatomyositis, mixed connective tissue disease, autoimmune hemolytic anemia, thyroid autoimmune disease, ulcerative colitis.
In a preferred embodiment, the treatment refers to a method of alleviating or alleviating the symptoms of the disease and its complications; by preventing is meant reducing or eliminating the onset of symptoms or complications of a disease, condition, or disorder.
Compared with the prior art, the invention has the main advantages that:
(1) the invention provides a pyrazole-4, 6-diketone compound with a novel structure shown in a formula (I).
(2) The pyrazole-4, 6-dione compound shown in the formula (I) provided by the invention has a remarkable inhibiting effect on the growth of tumor cells.
(3) The pyrazole-4, 6-dione compound shown in the formula (I) provided by the invention has the advantages of cheap and easily-obtained starting materials, shorter synthetic route and simpler operation, and is suitable for industrial large-scale production.
It is to be understood that within the scope of the present invention, the above-described technical features of the present invention and those specifically described below (including the examples) may be combined with each other to constitute a new or preferred technical solution.
Detailed Description
The process of the present invention is further illustrated by the following examples. It should be properly understood that the preparation methods of the embodiments of the present invention are only used for illustrating the present invention and are not limited to the present invention, and the simple modification of the preparation method of the present invention based on the concept of the present invention is within the scope of the present invention as claimed.
Abbreviations used herein:
DCC: dicyclohexylcarbodiimide
EDCI: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
DMC: 2-chloro-1, 3-dimethylimidazoline chloride
HOBt: 1-carbonyl benzotriazole
TLC: thin layer chromatography
Boc group: tert-butyloxycarbonyl radical
Preparation of compound 6:
preparation of compound 2: adding sodium ethoxide solid (4g, 0.01mol) into absolute ethyl alcohol (40ml), stirring and dissolving at room temperature, pouring (13.20g, 0.02mol) malononitrile, slowly heating to reflux, detecting by TLC, controlling the temperature to 20 ℃ after reaction, stirring and crystallizing, filtering, leaching with ethanol, leaching the obtained solid under reduced pressure, drying, transferring to a three-neck flask, pouring purified water, stirring at room temperature to dissolve, adjusting the pH to 3-4 with 5mol/L hydrochloric acid, precipitating crystals, filtering, recrystallizing a filter cake with purified water to obtain white needle-shaped crystals, and drying under reduced pressure to obtain a compound 2 with the yield of 85.6% and the purity of 99.92%.
Preparation of compound 3:
adding the intermediate 2 into 500ml of water, stirring for dissolving, adding 50ml of hydrazine hydrate, slowly heating to reflux, detecting by TLC (thin layer chromatography), cooling to 0 ℃ for crystallization after the reaction is finished, filtering to separate out a precipitate, and drying under reduced pressure to obtain the compound 3, wherein the yield is 87.8%, and the purity is 99.89%.
Preparation of compound 4:
adding the compound 3 into 0.2M NaOH (200ml), stirring for dissolving, heating to reflux reaction, detecting by TLC, cooling to 0 ℃ after the reaction is finished, adjusting the pH of a reaction solution to 3-4 by using 5mol/L hydrochloric acid, filtering, and drying under reduced pressure to obtain an intermediate 4, wherein the yield is 92.5%, and the purity is 99.90%.
Preparation of compound 5:
dissolving the compound 4(150g,0.90mol) in acetic anhydride (500ml), adding DCC (240.5g,1.17mol), heating to reflux, detecting by TLC, cooling to 0 ℃ for crystallization after the reaction is finished, carrying out suction filtration, leaching a filter cake by using methyl tert-butyl ether, and drying under reduced pressure to obtain the compound 5 with the yield of 91.7% and the purity of 99.88%.
Preparation of compound 6:
adding 3-bromo-4-fluorobenzoic acid (2.19g, 0.1mol) into 300ml of dichloromethane, sequentially adding EDCI (1.92g, 0.1mol), HOBt (1.35g, 0.1mol) and intermediate 5(83.6g, 0.08mol), stirring at room temperature for reaction, detecting by TLC, filtering after the reaction is finished, concentrating, decompressing and evaporating to dryness, and separating by a column layer to obtain the compound 6, wherein the yield is 90.5%, and the purity is 99.87%.
Example 1
Preparation of compound TM 1:
preparation of Compound 10-1:
adding the compound 8(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-1(8.90g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, ending the reaction, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-1, wherein the yield is 91.8 percent and the purity is 99.78 percent.
Preparation of Compound 11-1:
dissolving the compound 10-1(23.13g, 0.1mol) in 150mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc groups, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11, wherein the yield is 90.3%, and the purity is 99.85%.
Preparation of compound TM 1:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-1(15.74g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM1, wherein the yield is 92.4% and the purity is 99.92%.
1HNMR(400MHz,DMSOd6):δ12.15(s,1H),9.76(s,1H),8.98(s,1H),7.82～7.74(m,3H),4.66(s,2H),4.32(s,2H),3.42(s,2H),2.76(s,6H)；
13CNMR(100MHz,DMSOd6):173.4,168.5,164.6,159.8,155.5,150.2,141.1,133.4,133.5,128.9,118.7,112.2,98.7,78.1,54.8,45.5(2C),30.4.
MS(m/z):481.24[M+H]+；
Example 2
Preparation of compound TM 2:
preparation of Compound 10-2:
adding the compound 8(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-2(12.89g, 0.13mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, ending the reaction, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-2, wherein the yield is 91.5% and the purity is 99.77%.
Preparation of Compound 11-2:
dissolving the compound 10-2(25.64g, 0.1mol) in 150mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc groups, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-2, wherein the yield is 91.1%, and the purity is 99.89%.
Preparation of compound TM 2:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-2(18.75g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM2, wherein the yield is 92.1% and the purity is 99.90%.
1HNMR(400MHz,DMSO-d6)δ12.15(s,1H),9.76(s,1H),8.98(s,1H),7.82～7.74(m,3H),4.35(s,2H),3.92(s,2H),3.55～3.47(m,1H),1.74～1.69(m,2H),1.50～1.43(m,4H),1.23～1.11(m,4H)；
13C-NMR(100MHz,DMSO-d6):168.4,157.6,155.5,150.2,141.1,133.4,132.6,129.5,120.9,118.7,112.2,98.7,54.8,50.1,35.6(2C),30.5,27.0,25.6,26.7(2C).
MS(m/z):506.12[M+H]+；
Example 3
Preparation of compound TM 3:
preparation of Compound 10-3:
adding the compound 8(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-3(11.18g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, ending the reaction, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-3, wherein the yield is 92.0% and the purity is 99.82%.
Preparation of Compound 11-3:
dissolving the compound 10-3(25.03g, 0.1mol) in 180mL of ethyl acetate, dropwise adding 30mL of hydrochloric acid with the concentration of 3mol/L, removing Boc groups, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-3, wherein the yield is 91.6%, and the purity is 99.90%.
Preparation of compound TM 3:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-3(18.02g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM3, wherein the yield is 92.1% and the purity is 99.90%.
1HNMR(400MHz,DMSO-d6)δ12.15(s,1H),9.76(s,1H),8.98(s,1H),7.82～7.74(m,3H),7.23～7.03(m,5H),4.65(s,2H),3.42(s,2H)；
13C-NMR(100MHz,DMSO-d6):168.4,157.6,155.5,150.2,141.1,137.1,133.4,134.3,130.4,129.5,128.8(2C),127.5,121.8(2C),120.9,118.7,112.2,98.7,54.8,30.5.
MS(m/z):500.18[M+H]+；
Example 4
Preparation of compound TM 4:
preparation of Compound 10-4:
adding the compound 8(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-4(13.33g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, ending the reaction, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-4, wherein the yield is 92.2% and the purity is 99.85%.
Preparation of Compound 11-4:
dissolving the compound 10-4(26.83g, 0.1mol) in 150mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-4, wherein the yield is 91.8%, and the purity is 99.91%.
Preparation of compound TM 4:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-4(20.18g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM4, wherein the yield is 91.7%, and the purity is 99.87%.
1HNMR(400MHz,DMSO-d6)δ12.15(s,1H),9.76(s,1H),8.98(s,1H),7.82～7.74(m,3H),7.23～7.03(m,4H),4.65(s,2H),3.42(s,2H)；
13C-NMR(100MHz,DMSO-d6):168.4,162.9,157.6,155.5,150.2,141.1,137.1,133.4,134.3,130.4,129.5,128.8(2C),127.5,121.8(2C),118.7,112.2,98.7,54.8,30.5.
MS(m/z):518.31[M+H]+；
Example 5
Preparation of compound TM 5:
preparation of Compound 10-5:
adding the compound 8(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-5(11.29g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, ending the reaction, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-5, wherein the yield is 91.9% and the purity is 99.81%.
Preparation of Compounds 11-5:
dissolving the compound 10-5(25.13g, 0.1mol) in 150mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-5, wherein the yield is 92.0%, and the purity is 99.92%.
Preparation of compound TM 5:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-5(18.14g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM5, wherein the yield is 91.9%, and the purity is 99.89%.
1HNMR(400MHz,DMSO-d6)δ12.15(s,1H),9.76(s,1H),8.98(s,1H),7.82～7.74(m,3H),7.33～7.23(m,3H),7.11～7.04(m,1H),4.65(s,2H),3.42(s,2H)；
13C-NMR(100MHz,DMSO-d6):168.4,162.9,157.6,155.5,150.2,141.1,137.1,133.4,134.3,130.4,129.5,128.8,127.5,124.8,121.8,118.7,112.2,98.7,48.8,30.5.
MS(m/z):501.16[M+H]+；
Example 6
Preparation of compound TM 6:
preparation of Compound 10-6:
adding the compound 8(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-6(16.46g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, ending the reaction, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-6, wherein the yield is 92.2% and the purity is 99.84%.
Preparation of Compounds 11-6:
dissolving the compound 10-6(29.44g, 0.1mol) in 150mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc groups, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-6, wherein the yield is 92.2%, and the purity is 99.91%.
Preparation of compound TM 6:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-6(23.71g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM6, wherein the yield is 92.4% and the purity is 99.91%.
1HNMR(400MHz,DMSO-d6)δ12.15(s,1H),9.76(s,1H),8.98(s,1H),7.82～7.74(m,3H),7.63(s,1H),7.23～7.33(m,2H),4.92(s,2H),3.57(s,2H),3.32(s,3H),2.15(s,3H)；
13C-NMR(100MHz,DMSO-d6):168.4,167.9,157.6,155.5,150.2,141.1,135.1,133.4,132.5,131.0,129.5,128.1,125.4,123.3,122.8,120.9,118.7,112.2,98.7,56.4,54.8,27.0,18.2.
MS(m/z):544.22[M+H]+；
Example 7
Preparation of compound TM 7:
preparation of Compounds 10-7:
adding the compound 8(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-7(15.98g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, ending the reaction, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-7 with the yield of 92.0% and the purity of 99.82%.
Preparation of Compounds 11-7:
dissolving the compound 10-7(29.03g, 0.1mol) in 150mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-7, wherein the yield is 91.8%, and the purity is 99.88%.
Preparation of compound TM 7:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-7(22.82g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM7, wherein the yield is 92.0% and the purity is 99.87%.
1HNMR(400MHz,DMSO-d6)δ12.15(s,1H),10.56(s,1H),9.76(s,1H),8.98(s,1H),7.82～7.74(m,3H),7.23～7.13(m,4H),4.65(s,2H),3.72(s,2H)；
13C-NMR(100MHz,DMSO-d6):168.4,157.6,155.5,150.2,141.1,136.2(2C),133.4,130.3,129.5,126.8,123.2(2C),122.5,120.9,118.7,115.2(2C),112.2,98.7,54.8,27.2.
MS(m/z):540.13[M+H]+；
Example 8
Preparation of compound TM 8:
preparation of Compounds 10-8:
adding the compound 8(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-8(32.93g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, ending the reaction, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-8, wherein the yield is 92.5% and the purity is 99.87%.
Preparation of Compounds 11-8:
dissolving the compound 10-8(43.16g, 0.1mol) in 150mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-8, wherein the yield is 92.4%, and the purity is 99.90%.
Preparation of compound TM 8:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked bottle, pouring 80ml of toluene, adding the compound 11-8(39.78g, 0.12mol), heating to reflux reaction, detecting by TLC to finish the reaction, cooling to 0 ℃ for crystallization, finishing crystallization, filtering, leaching a filter cake by using a proper amount of toluene, and drying under reduced pressure to obtain the compound TM8 with the yield of 92.3% and the purity of 99.90%.
1HNMR(400MHz,DMSO-d6)δ12.15(s,1H),9.76(s,1H),8.98(s,1H),7.82～7.74(m,4H),7.23～7.33(m,3H),4.72(s,2H),3.49(s,2H),3.11(m,4H)；2.74(m,1H)；2.45(m,8H)；2.36(s,3H)；1.82(m,4H)；
13C-NMR(100MHz,DMSO-d6):168.4,167.2,157.6,155.5,150.2,141.1,133.4,132.7,129.5,120.9,120.6(2C),118.7,118.4,118.3,117.7(2C),112.2,98.7,63.4(2C),56.7(2C),54.8,54.3(2C),53.3,45.3,29.4(2C),27.0.
MS(m/z):681.16[M+H]+；
Example 9
Preparation of compound TM 9:
preparation of Compounds 10-9:
adding the compound 8(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-9(16.46g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, ending the reaction, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-9, wherein the yield is 92.1% and the purity is 99.85%.
Preparation of Compounds 11-8:
dissolving the compound 10-9(19.44g, 0.1mol) in 150mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-9, wherein the yield is 92.0%, and the purity is 99.87%.
Preparation of compound TM 9:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-9(23.31g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM9, wherein the yield is 92.0% and the purity is 99.89%.
MS(m/z):544.15[M+H]+；1H-NMR(400MHz,DMSO-d6):δ11.08(s,1H),10.24(s,1H),8.70(s,1H),7.55(s,1H),7.28～7.16(m,5H),4.83～4.64(m,2H),3.77(s,3H),3.46(s,2H),2.68～2.54(m,2H)；2.18(s,3H)；13C-NMR(400MHz,DMSO-d6):δ173.0,168.8,167.9,162.4,158.9,149.8,137.7,135.5,130.8,128.3,125.7,123.0,122.5,121.5,119.4,118.9,118.6,115.3,114.6,72.2,56.6,39.7,35.5,19.9.
Example 10
Preparation of compound TM 10:
preparation of Compounds 10-10:
adding the compound 8-1(23.73g and 0.1mol) into dried dichloromethane, sequentially adding the compound 9-10(16.46g and 0.12mol), HOBt (13.51g and 0.1mol) and EDCI (19.17g and 0.1mol), stirring at room temperature, detecting by TLC, finishing the reaction, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-10, wherein the yield is 91.7 percent and the purity is 99.82 percent.
Preparation of Compounds 11-10:
dissolving 10-10(35.64g, 0.1mol) of the compound in 180mL of ethyl acetate, dropwise adding 30mL of hydrochloric acid with the concentration of 3mol/L, removing Boc groups, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain 11-10 of the compound, wherein the yield is 92.0%, and the purity is 99.87%.
Preparation of compound TM 10:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-10(30.76g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM10, wherein the yield is 92.2% and the purity is 99.91%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),7.71～7.54(m,4H),7.45(s,1H),7.25～7.17(m,5H),3.71(s,3H),3.59(s,2H),2.15(s,3H)；
13C-NMR(400MHz,DMSO-d6):δ172.8,168.8,167.7,162.8,158.6,149.7,142.4,137.5,135.7,131.2(2C),130.4,128.5,125.8,124.3,123.4,122.3,121.2,119.5,118.7,118.4,115.1,114.8,113.5(2C),72.4,56.8,19.7.
MS(m/z):606.20[M+H]+；
Example 11
Preparation of compound TM 11:
preparation of Compounds 10-11:
adding the compound 8-1(23.73g and 0.1mol) into dried dichloromethane, sequentially adding the compound 9-11(8.90g and 0.12mol), HOBt (13.51g and 0.1mol) and EDCI (19.17g and 0.1mol), stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-11, wherein the yield is 92.0 percent and the purity is 99.85 percent.
Preparation of Compounds 11-11:
dissolving the compound 10-11(29.34g, 0.1mol) in 180mL of ethyl acetate, dropwise adding 30mL of hydrochloric acid with the concentration of 3mol/L, removing Boc groups, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-11, wherein the yield is 92.4%, and the purity is 99.89%.
Preparation of compound TM 11:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-11(23.19g, 0.12mol), heating to reflux reaction, detecting by TLC to finish the reaction, cooling to 0 ℃ for crystallization, finishing crystallization, filtering, leaching a filter cake by using a proper amount of toluene, and drying under reduced pressure to obtain the compound TM11 with the yield of 92.0% and the purity of 99.88%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),7.71～7.54(m,3H),7.75(s,1H),7.25～7.17(m,3H),4.15(s,2H),3.59(s,2H),2.33(s,6H)；
13C-NMR(400MHz,DMSO-d6):δ168.8,167.7,162.8,158.6,149.7,142.4,137.5,131.2,130.4,128.5(2C),125.8(2C),123.4,121.2,119.5,114.8,110.5,99.5,72.4,47.4(2C),31.2.
MS(m/z):543.13[M+H]+；
Example 12
Preparation of compound TM 12:
preparation of Compounds 10-12:
adding the compound 8-1(23.73g and 0.1mol) into dried dichloromethane, sequentially adding the compound 9-12(8.90g and 0.12mol), HOBt (13.51g and 0.1mol) and EDCI (19.17g and 0.1mol), stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-12, wherein the yield is 92.0 percent and the purity is 99.85 percent.
Preparation of Compounds 11-12:
dissolving the compound 10-12(29.34g, 0.1mol) in 180mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-12, wherein the yield is 92.4%, and the purity is 99.89%.
Preparation of compound TM 12:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-12(23.19g, 0.12mol), heating to reflux reaction, detecting by TLC to finish the reaction, cooling to 0 ℃ for crystallization, finishing crystallization, filtering, leaching a filter cake by using a proper amount of toluene, and drying under reduced pressure to obtain the compound TM12 with the yield of 92.0% and the purity of 99.88%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),7.71～7.54(m,3H),7.75(s,1H),7.25～7.17(m,3H),3.59(s,2H),3.49～3.41(m,1H),1.59～1.22(m,10H)；
13C-NMR(400MHz,DMSO-d6):δ168.8,167.7,162.8,158.6,149.7,142.4,137.5,131.2,130.4,128.5(2C),125.8(2C),123.4,121.2,119.5,114.8,110.5,99.5,55.4,33.4(2C),31.2,26.8(2C),23.9.
MS(m/z):568.09[M+H]+；
Example 13
Preparation of compound TM 13:
preparation of Compounds 10-13:
adding the compound 8-1(23.73g and 0.1mol) into dried dichloromethane, sequentially adding the compound 9-13(11.18g and 0.12mol), HOBt (13.51g and 0.1mol) and EDCI (19.17g and 0.1mol), stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-13, wherein the yield is 91.8 percent and the purity is 99.84 percent.
Preparation of Compounds 11-13:
dissolving the compound 10-13(31.24g, 0.1mol) in 180mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-13, wherein the yield is 92.6%, and the purity is 99.91%.
Preparation of compound TM 13:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-13(25.47g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM13, wherein the yield is 91.7%, and the purity is 99.82%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),7.75(s,1H),7.71～7.54(m,5H),7.25～7.17(m,5H),7.15～7.07(m,1H),3.59(s,2H)；
13C-NMR(400MHz,DMSO-d6):δ168.8,167.7,162.8,158.6,149.7,142.4,137.5,136.7,131.2,130.4,129.1(2C),128.5(2C),127.4(2C),125.8(2C),123.4,122.5,121.2,119.5,114.8,110.5,99.5,31.2.
MS(m/z):562.21[M+H]+；
Example 14
Preparation of compound TM 14:
preparation of Compounds 10-14:
adding the compound 8-1(23.73g and 0.1mol) into dried dichloromethane, sequentially adding the compound 9-14(13.33g and 0.12mol), HOBt (13.51g and 0.1mol) and EDCI (19.17g and 0.1mol), stirring at room temperature, detecting by TLC, finishing the reaction, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-14, wherein the yield is 91.4 percent and the purity is 99.81 percent.
Preparation of Compounds 11-14:
dissolving the compound 10-14(33.04g, 0.1mol) in 180mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-14, wherein the yield is 92.0%, and the purity is 99.87%.
Preparation of compound TM 14:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-14(27.63g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM14, wherein the yield is 91.1% and the purity is 99.80%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),7.99～7.75(m,2H),7.71～7.54(m,4H),7.25～7.17(m,5H),3.59(s,2H)；
13C-NMR(400MHz,DMSO-d6):δ168.8,167.7,162.8,161.5,158.6,149.7,142.4,137.5,136.7,133.4,130.4,128.5(2C),125.8(2C),127.7(2C),123.4,122.5,121.2,119.5,117.1(2C),110.5,99.5,31.2.
MS(m/z):580.15[M+H]+；
Example 15
Preparation of compound TM 15:
preparation of Compounds 10-15:
adding the compound 8-1(23.73g and 0.1mol) into dried dichloromethane, sequentially adding the compound 9-15(11.29g and 0.12mol), HOBt (13.51g and 0.1mol) and EDCI (19.17g and 0.1mol), stirring at room temperature, detecting by TLC, finishing the reaction, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-15, wherein the yield is 92.0 percent and the purity is 99.87 percent.
Preparation of Compounds 11-15:
dissolving the compound 10-15(31.34g, 0.1mol) in 180mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-15, wherein the yield is 92.3%, and the purity is 99.89%.
Preparation of compound TM 15:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-15(25.59g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM15, wherein the yield is 91.9%, and the purity is 99.88%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),8.03～7.92(m,3H),7.81～7.70(m,3H),7.25～7.17(m,5H),3.59(s,2H)；
13C-NMR(400MHz,DMSO-d6):δ168.8,167.7,162.8,158.6,154.3,149.7,146.8,142.4,139.4,137.5,136.7,133.4,130.4,128.5(2C),125.8(2C),123.4,122.5,121.2,119.5,117.9,113.5,99.5,31.2.
MS(m/z):563.11[M+H]+；
Example 16
Preparation of compound TM 16:
preparation of Compounds 10-16:
adding the compound 8-1(23.73g and 0.1mol) into dried dichloromethane, sequentially adding the compound 9-16(17.18g and 0.12mol), HOBt (13.51g and 0.1mol) and EDCI (19.17g and 0.1mol), stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-16, wherein the yield is 91.5 percent and the purity is 99.84 percent.
Preparation of Compounds 11-16:
dissolving the compound 10-16(36.24g, 0.1mol) in 180mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-16, wherein the yield is 91.8%, and the purity is 99.82%.
Preparation of compound TM 16:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-16(31.48g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM16, wherein the yield is 91.4%, and the purity is 99.85%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),8.03～7.92(m,2H),7.85～7.71(m,4H),7.57～7.41(m,4H),7.25～7.17(m,4H),3.59(s,2H)；
13C-NMR(400MHz,DMSO-d6):δ168.8,167.7,162.8,158.6,154.3,149.7,146.8,142.4,139.4,137.5,135.7,133.4,132.8,130.4,129.1,128.5(2C),126.7,125.8(2C),124.3,122.5,120.5,119.5,119.1,117.9,116.7,113.5,99.5,31.2.
MS(m/z):612.16[M+H]+；
Example 17
Preparation of compound TM 17:
preparation of Compounds 10-17:
adding the compound 8-1(23.73g and 0.1mol) into dried dichloromethane, sequentially adding the compound 9-17(15.98g and 0.12mol), HOBt (13.51g and 0.1mol) and EDCI (19.17g and 0.1mol), stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-17, wherein the yield is 91.9 percent and the purity is 99.86 percent.
Preparation of Compounds 11-17:
dissolving the compound 10-17(33.52g, 0.1mol) in 180mL ethyl acetate, dripping 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-17, wherein the yield is 92.1%, and the purity is 99.89%.
Preparation of compound TM 17:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-17(30.27g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM17, wherein the yield is 91.7%, and the purity is 99.86%.
1H-NMR(400MHz,DMSO-d6):δ12.11(s,1H),11.03(s,1H),10.20(s,1H),8.74(s,1H),7.71～7.54(m,3H),7.75(s,1H),7.25～7.17(m,3H),7.11～7.04(m,4H),3.59(s,2H)；
13C-NMR(400MHz,DMSO-d6):δ168.8,167.7,162.8,158.6,150.7,149.7,142.4,139.1,137.5,136.2,131.2,130.4,128.5(2C),125.8(2C),124.6(2C),123.4,121.2,119.5,117.0(2C),114.8,110.5,99.5,31.2；
MS(m/z):602.18[M+H]+；
Example 18
Preparation of compound TM 18:
preparation of Compounds 10-18:
adding the compound 8-1(23.73g and 0.1mol) into dried dichloromethane, sequentially adding the compound 9-18(32.93g and 0.12mol), HOBt (13.51g and 0.1mol) and EDCI (19.17g and 0.1mol), stirring at room temperature, detecting by TLC, finishing the reaction, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-18, wherein the yield is 92.4 percent and the purity is 99.88 percent.
Preparation of Compounds 11-18:
dissolving the compound 10-18(49.37g, 0.1mol) in 180mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-18, wherein the yield is 92.3%, and the purity is 99.92%.
Preparation of compound TM 18:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-18(47.22g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM18, wherein the yield is 92.1% and the purity is 99.88%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),7.71～7.54(m,3H),7.75(s,1H),7.31～7.22(m,5H),7.11～6.94(m,2H),3.59(s,2H),3.34～7.21(m,4H),2.77～2.63(m,1H),2.36～2.18(m,11H),1.77～1.65(m,4H)；
13C-NMR(400MHz,DMSO-d6):δ168.8,167.7,162.8,158.6,149.7,145.7,142.4,137.5,131.2,130.4,129.4,128.5(2C),125.8(2C),123.4,122.6(2C),121.2,119.5,115.2(2C),114.8,110.5,99.5,76.2,66.1(2C),61.5(2C),55.3(2C),47.6,31.2,29.3(2C).
MS(m/z):743.24[M+H]+；
Example 19
Preparation of compound TM 19:
preparation of Compounds 10-19:
adding the compound 8-1(23.73g and 0.1mol) into dried dichloromethane, sequentially adding the compound 9-19(17.79g and 0.12mol), HOBt (13.51g and 0.1mol) and EDCI (19.17g and 0.1mol), stirring at room temperature, detecting by TLC, finishing the reaction, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-19, wherein the yield is 91.7 percent and the purity is 99.80 percent.
Preparation of Compounds 11-19:
dissolving the compound 10-19(36.85g, 0.1mol) in 180mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-19, wherein the yield is 91.8%, and the purity is 99.89%.
Preparation of compound TM 19:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compounds 11-19(32.20g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM19, wherein the yield is 91.6%, and the purity is 99.84%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),7.84～7.75(m,2H),7.70～7.56(m,5H),7.35～7.20(m,5H),3.59(s,2H)；
13C-NMR(400MHz,DMSO-d6):δ168.8,167.7,162.8,158.6,149.7,142.4,139.2,138.4,137.5,131.2,130.4,128.5(2C),127.3,125.8(2C),124.6,124.3,123.4,123.0,122.5,121.2,119.5,114.8,111.0,110.5,99.5,31.2.
MS(m/z):618.19[M+H]+；
Example 20
Preparation of compound TM 20:
preparation of Compounds 10-20:
adding the compound 8-2(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-20(8.90g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-20, wherein the yield is 91.1% and the purity is 99.75%.
Preparation of Compounds 11-20:
dissolving 10-20(24.53g, 0.1mol) of the compound in 180mL of ethyl acetate, dropwise adding 30mL of hydrochloric acid with the concentration of 3mol/L, removing Boc groups, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain 11-20 of the compound, wherein the yield is 91.2%, and the purity is 99.83%.
Preparation of compound TM 20:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-20(17.43g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM20, wherein the yield is 91.0% and the purity is 99.80%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),8.11～7.98(m,2H),7.25～7.17(m,1H),4.88～4.81(m,2H),4.31(s,2H),3.59(s,2H),2.71～2.64(m,2H),2.26(s,6H)；
13C-NMR(400MHz,DMSO-d6):δ170.1,168.6,167.8,159.2,149.7,145.6,142.4,133.1,132.3,128.2,118.5,111.0,99.6,79.2,47.2(2C),40.1,33.7,31.2.
MS(m/z):495.32[M+H]+；
Example 21
Preparation of compound TM 21:
preparation of Compounds 10-21:
adding the compound 8-2(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-21(11.90g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-21, wherein the yield is 91.4% and the purity is 99.78%.
Preparation of Compounds 11-21:
dissolving the compound 10-21(27.04g, 0.1mol) in 180mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-21, wherein the yield is 91.9%, and the purity is 99.88%.
Preparation of compound TM 21:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked bottle, pouring 80ml of toluene, adding the compound 11-21(20.43g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM21, wherein the yield is 92.1% and the purity is 99.89%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),8.11～7.98(m,2H),7.25～7.17(m,1H),4.31(s,2H),3.59(s,2H),3.51～3.42(m,1H),2.71～2.64(m,2H),1.74～1.69(m,2H),1.50～1.43(m,4H),1.23～1.11(m,4H)；
13C-NMR(400MHz,DMSO-d6):δ170.1,168.6,167.8,159.2,149.7,145.6,142.4,133.1,132.3,128.2,118.5,111.0,99.6,50.5,40.1,35.6(2C),33.7,31.2,25.6,26.7(2C).
MS(m/z):520.11[M+H]+；
Example 22
Preparation of compound TM 22:
preparation of Compounds 10-22:
adding the compound 8-2(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-22(11.18g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-22, wherein the yield is 91.6% and the purity is 99.79%.
Preparation of Compounds 11-22:
dissolving the compound 10-22(26.43g, 0.1mol) in 180mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-22, wherein the yield is 91.1%, and the purity is 99.82%.
Preparation of compound TM 22:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked bottle, pouring 80ml of toluene, adding the compound 11-22(19.71g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM22, wherein the yield is 91.5%, and the purity is 99.82%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),8.11～7.98(m,2H),7.25～7.17(m,6H),4.31(s,2H),3.59(s,2H),2.71～2.64(m,2H)；
13C-NMR(400MHz,DMSO-d6):δ170.1,168.6,167.8,159.2,149.7,145.6,142.4,139.5,133.1,132.3,128.8(2C),128.2,127.1,121.8(2C),118.5,111.0,99.6,40.1,33.7,31.2.
MS(m/z):514.17[M+H]+；
Example 23
Preparation of compound TM 23:
preparation of Compounds 10-23:
adding the compound 8-2(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-23(13.33g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-23, wherein the yield is 91.0% and the purity is 99.74%.
Preparation of Compounds 11-23:
dissolving the compound 10-23(28.23g, 0.1mol) in 180mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-23, wherein the yield is 91.4%, and the purity is 99.83%.
Preparation of compound TM 23:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compounds 11-23(21.86g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM23, wherein the yield is 91.7%, and the purity is 99.84%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),8.11～7.98(m,2H),7.25～7.17(m,5H),4.31(s,2H),3.59(s,2H),2.71～2.64(m,2H)；
13C-NMR(400MHz,DMSO-d6):δ170.1,168.6,167.8,162.3,159.2,149.7,145.6,142.4,133.1,132.3,131.5,128.2,121.8(2C),118.5,115.2(2C),111.0,99.6,40.1,33.7,31.2.
MS(m/z):532.24[M+H]+；
Example 24
Preparation of compound TM 24:
preparation of Compounds 10-24:
adding the compound 8-2(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-24(11.29g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-24 with the yield of 91.6% and the purity of 99.77%.
Preparation of Compounds 11-24:
dissolving the compound 10-24(26.53g, 0.1mol) in 180mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-24, wherein the yield is 91.8%, and the purity is 99.85%.
Preparation of compound TM 24:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-24(19.82g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM24, wherein the yield is 91.8%, and the purity is 99.87%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),8.11～7.98(m,2H),7.33～7.19(m,4H),7.11～7.04(m,1H),4.31(s,2H),3.59(s,2H),2.71～2.64(m,2H)；
13C-NMR(400MHz,DMSO-d6):δ170.1,168.6,167.8,159.2,151.3,149.7,147.3,145.6,142.4,139.2,133.1,132.3,128.2,124.5,118.5,115.6,111.0,99.6,40.1,33.7,31.2.
MS(m/z):515.19[M+H]+；
Example 25
Preparation of compound TM 25:
preparation of Compounds 10-25:
adding the compound 8-2(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-25(16.46g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-25 with the yield of 91.0% and the purity of 99.71%.
Preparation of Compounds 11-25:
dissolving the compound 10-25(30.84g, 0.1mol) in 180mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-25, wherein the yield is 91.3%, and the purity is 99.83%.
Preparation of compound TM 25:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-25(24.99g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM25, wherein the yield is 91.0% and the purity is 99.81%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),8.11～7.98(m,2H),7.82～7.74(m,3H),7.25～7.17(m,1H),4.31(s,2H),3.59(s,2H),3.32(s,3H),2.71～2.64(m,2H),2.15(s,3H)；
13C-NMR(400MHz,DMSO-d6):δ170.1,168.6,167.8,159.2,157.4,149.7,145.6,142.4,137.3,133.1,132.3,130.3,128.2,122.1,118.5,114.2,111.0,103.9,99.6,55.6,40.1,33.7,31.2,15.9.
MS(m/z):558.07[M+H]+；
Example 26
Preparation of compound TM 26:
preparation of Compounds 10-26:
adding the compound 8-2(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-26(15.98g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-26, wherein the yield is 91.9% and the purity is 99.82%.
Preparation of Compounds 11-26:
dissolving the compound 10-26(30.44g, 0.1mol) in 180mL ethyl acetate, dripping 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-26, wherein the yield is 91.9%, and the purity is 99.87%.
Preparation of compound TM 26:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked bottle, pouring 80ml of toluene, adding the compound 11-26(24.51g, 0.12mol), heating to reflux reaction, detecting by TLC to finish the reaction, cooling to 0 ℃ for crystallization, finishing crystallization, filtering, leaching a filter cake by using a proper amount of toluene, and drying under reduced pressure to obtain the compound TM26 with the yield of 92.2% and the purity of 99.90%.
1H-NMR(400MHz,DMSO-d6):δ12.15(s,1H),11.03(s,1H),10.20(s,1H),8.74(s,1H),8.11～7.98(m,2H),7.25～7.17(m,5H),4.31(s,2H),3.59(s,2H),2.71～2.64(m,2H)；
13C-NMR(400MHz,DMSO-d6):δ170.1,168.6,167.8,159.2,149.7,146.5,145.6,142.4,137.2,136.4,133.1,132.3,128.2,123.2(2C),118.5,115.2(2C),111.0,99.6,40.1,33.7,31.2.
MS(m/z):554.30[M+H]+；
Example 27
Preparation of compound TM 27:
preparation of Compounds 10-27:
adding the compound 8-2(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-27(32.93g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-27, wherein the yield is 92.3% and the purity is 99.87%.
Preparation of Compounds 11-27:
dissolving the compound 10-27(46.17g, 0.1mol) in 180mL ethyl acetate, dripping 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-27, wherein the yield is 92.1%, and the purity is 99.89%.
Preparation of compound TM 27:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compound 11-27(41.46g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM27, wherein the yield is 92.4% and the purity is 99.91%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),8.11～7.98(m,2H),7.82～7.74(m,4H),7.25～7.17(m,1H),4.31(s,2H),3.59(s,2H),3.34～7.21(m,4H),2.77～2.63(m,3H),2.36～2.18(m,11H),1.77～1.65(m,4H)；
13C-NMR(400MHz,DMSO-d6):δ170.1,168.6,167.8,159.2,149.7,146.6,145.6,142.4,133.1,132.3,128.2,127.3,126.1(2C),118.5,113.4(2C),111.0,99.6,63.4(2C),70.5,56.7(2C),54.3(2C),46.8,40.1,33.7,31.2,29.4(2C).
MS(m/z):695.27[M+H]+；
Example 28
Preparation of compound TM 28:
preparation of Compounds 10-28:
adding the compound 8-2(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-28(18.02g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-28, wherein the yield is 91.5% and the purity is 99.82%.
Preparation of Compounds 11-28:
dissolving the compound 10-28(32.14g, 0.1mol) in 180mL ethyl acetate, dropwise adding 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-28, wherein the yield is 91.1%, and the purity is 99.80%.
Preparation of compound TM 28:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked flask, pouring 80ml of toluene, adding the compounds 11-28(26.55g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM28, wherein the yield is 91.8%, and the purity is 99.87%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),8.18～7.96(m,4H),7.62～7.54(m,2H),7.25～7.17(m,1H),4.31(s,2H),3.59(s,2H),2.71～2.64(m,2H)；
13C-NMR(400MHz,DMSO-d6):δ174.0,170.1,168.6,167.8,159.2,155.2,149.7,145.6,142.4,133.1,132.3,131.2,128.2,122.5,123.6,120.3,119.1,118.5,111.0,99.6,40.1,33.7,31.2.
MS(m/z):571.22[M+H]+；
Example 29
Preparation of compound TM 29:
preparation of Compounds 10-29:
adding the compound 8-2(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-29(17.18g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-29, wherein the yield is 91.2% and the purity is 99.81%.
Preparation of Compounds 11-29:
dissolving the compound 10-29(31.44g, 0.1mol) in 180mL ethyl acetate, dripping 30mL hydrochloric acid with the concentration of 3mol/L, removing Boc group, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain the compound 11-29, wherein the yield is 91.4%, and the purity is 99.83%.
Preparation of compound TM 29:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked bottle, pouring 80ml of toluene, adding the compound 11-29(25.71g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM29, wherein the yield is 91.4%, and the purity is 99.85%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),8.38～8.32(m,1H),8.11～7.98(m,4H),7.62～7.47(m,3H),7.25～7.18(m,2H),4.31(s,2H),3.59(s,2H),2.71～2.64(m,2H)；
13C-NMR(400MHz,DMSO-d6):δ170.1,168.6,167.8,159.2,149.7,145.6,142.4,136.2,134.7,133.1,132.3,129.5,128.2,127.0,126.6,124.3,122.7,121.3,119.5,118.5,117.1,111.0,99.6,40.1,33.7,31.2.
MS(m/z):564.16[M+H]+；
Example 30
Preparation of compound TM 30:
preparation of Compounds 10-30:
adding the compound 8-2(18.92g, 0.1mol) into dried dichloromethane, sequentially adding the compound 9-30(15.31g, 0.12mol), HOBt (13.51g, 0.1mol) and EDCI (19.17g, 0.1mol), stirring at room temperature, detecting by TLC, ending the reaction, evaporating to dryness under reduced pressure, and separating by a column layer to obtain the compound 10-30, wherein the yield is 91.6% and the purity is 99.83%.
Preparation of Compounds 11-30:
dissolving 10-30(29.88g, 0.1mol) of the compound in 180mL of ethyl acetate, dropwise adding 30mL of hydrochloric acid with the concentration of 3mol/L, removing Boc groups, washing with purified water, drying an organic layer with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain 11-30 of the compound, wherein the yield is 91.9%, and the purity is 99.88%.
Preparation of compound TM 30:
adding the intermediate 6(18.41g, 0.05mol) into a 100ml three-necked bottle, pouring 80ml of toluene, adding the compound 11-30(23.84g, 0.12mol), heating to reflux reaction, detecting by TLC, cooling to 0 ℃ for crystallization, filtering, leaching a filter cake with proper amount of toluene, and drying under reduced pressure to obtain the compound TM30, wherein the yield is 92.0% and the purity is 99.89%.
1H-NMR(400MHz,DMSO-d6):δ11.03(s,1H),10.20(s,1H),8.74(s,1H),8.11～7.98(m,2H),7.53～7.40(m,4H),7.25～7.17(m,1H),4.31(s,2H),3.59(s,2H),2.71～2.64(m,2H)；
13C-NMR(400MHz,DMSO-d6):δ170.1,168.6,167.8,159.2,149.7,145.6,142.4,136.5,134.2,133.1,132.3,130.1(2C),128.2,119.3(2C),118.5,111.0,99.6,40.1,33.7,31.2.
MS(m/z):548.27[M+H]+；
In vitro cytotoxic Activity assay for cancer cells
In order to investigate the ability of the target compound synthesized in this experiment to inhibit tumor cell proliferation, we determined the in vitro cytotoxicity of the compound of the present invention against four tumor cells, lymphoma cell line (Raji), breast cancer cell (MCF7), leukemia cell (K562) and head and neck squamous cell carcinoma cell (HN 5). The assay used was a standard MTT assay.
The experimental method specifically comprises the following steps:
four tumor cells, namely lymphoma cell strains, breast cancer cells, leukemia cells and head and neck squamous carcinoma cells (Shanghai and Nippon Biotech Co., Ltd.) are subjected to trypsinization for 10min, then liquid is discarded, 5% serum culture solution is used for blowing and beating, the cell concentration is adjusted to 300-400/mu L, medicines are sequentially added, a blank group only containing the culture solution is reserved, and the blank group is cultured in an incubator for 24 h. Discarding supernatant, adding diluted target compounds with different concentrations into a 96-well plate (Shanghai horizontal biology science and technology Co., Ltd.), adding cell liquid only into a control group, setting three auxiliary wells for each group of concentration, mixing uniformly, continuing culturing for 36h, observing cell morphology change in different time periods, adding prepared MTT solution into each well for color development after the cells and the medicine fully act, and continuing culturing for 6 h. Discarding the upper layer liquid, dissolving 100 μ LDMSO to form purple crystal, selecting 490nm, and measuring absorbance with enzyme labeling instrument (HBS-1096A enzyme labeling analyzer, Nanjing DeFei laboratory instruments Co., Ltd.). By the formula: the cell inhibition ratio (%) (1-a experiment/a control) × 100%, and IC was determined50Values (cell viability vs log dose mapping).
The results of in vitro toxicity tests of the compounds TM 1-8 on the proliferation inhibition of four tumor cells, namely lymphoma cell lines (Raji), breast cancer cells (MCF7), leukemia cells (K562) and head and neck squamous cell carcinoma cells (HN5) are shown in Table 1.
TABLE 1 partial compound toxicity test (IC) on tumor cells50,μM)a
Note that the values in table a are the average values of 3 experiments; b the action time of the medicine is 36h
The novel anti-tumor active compound TM 1-30 provided by the invention has high growth inhibition activity on four tumor cells, namely lymphoma cell strain (Raji), breast cancer cell (MCF7), leukemia cell (K562) and head and neck squamous carcinoma cell (HN5), and the inhibition rate of the compound TM10 on the lymphoma cell strain (Raji) and the leukemia cell (K562) reaches the nM level; the inhibition rate of TM19 on MCF7 reaches nM level; and the inhibition rate of TM26 to Raji and MCF7 reaches nM level; the inhibition rate of the three compounds on four tumor cells is obviously higher than that of a control compound ibrutinib; the inhibitory activity and selectivity of the compound TM25 on MCF7 cells are superior to those of the other three cells.
The compound TM10 of the invention also shows good physical properties, and the water solubility reaches 0.115 mg/ml; meanwhile, the metabolism of the mouse in vivo is good, and the bioavailability reaches 96.8%.
Claims (13)
1. A hydrate, solvate, prodrug, stereoisomer or tautomer of a pyrazole-4, 6-dione compound represented by formula I or a pharmaceutically acceptable salt thereof:
wherein R is independently selected from H, halogen, aryl, heteroaryl, C1-4Alkyl radical, C1-6Alkoxy radical, C3-6Cycloalkyl radical, C2-6Heterocycloalkyl, aryloxy, -NR2R3(ii) a Or substituted aryl, substituted heteroaryl, substituted C3-6Cycloalkyl, substituted C2-6Heterocycloalkyl, substituted aryloxy, substituted C1-6One or more independent groups in the alkoxy group, wherein the substituent groups are selected from halogen, aryl, heteroaryl, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-4Alkyl, substituted C2-6Heterocycloalkyl, halogen substituted C2-6Heterocycloalkyl radical, C2-6One or more substituents in the heterocycloalkyl group. R2Independently selected from H or C1-4An alkyl group;
R3independently selected from H, C1-4Alkyl radical, C3-6Cycloalkyl radical, C1-3Haloalkyl, aryl, heteroaryl, C1-6Alkoxy radical, C1-6Alkylamino, substitutedC of (A)2-6Heterocycloalkyl, halogen substituted C2-6Heterocycloalkyl radical, C2-6One or more of heterocycloalkyl;
z is independently selected from C1-4Alkyl or aryl.
2. Pyrazole-4, 6-diones according to claim 1, characterized in that the pharmaceutically acceptable salts are salts of inorganic or organic acids, including but not limited to: hydrochloride, nitrate, borate, hydrocyanate, hydrofluoride, hydrobromide, hydroiodide, nitrite, perhalogenate, halate, hypohalite, metaaluminate, sulfate, phosphate, nitrate; the organic acid salts include, but are not limited to: formate, acetate, propionate, butyrate, acrylate, oxalate, malonate, succinate, benzoate, phthalate, mesylate, ethanesulfonate, benzenesulfonate, phenylmethanesulfonate, p-toluenesulfonate, thioacetate, trifluoroacetate, tartrate, malate, citrate, ascorbate, salicylate, caffeic acid, fumarate, lactate, citrate, glutamate, camphorate, camphorsulfonate, and the like.
3. The pyrazole-4, 6-dione compound according to claim 1, wherein the compound of formula (I) is a compound of any one of the following structures:
or a hydrate, solvate, prodrug, stereoisomer, or tautomer of a pharmaceutically acceptable salt thereof.
4. Pyrazole-4, 6-diones according to claim 1, characterized in that they comprise the following steps:
preparation of compound 6:
general synthesis of compound 11:
preparation of compound I:
wherein, R, R1And Z is as defined for the compound of formula (I) according to the first aspect of the invention.
5. The process for preparing pyrazole-4, 6-diones according to claim 4, wherein the reaction step comprises:
step 1: carrying out condensation reaction on the compound 1 in a sodium ethoxide solution to obtain a compound 2;
step 2: reacting the compound 2 with hydrazine hydrate to obtain a compound 3;
and step 3: reacting the compound 3 under an alkaline condition to obtain a compound 4;
and 4, step 4: the compound 4 is subjected to temperature-controlled reflux dehydration to generate an intermediate compound 5;
and 5: and reacting the compound 5 with 3-bromo-4-fluorobenzoic acid, EDCI and HOBt in dichloromethane to obtain a compound 6.
Step 6: reaction of compound 8 with compound 9 affords compound 10.
And 7: hydrolysis of compound 10 affords compound 11.
And 8: reacting the compound 6 with the compound 11 in an organic solvent, crystallizing, filtering and drying to obtain the target compound I.
6. The method for preparing pyrazole-4, 6-diones according to claim 4, wherein the reaction comprises the following steps:
step 1: adding sodium ethoxide into an ethanol solvent, stirring for dissolving, adding the compound 1, heating to reflux, detecting by TLC, cooling for crystallization after the reaction is finished, performing suction filtration, and drying to obtain a compound 2.
Step 2: adding the compound 2 into water, stirring for dissolving, adding hydrazine hydrate, heating to reflux, detecting by TLC, cooling to separate out solid after the reaction is finished, filtering, and drying to obtain a compound 3.
And step 3: and adding the compound 3 into an alkali solution, stirring for dissolving, heating to reflux, detecting by TLC (thin layer chromatography), cooling after the reaction is finished, adding hydrochloric acid to adjust the PH to 3-4, separating out a solid, filtering, and drying to obtain a compound 4.
And 4, step 4: dissolving the compound 4 in an acetic anhydride solution, adding a condensing agent, heating to reflux, detecting by TLC (thin layer chromatography), cooling and crystallizing after the reaction is finished, performing suction filtration, leaching a filter cake by using methyl tert-butyl ether, and drying to obtain a compound 5.
And 5: dissolving 3-bromo-4-fluorobenzoic acid in dried dichloromethane, sequentially adding EDCI, HOBt and the compound 5, stirring at room temperature for reaction, detecting by TLC, filtering after the reaction is finished, concentrating, evaporating to dryness under reduced pressure, and separating by a column layer to obtain a compound 6.
Step 6: adding the compound 8 into dried dichloromethane, sequentially adding the compound 9 and a condensing agent, stirring at room temperature, detecting by TLC, reacting, evaporating to dryness under reduced pressure, and separating by a column layer to obtain a compound 10.
And 7: dissolving the compound 10 in an organic solvent, dropwise adding hydrochloric acid, removing Boc groups, extracting with an extracting agent, drying with anhydrous sodium sulfate, filtering, concentrating, and evaporating to dryness under reduced pressure to obtain a compound 11.
And 8: dissolving the compound 6 in an organic solvent, adding the compound 11, heating until reflux reaction, finishing TLC detection reaction, cooling for crystallization, leaching a filter cake with the organic solvent, and drying to obtain a compound I.
7. The method for preparing pyrazole-4, 6-diones according to claim 6, wherein the base in step 3 is one or two of sodium hydride, potassium hydroxide, sodium hydroxide, and lithium hydroxide.
8. The process for producing pyrazole-4, 6-diones according to claim 6, wherein the condensing agent in step 4 is one or two of dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and 2-chloro-1, 3-dimethylimidazolidine chloride.
9. The process for producing pyrazole-4, 6-diones according to claim 6, wherein the condensing agent in step 6 is one or two of dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 2-chloro-1, 3-dimethylimidazolidine chloride, and 1-carbonylbenzotriazole.
10. The method for preparing pyrazole-4, 6-diones according to claim 6, wherein the organic solvent of step 7 is one of ethyl acetate, dichloromethane, methanol, and ethanol.
11. The method for preparing pyrazole-4, 6-diones according to claim 6, wherein the organic solvent in step 8 is one of toluene, benzene, and xylene.
12. A pharmaceutical composition, comprising: a therapeutically effective amount of a compound of formula (I) as described herein, or one or more of a pharmaceutically acceptable salt, tautomer, optical isomer, pharmaceutically acceptable solvate thereof, and optionally a pharmaceutically acceptable carrier, excipient, adjuvant, or diluent.
13. An application of pyrazole-4, 6-diketone compounds shown in formula (I) is characterized in that the pyrazole-4, 6-diketone compounds can be used for treating diseases related to tyrosine kinase expression abnormity or high tyrosine kinase activity. Their use in the treatment or prevention of diseases in which BTK plays a role.
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| US20080076921A1 (en) * | 2006-09-22 | 2008-03-27 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
| CN108779078A (en) * | 2015-10-12 | 2018-11-09 | 北京大学深圳研究生院 | New inhibitor and probe of kinases and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080076921A1 (en) * | 2006-09-22 | 2008-03-27 | Pharmacyclics, Inc. | Inhibitors of bruton's tyrosine kinase |
| CN108779078A (en) * | 2015-10-12 | 2018-11-09 | 北京大学深圳研究生院 | New inhibitor and probe of kinases and application thereof |
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