WO2019134573A1 - Procédé de préparation d'un composé de diphénylaminopyrimidine deutéré et forme cristalline de celui-ci - Google Patents

Procédé de préparation d'un composé de diphénylaminopyrimidine deutéré et forme cristalline de celui-ci Download PDF

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WO2019134573A1
WO2019134573A1 PCT/CN2018/124155 CN2018124155W WO2019134573A1 WO 2019134573 A1 WO2019134573 A1 WO 2019134573A1 CN 2018124155 W CN2018124155 W CN 2018124155W WO 2019134573 A1 WO2019134573 A1 WO 2019134573A1
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compound
formula
group
sodium
agent
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PCT/CN2018/124155
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Chinese (zh)
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王义汉
李焕银
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深圳市塔吉瑞生物医药有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the technical field of medicine, in particular to a preparation method of a high-purity deuterated diphenylaminopyrimidine compound and a crystal form thereof, and the invention also provides a pharmaceutical composition comprising the compound of the invention, and the use of the composition for treating various kinds The method of disease.
  • ALK kinase is a potential anti-tumor drug target.
  • the first small molecule inhibitor against the ALK fusion gene was crizotinib developed by Pfizer, although it achieved an objective response rate of 60-74% and good median progression-free survival in patients with ALK-positive non-small cell lung cancer (8 -11 months), but most patients have relapsed after 1 year of treatment, which is acquired resistance, which leads to limited efficacy of crizotinib in patients with central nervous system metastasis.
  • Several second-generation ALK inhibitors have been able to overcome the lack of resistance to crizotinib treatment, but are still ineffective for some mutations.
  • the present invention relates to (2-((5-chloro-2-((2-methoxy-4-(4-(4-(methyl-d3)piperazin-1-yl)piperidin-1-yl)) Process for the preparation of phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (compound of formula (A)), the preparation of key intermediate compound (D).
  • the invention further relates to Form I of a compound of formula (A), and to a pharmaceutical composition comprising the Form I, a method of treating ALK-mediated cancer using the Form I, and a pharmaceutical use.
  • the method for preparing the compound of the formula (A) provided by the invention is environmentally friendly, has good atomic economy, is cheap and easy to obtain raw materials, uses less acid, and the reaction is usually heated, does not require microwave reaction, and is convenient for industrialization.
  • the treatment is simple, no column chromatography is needed, and the crystal precipitated in the post-treatment purification process is a crystalline form of the medicine, and the recrystallization step is avoided, and the yield is high.
  • the method for preparing the compound of the formula (D) provided by the invention uses the most common industrial grade dichloromethane as a solvent, avoids the use of the strong carcinogenic solvent dichloroethane, uses a more environmentally friendly molecular sieve as an absorbent, and has more atomic economy. Well, the post-treatment only needs extraction and back-extraction, and the operation is simple, and no column chromatography is required, and the yield is higher.
  • the method for preparing the compound of the formula (E) provided by the invention has the advantages that the raw material is cheap and easy to obtain, the condition is mild (using acetone/water as a solvent, NaOH is used as a base), the reagent used is more economical, environmentally friendly, and the atomic economy is higher, and the column layer is not required. Analysis, the post-treatment process is more convenient. In the deprotection process, we only use the organic solvent of acid, and the produced product can be filtered. It does not involve heavy metals and hydrogenation process, and the reaction is simple, safe and easy to operate.
  • the method includes the following steps:
  • the method includes the following steps:
  • X is selected from halogen
  • the method includes the following steps:
  • PG is selected from the group consisting of Boc, Cbz, Fmoc, Alloc, Teco, formyl, acetyl, trifluoroacetyl, phthalimide, trityl, Bn, p-methoxybenzyl and Ts;
  • the method includes the following steps:
  • PG is selected from the group consisting of Boc, Cbz, Fmoc, Alloc, Teco, formyl, acetyl, trifluoroacetyl, phthalimide, trityl, Bn, p-methoxybenzyl and Ts;
  • PG is selected from the group consisting of Boc, Cbz, Fmoc, Alloc, Teco, formyl, acetyl, trifluoroacetyl, phthalimide, trityl, Bn, p-methoxybenzyl and Ts;
  • PG is selected from the group consisting of Boc, Cbz, Fmoc, Alloc, Teco, formyl, acetyl, trifluoroacetyl, phthalimide, trityl, Bn, p-methoxybenzyl and Ts;
  • the invention provides a method of preparing a compound of formula (D):
  • the method comprises the steps of contacting a compound of formula (E) with a compound of formula (F) under reaction conditions sufficient to form a compound of formula (D):
  • the invention provides a method of preparing a compound of formula (D):
  • the method includes the following steps:
  • PG is selected from the group consisting of Boc, Cbz, Fmoc, Alloc, Teco, formyl, acetyl, trifluoroacetyl, phthalimide, trityl, Bn, p-methoxybenzyl and Ts;
  • the invention provides a method of preparing a compound of formula (E):
  • the invention provides a method of preparing a compound of formula (F):
  • X is selected from halogen
  • the invention provides a crystal (2-((5-chloro-2-((2-(methyl))))) Pyridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (compound of formula (A)) Form I, characterized in that the X-ray powder diffraction pattern comprises the following peaks: 6.099, 9.584, 17.216, 18.801, 19.321, 20.062, 27.601 ° 2 ⁇ ⁇ 0.2 ° 2 ⁇ , which uses a wavelength on the diffractometer Determination of Cu-K ⁇ radiation.
  • the invention provides a crystal (2-((5-chloro-2-((2-(methyl))))) Process for the preparation of crystalline form I of pyridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (compound of formula (A)), the process comprising the steps of:
  • the invention provides a pharmaceutical composition comprising a crystalline form (A) compound and a pharmaceutically acceptable excipient.
  • the present crystalline form (A) compound is provided in the pharmaceutical composition in an effective amount.
  • the present crystalline form (A) compound is provided in a therapeutically effective amount.
  • the present crystalline form (A) compound is provided in a prophylactically effective amount.
  • the present invention provides a process for the preparation of a pharmaceutical composition as described above, comprising the steps of: mixing a pharmaceutically acceptable excipient with a compound of formula (A) to form a pharmaceutical composition .
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form (A) compound and a pharmaceutically acceptable excipient, further comprising other therapeutic agents.
  • the invention provides a method of treating a cancer-related disorder resulting from an ALK mutation in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention.
  • the cancer is selected from the group consisting of non-small cell lung cancer, breast cancer, neurological tumors (such as glioblastoma and neuroblastoma); esophageal cancer, soft tissue cancer (such as rhabdomyosarcoma, etc.); Forms of lymphoma, such as non-Hodgkin's lymphoma (NHL) known as anaplastic large cell lymphoma (ALCL); various forms of leukemia.
  • NHL non-Hodgkin's lymphoma
  • ACL anaplastic large cell lymphoma
  • the non-small cell lung cancer is an ALK positive non-small cell lung cancer.
  • the compound is administered orally, subcutaneously, intravenously or intramuscularly. In a specific embodiment, the compound is administered chronically.
  • Figure 1 shows X-ray powder diffraction (XRPD) of Form I of the compound of formula (A).
  • Figure 2 shows a differential scanning calorimetry (DSC) curve and a thermogravimetric analysis (TGA) curve for Form I of the compound of formula (A).
  • deuterated means that one or more hydrogens in the compound or group are replaced by deuterium; deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuteration may be monosubstituted, disubstituted, polysubstituted or fully substituted.
  • deuterated is used interchangeably with “one or more deuterated”.
  • the strontium isotope content of strontium in the deuterated position is at least 0.015%, preferably greater than 30%, more preferably greater than 50%, and even more preferably greater than 75%, more preferably greater than the natural strontium isotope content.
  • the ground is greater than 95%, more preferably greater than 99%.
  • non-deuterated compound means a compound containing a proportion of germanium atoms not higher than the natural helium isotope content (0.015%).
  • the term "independently selected from” is that a plurality of groups are respectively selected from certain substituents, and each group is not related to each other, for example, "m, n is independently selected from 0 or 1", meaning m It is selected from 0 or 1, n is selected from 0 and 1, and there is no correlation between m and n.
  • compound of the invention refers to a compound of formula (I).
  • the term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (I).
  • pharmaceutically acceptable salt means that it is suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergies, etc., and with reasonable benefits, within the scope of sound medical judgment. / Those dangerous proportions of those salts.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and inorganic and organic bases.
  • non-toxic acid addition salts examples include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts with organic acids such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Also included are salts formed using conventional methods in the art, for example, ion exchange methods.
  • adipic acid salts alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cyclopentanoate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerol Phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate Salt, pectin
  • Pharmaceutically acceptable salts derived from suitable bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like.
  • other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed with counterions, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrate, lower alkyl sulfonate and aryl sulfonate.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a specific ratio.
  • Hydrophilate means a complex formed by the coordination of a compound of the invention with water.
  • the invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein.
  • isotopes which may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. , 31 P, 32 P, 35 S, 18 F and 36 Cl. a compound, or an enantiomer, a diastereomer, an isomer, or a pharmaceutically acceptable salt or solvate of the present invention, wherein an isotope or other isotopic atom containing the above compound is within the scope of the present invention .
  • isotopically-labeled compounds of the present invention such as the radioisotopes of 3 H and 14 C, are also among them, useful in tissue distribution experiments of drugs and substrates. ⁇ , ie 3 H and carbon-14, ie 14 C, are easier to prepare and detect and are preferred in isotopes.
  • Isotopically labeled compounds can be prepared in a conventional manner by substituting a readily available isotopically labeled reagent with a non-isotopic reagent using the protocol of the examples.
  • DIPEA N,N-diisopropylethylamine
  • Typical embodiments of the compounds according to the invention can be synthesized using the general reaction schemes described below. As will be apparent from the description herein, the general scheme can be altered by replacing the starting materials with other materials having similar structures to produce correspondingly different products. Given the desired product in which the substituent is defined, the desired starting material can usually be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. To synthesize the compounds of the embodiments of the present disclosure, detecting the structure of the compound to be synthesized will provide for the identification of each substituent. In view of the examples herein, the nature of the final product will typically reveal the characteristics of the desired starting materials through a simple inspection process.
  • the compounds of the present disclosure can be prepared from readily available starting materials using, for example, the general methods and procedures below. It should be understood that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can be used unless otherwise stated. Optimum reaction conditions can vary with the particular reactants or solvents employed, but one skilled in the art can determine the conditions by routine optimization procedures.
  • the compounds of the present disclosure may contain one or more chiral centers.
  • the compound can be prepared as a pure stereoisomer or isolated as a pure stereoisomer, either as a separate enantiomer or diastereomer or as a stereoisomeric A mixture of rich bodies. All such stereoisomers (and enriched mixtures) are included within the scope of the invention unless otherwise stated. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optional active starting materials or stereoselective reagents well known in the art. Alternatively, the racemic mixture of the compound can be isolated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known methods or by obvious modifications thereof.
  • many starting materials are available from commercial suppliers such as Shanghai Tebo Chemical Technology Co., Ltd. (Shanghai, China), Saen Chemical Technology (Shanghai) Co., Ltd. (Shanghai, China), Shanghai Houyi Chemical Technology Co., Ltd. (Shanghai, China) ), Shanghai Jinlu Pharmaceutical Technology Co., Ltd. (Shanghai, China), Anhui Dexinjia Biomedical Co., Ltd. (Anhui, China), Tianjin Famosi Pharmaceutical Technology Co., Ltd. (Tianjin, China), Hunan Hezhong Pharmaceutical Technology Co., Ltd. (Hunan, China) ).
  • reaction products from each other and/or from the starting materials.
  • the desired product of each step or series of steps is separated and/or purified (hereinafter referred to as separation) by the techniques common in the art to the desired degree of homogeneity.
  • separations include multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation or chromatography.
  • Chromatography can include any number of methods including, for example, reverse phase and normal phase chromatography; size exclusion chromatography; ion exchange chromatography; high, medium and low pressure liquid chromatography and equipment; small scale analytical chromatography; Bed (SMB) and preparative thin or thick layer chromatography, as well as small-scale thin layer and flash chromatography techniques.
  • Another type of separation process involves treating the mixture with an agent that is selected to bind or separate from the product, unreacted starting materials, reaction byproducts, and the like.
  • agents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, and the like.
  • the reagent may be an acid (in the case of a basic substance), a base (in the case of an acidic substance), a binding reagent such as an antibody, a binding protein, a selective chelating agent such as a crown ether, a liquid/liquid example extraction reagent (LIX). )Wait.
  • a single stereoisomer, such as an enantiomer, substantially free of its stereoisomers can be obtained by resolution of the externally-spinning mixture, for example, using optically active resolving agents to form diastereomeric Method of conformation (Stereochemistry of Carbon Compounds, (1962), EL Eliel, McGraw Hill; Lochmuller, CH, (1975) J. Chromatogr., 113: (3) 283-302).
  • the racemic mixture of the chiral compound of the present invention can be isolated and resolved by any suitable method, including: (1) formation of an ionic diastereomeric salt with a chiral compound, and fractional crystallization Or other methods of separation; (2) formation of enantiomers with chiral derivatization reagents, separation of diastereomers, and conversion to pure stereoisomers; and (3) direct in chiral conditions Substantially pure or enriched stereoisomers are separated.
  • the present disclosure provides, in some embodiments, a method of preparing a compound of formula (A).
  • Scheme 1 represents an exemplary synthesis of a compound of formula (A) and can be carried out in accordance with the embodiments described herein.
  • the exemplary synthesis shown in Scheme 1 is expected to be particularly advantageous.
  • the invention provides a method of preparing a compound of formula (A):
  • the method includes the following steps:
  • the reaction conditions of step a) comprise a reducing agent; preferably wherein the reducing agent is selected from the group consisting of sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride or lithium aluminum hydride; The reducing agent is selected from sodium cyanoborohydride or sodium triacetoxyborohydride.
  • the reaction conditions of step a) include a water absorbing agent or a dehydrating agent; preferably, wherein the water absorbing agent is selected from the group consisting of molecular sieves, anhydrous sodium sulfate, anhydrous magnesium sulfate, calcium oxide, and calcium chloride; Wherein the water absorbing agent is selected from the group consisting of molecular sieves; preferably, wherein the water absorbing agent is a molecular sieve; preferably wherein the dehydrating agent is selected from the group consisting of tetraisopropyl titanate, tetraethyl titanate, tetrabutyl titanate, and tetrapropyl titanate; preferably, wherein the dehydrating agent is selected from the group consisting of titanium Tetraisopropyl acid.
  • the reaction conditions of step a) comprise a base; preferably, wherein the base is selected from the group consisting of DIPEA, TEA, NMM, and DBU; preferably, wherein the base is selected from the group consisting of sodium hydroxide, An inorganic base of potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride and potassium hydride; preferably wherein the base is selected from the group consisting of calcium hydride An alkaline earth metal base; preferably, wherein the base is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, lithium t-butoxide, and an organometallic base of aluminum isopropoxide; more preferably, wherein The base is selected from the group consisting of DIPEA, TEA, NMM, DBU, sodium carbonate, potassium carbonate or ces
  • the feed ratio of the compound of formula (E) to the compound of formula (F) is from 0.8/1 to 1.3/1 (molar ratio), preferably from 1/1 to 1.3/1 (molar) The ratio is preferably 1.3/1 (molar ratio).
  • the reaction solvent is dichloromethane.
  • the reaction conditions of step b) comprise a reducing agent; preferably wherein the reducing agent is selected from the group consisting of Pd/CH 2 , Ni-H 2 , Pd(OH) 2 -H 2 , reduced iron powder - Ammonium chloride, reduced iron powder-acetic acid, zinc powder-ammonium chloride or stannous chloride; preferably, wherein the reducing agent is selected from the group consisting of Pd/CH 2 or reduced iron powder-ammonium chloride.
  • reaction conditions of step c) comprise an alcoholic solution of a mineral acid; preferably, wherein the alcoholic solution of the mineral acid is selected from the group consisting of a solution of hydrochloric acid in isopropanol.
  • step c) the acid is used in an amount of from 1.3 to 2 times (molar ratio), preferably 1.5 times (molar ratio), of the compound of formula (B).
  • the feed ratio of the compound of formula (C) to the compound of formula (B) is from 0.8/1 to 1.2/1 (molar ratio), preferably 1/1 (molar ratio).
  • the reaction solvent of step c) is selected from the group consisting of ethylene glycol monomethyl ether, DMAC, DMSO, DMF, and NMP; preferably, the reaction solvent is selected from the group consisting of ethylene glycol monomethyl ether.
  • the reaction temperature of step c) is from about 100 ° C to about 150 ° C; preferably, the reaction temperature is about 120 ° C.
  • the invention provides a method of preparing a compound of formula (A):
  • the method includes the following steps:
  • X is selected from halogen
  • the reaction conditions of step a) comprise a base; preferably, wherein the base is selected from the group consisting of DIPEA, TEA, NMM or DBU; preferably, wherein the base is selected from the group consisting of DIPEA.
  • the reaction conditions of step b) comprise a reducing agent; preferably wherein the reducing agent is selected from the group consisting of sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride or lithium aluminum hydride; The reducing agent is selected from sodium cyanoborohydride or sodium triacetoxyborohydride.
  • the reaction conditions of step b) comprise a water absorbing agent or a dehydrating agent; preferably, wherein the water absorbing agent is selected from the group consisting of molecular sieves, anhydrous sodium sulfate, anhydrous magnesium sulfate, calcium oxide or calcium chloride; Wherein the water absorbing agent is selected from the group consisting of molecular sieves; preferably, wherein the water absorbing agent is a molecular sieve; preferably wherein the dehydrating agent is selected from the group consisting of tetraisopropyl titanate, tetraethyl titanate, tetrabutyl titanate or tetrapropyl titanate; preferably, wherein the dehydrating agent is selected from the group consisting of titanium Tetraisopropyl acid.
  • the reaction conditions of step b) comprise a base; preferably, wherein the base is selected from the group consisting of DIPEA, TEA, NMM, and DBU; preferably, wherein the base is selected from the group consisting of sodium hydroxide, An inorganic base of potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride and potassium hydride; preferably wherein the base is selected from the group consisting of calcium hydride An alkaline earth metal base; preferably, wherein the base is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, lithium t-butoxide, and an organometallic base of aluminum isopropoxide; more preferably, wherein The base is selected from the group consisting of DIPEA, TEA, NMM, DBU, sodium carbonate, potassium carbonate or ces
  • the feed ratio of the compound of formula (E) to the compound of formula (F) is from 0.8/1 to 1.3/1 (molar ratio), preferably from 1/1 to 1.3/1 (molar) The ratio is preferably 1.3/1 (molar ratio).
  • the reaction solvent is dichloromethane.
  • the reaction conditions of step c) comprise a reducing agent; preferably wherein the reducing agent is selected from the group consisting of Pd/CH 2 , Ni-H 2 , Pd(OH) 2 -H 2 , reduced iron powder - Ammonium chloride, reduced iron powder-acetic acid, zinc powder-ammonium chloride or stannous chloride; preferably, wherein the reducing agent is selected from the group consisting of Pd/CH 2 or reduced iron powder-ammonium chloride.
  • reaction conditions of step d) comprise an alcoholic solution of a mineral acid; preferably, wherein the alcoholic solution of the mineral acid is selected from the group consisting of a solution of hydrochloric acid in isopropanol.
  • step d) the acid is used in an amount of from 1.3 to 2 (molar ratio), preferably 1.5 times (molar ratio), of the compound of formula (B).
  • the feed ratio of the compound of formula (C) to the compound of formula (B) is from 0.8/1 to 1.2/1 (molar ratio), preferably 1/1 (molar ratio).
  • the reaction solvent of step d) is selected from the group consisting of ethylene glycol monomethyl ether, DMAC, DMSO, DMF, and NMP; preferably, the reaction solvent is selected from the group consisting of ethylene glycol monomethyl ether.
  • the reaction temperature of step d) is from about 100 ° C to about 150 ° C; preferably, the reaction temperature is about 120 ° C.
  • Scheme 2 represents an exemplary synthesis of a compound of formula (A) and can be carried out in accordance with the embodiments described herein. This exemplary synthesis is expected to provide another efficient and pooled synthetic method for the preparation of compounds of formula (D).
  • the present disclosure provides a method of preparing a compound of formula (A):
  • the method includes the following steps:
  • PG is selected from the group consisting of Boc, Cbz, Fmoc, Alloc, Teco, formyl, acetyl, trifluoroacetyl, phthalimide, trityl, Bn, p-methoxybenzyl and Ts;
  • the reaction conditions of step a) comprise a base; preferably wherein the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; preferably, wherein the base is selected Since potassium carbonate.
  • the reaction solvent of step a) is selected from the group consisting of DMAC, DMF, NMP, DMSO, or a solvent formed by mixing above; preferably, the reaction solvent is DMF.
  • the reaction temperature of step a) is from about 60 ° C to about 120 ° C; preferably, the reaction temperature is about 70 ° C.
  • reaction conditions of step b) comprise an alcoholic solution of a mineral acid; preferably, the alcoholic solution of the mineral acid is a solution of hydrochloric acid in isopropanol.
  • the hydrazine methylating agent of step c) is selected from the group consisting of triterpium iodomethane, deuterated formaldehyde heavy aqueous solution and NaBD 3 CN, deuterated paraformaldehyde and deuterated formic acid, deuterated methanol and two (triphenylphosphine)cyclopentadienylphosphonium chloride (II); preferably wherein said hydrazine methylating agent is selected from the group consisting of triterpium iodomethane; preferably wherein said hydrazine methylating agent And a NaBD 3 CN; preferably, wherein the hydrazine methylation agent is selected from the group consisting of deuterated paraformaldehyde and deuterated formic acid; preferably, wherein the hydrazine methylation agent is selected from the group consisting of Deuterated methanol and bis(triphenylphosphine)cyclopen
  • the reaction conditions of step d) comprise a reducing agent; preferably wherein the reducing agent is selected from the group consisting of Pd/CH 2 , Ni-H 2 , Pd(OH) 2 -H 2 , reduced iron powder - Ammonium chloride, reduced iron powder-acetic acid, zinc powder-ammonium chloride and stannous chloride; preferably, wherein the reducing agent is selected from Pd/CH 2 or reduced iron powder-ammonium chloride.
  • the reducing agent is selected from the group consisting of Pd/CH 2 , Ni-H 2 , Pd(OH) 2 -H 2 , reduced iron powder - Ammonium chloride, reduced iron powder-acetic acid, zinc powder-ammonium chloride and stannous chloride; preferably, wherein the reducing agent is selected from Pd/CH 2 or reduced iron powder-ammonium chloride.
  • reaction conditions of step e) comprise an alcoholic solution of a mineral acid; preferably, wherein the alcoholic solution of the mineral acid is selected from the group consisting of a solution of hydrochloric acid in isopropanol.
  • the acid in step e), is used in an amount of from 1.3 to 2 (molar ratio), preferably 1.5 times (molar ratio), of the compound of formula (B).
  • the feed ratio of the compound of formula (C) to the compound of formula (B) is from 0.8/1 to 1.2/1 (molar ratio), preferably 1/1 (molar ratio).
  • the reaction solvent of step e) is selected from the group consisting of ethylene glycol monomethyl ether, DMAC, DMSO, DMF, and NMP; preferably, the reaction solvent is selected from the group consisting of ethylene glycol monomethyl ether.
  • the reaction temperature of step e) is from about 100 ° C to about 150 ° C; preferably, the reaction temperature is about 120 ° C.
  • Scheme 3 represents an exemplary synthesis of a compound of formula (A) and can be carried out in accordance with the embodiments described herein. The specific reaction conditions and reagents used in Scheme 3 are discussed below.
  • the present disclosure provides a method of preparing a compound of formula (A):
  • the method includes the following steps:
  • PG is selected from the group consisting of Boc, Cbz, Fmoc, Alloc, Teco, formyl, acetyl, trifluoroacetyl, phthalimide, trityl, Bn, p-methoxybenzyl and Ts;
  • PG is selected from the group consisting of Boc, Cbz, Fmoc, Alloc, Teco, formyl, acetyl, trifluoroacetyl, phthalimide, trityl, Bn, p-methoxybenzyl and Ts;
  • PG is selected from the group consisting of Boc, Cbz, Fmoc, Alloc, Teco, formyl, acetyl, trifluoroacetyl, phthalimide, trityl, Bn, p-methoxybenzyl and Ts;
  • the reaction conditions of step a) comprise a base; preferably wherein the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; preferably, wherein the base is Selected from potassium carbonate.
  • the reaction solvent of step a) is selected from the group consisting of DMAC, DMF, NMP, DMSO, or a solvent formed by mixing above; preferably, the reaction solvent is DMF.
  • the reaction temperature of step a) is from about 60 ° C to about 120 ° C; preferably, the reaction temperature is about 70 ° C.
  • the reaction conditions of step b) comprise a reducing agent; preferably wherein the reducing agent is selected from the group consisting of Pd/CH 2 , Ni-H 2 , Pd(OH) 2 -H 2 , reduced iron powder - Ammonium chloride, reduced iron powder-acetic acid, zinc powder-ammonium chloride and stannous chloride; preferably, wherein the reducing agent is Pd/CH 2 or reduced iron powder-ammonium chloride.
  • the reducing agent is selected from the group consisting of Pd/CH 2 , Ni-H 2 , Pd(OH) 2 -H 2 , reduced iron powder - Ammonium chloride, reduced iron powder-acetic acid, zinc powder-ammonium chloride and stannous chloride; preferably, wherein the reducing agent is Pd/CH 2 or reduced iron powder-ammonium chloride.
  • reaction conditions of step c) comprise an alcoholic solution of a mineral acid; preferably, wherein the alcoholic solution of the mineral acid is selected from the group consisting of a solution of hydrochloric acid in isopropanol.
  • the reaction solvent of step c) is selected from the group consisting of ethylene glycol monomethyl ether, DMAC, DMSO, DMF or NMP; preferably, the reaction solvent is selected from the group consisting of ethylene glycol monomethyl ether.
  • the reaction temperature of step c) is from about 100 ° C to about 150 ° C; preferably, the reaction temperature is about 120 ° C.
  • reaction conditions of step d) comprise an alcoholic solution of a mineral acid; preferably, the alcoholic solution of the mineral acid is a solution of hydrochloric acid in isopropanol.
  • the hydrazine methylating agent of step e) is selected from the group consisting of triterpium iodomethane, deuterated formaldehyde heavy aqueous solution and NaBD 3 CN, deuterated paraformaldehyde and deuterated formic acid, deuterated methanol and two (triphenylphosphine)cyclopentadienylphosphonium chloride (II); preferably wherein said hydrazine methylating agent is selected from the group consisting of triterpium iodomethane; preferably wherein said hydrazine methylating agent And a NaBD 3 CN; preferably, wherein the hydrazine methylation agent is selected from the group consisting of deuterated paraformaldehyde and deuterated formic acid; preferably, wherein the hydrazine methylation agent is selected from the group consisting of Deuterated methanol and bis(triphenylphosphine)cyclopen
  • one embodiment is a compound of formula (C):
  • Another embodiment is a compound of formula (D):
  • Another embodiment is a compound of formula (J):
  • Another embodiment is a compound of formula (K):
  • Another embodiment is a compound of formula (P):
  • Another embodiment is a compound of formula (F):
  • Another embodiment is a compound of formula (L):
  • Another embodiment is a compound of formula (O):
  • Another embodiment is a compound of formula (N):
  • the invention provides crystalline forms of the compounds of formula (A) as specified herein.
  • Crystalline Form (A) Compound Form I is characterized by an X-ray powder diffraction pattern comprising: 6.999, 9.584, 17.216, 18.801, 19.321, 20.062, 27.601 ° 2 ⁇ ⁇ 0.2 ° 2 ⁇ , which is passed through a diffractometer using Cu- K ⁇ radiation is in Determination of the wavelength.
  • crystalline Form I of Compound (A) is characterized by an X-ray powder diffraction pattern comprising: 6.999, 8.575, 9.584, 11.321, 14.34, 17.216, 18.801, 19.321, 20.062, 21.841, 23.940 , 27.601 ° 2 ⁇ ⁇ 0.2 ° 2 ⁇ , which uses a wavelength on the diffractometer Determination of Cu-K ⁇ radiation.
  • crystalline Form I of Compound (A) is characterized by an X-ray powder diffraction pattern comprising the following peaks: 6.099, 8.575, 9.584, 10.779, 11.321, 11.958, 13.435, 14.046, 14.34, 15.881, 17.216 , 18.801, 19.321, 20.062, 20.922, 21.841, 22.52, 23.059, 23.940, 24.357, 25.379, 26.259, 27.601, 29.179, 32.080 ° 2 ⁇ ⁇ 0.2 ° 2 ⁇ , which uses a wavelength on the diffractometer Determination of Cu-K ⁇ radiation.
  • crystalline Form (A) Compound Form I is further characterized by a full X-ray powder diffraction pattern substantially as shown in FIG.
  • crystalline Form I of Compound (A) is characterized by a differential scanning calorimetry (DSC) curve comprising a dissolution temperature of about 213.2 °C.
  • Crystalline Form (A) Compound Form I is also characterized by a DSC curve substantially as shown in Figure 2.
  • the present invention provides a process for the preparation of Form I of the compound of formula (A) as specified herein, the process comprising the steps of:
  • the salt described in step a) is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrofluoride, methanesulfonate, p-toluenesulfonate, trifluoroacetic acid
  • the water described in step b) is selected from the group consisting of distilled water, deionized water, and drinking water; the volume of water used is from 1 to 20 times the mass of the salt of the compound of formula (A).
  • the base described in step c) is selected from the group consisting of inorganic bases, organic bases or organometallic bases; preferably, the inorganic base is selected from the group consisting of ammonia, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide , sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride, potassium hydride; preferably, the organometallic base is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, tert-butyl Lithium alkoxide, aluminum isopropoxide; preferably, the organic base is selected from the group consisting of diisopropylethylamine, triethylamine, N-methylmorpholine, 1,8-diazabicycloundec-7-ene Preferably, wherein the base is selected from the group consisting of ammonia, sodium hydroxide, potassium
  • the temperature in step c) is from about 60 °C to about 100 °C.
  • compositions, formulations and kits are provided.
  • the invention provides a pharmaceutical composition comprising a crystalline form (A) compound of the invention and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the active component.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active component.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active component.
  • a pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum white) Protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene - Block
  • kits e.g., pharmaceutical packs.
  • the kits provided may include the crystalline form (A) compounds of the invention, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles) containing the crystalline form (A) compound of the invention, other therapeutic agents. , syringe and / or dispersible packaging or other suitable container).
  • provided kits can also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the crystalline form (A) compound of the invention and/or other therapeutic agent.
  • a crystalline form (A) compound of the invention provided in a first container and a second container is combined with other therapeutic agents to form a unit dosage form.
  • formulation examples illustrate representative pharmaceutical compositions that can be prepared in accordance with the present invention.
  • the invention is not limited to the following pharmaceutical compositions.
  • Exemplary Formulation 1 - Tablet The crystalline form (A) compound of the present invention in dry powder form can be mixed with the dried gel adhesive in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 0.3-30 mg tablets (each tablet contains 0.1-10 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 2 - Tablet The crystalline form (A) compound of the present invention in dry powder form can be mixed with the dried gel adhesive in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 30-90 mg tablet (each tablet contains 10-30 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 3 - Tablet The crystalline form (A) compound of the present invention in dry powder form can be mixed with the dried gel adhesive in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 4-Tablet The crystalline form (A) compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 150-240 mg tablet (each tablet contains 50-80 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 5 - Tablet The crystalline form (A) compound of the present invention in dry powder form can be mixed with the dried gel adhesive in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 240-270 mg tablets (each tablet contains 80-90 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 6-Tablet The crystalline form (A) compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into a 270-450 mg tablet (each tablet contains 90-150 mg of active compound) in a tablet press.
  • Exemplary Formulation 7-Tablet The crystalline form (A) compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 450-900 mg tablets (each tablet contains 150-300 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 8-Capsule The crystalline form (A) compound of the present invention in the form of a dry powder may be mixed with a starch diluent in a weight ratio of about 1:1. The mixture was filled into 250 mg capsules (each capsule containing 125 mg of active compound).
  • Exemplary Formulation 9-Liquid The crystalline form (A) compound of the present invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended through a No. 10 sieve. The U.S. sieve was then mixed with an aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) prepared in advance. Sodium benzoate (10 mg), flavor and color are diluted with water and added with stirring. Then, sufficient water can be added to give a total volume of 5 mL.
  • Exemplary Formulation 10 - Injection The crystalline form (A) compound of the present invention can be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg/mL.
  • the pharmaceutical composition provided by the present invention can be administered by a variety of routes including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intrasynovial administration, intrasternal administration. , intracerebroventricular administration, intralesional administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound of formula (A) provided herein is administered.
  • the amount of compound actually administered can be determined by the physician. .
  • a compound of formula (A) provided herein is administered to a subject at risk of developing the condition, typically based on a physician's recommendation and administered under the supervision of a physician, the dosage
  • the level is as described above.
  • Subjects at risk of developing a particular condition typically include subjects with a family history of the condition, or those subjects that are particularly susceptible to developing the condition by genetic testing or screening.
  • long-term administration can also be administered chronically.
  • Long-term administration refers to administration of a compound or a pharmaceutical composition thereof for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can be continuously administered indefinitely, For example, the rest of the subject.
  • chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, for example, within a therapeutic window.
  • a pharmaceutical composition of the present invention can be further delivered using various methods of administration.
  • a pharmaceutical composition can be administered by bolus injection, for example, to increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic level of the active ingredient through the body, for example, an intramuscular or subcutaneous bolus dose that causes a slow release of the active ingredient, while a bolus that is delivered directly to the vein (eg, via IV IV drip) ) can be delivered more quickly, so that the concentration of the active ingredient in the blood is rapidly increased to an effective level.
  • the pharmaceutical composition can be administered in a continuous infusion form, for example, by IV intravenous drip to provide a steady state concentration of the active ingredient in the subject's body.
  • a bolus dose of the pharmaceutical composition can be administered first, followed by continued infusion.
  • Oral compositions can be in the form of a bulk liquid solution or suspension or bulk powder. More generally, however, the composition is provided in unit dosage form for ease of precise dosing.
  • the term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human and other mammals, each unit containing a predetermined quantity of active material suitable to produce the desired therapeutic effect with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of the liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions.
  • the compound will generally be a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being useful for forming the desired form of administration.
  • a carrier or excipient and a processing aid is included in a minor component.
  • a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, each preferably providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.
  • a transdermal dose is generally selected in an amount of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably about 0.1. To about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the injection dose level ranges from about 1 mg/kg/hr to at least 10 mg/kg/hr from about 1 to about 120 hours, especially 24 to 96 hours.
  • a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be administered.
  • the maximum total dose cannot exceed about 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous vehicles as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • the solid form may include, for example, any of the following components, or a compound having similar properties: a binder, for example, microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as mint, water Methyl salicylate or orange flavoring.
  • a binder for example, microcrystalline cellulose, tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn star
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound will typically be a minor component, often from about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient.
  • the active component When formulated as an ointment, the active component is typically combined with a paraffin or water miscible ointment base.
  • the active ingredient can be formulated as a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and generally include other ingredients for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of the invention.
  • transdermal administration can be accomplished using a reservoir or a porous membrane type, or a patch of a plurality of solid matrices.
  • compositions for oral administration, injection or topical administration are merely representative.
  • Other materials as well as processing techniques and the like are set forth in Remington's Pharmaceutical Sciences, 17 th edition , 1985, Mack Publishing Company, Easton, in Section 8 Pennsylvania, herein incorporated by reference in this document.
  • the compounds of the invention may also be administered in sustained release form or from a sustained release delivery system.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention further relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are alpha-, beta- and gamma-cyclodextrins consisting of 6, 7 and 8 alpha-1,4-linked glucose units, respectively, optionally including one on the attached sugar moiety. Or a plurality of substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted.
  • the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, sulfobutylether beta-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation comprises hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • the present invention provides administration of a compound of the formula (A) to a subject in need of treatment, or administration of the pharmaceutical composition of the present invention for the treatment of cancer.
  • the cancer is an ALK-driven cancer.
  • the cancer is non-small cell lung cancer.
  • a “therapeutically effective amount” is an amount effective to detect the growth or spread of killing or inhibiting cancer cells; the size or number of weights; or other measure of the level, stage, progression or severity of cancer. The exact amount required can vary from subject to subject, depending on the race, age and general health of the subject, the severity of the disease, the particular anticancer agent, its mode of administration, combination therapy with other therapies, and the like.
  • various compounds disclosed herein inhibit tyrosine kinase activity of ALK, fak, and c-met, particularly tyrosine kinases believed to mediate the growth, progression, and/or metastasis of cancer.
  • a variety of compounds as disclosed herein have also been found to have potent in vitro activity against cancer cell lines. Thus, such compounds are useful in the treatment of cancer, including solid tumors as well as lymphomas, and include cancers that are resistant to other therapies.
  • the cancer is an ALK-driven cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is an ALK positive NSCLC. In some embodiments, the cancer is a locally advanced or metastatic ALK-positive NSCLC. In some embodiments, the cancer/patient has been previously treated with crizotinib or another tyrosine kinase inhibitor. In some embodiments, the cancer/patient has not previously been treated with an ALK inhibitor.
  • NSCLC non-small cell lung cancer
  • the cancer is an ALK positive NSCLC.
  • the cancer is a locally advanced or metastatic ALK-positive NSCLC.
  • the cancer/patient has been previously treated with crizotinib or another tyrosine kinase inhibitor. In some embodiments, the cancer/patient has not previously been treated with an ALK inhibitor.
  • Such cancers include, but are not limited to, breast cancer, non-small cell lung cancer, neurological tumors (such as glioblastoma and neuroblastoma); esophageal cancer, soft tissue cancer (such as rhabdomyosarcoma, etc.); various forms of lymphoma, Non-Hodgkin's lymphoma (NHL) such as known as anaplastic large cell lymphoma (ALCL); various forms of leukemia; and includes cancers mediated by ALK or c-met.
  • NDL Non-Hodgkin's lymphoma
  • ACL anaplastic large cell lymphoma
  • leukemia includes cancers mediated by ALK or c-met.
  • Anaplastic lymphoma kinase is a transmembrane receptor tyrosine kinase that belongs to the insulin receptor subfamily.
  • the ALK receptor tyrosine kinase was originally identified for its involvement in human non-Hodgkin's lymphoma subtypes known as anaplastic large cell lymphoma (ALCL).
  • ALK typically has a restricted distribution in mammalian cells and is found to be at a significant level in the nervous system only during embryonic development, indicating the role of ALK in brain development.
  • normal ALK In addition to its role in normal development, expression of full-length normal ALK has been detected in cell lines derived from various tumors, such as glioblastoma, neuroectodermal tumors, and glioblastoma, and breast. Cancer and melanoma lines.
  • translocations affect the ALK gene, leading to expression of the original cell fusion kinase, the most common of which is NPM-ALK.
  • NPM-ALK anaplastic large cell lymphoma
  • ACL anaplastic large cell lymphoma
  • NMP nucleolar phosphoprotein
  • This mutant protein, NPM-ALK has a constitutively active tyrosine kinase domain that is responsible for its carcinogenic properties by activating downstream effectors.
  • ALK positive lymphoid cancer cells The constitutively activated chimeric ALK has been shown to be present in approximately 60% of inflammatory myofibroblastic tumors (IMTs), a slow-growing sarcoma that primarily affects children and young adults. Furthermore, current reports have described the appearance of the variant ALK fusion TPM4-ALK in the case of esophageal squamous cell carcinoma (SCC).
  • IMTs myofibroblastic tumors
  • SCC esophageal squamous cell carcinoma
  • ALK is one of the few examples of RTKs involved in neoplasia in both non-hematopoietic malignancies and hematopoietic malignancies.
  • EML4 thorny animal microtubule-associated protein-like 4
  • ALK anaplastic lymphoma kinase
  • an ALK inhibitor can create a durable cure when used as a single therapeutic agent or in combination with current chemotherapy for ALCL, IMT, proliferative disorders, glioblastoma, and other possible solid tumors cited herein, Or as a single therapeutic agent can be used to prevent the maintenance of relapse in patients in need of such treatment.
  • a compound as disclosed herein can be administered as part of a therapeutic regimen wherein the compound is the only active agent, or in combination with one or more other therapeutic agents that are part of a combination therapy.
  • the therapeutic agent being administered can be formulated to simultaneously or sequentially administer separate compositions at different time points (eg, within 72 hours, 48 hours, or 24 hours of each other), Alternatively, the therapeutic agents can be formulated together as a single pharmaceutical composition and administered simultaneously.
  • administration of a compound of the invention may be mediated by at least one additional treatment known to those skilled in the art for preventing or treating cancer, such as radiation therapy or cytostatics, cytotoxic agents, other anticancer agents, and other drugs. Symptoms of cancer or any side effects of drugs.
  • additional therapeutic agents include agents suitable for immunotherapy (such as, for example, PD-1 or PDL-1 inhibitors), anti-angiogenic agents (such as, for example, bevacizumab), and/or chemotherapy.
  • such combination products employ a compound as disclosed herein in an acceptable dosage range.
  • the compounds as disclosed herein can be administered sequentially with other anticancer or cytotoxic agents.
  • the compounds as disclosed herein can be administered prior to, concurrently with, or subsequent to the administration of other anticancer or cytotoxic agents.
  • a typical chemotherapy regimen consists of a DNA alkylating agent, a DNA intercalating agent, a CDK inhibitor, or a microtubule poison.
  • the dose of chemotherapy used is just below the maximum tolerated dose, and thus dose limiting toxicity typically includes nausea, vomiting, diarrhea, hair loss, neutropenia, and the like.
  • antineoplastic agents are available for commercial use, clinical evaluation, and preclinical development, which can be selected for treatment of cancer by combination chemotherapy.
  • antineoplastic agents There are several major classes of such antineoplastic agents, namely, antibiotic agents, alkylating agents, antimetabolites, antihormonal agents, immunizing agents, interferon-type agents, and a class of confounding agents.
  • an anticancer alkylating agent or an intercalating agent eg, nitrogen mustard, chlorambucil, cyclophosphamide, melphalan, and ifosfamide
  • Antimetabolites eg methotrexate
  • anti-caking agents or pyrimidine antagonists eg 5-fluorouracil, cytarabine and gemcitabine
  • spindle inhibitors eg vinblastine, vincristine, vinorelbine
  • podophyllotoxin eg etoposide, irinotecan, topotecan
  • antibiotics eg doxorubicin, bleomycin and mitomycin
  • nitrosoureas eg Camo) Statin, lomustine
  • inorganic ions such as cisplatin, carboplatin, oxaliplatin or oxiplatin
  • enzymes such as asparaginase
  • Proteasome inhibitors such as sputum, other proteasome inhibition and (such as Src, Bcr / Abl, kdr, flt3, aurora-2, glycogen synthase kinase 3 (GSK-3), EGFR) Enzymes (such as Iressa, Tarceva, etc.), VEGF-R kinases, inhibitors of PDGF-R kinase, etc.; antibodies, soluble receptors or other receptor antagonists that are resistant to receptors or hormones involved in cancer ( Including receptors such as EGFR, ErbB2, VEGFR, PDGFR and IGF-R; and drugs such as Herceptin, Avastin, Erbitux, etc.) Examples of other therapeutic agents include, but are not limited to, sterol, alemtuzmab, hexa Melamine, amifostine, nastrozole, antibodies against prostate-specific membrane antigens (eg MLN-591,
  • the compounds of the present invention can be prepared using the methods disclosed herein and in routine variations that are apparent from the present disclosure, as well as methods well known in the art. In addition to the teachings herein, conventional well-known synthetic methods can also be used. The synthesis of the compounds described herein can be accomplished as described in the Examples below. If commercially available, the reagents can be purchased commercially, for example, from Saan Chemical Technology (Shanghai) Co., Ltd. or other chemical suppliers. Starting materials for the following reactions can be obtained from commercial sources unless otherwise stated.
  • Step 1 Synthesis of methyl p-toluenesulfonate-d 3
  • Step 2 Synthesis of tert-butyl 1-(methyl-d 3 )-4-piperazinecarboxylate
  • the crystalline form of the compound (A) was analyzed by XRPD, DSC and TGA.
  • the XRPD pattern was collected using a PANalytical X'Pert PRO MPD diffractometer, using the following experimental setup: 40 kV, 40 mA, The scan range is 4-40°2 ⁇ , and the step size is 0.02°2 ⁇ .
  • NETZSCH On the 449F3STA449F3A-1029-M differential scanning calorimeter-thermogravimetric analyzer, DSC analysis and TGA analysis were performed at a heating rate of 10 ° C/min using a sample of about 3 to 6 mg in the range of 25 ° C to 400 ° C.
  • Form I of the compound of formula (A) was prepared as in Example 2.
  • Form I of the compound of formula (A) is characterized by XRPD, DSC and TGA.
  • the XRPD pattern is shown in Figure 1, and the XRPD pattern analysis data is shown in Table 1.
  • the TGA showed no weight loss below about 50 °C, and a weight loss of about 0.9% was observed at about 50 ° C to about 200 ° C, followed by decomposition ( Figure 2).
  • the DSC thermogram shows the dissolution temperature of Form I of the compound of formula (A) at about 213.2 ° C ( Figure 2).
  • Example 6 Biological evaluation of a compound of formula (A) having Form I
  • Test compounds were dissolved in DMSO to make a 20 mM stock solution. Compounds were diluted to 0.1 mM in DMSO (100 times the final concentration of the dilution) before use and diluted in 3 folds at 11 concentrations. Dilute to 4 times the final concentration of the dilution solution with the buffer.
  • the compound of formula (A) was tested in the above kinase inhibition assay and was found to have a more potent activity against ALK and ALK [L1196M] than undeuterated Brigatinib.
  • the test results are summarized in Table 2 below.
  • the in vitro antiproliferative activity of the compounds of the present invention against three cells cultured in vitro was examined by the CellTiter-Glo method.
  • the experimental results show that the compound of the present invention has a strong inhibitory effect on the in vitro proliferation of EML4-ALK and EML4-ALK L1196M mutant cells cultured in vitro.
  • BaF3 parental contains 10 ng/ml IL-3, 0% fetal calf Serum, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin in RPMI1640 medium
  • Reagents and consumables RPMI-1640 (GIBCO, catalog number A10491-01); fetal bovine serum (GIBCO, catalog number 10099141); 0.25% trypsin (GIBCO, catalog number 25200); penicillin-streptomycin, liquid (GIBCO, Cat. No. 15140-122); DMSO (Sigma, Cat. No. D2650); CellTiter-Glo Test Kit (Promega, Cat. No. G7572), 96-well Board (Corning, catalog number 3365).
  • the cells in the logarithmic growth phase were diluted with the culture medium to a specific cell concentration, and 90 ⁇ l of the cell suspension was added to the 96-well plate to bring the cell density to the specified concentration. Incubate overnight at 37 ° C in a 5% carbon dioxide gas incubator.
  • the compound of the formula (A) was tested in the above cytotoxicity test, and it was found that the compound of the formula (A) had a more potent activity against Ba/F3ALK and Ba/F3ALK [L1196M] than the undeuterated compound Brigitinib.
  • the results of inhibition of in vitro proliferation of cancer cells are summarized in Table 3 below.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • phosphate buffer 100 mM, pH 7.4.
  • the pH of the solution was adjusted to 7.4, diluted 5 times with ultrapure water before use, and magnesium chloride was added to obtain a phosphate buffer (100 mM) containing 100 mM potassium phosphate, 3.3 mM magnesium chloride, and a pH of 7.4.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • Formulation stop solution acetonitrile solution containing 50 ng/mL propranolol hydrochloride and 200 ng/mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer (pH 7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL. 25057.5 ⁇ L of phosphate buffer (pH 7.4) was taken into a 50 mL centrifuge tube, and 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution having a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the compounds of the present invention their metabolic stability in human and rat liver microsomes was evaluated.
  • the half-life and liver intrinsic clearance as indicators of metabolic stability are shown in Table 4 below.
  • the compound of the present invention can significantly prolong the half-life and be more stable in metabolism.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at the last time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube, indicating the name and time of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
  • mice Female, 6-8 weeks, weighed about 18-20 grams, a total of 80 mice purchased from Shanghai Sippur-Beikai Experimental Animal Co., Ltd. for research. After the animals arrive, they can be started in the experimental environment for 3-7 days. Animals were housed in an IVC (independent air supply system) cage at the SPF level animal house (5 per cage). All cages, litter and drinking water must be sterilized before use. All laboratory personnel should wear protective clothing and latex gloves when operating in the animal room. The animal information card for each cage should indicate the number of animals in the cage, gender, strain, date of receipt, dosing schedule, experiment number, group, and start date of the experiment. Cage, feed and drinking water are changed twice a week.
  • IVC independent air supply system
  • BA/F3 EML4-ALK-L1196M
  • the test compound was orally administered daily at a dose of 50 mg/kg.
  • the experimental indicator is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameters were measured twice a week using vernier calipers.
  • the anti-tumor efficacy is determined by dividing the average tumor-increased volume of the treated animals by the average tumor-increased volume of the untreated animals.
  • the tumor volume changes of each group are shown in Table 5 below.
  • mice were 11 days after administration of the packet, and the vehicle control group positive drug Brigatinib, the mean tumor volume of 50mg / kg administered group reaches 1,166mm 3 and 6mm 3.
  • Example 6 Example of a pharmaceutical composition
  • compositions and dosage forms of the compounds disclosed herein for use in therapeutic or prophylactic applications in humans can be as follows:
  • tablets (a)-(c) can be enteric coated by conventional means to, for example, provide a coating of cellulose acetate phthalate.
  • a tablet suitable for oral administration contains about 30 mg, about 90 mg, about 150 mg, or about 180 mg of substantially pure Form A of bogtinib, along with one or more pharmaceutically acceptable Excipients, such as those described herein.
  • "about” means modifying a value of ⁇ 5%.
  • Aerosol formulations (h)-(k) can be used in conjunction with standard metered dose aerosol dispensers, and the suspending agents sorbitan trioleate and soy lecithin can be substituted suspending agents such as sorbitan Monooleate, sorbitan sesquioleate, polyglyceryl oleate or oleic acid.
  • the present invention relates to the following technical solutions:
  • the method includes the following steps:
  • reaction conditions of step a) comprise a reducing agent; preferably wherein said reducing agent is selected from the group consisting of sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride Or lithium aluminum hydride.
  • the reaction condition of step a) comprises a water absorbing agent or a dehydrating agent; preferably, wherein the water absorbing agent is selected from the group consisting of molecular sieves, anhydrous sodium sulfate, and no Water magnesium sulfate, calcium oxide or calcium chloride; preferably, wherein the water absorbing agent is a molecular sieve; preferably wherein the dehydrating agent is selected from the group consisting of tetraisopropyl titanate, tetraethyl titanate, tetrabutyl titanate or tetrapropyl titanate; preferably, wherein the dehydrating agent is selected from the group consisting of titanium Tetraisopropyl acid.
  • the reaction condition of step a) comprises a base; preferably, the base is selected from the group consisting of DIPEA, TEA, NMM or DBU; Wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride or potassium hydride; Preferably, the base is selected from the group consisting of alkaline earth metal bases of calcium hydride; preferably wherein the base is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, lithium t-butoxide or isopropyl An organometallic base of aluminum alkoxide.
  • the compounding ratio of the compound of the formula (E) to the compound of the formula (F) is from 0.8/1 to 1.3/1 (molar ratio), It is preferably from 1/1 to 1.3/1 (molar ratio), preferably 1.3/1 (molar ratio).
  • reaction solvent is dichloromethane
  • reaction condition of step b) comprises a reducing agent; preferably, wherein the reducing agent is selected from the group consisting of Pd/CH 2 , Ni-H 2 , Pd (OH) 2 -H 2 , reduced iron powder - ammonium chloride, reduced iron powder - acetic acid, zinc powder - ammonium chloride or stannous chloride.
  • the reducing agent is selected from the group consisting of Pd/CH 2 , Ni-H 2 , Pd (OH) 2 -H 2 , reduced iron powder - ammonium chloride, reduced iron powder - acetic acid, zinc powder - ammonium chloride or stannous chloride.
  • reaction condition of step c) comprises an alcohol solution of a mineral acid; preferably, wherein the alcohol solution of the mineral acid is selected from isopropanol of hydrochloric acid Solution.
  • the acid is used in an amount of from 1.3 to 2 (molar ratio), preferably 1.5 times (molar ratio), of the compound of the formula (B).
  • the compounding ratio of the compound of the formula (C) to the compound of the formula (B) is from 0.8/1 to 1.2/1 (molar ratio), It is preferably 1/1 (molar ratio).
  • reaction solvent of step c) is selected from the group consisting of ethylene glycol monomethyl ether, DMAC, DMSO, DMF and NMP; preferably, the reaction solvent is selected from the group consisting of ethylene Alcohol monomethyl ether.
  • reaction temperature of step c) is from about 100 ° C to about 150 ° C; preferably, the reaction temperature is about 120 ° C.
  • the method includes the following steps:
  • X is selected from halogen
  • reaction conditions of step a) comprise a base; preferably wherein the base is selected from the group consisting of DIPEA, TEA, NMM or DBU.
  • reaction conditions of step b) comprise a reducing agent; preferably wherein the reducing agent is selected from the group consisting of sodium cyanoborohydride, sodium borohydride, three Sodium acetoxyborohydride or lithium aluminum hydride.
  • the reaction condition of step b) comprises a water absorbing agent or a dehydrating agent; preferably, wherein the water absorbing agent is selected from the group consisting of molecular sieves, anhydrous sodium sulfate, and no Water magnesium sulfate, calcium oxide or calcium chloride; preferably, wherein the water absorbing agent is a molecular sieve; preferably wherein the dehydrating agent is selected from the group consisting of tetraisopropyl titanate, tetraethyl titanate, tetrabutyl titanate, and tetrapropyl titanate; preferably, wherein the dehydrating agent is selected from the group consisting of titanium Tetraisopropyl acid.
  • the reaction condition of step b) comprises a base; preferably, the base is selected from the group consisting of DIPEA, TEA, NMM or DBU; Wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride or potassium hydride; Preferably, the base is selected from the group consisting of alkaline earth metal bases of calcium hydride; preferably wherein the base is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, lithium t-butoxide or isopropyl An organometallic base of aluminum alkoxide.
  • step b) wherein in step b), preferably, wherein the dehydrating agent is selected from a compound of formula (E) and a compound of formula (F) has a charge ratio of 0.8. /1 to 1.3/1 (molar ratio), preferably 1/1 to 1.3/1 (molar ratio), preferably 1.3/1 (molar ratio).
  • reaction solvent is dichloromethane
  • reaction conditions of step c) comprise a reducing agent; preferably wherein the reducing agent is selected from the group consisting of Pd/CH 2 , Ni-H 2 , Pd (OH) 2 -H 2 , reduced iron powder - ammonium chloride, reduced iron powder - acetic acid, zinc powder - ammonium chloride or stannous chloride.
  • the reducing agent is selected from the group consisting of Pd/CH 2 , Ni-H 2 , Pd (OH) 2 -H 2 , reduced iron powder - ammonium chloride, reduced iron powder - acetic acid, zinc powder - ammonium chloride or stannous chloride.
  • reaction condition of step d) comprises an alcohol solution of a mineral acid; preferably, wherein the alcohol solution of the mineral acid is selected from isopropanol of hydrochloric acid Solution.
  • the acid is used in an amount of from 1.3 to 2 (molar ratio), preferably 1.5 times (molar ratio), of the compound of the formula (B).
  • the compounding ratio of the compound of the formula (C) to the compound of the formula (B) is from 0.8/1 to 1.2/1 (molar ratio), It is preferably 1/1 (molar ratio).
  • reaction solvent of step d) is selected from the group consisting of ethylene glycol monomethyl ether, DMAC, DMSO, DMF or NMP; preferably, the reaction solvent is selected from the group consisting of ethylene Alcohol monomethyl ether.
  • reaction temperature of step d) is from about 100 ° C to about 150 ° C; preferably, the reaction temperature is about 120 ° C.
  • the method includes the following steps:
  • PG is selected from the group consisting of Boc, Cbz, Fmoc, Alloc, Teco, formyl, acetyl, trifluoroacetyl, phthalimide, trityl, Bn, p-methoxybenzyl or Ts;
  • reaction conditions comprise a base; preferably wherein the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate; preferably, The base described therein is selected from the group consisting of potassium carbonate.
  • reaction solvent of step a) is selected from the group consisting of DMAC, DMF, NMP, DMSO, or a solvent formed by mixing above; preferably, the reaction solvent is DMF.
  • reaction temperature of step a) is from about 60 ° C to about 120 ° C; preferably, the reaction temperature is about 70 ° C.
  • reaction condition of step b) comprises an alcohol solution of a mineral acid; preferably, the alcohol solution of the mineral acid is a solution of hydrochloric acid in isopropanol.
  • hydrazine methylating agent of step c) is selected from the group consisting of triterpium iodomethane, deuterated formaldehyde heavy aqueous solution and NaBD 3 CN, ⁇ Polyoxymethylene and deuterated formic acid, deuterated methanol and bis(triphenylphosphine)cyclopentadienylphosphonium chloride (II).
  • reaction conditions of step d) comprise a reducing agent; preferably wherein the reducing agent is selected from the group consisting of Pd/CH 2 , Ni-H 2 , Pd (OH) 2 -H 2 , reduced iron powder-ammonium chloride, reduced iron powder-acetic acid, zinc powder-ammonium chloride and stannous chloride.
  • the reducing agent is selected from the group consisting of Pd/CH 2 , Ni-H 2 , Pd (OH) 2 -H 2 , reduced iron powder-ammonium chloride, reduced iron powder-acetic acid, zinc powder-ammonium chloride and stannous chloride.
  • reaction condition of step e) comprises an alcohol solution of a mineral acid; preferably, wherein the alcohol solution of the mineral acid is selected from isopropanol of hydrochloric acid Solution.
  • reaction solvent of step e) is selected from the group consisting of ethylene glycol monomethyl ether, DMAC, DMSO, DMF or NMP; preferably, the reaction solvent is selected from the group consisting of ethylene Alcohol monomethyl ether.
  • reaction temperature of step e) is from about 100 °C to about 150 °C; preferably, the reaction temperature is about 120 °C.
  • the method includes the following steps:
  • PG is selected from the group consisting of Boc, Cbz, Fmoc, Alloc, Teco, formyl, acetyl, trifluoroacetyl, phthalimide, trityl, Bn, p-methoxybenzyl or Ts;
  • PG is selected from the group consisting of Boc, Cbz, Fmoc, Alloc, Teco, formyl, acetyl, trifluoroacetyl, phthalimide, trityl, Bn, p-methoxybenzyl or Ts;
  • PG is selected from the group consisting of Boc, Cbz, Fmoc, Alloc, Teco, formyl, acetyl, trifluoroacetyl, phthalimide, trityl, Bn, p-methoxybenzyl or Ts;
  • reaction conditions comprise a base; preferably wherein the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate; preferably Wherein the base is selected from the group consisting of potassium carbonate.
  • reaction solvent of step a) is selected from the group consisting of DMAC, DMF, NMP, DMSO, or a solvent formed by mixing above; preferably, the reaction solvent is DMF.
  • reaction temperature of step a) is from about 60 °C to about 120 °C; preferably, the reaction temperature is about 70 °C.
  • step b) reaction conditions comprise a reducing agent; preferably wherein said reducing agent is selected from Pd / CH 2, Ni-H 2, Pd (OH) 2 -H 2 , reduced iron powder-ammonium chloride, reduced iron powder-acetic acid, zinc powder-ammonium chloride and stannous chloride.
  • said reducing agent is selected from Pd / CH 2, Ni-H 2, Pd (OH) 2 -H 2 , reduced iron powder-ammonium chloride, reduced iron powder-acetic acid, zinc powder-ammonium chloride and stannous chloride.
  • reaction condition of step c) comprises an alcohol solution of a mineral acid; preferably, wherein the alcohol solution of the mineral acid is selected from isopropanol of hydrochloric acid Solution.
  • reaction solvent of step c) is selected from the group consisting of ethylene glycol monomethyl ether, DMAC, DMSO, DMF or NMP; preferably, the reaction solvent is selected from the group consisting of ethylene Alcohol monomethyl ether.
  • reaction temperature of step c) is from about 100 °C to about 150 °C; preferably, the reaction temperature is about 120 °C.
  • reaction condition of step d) comprises an alcoholic solution of a mineral acid; preferably, the alcoholic solution of the mineral acid is a solution of hydrochloric acid in isopropanol.
  • hydrazine methylating agent of step e) is selected from the group consisting of triterpium iodomethane, deuterated formaldehyde heavy aqueous solution and NaBD 3 CN, ⁇ Polyoxymethylene and deuterated formic acid, deuterated methanol and bis(triphenylphosphine)cyclopentadienylphosphonium chloride (II).
  • the method comprises the steps of contacting a compound of formula (E) with a compound of formula (F) under reaction conditions sufficient to form a compound of formula (D):
  • reaction conditions comprise a reducing agent; preferably wherein the reducing agent is selected from the group consisting of sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride or aluminum hydride lithium.
  • the reaction condition comprises a water absorbing agent or a dehydrating agent; preferably, wherein the water absorbing agent is selected from the group consisting of molecular sieves, anhydrous sodium sulfate, anhydrous magnesium sulfate, Calcium oxide or calcium chloride; preferably wherein said water absorbing agent is a molecular sieve; preferably wherein the dehydrating agent is selected from the group consisting of tetraisopropyl titanate, tetraethyl titanate, tetrabutyl titanate or tetrapropyl titanate; preferably, wherein the dehydrating agent is selected from the group consisting of titanium Tetraisopropyl acid.
  • reaction conditions comprise a base; preferably wherein the base is selected from the group consisting of DIPEA, TEA, NMM or DBU; preferably wherein The base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride or potassium hydride; preferably, The base is selected from the group consisting of alkaline earth metal bases of calcium hydride; preferably, the base is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, lithium t-butoxide or aluminum isopropoxide. Metal base.
  • the compounding ratio of the compound of the formula (E) to the compound of the formula (F) is from 0.8/1 to 1.3/1 (molar ratio), preferably 1/ 1 to 1.3/1 (molar ratio), preferably 1.3/1 (molar ratio).
  • reaction solvent is dichloromethane
  • X is selected from halogen
  • reaction conditions comprise a base; preferably, wherein the base is selected from the group consisting of DIPEA, TEA, NMM or DBU.
  • the method includes the following steps:
  • PG is selected from the group consisting of Boc, Cbz, Fmoc, Alloc, Teco, formyl, acetyl, trifluoroacetyl, phthalimide, trityl, Bn, p-methoxybenzyl or Ts;
  • reaction conditions comprise a base; preferably wherein the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate; preferably, The base described therein is selected from the group consisting of potassium carbonate.
  • reaction solvent is selected from the group consisting of DMAC, DMF, NMP, DMSO, or a solvent formed by mixing above; preferably, the reaction solvent is DMF.
  • reaction temperature of step a) is from about 60 °C to about 120 °C; preferably, the reaction temperature is about 70 °C.
  • step b) the reaction conditions comprise an alcoholic solution of a mineral acid; preferably, the alcoholic solution of the mineral acid is a solution of hydrochloric acid in isopropanol.
  • hydrazine methylating agent of step c) is selected from the group consisting of triterpium iodomethane, deuterated formaldehyde heavy aqueous solution or NaBD 3 CN, ⁇ Polyoxymethylene and deuterated formic acid, deuterated methanol and bis(triphenylphosphine)cyclopentadienylphosphonium chloride (II).
  • the method includes the following steps:
  • the compound of formula (B) is contacted with a compound of formula (C) under reaction conditions sufficient to produce a compound of formula (A):
  • reaction conditions comprise an alcoholic solution of a mineral acid; preferably, wherein the alcoholic solution of the mineral acid is selected from the group consisting of a solution of hydrochloric acid in isopropanol.
  • reaction solvent is selected from the group consisting of ethylene glycol monomethyl ether, DMAC, DMSO, DMF or NMP; preferably, the reaction solvent is selected from ethylene glycol monomethyl ether .
  • reaction temperature is from about 100 °C to about 150 °C; preferably, the reaction temperature is about 120 °C.
  • reaction conditions comprise a reducing agent; preferably wherein said reducing agent is selected from Pd / CH 2, Ni-H 2, Pd (OH) 2 -H 2, reduced iron Powder - ammonium chloride, reduced iron powder - acetic acid, zinc powder - ammonium chloride or stannous chloride.
  • Crystalline Form (A) Compound Form I, characterized in that the X-ray powder diffraction pattern comprises the following peaks: 6.099, 9.584, 17.216, 18.801, 19.321, 20.062, 27.601 ° 2 ⁇ ⁇ 0.2 ° 2 ⁇ , which is used on a diffractometer Wavelength is Determination of Cu-K ⁇ radiation.
  • the salt of step a) is selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrofluoride, methanesulfonate, p-toluene
  • step b) is selected from the group consisting of distilled water, deionized water and drinking water; the volume of water used is the mass of the salt of the compound of formula (A) 1 to 20 times;
  • the base in the step c) is selected from an inorganic base, an organic base or an organometallic base; preferably, the inorganic base is selected from the group consisting of ammonia water and sodium hydroxide.
  • the organometallic base is selected from the group consisting of sodium methoxide, sodium ethoxide, Sodium tert-butoxide, potassium t-butoxide, lithium t-butoxide, aluminum isopropoxide; preferably, the organic base is selected from the group consisting of diisopropylethylamine, triethylamine, N-methylmorpholine, 1,8- Diazabicycloundec-7-ene; more preferably, the base is selected from aqueous ammonia or sodium hydroxide.
  • step c) The method of any of claims 80-83, wherein the temperature in step c) is from about 60 °C to about 100 °C.
  • a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a crystalline form I of a compound of formula (A) according to any one of claims 74-79.
  • a method of treating ALK-mediated cancer comprising administering a crystalline form I of the compound of formula (A) according to any one of claims 74-79 or a pharmaceutical composition of claim 85.
  • non-small cell lung cancer is ALK-positive non-small cell lung cancer; wherein said lymphoma is anaplastic large cell lymph tumor.

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Abstract

L'invention concerne un procédé de préparation d'un composé de formule (A) et une forme cristalline de celui-ci. L'invention concerne en outre une composition pharmaceutique comprenant la forme cristalline du composé de formule (A), et une méthode de traitement de maladies associées à ALK au moyen de la composition.
PCT/CN2018/124155 2018-01-04 2018-12-27 Procédé de préparation d'un composé de diphénylaminopyrimidine deutéré et forme cristalline de celui-ci WO2019134573A1 (fr)

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WO2009045476A1 (fr) * 2007-10-02 2009-04-09 Concert Pharmaceuticals, Inc. Dérivés de pyrimidinedione
CN106188138A (zh) * 2015-12-02 2016-12-07 深圳市塔吉瑞生物医药有限公司 一种二氨基嘧啶化合物及包含该化合物的组合物
WO2017088784A1 (fr) * 2015-11-27 2017-06-01 正大天晴药业集团股份有限公司 Dérivés de brigatinib modifiés par deutérium, compositions pharmaceutiques les contenant et utilisation correspondante

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009045476A1 (fr) * 2007-10-02 2009-04-09 Concert Pharmaceuticals, Inc. Dérivés de pyrimidinedione
WO2017088784A1 (fr) * 2015-11-27 2017-06-01 正大天晴药业集团股份有限公司 Dérivés de brigatinib modifiés par deutérium, compositions pharmaceutiques les contenant et utilisation correspondante
CN106188138A (zh) * 2015-12-02 2016-12-07 深圳市塔吉瑞生物医药有限公司 一种二氨基嘧啶化合物及包含该化合物的组合物

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