WO2023216871A1 - Egfr抑制剂及其用途 - Google Patents

Egfr抑制剂及其用途 Download PDF

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Publication number
WO2023216871A1
WO2023216871A1 PCT/CN2023/090563 CN2023090563W WO2023216871A1 WO 2023216871 A1 WO2023216871 A1 WO 2023216871A1 CN 2023090563 W CN2023090563 W CN 2023090563W WO 2023216871 A1 WO2023216871 A1 WO 2023216871A1
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Prior art keywords
pharmaceutically acceptable
acceptable salt
compound according
compound
cancer
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PCT/CN2023/090563
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English (en)
French (fr)
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陈金山
瑞吉屋·乔布拉
顾家敏
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元启(苏州)生物制药有限公司
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Publication of WO2023216871A1 publication Critical patent/WO2023216871A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • 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
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • 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
    • C07B2200/07—Optical isomers

Definitions

  • the present application relates to novel EGFR inhibitors and their use, for example, in the treatment of various cancers.
  • EGFR Epidermal Growth Factor Receptor
  • NSCLC non-small cell lung cancer
  • Ring A is a benzene ring or a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O and S;
  • X is O or N (R N );
  • Y is O, N( RN ) or CH 2 ;
  • R N is each independently H or C 1-3 alkyl;
  • R 1 is H or C 1-3 alkyl;
  • R 2 is C 1-3 alkyl, C 2- 4 alkenyl, C 2-4 alkynyl, halogen, C 1-3 alkoxy, cyano or N(R N ) 2 .
  • the present application further provides methods of inhibiting EGFR, comprising contacting EGFR with a compound of the present application or a salt thereof.
  • the present application also provides methods of treating a subject suffering from cancer associated with mutated EGFR, comprising administering to the subject a compound of the present application or a salt thereof.
  • the present application relates to the use of the above-mentioned compounds in the preparation of a medicament for preventing, inhibiting or treating cancer associated with mutated EGFR.
  • next-generation EGFR TKIs should not inhibit wild-type EGFR. High selectivity across the human kinome will reduce off-target toxicity of compounds.
  • Another desirable property of next-generation EGFR TKIs is their ability to effectively penetrate into the brain (blood-brain barrier penetration) to enable the treatment of brain metastases and leptomeningeal diseases. Additionally, next-generation EGFR TKIs should exhibit reduced resistance compared with existing EGFR TKIs to increase the duration of response in patients.
  • next-generation EGFR TKIs will enable the use of third-generation TKIs, such as osimertinib, in patients who have progressed on second-line therapy (e.g., genotype EGFR del 19/L858R T790M C797S) who currently have no targeted therapy options.
  • third-generation TKIs such as osimertinib
  • genotype EGFR del 19/L858R T790M C797S e.g., genotype EGFR del 19/L858R T790M C797S
  • these properties may also allow next-generation EGFR TKIs to provide treatment options for patients who have progressed on first-line osimertinib for EGFR C797S mutations.
  • the present application includes compounds for the treatment of cancers expressing mutant EGFR, including various oncogenic and resistance mutations of del 19, L858R, T790M, C797S, and combinations thereof.
  • the present application provides EGFR inhibitors having the structure of formula (I), (IA), (II) or (IIA):
  • Ring A is a benzene ring or a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms selected from N, O and S;
  • X is O or N(R N );
  • Y is O, N(R N ) or CH 2 ;
  • R N is each independently H or C 1-3 alkyl
  • R 1 is H or C 1-3 alkyl
  • R 2 is C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen, C 1-3 alkoxy, cyano or N( RN ) 2 .
  • alkyl refers to straight and branched chain saturated hydrocarbon radicals.
  • C n means that the alkyl group has "n" carbon atoms.
  • C4 alkyl refers to an alkyl group with 4 carbon atoms.
  • C 1-6 alkyl refers to the full range (i.e. 1 to 6 carbon atoms) and all subsets (e.g. 1-5, 2-5, 1-4, 2-3, 1, 2, 3, 4, 5 and 6 carbon atoms) alkyl groups with carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2-methylpropyl), and tert-butyl (1,1-dimethylethyl). base). Unless otherwise stated, an alkyl group may be an unsubstituted alkyl group or a substituted alkyl group.
  • Alkenyl is an alkyl group having at least one double bond.
  • An alkynyl group is an alkyl group having at least one triple bond.
  • alkoxy or the term “alkoxy” refers to an "-O-alkyl” group.
  • heterocyclic ring refers to a heterocyclic ring that is aromatic and has 1, 2, or 3 ring heteroatoms independently selected from N, O, and S.
  • the ring may contain 5 or 6 ring atoms (ie, 2, 3, 4 or 5 ring carbon atoms).
  • Rings specifically contemplated include pyrazolyl, thienyl, furyl, pyridyl, pyrrolyl, oxazolyl, quinolyl, thienyl, isoquinolyl, indolyl, triazinyl, triazolyl, iso Thiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl and Thiadiazolyl.
  • Ring A is a benzene ring. In many cases, Ring A is a 5- or 6-membered heteroaromatic ring. In some cases, Ring A is a 5-membered heteroaromatic ring.
  • X is O.
  • X is N N .
  • X is NH.
  • R N is C 1-3 alkyl, for example, X is N(C 1-3 alkyl), such as NMe.
  • Y is CH2 .
  • Y is O.
  • Y is N( RN ), such as NH or N(C 1-3 alkyl), such as NMe.
  • R 1 is H. In many cases, R 1 is C 1-3 alkyl. In some cases, R1 is Me. In many cases, R2 is C1-3 alkyl. In some cases, R2 is Me. In many cases, R2 is C1-3 alkoxy. In some cases, R2 is OMe. In many cases, R2 is halogen. In some cases, R is F, Cl, or Br. In many cases, R2 is cyano. In some cases, R2 is C2-4 alkenyl or C2-4 alkynyl. In some cases, R2 is N( RN ) 2 , such as NH2 , NH(Me), or N(Me) 2 .
  • Compounds of the present application include all pharmaceutically acceptable isotopically labeled compounds, wherein one or more atoms in the compound of the present application may be identified by having the same atomic number but an atomic mass or mass number less commonly found in nature or Substitution of atoms with different mass numbers, examples of which include isotopes of hydrogen such as 2H and 3H .
  • one or more hydrogen atoms in the compounds of the present application are specifically deuterium ( 2H ).
  • compounds of the present application have at least one deuterium in them.
  • salts refers to relatively non-toxic inorganic or organic acid addition salts of the compounds provided herein. These salts may be prepared in situ during the final isolation and purification of the compounds provided herein, or by separately reacting the free base form of the compound with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include hydrobromide, hydrochloric acid Salt, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphoric acid Salt, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, lauryl sulfonate acid salts and amino acid salts (for example, see Berge et al. (1977) "Pharmaceutical Salts", J.Pharm.Sci.66:1-19.).
  • compounds provided herein may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to relatively non-toxic inorganic base or organic base addition salts of the compounds provided herein. These salts may likewise be prepared in situ during the final isolation and purification of the compound, or by separately reacting the free acid form of the purified compound with a suitable base, such as a hydroxide, carbonate or salt of a pharmaceutically acceptable metal cation. It is prepared by reacting bicarbonate, ammonia, or pharmaceutically acceptable organic primary, secondary or tertiary amines.
  • Representative alkali metal or alkaline earth metal salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, aluminum salts, and the like.
  • Representative organic amines useful in forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, eg, Berge et al., supra).
  • the compounds of the present application can be used in methods of inhibiting EGFR in cells.
  • the method includes contacting the EGFR with a compound disclosed herein or a salt thereof.
  • the EGFR is mutant EGFR.
  • Mutated EGFRs considered include, but are not limited to: EGFR del 19 T790M, EGFR del 19 C797S, EGFR del 19 C797X (X G or N), EGFR del 19 T790M C797S, EGFR del T790M C797X (X G or N), EGFR del 19L792X ( X F, H, or Y), EGFR DEL19 T790M L792X (x F, H, or Y), EGFR L858R, EGFR L858R R790M, EGFR L858R C797S, EGFR L858R C797X (X G or N), EGFR L858R T790M C797
  • mutants of EGFR include one or more of del 19, L858R, T790M, and C797S.
  • the mutated EGFR is EGFR del 19 T790M C797S. Inhibition of EGFR can be assessed using any known technique, including, for example, the assays described in the Examples below.
  • the compounds of the present application are useful in methods of treating cancer in subjects suffering from cancer, particularly cancers associated with abnormal EGFR activity.
  • cancers express EGFR mutations.
  • the mutant EGFR includes one or more of del 19, L858R, T790M, and C797S.
  • the mutated EGFR is EGFR del 19 T790M C797S.
  • subjects had previously received cancer therapy (i.e., the EGFR inhibitor was second-line or higher-line therapy).
  • the prior cancer treatment was gefitinib, erlotinib, afatinib, dacomitinib, osimertinib, orglutinib One or more of olumtinib, clawinib or AC0010.
  • prior therapy involved osimertinib.
  • Cancers specifically contemplated for treatment include, but are not limited to, non-small cell lung cancer, brain cancer, colorectal cancer, bladder cancer, urothelial cancer, breast cancer, prostate cancer, ovarian cancer, head and neck cancer, pancreatic cancer, gastric cancer, or Mesothelioma.
  • the cancer is non-small cell lung cancer.
  • compositions typically include a pharmaceutically acceptable carrier. Therefore, the present application also provides pharmaceutical compositions comprising a compound of the present application (for example, a compound of formula (I), formula (IA), formula (II) or formula (IIA) or a pharmaceutically acceptable salt thereof) , as previously described herein, and one or more pharmaceutically acceptable carriers.
  • the phrase "pharmaceutically acceptable” refers to those ligands that, within the scope of sound medical judgment, are suitable for contact with human and animal tissue without undue toxicity, irritation, allergic reactions, or other problems or complications. , materials, compositions and/or dosage forms, with a reasonable benefit/risk ratio proportionate.
  • the phrase "pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material.
  • pharmaceutically acceptable carrier includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents that are compatible with drug administration. wait. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the patient.
  • materials useful as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch, potato starch, substituted or unsubstituted cyclodextrins; (2) starches, such as corn starch, potato starch, substituted or unsubstituted cyclodextrins; 3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; ( 8) Excipients, such as cocoa butter, suppository wax; (9) Oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil; (10) Glycols, such as propylene glycol; (11) Polyols, such as glycerol, sorbitol, mannitol, polyethylene glycol;
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents can also be present in the compositions. , preservatives and antioxidants.
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbic acid Palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; (3) Metal chelating agent, Such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.
  • oil-soluble antioxidants such as ascorbic acid Palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, prop
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Protection against the action of microorganisms is ensured by the addition of various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol sorbic acid, etc. It is also desirable to include a tonicity adjusting agent in the composition, such as sugars and the like. In addition, prolonged absorption of injectable pharmaceutical dosage forms may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.
  • compositions prepared herein can be administered in a variety of forms depending on the condition to be treated and the age, condition and weight of the patient.
  • the compositions when administered orally, they may be formulated as tablets, capsules, granules, powders or syrups; or, for parenteral administration, they may be formulated as injections (intravenous, intramuscular or subcutaneous), Infusion preparation or suppository.
  • injections intravenous, intramuscular or subcutaneous
  • Infusion preparation or suppository for administration via the ocular mucosal route, they may be formulated as eye drops or eye ointments.
  • compositions may be prepared in conventional manner in conjunction with the methods described herein, and the active ingredients may be mixed, if desired, with any conventional additives or excipients, such as binders, disintegrants, lubricants, flavoring agents, enhancers, etc. Solvents, suspending aids, emulsifiers or coating agents.
  • compositions suitable for oral administration may be capsules (eg gelatin capsules), cachets, pills, tablets, lozenges (using a flavoring base, usually sucrose and acacia or tragacanth), powders, lozenges, In the form of granules, either as solutions, suspensions in aqueous or non-aqueous liquids, oil-in-water or water-in-oil liquid emulsions, or as elixirs or syrups, tablets (using an inert base such as gelatin and glycerol or sucrose and gum arabic) and/or as a mouthwash, etc., each containing a predetermined amount of a compound provided herein as an active ingredient.
  • the compositions may also be administered as pills, granules or pastes.
  • Oral compositions generally include an inert diluent or edible carrier.
  • binders and/or adjuvant materials can be included as part of the oral compositions.
  • the active ingredient may be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or mixed with any of the following: (1) Fillers or augmentants Dosing agents, such as starch, cyclodextrin, lactose, sucrose, saccharin, glucose, mannitol and/or silicic acid; (2) Binders, such as carboxymethyl cellulose, microcrystalline cellulose, tragacanth, alginic acid Salt, gelatin, polyvinylpyrrolidone, sucrose, and/or gum arabic; (3) humectants, such as glycerin; (4) disintegrants, such as agar, calcium carbonate, potato starch, corn starch or tapioca starch, alginic acid, Primo
  • compositions may also contain buffering agents.
  • Solid compositions of a similar type may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.
  • Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may use a binder (eg, gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrating agent (eg, sodium starch glycolate or croscarmellose sodium), surfactants or dispersants.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • Tablets and other solid dosage forms such as dragees, capsules, pills and granules may optionally be scored or prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide slow or controlled release of the active ingredient therein, for example using different proportions of hydroxypropyl methylcellulose to provide the desired release profile, or using other polymer matrices, liposomes, microspheres and/or nanoparticles. They may be sterilized, for example, by filtration through a bacteria-retaining filter, or by the addition immediately before use of a sterilizing agent in the form of a sterile solid composition soluble in sterile water or some other sterile injectable medium. .
  • compositions may also optionally contain opacifying agents and may be such that they are only, or preferably, in specific parts of the gastrointestinal tract.
  • Compositions that release active ingredients in a delayed manner examples include polymers and waxes.
  • the active ingredient can also be in microencapsulated form, if appropriate, together with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Benzyl esters, propylene glycol, 1,3-butanediol, oils (especially cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerin, tetrahydrofuranol, polyethylene glycol and sorbitan esters of fats acid esters, and their mixtures.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isoprop
  • the oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions may contain, besides the active compound, suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and yellow sorbitol. Gum, and their mixtures.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and yellow sorbitol. Gum, and their mixtures.
  • compositions suitable for parenteral administration may include one or more compounds provided herein with one or more pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or Sterile powders (which may be reconstituted before use into sterile injectable solutions or dispersions, which may contain antioxidants, buffers, bacteriostatic agents, solutes or suspending agents that render the composition isotonic with the blood of the intended recipient or thickener) combination.
  • aqueous and non-aqueous carriers examples include water for injection (e.g., sterile water for injection), bacteriostatic water, ethanol, polyols (such as glycerin, propylene glycol, polyethylene glycol such as liquid polyethylene glycol, etc.), sterile buffers (such as citrate buffer) and suitable mixtures thereof, vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and Cremophor EL TM ( BASF, Parsippany, NJ).
  • water for injection e.g., sterile water for injection
  • polyols such as glycerin, propylene glycol, polyethylene glycol such as liquid polyethylene glycol, etc.
  • sterile buffers such as citrate buffer
  • suitable mixtures thereof examples include vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and Cremophor EL TM ( BASF, Parsippany, NJ
  • the composition should be stable under the conditions of manufacture and storage and must be preserved to prevent contamination by microorganisms such as bacteria and fungi.
  • microorganisms such as bacteria and fungi.
  • the effects of microorganisms can be prevented by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc.
  • isotonic agents such as sugars, polyols (such as mannitol), sorbitol and sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the required amounts of the active compound in combination with one or more of the ingredients enumerated above, as required, in the appropriate solvent, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the method of preparation is freeze-drying (lyophilization), which yields a powder of the active ingredient plus any additional required ingredients from a previously sterile-filtered solution.
  • Injectable depot forms can be prepared by forming micro- or nanoencapsule matrices of the compounds of the present application in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of agent to polymer, and the properties of the specific polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Long-acting injectable compositions may also be prepared by entrapping the agent in liposomes, microemulsions, or nanoemulsions that are compatible with body tissues.
  • the compounds may be delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant (eg a gas such as carbon dioxide) or from a nebulizer.
  • a suitable propellant eg a gas such as carbon dioxide
  • intranasal delivery can be accomplished, inter alia, as described in Hamajima et al., Clin. Immunol. Immunopathol., 88(2), 205-10 (1998).
  • Liposomes may also be used (e.g., as described in U.S. Patent No. 6,472,375, which are incorporated herein by reference in their entirety), microcapsules and nanocapsules.
  • Biodegradable targetable microparticle delivery systems or biodegradable targetable nanoparticle delivery systems may also be used (eg, as described in U.S. Patent No. 6,471,996, which is incorporated herein by reference in its entirety).
  • the therapeutic compounds described herein may also be administered systemically via transmucosal or transdermal means.
  • Dosage forms for topical or transdermal administration of the compounds provided herein include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants.
  • the active ingredient can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • penetrants suitable for the barrier to be penetrated are used in the composition. Such penetrants are generally known in the art and include, for example, detergents, bile salts, and fusidic acid derivatives for transmucosal administration.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds may be formulated into ointments, salves, gels or creams well known in the art.
  • ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, fibers derivatives, polyethylene glycols, siloxanes, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.
  • powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances.
  • Sprays may also contain commonly used propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.
  • the compounds provided herein can be administered via aerosol. This is accomplished by preparing aqueous aerosols, liposomal formulations, or solid particles containing the compounds or compositions provided herein.
  • Non-aqueous (eg, fluorocarbon propellant) suspensions may be used.
  • sonic nebulizers may also be used because they minimize the exposure of the agent to shear forces, which can cause degradation of the compound.
  • aqueous aerosols may be prepared by formulating an aqueous solution or suspension of the agent with conventional pharmaceutically acceptable carriers and stabilizers.
  • Carriers and stabilizers vary with the requirements of the particular composition but generally include nonionic surfactants ( (Polysorbate), (poloxamer), sorbitan ester, lecithin, (polyethoxylate), pharmaceutically acceptable cosolvents (such as polyethylene glycol), harmless proteins (such as serum albumin), sorbitan esters, oleic acid, lecithin, amino acids (such as glycine ), buffers, salts, sugars or sugar alcohols. Aerosols are usually prepared from isotonic solutions.
  • Transdermal patches have the added advantage of providing controlled delivery of the compounds provided herein to the body.
  • dosage forms may be prepared by dissolving or dispersing the agent in an appropriate medium.
  • Absorption enhancers may also be used to increase the flux of compounds across the skin. The rate of this flux can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • compositions may also be formulated as suppositories or retention enemas for rectal and/or vaginal delivery.
  • Compositions presented as suppositories may be prepared by mixing one or more compounds provided herein with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter. , glycerides, polyethylene glycols, suppository waxes, or salicylates, which are solid at room temperature but liquid at body temperature and therefore melt in the rectal or vaginal cavity and release the active agent.
  • suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray compositions containing suitable carriers known in the art.
  • the therapeutic compounds can also be prepared with carriers that will protect the therapeutic compound against rapid elimination from the body, such as controlled release compositions, including implants and microencapsulated delivery systems.
  • Biodegradable biocompatible polymers may be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
  • Such compositions can be prepared using standard techniques or are commercially available from, for example, Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposome suspensions including liposomes targeted to selected cells harboring monoclonal antibodies directed against cellular antigens, may also be used as pharmaceutically acceptable carriers. These can be determined by those skilled in the art Prepared by known methods, for example, as described in U.S. Patent No. 4,522,811, which is incorporated herein by reference in its entirety.
  • the compounds provided herein may be administered to humans and other animals for treatment by any suitable route of administration, including oral, nasal (e.g., by spray), rectal, intravaginal, parenteral, intracisternal and topically (e.g., via powder, ointment, or drops), including bucally and sublingually.
  • the compounds provided herein and/or the pharmaceutical compositions provided herein which can be used in a suitably hydrated form, can be formulated into a pharmaceutically acceptable form by conventional methods known to those skilled in the art. dosage form.
  • the pharmaceutical composition is an oral or parenteral solution.
  • Another embodiment is a lyophilized formulation that can be reconstituted prior to administration.
  • the compositions may also include tablets, capsules or powders.
  • the actual dosage levels of the active ingredients in the pharmaceutical compositions provided herein can be varied to obtain a "therapeutically effective amount" that achieves the desired therapeutic response in a particular patient, composition, and mode of administration without toxicity to the patient. Amount of active ingredient.
  • compositions provided herein can be provided for parenteral administration in an aqueous solution containing about 0.1% to 10% (w/v) of a compound disclosed herein, as well as other substances.
  • a typical dosage range may be from about 0.01 to about 50 mg/kg body weight per day, administered in 1 to 4 divided doses. Each divided dose may contain the same or a different compound.
  • the dosage will be a therapeutically effective amount depending on several factors, including the patient's overall health, as well as the composition and route of administration of the selected compound.
  • Dosage forms or compositions may be prepared containing from 0.005% to 100% of a compound of the present application, with the balance consisting of a non-toxic carrier. Methods of preparing these compositions are known to those skilled in the art. Contemplated compositions may contain from 0.001% to 100% active ingredient. In one embodiment, the amount is from 0.1% to 95%, in another embodiment, from 75% to 85%. Although dosage will depend on patient The patient's symptoms, age and weight, the nature and severity of the disease to be treated or prevented, the route of administration and the drug form, but generally the daily dose is recommended for adult patients to take 0.01mg to 2000mg of the compound, which can be taken alone Dosing in one dose or in divided doses. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is usually an amount of the compound that produces a therapeutic effect.
  • administering a composition to a human subject should be limited to a controlled substance that provides for self-administration by the human subject by any technique (e.g., oral, inhaled , topical application, injection, insertion, etc.). Intended to be the broadest reasonable interpretation consistent with the law or statute defining patentable subject matter.
  • administration of a composition includes methods performed on the human body and the activities described above.
  • the compounds of the present application may be prepared in the manner described in the following examples, or using other synthetic techniques, and using common laboratory techniques, within the skill of the organic chemist.
  • cerium diammonium nitrate (19.1g, 0.0884mol) was added to compound c-3 (7.0 g, 0.0221 mol) in a mixed solution of acetonitrile (200 mL) and water (50 mL), and stirred at 25°C for 5 hours.
  • LCMS showed the desired MS.
  • Saturated aqueous sodium sulfite solution and saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Triphenylphosphine (13.4 g, 0.051 mol) was added to a solution of compound c-6 (6.0 g, 0.0255 mol) in tetrahydrofuran (20 mL) and water (12 mL). After stirring at room temperature for 24 hours under N2 protection, LCMS showed that the desired MS was detected. The solvent was removed under reduced pressure to obtain the crude product, which was subjected to flash chromatography (DCM/MeOH eluting from 100/0 to 90/10 in 30 minutes) to afford compound c-7 (3.5 g, 52.5% yield) as a yellow oil. Rate).
  • kinase Buffer 1x Kinase Buffer was prepared.
  • EGFR L858R/T790M/C797S was purchased from Invitrogen (Cat. A33556)
  • EGFR (d746-750/T790M C797S) was purchased from Carna (Cat. 08-565)
  • the enzyme was diluted with kinase buffer to 2.5x final concentration.
  • the kinase substrate 22 used was from GL China (Cat. 112393).

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Abstract

一种具有式(I)、(IA)、(II)或(IIA)结构的化合物或其药学上可接受的盐，以及此类化合物或其盐用于抑制包括突变型EGFR在内的EGFR的用途，包括用于治疗与例如异常EGFR活性相关的癌症。

Description

EGFR抑制剂及其用途
相关申请的交叉引用
本申请基于申请号为202210499022.1、申请日为2022年05月09日的中国专利申请提出，并要求该中国专利申请的优先权，该中国专利申请的全部内容在此引入本申请作为参考。
技术领域
本申请涉及新的EGFR抑制剂及其在例如治疗多种癌症中的用途。
背景技术
表皮生长因子受体(Epidermal Growth Factor Receptor，EGFR)是一种转导有丝***信号的受体酪氨酸激酶。在大约12％至47％的具有腺癌组织学的非小细胞肺癌(NSCLC)肿瘤中发现EGFR基因突变(Midha,A.et al.Am J Cancer Res.2015；5(9):2892-2911)。
目前急需有效且临床相关的EGFR抑制剂，其可以抑制EGFR突变体，但对野生型EGFR表现出选择性。
发明内容
本申请提供了具有式(I)、(IA)、(II)或(IIA)结构的化合物或其药学上可接受的盐：

其中，环A为苯环或含选自N、O和S的1、2或3个杂原子的5-或6-元杂芳环；X为O或N(RN)；Y为O、N(RN)或CH2；RN各自独立地为H或C1-3烷基；R1为H或C1-3烷基；以及R2为C1-3烷基、C2-4烯基、C2-4炔基、卤素、C1-3烷氧基、氰基或N(RN)2。
本申请还提供了下表1中示出的化合物或其药学上可接受的盐：
表1，本申请的示例性化合物


本申请进一步提供了抑制EGFR的方法，包括使EGFR与本申请的化合物或其盐接触。此外，本申请还提供了治疗患有与突变EGFR相关的癌症的受试者的方法，包括向受试者施用本申请的化合物或其盐。
另一方面，本申请涉及上述化合物在制备用于预防、抑制或治疗与突变EGFR相关的癌症的药物中的用途。
具体实施方式
医学上需要新的EGFR酪氨酸激酶抑制剂(TKI)，它可以治疗对当前EGFR治疗方案耐药的肺癌，例如当前的护理标准奥希替尼(Osimertinib)治疗中出现的EGFR C797S突变相关癌症。为了促进有效给药并降低EGFR介导的靶向毒性，下一代EGFR TKI不应抑制野生型EGFR。跨人类激酶组的高选择性将降低化合物的脱靶毒性。下一代EGFR TKI的另一个理想特性是能够有效地渗透到大脑中(血脑屏障渗透)，以能够治疗脑转移和软脑膜疾病。此外，与现有EGFR TKI相比，下一代EGFR TKI应表现出降低的耐药性，以在患者中增加响应的持续时间。
下一代EGFR TKI的上述特性将使得能够使用第三代TKI，例如奥希替尼治疗二线治疗进展的患者(例如基因型EGFR del 19/L858R T790M C797S)，这些患者目前没有靶向治疗选择。此外，这些特性也有可能让下一代EGFR TKI为接受EGFR C797S突变的奥希替尼一线治疗进展的患者提供治疗选择。下一代EGFR TKI对T790M、C797X(X＝S、G、N)和L792X(X＝F、H、Y)等耐药性突变的活性有可能通过NSCLC肿瘤中EGFR靶内突变延迟耐药性的发展。
本申请包括用于治疗表达突变EGFR的癌症的化合物，其中突变EGFR包括del 19、L858R、T790M、C797S及其组合的各种致癌和抗性突变。本申请提供了具有式(I)、(IA)、(II)或(IIA)结构的EGFR抑制剂：

其中，环A为苯环或含选自N、O和S的1、2或3个杂原子的5-或6-元杂芳环；
X为O或N(RN)；
Y为O、N(RN)或CH2；
RN各自独立地为H或C1-3烷基；
R1为H或C1-3烷基；以及
R2为C1-3烷基、C2-4烯基、C2-4炔基、卤素、C1-3烷氧基、氰基或N(RN)2。
如本文所用，术语“烷基”是指直链和支链的饱和烃基。术语Cn是指烷基具有“n”个碳原子。例如，C4烷基是指具有4个碳原子的烷基。C1-6烷基是指具有完整范围(即1至6个碳原子)及所有子集(例如1-5、2-5、1-4、2-3、1、2、3、4、5和6个碳原子)碳原子数的烷基基团。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基(2-甲基丙基)和叔丁基(1,1-二甲基乙基)。除非另有说明，否则烷基基团可以是未取代的烷基基团或取代的烷基基团。烯基是具有至少一个双键的烷基基团。炔基基团是具有至少一个三键的烷基基团。
如本文所用，术语“烷氧基”或“烷氧”一词是指“-O-烷基”基团。
如本文所用，术语“杂芳环”是指芳香性且具有独立选自N、O和S的1、2或3个环杂原子的杂环。该环可包含5或6个环原子(即，2、3、4或5个环碳原子)。具体考虑的环包括吡唑基、噻吩基、呋喃基、吡啶基、吡咯基、噁唑基、喹啉基、噻吩基、异喹啉基、吲哚基、三嗪基、***基、异噻唑基、异噁唑基、咪唑基、苯并噻唑基、吡嗪基、嘧啶基、噻唑基和 噻二唑基。
在多种情况下，环A是苯环。在多种情况下，环A是5元或6元杂芳环。在某些情况下，环A是5元杂芳环。
在多种情况下，X是O。在某些情况下，X是NRN。在某些情况下，X是NH。在多种情况下，RN是C1-3烷基，例如，X是N(C1-3烷基)，例如NMe。在多种情况下，Y是CH2。在一些情况下，Y是O。在一些情况下，Y是N(RN)，例如NH或N(C1-3烷基)，例如NMe。
在多种情况下，R1是H。在多种情况下，R1是C1-3烷基。在某些情况下，R1是Me。在多种情况下，R2是C1-3烷基。在某些情况下，R2是Me。在多种情况下，R2是C1-3烷氧基。在某些情况下，R2是OMe。在多种情况下，R2是卤素。在某些情况下，R2是F、Cl或Br。在多种情况下，R2是氰基。在一些情况下，R2是C2-4烯基或C2-4炔基。在一些情况下，R2是N(RN)2，例如NH2、NH(Me)或N(Me)2。
在多种情况下，本申请所描述的化合物或其药学上可接受的盐具有上文表1中所示的结构。
本申请的化合物包括所有药学上可接受的同位素标记的化合物，其中本申请化合物中的一个或多个原子可被具有相同原子序数但原子质量或质量序数与自然界中通常较少发现的原子质量或质量序数不同的原子取代，其中的实例包括氢的同位素，例如2H和3H。在一些情况下，本申请化合物中的一个或多个氢原子具体为氘(2H)。在一些情况下，本申请化合物中具有至少一个氘。
术语“药学上可接受的盐”是指本申请提供的化合物的相对无毒的无机酸或有机酸加成盐。这些盐可以在本申请提供的化合物的最终分离和纯化过程中原位制备，或通过单独使游离碱形式的化合物与合适的有机酸或无机酸反应并分离由此形成的盐来制备。代表性的盐包括氢溴酸盐、盐酸 盐、硫酸盐、硫酸氢盐、磷酸盐、硝酸盐、乙酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐、月桂基磺酸盐和氨基酸盐等(例如参见Berge et al.(1977)"Pharmaceutical Salts",J.Pharm.Sci.66:1-19.)。
在一些实施方式中，本申请提供的化合物可以含有一个或多个酸性官能团，因此能够与药学上可接受的碱形成药学上可接受的盐。在这些情况下，术语“药学上可接受的盐”是指本申请提供的化合物的相对无毒的无机碱或有机碱加成盐。这些盐同样可以在化合物的最终分离和纯化过程中原位制备，或者通过单独使游离酸形式的经纯化的化合物与合适的碱，例如药学上可接受的金属阳离子的氢氧化物、碳酸盐或碳酸氢盐，或者氨，或者药学上可接受的有机伯胺、仲胺或叔胺反应来制备。代表性的碱金属或碱土金属盐包括锂盐、钠盐、钾盐、钙盐、镁盐和铝盐等。可用于形成碱加成盐的代表性有机胺包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等(参见例如Berge等人，同上)。
治疗靶标
本申请的化合物可用于抑制细胞中EGFR的方法。在多种情况下，该方法包括使EGFR与本申请公开的化合物或其盐接触。在一些情况下，EGFR是突变EGFR。所考虑的突变EGFR包括但不限于：EGFR del 19 T790M、EGFR del 19 C797S、EGFR del 19 C797X(X G或N)、EGFR del 19 T790M C797S、EGFR del T790M C797X(X G或N)、EGFR del 19L792X(X F,H,或Y)、EGFR del19 T790M L792X(X F,H,或Y)、EGFR L858R、EGFR L858R R790M、EGFR L858R C797S,EGFR L858R C797X(X G或N)、EGFR L858R T790M C797S、EGFR L858R T790M C797X(X G或N)、EGFR L858R L792X(X F,H或Y)和EGFR L858R T790M L792X(X F,H或Y)，其中del 19 表示外显子19缺失。在多种情况下，EGFR的突变体包含del 19、L858R、T790M和C797S中的一种或多种。在某些情况下，突变EGFR是EGFR del 19 T790M C797S。可以使用任何已知技术评估EGFR的抑制，包括例如以下实施例中描述的测定法。
本申请的化合物可用在患有癌症的受试者中治疗癌症，特别是与异常EGFR活性相关的癌症的方法。在多种情况下，癌症表达EGFR突变。在一些情况下，EGFR的突变体包含del 19、L858R、T790M和C797S中的一种或多种。在某些情况下，突变EGFR是EGFR del 19 T790M C797S。
在某些情况下，受试者之前曾接受过癌症疗法(即，EGFR抑制剂是二线或更高线疗法)。在某些情况下，先前的癌症治疗是吉非替尼(gefitinib)、厄洛替尼(erlotinib)、阿法替尼(afatinib)、达克替尼(dacomitinib)、奥希替尼、奥鲁替尼(olumtinib)、纳扎替尼(nazartinib)或AC0010中的一种或多种。在多种情况下，先前的疗法涉及奥希替尼。
具体考虑的用于治疗的癌症包括但不限于非小细胞肺癌、脑癌、结肠直肠癌、膀胱癌、尿路上皮癌、乳腺癌、***癌、卵巢癌、头颈癌、胰腺癌、胃癌，或间皮瘤。在某些情况下，癌症是非小细胞肺癌。在某些情况下，受试者患有脑转移。
药物组合物
本申请还包括药物组合物本身。药物组合物通常包括药学上可接受的载体。因此，本申请还提供了药物组合物，其包含本申请的化合物(例如，式(I)、式(IA)、式(II)或式(IIA)的化合物或其药学上可接受的盐)，如本文先前所述，以及一种或多种药学上可接受的载体。
如本文所用，短语“药学上可接受的”是指在合理的医学判断范围内，适合与人类和动物的组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症的那些配体、材料、组合物和/或剂型，与合理的收益/风险比 相称。
如本文所用，短语“药学上可接受的载体”是指药学上可接受的材料、组合物或溶媒，例如液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料。如本文所用，术语“药学上可接受的载体”包括与药物施用相容的缓冲剂、无菌注射用水、溶剂、分散介质、包衣、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂等。每种载体必须是“可接受的”，意味着与组合物的其他成分相容且对患者无害。可用作药学上可接受的载体的材料的一些实例包括：(1)糖，诸如乳糖、葡萄糖和蔗糖；(2)淀粉，诸如玉米淀粉、马铃薯淀粉、取代或未取代的环糊精；(3)纤维素及其衍生物，诸如羧甲基纤维素钠、乙基纤维素、醋酸纤维素；(4)黄蓍胶粉；(5)麦芽；(6)明胶；(7)滑石；(8)赋形剂，诸如可可脂、栓剂蜡；(9)油类，诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油、大豆油；(10)二醇类，诸如丙二醇；(11)多元醇，诸如甘油、山梨醇、甘露醇、聚乙二醇；(12)酯类，诸如油酸乙酯、月桂酸乙酯；(13)琼脂；(14)缓冲剂，诸如氢氧化镁、氢氧化铝；(15)海藻酸；(16)无热原水；(17)等渗盐水；(18)林格溶液；(19)乙醇；(20)磷酸盐缓冲溶液；以及(21)用于药物组合物的其他无毒相容物质。在某些实施方式中，本申请提供的药物组合物是非致热的，即当施用于患者时不会引起显著的温度升高。
组合物中也可存在润湿剂、乳化剂和润滑剂，诸如十二烷基硫酸钠和硬脂酸镁，以及着色剂、脱模剂、包衣剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂。
药学上可接受的抗氧化剂的实例包括：(1)水溶性抗氧化剂，诸如抗坏血酸、半胱氨酸盐酸盐、硫酸氢钠、焦亚硫酸钠、亚硫酸钠等；(2)油溶性抗氧化剂，诸如抗坏血酸棕榈酸酯、丁基羟基茴香醚(BHA)、丁基羟基甲苯(BHT)、卵磷脂、没食子酸丙酯、α-生育酚等；(3)金属螯合剂， 诸如柠檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸等。
药物组合物还可包含佐剂，诸如防腐剂、润湿剂、乳化剂和分散剂。通过加入各种抗菌剂和抗真菌剂，例如对羟基苯甲酸酯、三氯丁醇、苯酚山梨酸等，可以确保防止微生物的作用。还可取的是在组合物中包括张力调节剂，例如糖等。此外，可通过包含延迟吸收剂(诸如单硬脂酸铝和明胶)来延长可注射药物剂型的吸收。
如本领域所熟知的，本申请所制备的组合物可以多种形式给药，这取决于待治疗的病症和患者的年龄、状况和体重。例如，当组合物口服给药时，它们可以配制成片剂、胶囊、颗粒剂、散剂或糖浆剂；或者，对于肠胃外给药，它们可以配制成注射剂(静脉内、肌肉内或皮下)、滴注制剂或栓剂。对于通过眼粘膜途径给药，它们可以配制成滴眼剂或眼膏剂。这些组合物可以通过常规方式结合本文所描述的方法来制备，并且如果需要，活性成分可以与任何常规添加剂或赋形剂混合，例如粘合剂、崩解剂、润滑剂、矫味剂、增溶剂、悬浮助剂、乳化剂或包衣剂。
适合口服给药的组合物可以是胶囊(例如明胶胶囊)、扁囊剂、丸剂、片剂、锭剂(使用调味基础成分，通常是蔗糖和***胶或黄蓍胶)、粉剂、锭剂、颗粒剂的形式，或者为溶液、在水性或非水性液体中的悬浮液、水包油或油包水液体乳液，或者作为酏剂或糖浆，锭剂(使用惰性基质，例如明胶和甘油或蔗糖和***胶)和/或作为漱口水等，每一种都含有预定量的本文提供的化合物作为活性成分。组合物也可以以丸剂、冲剂或糊剂给药。口服组合物通常包括惰性稀释剂或可食用载体。
药学上相容的粘合剂和/或佐剂材料可以作为口服组合物的一部分包括在内。在用于口服给药的固体剂型(胶囊、片剂、丸剂、糖衣丸、散剂、颗粒剂等)中，活性成分可以与一种或多种药学上可接受的载体混合，例如柠檬酸钠或磷酸二钙，和/或与以下项中的任一种混合：(1)填充剂或增 量剂，诸如淀粉、环糊精、乳糖、蔗糖、糖精、葡萄糖、甘露醇和/或硅酸；(2)粘合剂，诸如羧甲基纤维素、微晶纤维素、黄蓍胶、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖，和/或***胶；(3)保湿剂，诸如甘油；(4)崩解剂，诸如琼脂、碳酸钙、马铃薯淀粉、玉米淀粉或木薯淀粉、海藻酸、Primogel、某些硅酸盐和碳酸钠；(5)溶液阻滞剂，诸如石蜡；(6)吸收促进剂，诸如季铵化合物；(7)润湿剂，诸如乙酰醇和单硬脂酸甘油酯；(8)吸收剂，诸如高岭土、膨润土；(9)润滑剂，诸如滑石、硬脂酸钙、硬脂酸镁、甾体、固体聚乙二醇、十二烷基硫酸钠，及它们的混合物；(10)助流剂，诸如胶体二氧化硅；(11)着色剂；以及(12)调味剂，诸如薄荷、水杨酸甲酯、橙子调味剂。在胶囊、片剂和丸剂的情况下，药物组合物还可以包含缓冲剂。类似类型的固体组合物也可使用诸如乳糖或牛奶糖以及高分子量聚乙二醇等赋形剂作为软和硬填充明胶胶囊中的填充剂。
片剂可以任选地使用一种或多种辅助成分通过压制或模压来制备。压制片剂可以使用粘合剂(例如，明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如，羟基乙酸淀粉钠或交联羧甲基纤维素钠)、表面活性剂或分散剂来制备。模压片剂可以通过在合适的机器中对经惰性液体稀释剂润湿的粉末状化合物的混合物进行模压来制备。
片剂和其他固体剂型，例如糖衣丸、胶囊、丸剂和颗粒剂可以任选地刻痕，或制备有包衣和壳，例如肠溶包衣和药物制剂领域熟知的其他包衣。它们也可以被配制为提供其中活性成分的缓慢或受控释放，例如使用不同比例的羟丙基甲基纤维素以提供所需的释放曲线，或使用其他聚合物基质、脂质体、微球体和/或纳米颗粒。它们可以通过例如通过细菌截留过滤器过滤，或通过在使用前立即加入可溶于无菌水或一些其他无菌可注射介质中的无菌固体组合物形式的灭菌剂来对它们进行灭菌。这些组合物还可以任选地包含遮光剂并且可以是它们仅或优选地在胃肠道的特定部分中任选地 以延迟方式释放活性成分的组合物。可以使用的包埋组合物的实例包括聚合物和蜡。如果合适的话，活性成分也可以与一种或多种上述赋形剂一起呈微囊化形式。
用于口服给药的液体剂型包括药学上可接受的乳液、微乳液、溶液、混悬液、糖浆剂和酏剂。除了活性成分之外，液体剂型可以包含本领域常用的惰性稀释剂，例如水或其他溶剂、增溶剂和乳化剂，例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油(特别是棉籽、花生、玉米、胚芽、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃醇、聚乙二醇和脱水山梨糖醇酯的脂肪酸酯，及它们的混合物。
除了惰性稀释剂之外，口服组合物还可含有佐剂，例如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂、着色剂、加香剂和防腐剂。
除活性化合物外，混悬液可含有助悬剂，例如乙氧基化异硬脂醇、聚氧乙烯山梨糖醇和山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂和黄蓍胶，及它们的混合物。
适用于肠胃外给药的药物组合物可以包括一种或多种本申请提供的化合物与一种或多种药学上可接受的无菌水性或非水性溶液、分散体、悬浮液或乳液、或无菌粉末(其可临用前重构为无菌可注射溶液或分散体，其可包含抗氧化剂、缓冲剂、抑菌剂、使组合物与预期接受者的血液等渗的溶质或悬浮剂或增稠剂)的组合。
可用于本申请提供的药物组合物的合适的水性和非水性载体的实例包括注射用水(例如，无菌注射用水)、抑菌水、乙醇、多元醇(诸如甘油、丙二醇、聚乙二醇如液体聚乙二醇等)、无菌缓冲液(诸如柠檬酸盐缓冲液)及其合适的混合物、植物油(诸如橄榄油)、可注射的有机酯(例如油酸乙酯)和Cremophor ELTM(BASF，Parsippany，NJ)。在所有情况下，该组合物必须是无菌的并且应该是流体以达到易于注射的程度。适当的流动性可 以例如通过使用包衣材料(诸如卵磷脂)、在分散体的情况下通过保持所需的粒度，以及通过使用表面活性剂来保持。
该组合物在制造和储存条件下应该是稳定的并且必须被保存以防止微生物(诸如细菌和真菌)的污染。可以通过各种抗菌剂和抗真菌剂，例如对羟基苯甲酸酯、氯丁醇、苯酚、抗坏血酸、硫柳汞等来防止微生物的影响。在许多情况下，优选地，在组合物中包含等渗剂，例如糖、多元醇(诸如甘露醇)、山梨糖醇和氯化钠。可通过在组合物中包含延迟吸收的试剂，例如单硬脂酸铝和明胶来延长可注射组合物的吸收。
可以通过将所需量的活性化合物与上文列举的成分中的一种或多种的组合(根据需要)并入适当的溶剂，然后过滤灭菌来制备无菌可注射溶液。通常，通过将活性化合物掺入无菌溶媒中来制备分散体，该溶媒含有基础分散介质和上文列举的那些所需的其他成分。在用于制备无菌注射溶液的无菌粉末的情况下，制备方法是冷冻干燥(冻干)，其为先前无菌过滤的溶液中产生活性成分加上任何额外的所需成分的粉末。
可通过在生物可降解的聚合物诸如聚丙交酯-聚乙交酯中形成本申请化合物的微囊或纳米囊基质来制备可注射的长效形式(Injectable depot form)。根据药剂与聚合物的比例，以及所使用的特定聚合物的性质，可以控制药物的释放速率。其他生物可降解的聚合物的实例包括聚(原酸酯)和聚(酸酐)。也可通过将药剂包埋在与身体组织相容的脂质体、微乳液或纳米乳液中来制备长效注射组合物。
对于通过吸入给药，化合物可以以气溶胶喷雾剂的形式从含有合适推进剂(例如气体如二氧化碳)的加压容器或分配器递送或从喷雾器递送。此类方法包括美国专利No.6,468,798中描述的方法。此外，可以完成鼻内递送，尤其如Hamajima et al.,Clin.Immunol.Immunopathol.,88(2),205-10(1998)中所述。也可以使用脂质体(例如，如美国专利No.6,472,375中所述， 其通过引用整体并入本文)、微囊和纳米囊。还可使用生物可降解的可靶向微粒递送***或生物可降解的可靶向纳米颗粒递送***(例如，如美国专利No.6,471,996中所述，其通过引用整体并入本文)。
本申请所描述的治疗性化合物也可以通过经粘膜或经皮方式进行全身给药。本申请提供的化合物的局部或经皮给药的剂型包括粉剂、喷雾剂、软膏剂、糊剂、乳膏剂、洗剂、凝胶剂、溶液、贴剂和吸入剂。可以在无菌条件下将活性成分与药学上可接受的载体以及可能需要的任何防腐剂、缓冲剂或推进剂混合。对于经粘膜或经皮给药，在组合物中使用适合待渗透屏障的渗透剂。此类渗透剂在本领域中通常是已知的，并且包括例如用于经粘膜给药的去污剂、胆汁盐和夫西地酸衍生物。经粘膜给药可以通过使用鼻喷雾剂或栓剂来完成。对于经皮给药，可将活性化合物配制成本领域公知的软膏、油膏、凝胶或乳膏。
除了本申请提供的一种或多种化合物之外，软膏、糊剂、乳膏和凝胶还可以含有赋形剂，例如动物和植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅氧烷、膨润土、硅酸、滑石粉和氧化锌，或它们的混合物。
除了本申请提供的化合物之外，粉末和喷雾剂还可以含有赋形剂，例如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末，或这些物质的混合物。喷雾剂还可以包含常用的推进剂，例如氯氟烃和挥发性未取代的烃，例如丁烷和丙烷。
本申请提供的化合物可以通过气雾剂给药。这通过制备含有本文提供的化合物或组合物的水性气雾剂、脂质体制剂或固体颗粒来实现。可以使用非水性(例如，碳氟化合物推进剂)悬浮液。在一些实施方式中，也可使用声波雾化器，这是因为它们使药剂暴露于剪切力的可能性最小化，而剪切力会导致化合物的降解。
通常，可通过将药剂的水溶液或悬浮液与常规药学上可接受的载体和稳定剂一起配制来制备水性气雾剂。载体和稳定剂随特定组合物的要求而变化，但通常包括非离子表面活性剂((聚山梨醇酯)、(泊洛沙姆)、脱水山梨糖醇酯、卵磷脂、(聚乙氧基化物))、药学上可接受的共溶剂(诸如聚乙二醇)、无害蛋白质(诸如血清白蛋白)、脱水山梨糖醇酯、油酸、卵磷脂、氨基酸(诸如甘氨酸)、缓冲液、盐、糖或糖醇。气雾剂通常由等渗溶液制备。
经皮贴剂具有将本申请提供的化合物控制递送至身体的额外优点。这种剂型可以通过将药剂溶解或分散在适当的介质中来制备。吸收促进剂也可用于增加化合物穿过皮肤的通量。可以通过提供速率控制膜或将化合物分散在聚合物基质或凝胶中来控制这种通量的速率。
药物组合物也可以制成栓剂或保留灌肠剂的形式用于直肠和/或***递送。作为栓剂呈现的组合物可以通过将一种或多种本申请提供的化合物与一种或多种合适的非刺激性赋形剂或载体混合来制备，所述赋形剂或载体包括例如可可脂、甘油酯、聚乙二醇、栓剂蜡或水杨酸盐，其在室温下为固体温度，但在体温下为液体，因此会在直肠或***腔中融化并释放活性剂。适用于***给药的组合物还包括***栓剂、棉条、乳膏、凝胶、糊剂、泡沫或含有本领域已知合适的载体的喷雾剂组合物。
治疗性化合物也可以与保护治疗性化合物免于从体内快速消除的载体一起制备，例如控释组合物，包括植入物和微囊化递送***。可以使用生物可降解的生物相容性聚合物，例如乙烯醋酸乙烯酯、聚酸酐、聚乙醇酸、胶原蛋白、聚原酸酯和聚乳酸。此类组合物可以使用标准技术制备，或从例如Alza Corporation和Nova Pharmaceuticals,Inc.商购获得。脂质体悬浮液(包括靶向于选定细胞的脂质体，该选定细胞具有针对细胞抗原的单克隆抗体)也可以用作药学上可接受的载体。这些可以根据本领域技术人员已 知的方法制备，例如，如美国专利No.4,522,811中所描述，该专利通过引用整体并入本文。
本申请提供的化合物可以通过任何合适的给药途径施用于人和其他动物用于治疗，这些合适的给药途径包括口服、经鼻(例如通过喷雾)、直肠、***内、肠胃外、脑池内和局部(例如通过粉末、软膏或滴剂)，且包括口腔和舌下。无论选择何种给药途径，可以通过本领域技术人员已知的常规方法将可以以合适的水合形式使用的本申请提供的化合物和/或本申请提供的药物组合物配制成药学上可接受的剂型。在另一个实施方式中，药物组合物是口服溶液或肠胃外溶液。另一个实施方式是可以在给药前重构的冻干制剂。作为固体，该组合物还可以包括片剂、胶囊或粉末。
可以改变本文提供的药物组合物中活性成分的实际剂量水平以获得“治疗有效量”，其是在对患者无毒性的情况下，对具体患者、组合物和给药模式实现所需治疗反应的活性成分的量。
本申请提供的化合物在药学上可接受的混合物中的浓度将根据包括以下若干项的因素而变化：待给药的化合物的剂量、所用化合物的药代动力学特性和给药途径。在一些实施方式中，本申请提供的组合物可以在含有约0.1％至10％(w/v)的本文公开的化合物以及其他物质的水溶液中提供，用于肠胃外给药。典型的剂量范围可为每天约0.01至约50mg/kg体重，分1～4次给药。每个分开的剂量可以包含相同或不同的化合物。剂量将是治疗有效量，这取决于几个因素，包括患者的整体健康状况，以及所选化合物的组成和给药途径。
可以制备包含0.005％至100％的本申请化合物的剂型或组合物，其中余量由无毒载体组成。制备这些组合物的方法是本领域技术人员已知的。预期的组合物可包含0.001％至100％的活性成分。在一个实施方式中，该量为0.1％至95％，在另一实施方式中，为75％至85％。虽然剂量将根据患 者的症状、年龄和体重、待治疗或预防的疾病的性质和严重程度、给药途径和药物形式而有所不同，但通常每日剂量为建议成年患者服用0.01mg至2000mg该化合物，可以单次给药或分次给药。可与载体材料组合以产生单一剂型的活性成分的量通常是产生治疗效果的化合物的量。
在禁止对人体实施的方法授予专利的司法管辖区，将组合物“施用”给人类受试者的含义应限于规定人类受试者将通过任何技术自我施用的受控物质(例如、口服、吸入、局部应用、注射、***等)。旨在与定义可专利主题的法律或法规一致的最广泛的合理解释。在不禁止为在人体上实施的方法申请专利的司法管辖区中，组合物的“施用”包括在人体上实施的方法和上述活动。
应当理解，虽然结合其详细描述来阅读本申请，但前述描述旨在说明而不是限制由所附权利要求的范围限定的本申请的范围。其他方面、优点和修改在权利要求的范围内。
本申请化合物的合成
本申请化合物可以按照以下实施例中描述的方式，或使用其他合成技术，并使用常见的实验室技术，在有机化学家的技能范围内制备。
实施例
按照以下实施例来制备本申请化合物。
实施例1：化合物1的制备
向2-氯-6-甲基异烟酸甲酯(2.0g，10.8mmol)的1,4-二氧六环(40ml)溶液中加入Me6Sn2(3.7g，11.3mmol)和Pd(PPh3)4(622.0mg，0.53mmol)。在N2保护下100℃搅拌反应2小时。LCMS监测反应完全后真空浓缩。将残余物溶解在乙腈(40mL)中并加入式a-3化合物(1.37g，5.4mmol)和PdAmphos(381.0mg，0.53mmol)。在N2保护下100℃再搅拌2小时。LCMS监测反应完全后直接真空浓缩。残余物通过柱层析纯化(PE/EtOAc＝100:0到3:2)得到黄色化合物a-4(500.0mg，12.5％收率)。LCMS(ESI)：C18H28N3O4Si[M+H]+ms/z，计算值378.2，实测378.2。
将LiOH(63.5mg，2.64mmol)加入到化合物a-4(500.0mg，1.32mmol)的四氢呋喃(5mL)和H2O(5ml)溶液中。在室温下搅拌反应4小时。LCMS显示检测到所需的MS。真空浓缩后用3N HCl调节至pH＝5并用EtOAc萃取。合并有机相，经无水硫酸钠干燥，过滤，并真空浓缩得到棕色化合物a-5(300mg，62.4％收率)。LCMS(ESI)：C17H26N3O4Si[M+H]+ms/z计算值364.2，实测364.2。
向化合物a-5(300.0mg，0.825mmol)的DMF(10ml)溶液中加入 N-甲基咪唑(NMI)(135.3mg，1.65mmol)和氯代-N,N,N',N'-四甲基甲脒六氟磷酸盐(TCFH)(347.4mg，1.24mmol)。搅拌30分钟后，将1-[(2S)-2-{2-[(叔丁基二甲基甲硅烷基)氧基]乙氧基}丙基]-1,3-苯并二唑-2-胺a-6(230.8mg，0.66mmol)加入到上述混合物中。室温搅拌16小时。LCMS显示检测到所需的MS。然后用水淬灭，EtOAc萃取，饱和食盐水洗涤，并用NaSO4干燥，过滤，并真空浓缩。得到棕色油状化合物a-7(500.0mg，54.9％收率)。产物无需纯化可直接用于下一步。LCMS(ESI)：C35H55N6O5Si2[M+H]+ms/z，计算值695.7，实测695.7。
化合物a-7(180.0mg，0.26mmol)在盐酸二氧六环(5ml)溶液中搅拌16小时。LCMS显示检测到所需的MS。真空浓缩得到粗产物，该粗产物通过C18反相柱(H2O(0.1％甲酸(FA)/MeCN＝90/10到50/50)纯化，得到类白色固体化合物a-8(60.0mg，51.7％收率)。LCMS(ESI)：C23H27N6O4[M+H]+ms/z，计算值451.3，实测451.3。
向化合物a-8(60.0mg，0.13mmol)的甲苯溶液中加入(氰基亚甲基)三丁基正膦(CMBP)(63.4mg，0.26mmol)。混合物在120℃下搅拌2小时，反应完成后减压除去有机溶剂。残余物通过制备型prep-HPLC(柱：Gemini 5um C18 150x 21.2mm，流动相：ACN～H2O(0.1％FA)，梯度：40～90，7.6min)纯化，得到类白色固体化合物1(10.49mg，97.8％纯度，17.8％收率，100％ee)。
LCMS(ESI)：C23H25N6O3[M+H]+ms/z计算值433.2，实测433.2。1H NMR(400MHz,DMSO-d6,ppm)12.71(s,1H),8.69(s,1H),7.94(s,1H),7.62(d,J＝8.0Hz,1H),7.56-7.53(m,2H),7.30–7.22(m,2H),4.50(t,J＝8.4Hz,1H),4.40-4.28(m,3H),4.13–4.09(m,1H),4.00–3.94(m,1H),3.87–3.78(m,1H),3.75(s,3H),2.57(s,3H),1.11(d,J＝5.6Hz,3H)。HPLC:254nm(97.8％),214nm(97.6％)。CHIRAL-HPLC:254nm(100.0％),214nm(100.0％)。
实施例2：化合物2的制备
向2-氯-6-甲氧基异烟酸甲酯(1.0g，4.96mmol)的1,4-二氧六环(20ml)溶液中加入PCy3(139.1mg，0.50mmol)、KOAc(973.5mg，9.92mmol)、化合物b-2(1.89g，7.44mmol)和Pd2(dba)3(285.2mg，0.50mmol)。在N2保护下80℃搅拌反应2小时。通过LCMS监测反应并加入化合物b-4(878.6mg，2.48mmol)、K3PO4(1.1g，4.96mmol)、Pd(dppf)Cl2(181.5mg，2.48mmol)和H2O(2ml)。继续在N2保护下80℃将反应再搅拌2小时。通过LCMS监测反应完全后，真空浓缩除去溶剂。残余物通过快速色谱法(DCM/MeOH＝100/0至70/30洗脱)得到棕色油状化合物b-5(600.0mg，30.7％收率)。LCMS(ESI)：C18H27N3O5Si[M+H]+ms/z，计算值394.2，实测394.2。
将LiOH(73.1mg，3.05mmol)溶于H2O(5ml)中并滴加到化合物b-5(600.0mg，1.52mmol)的THF(5mL)溶液中。室温下搅拌反应4小时。LCMS显示检测到所需的MS。真空浓缩除去溶剂，所得物用2N HCl 调节至pH＝5并用EtOAc萃取，NaSO4干燥，过滤旋干得到棕色固体化合物b-6(200mg，34.6％收率)。LCMS(ESI)：C17H25N3O5Si[M+H]+ms/z，计算值380.2，实测380.2。
向化合物b-6(200.0mg，0.527mmol)的DMF(10ml)溶液中加入NMI(86.0mg，1.05mmol)和TCFH(295.8mg，1.05mmol)。室温搅拌30分钟后，将化合物a-6(276.4mg，0.79mmol)加入到上述混合物中。25℃下搅拌反应16小时。LCMS显示检测到所需的MS。反应液用水淬灭，EtOAc萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，过滤并浓缩得到棕色油状化合物b-7，化合物无需纯化可直接用于下一步。LCMS(ESI)：C35H54N6O6Si2[M+H]+ms/z，计算值711.4，实测711.4。
化合物b-7(50.0mg，0.13mmol)在盐酸二氧六环溶液中搅拌16小时。LCMS显示检测到所需的MS。真空除去溶剂得到粗产物，该粗产物通过C18反相柱H2O(0.1％甲酸(FA)/MeCN＝100/0到0/100洗脱)得到类白色固体化合物b-8(15.0mg，43.5％收率)。LCMS(ESI)：C23H26N6O5[M+H]+ms/z，计算值467.1，实测467.1。
向化合物b-8(10.0mg，0.02mmol)的甲苯溶液中加入CMBP(10.3mg，0.04mmol)。混合物在120℃下搅拌反应2小时。LCMS显示反应完全后减压除去有机溶剂。残余物通过制备型prep-HPLC(柱：Gemini 5um C18 150 x 21.2mm，流动相：ACN～H2O(0.1％FA)，梯度：40～90，8.1min)纯化，得到化合物2(1mg，10.0％收率)。
1H NMR(400MHz,DMSO-d6,ppm):12.73(s,1H),8.47(s,1H),7.96(s,1H),7.62(d,J＝7.2Hz,1H),7.53(d,J＝7.2Hz,1H),7.31-7.20(m,2H),7.07(s,1H),4.51(t,J＝8.0Hz,1H),4.42-4.33(m,1H),4.31-4.28(m,2H),4.21-4.03(m,1H),3.95(s,4H),3.83-3.79(m,1H),3.75(s,3H),1.10(d,J＝5.2Hz,3H).HPLC(化合物2)纯度：254nm(99.7％),214nm(99.7％)。LCMS(ESI)(化合物2)：C23H24N6O4[M+H]+ms/z，计算值449.3，实测449.3。
实施例3：化合物3的制备
将50％氢氧化钠水溶液(25mL)和四正丁基硫酸氢铵(16.8g，0.0493mol)分别加入到化合物c-2(6.5g，0.0301mol)和化合物c-1(5.0g，0.0274mol)的甲苯(100mL)溶液中，40℃下搅拌17小时，LCMS显示检测到所需MS。向反应混合物中加入水并用甲苯萃取混合物。有机层用饱和盐水洗涤，用无水硫酸钠干燥并减压浓缩。残余物通过硅胶柱色谱法(PE:EtOAc＝100/0至0/100来洗脱)得到无色油状化合物c-3(7.0g，80.6％收率)。LCMS(ESI)：C19H25O4[M+H]+m/z，计算值317.1，实测317.3。
在冰冷却下，将硝酸铈二铵(19.1g，0.0884mol)加入到化合物c-3(7.0 g，0.0221mol)的乙腈(200mL)和水(50mL)混合溶液中，并在25℃下搅拌5小时。LCMS显示出所需的MS。将饱和亚硫酸钠水溶液和饱和碳酸氢钠水溶液加入到反应混合物中，用乙酸乙酯萃取混合物。有机层用饱和盐水洗涤，无水硫酸镁干燥并减压浓缩。残余物通过硅胶柱色谱(PE:EtOAc＝100/0至0/100来洗脱)分离和纯化，得到化合物c-4(5.0g，96.8％收率)。LCMS(ESI)：C12H19O3[M+H]+m/z，计算值211.1，实测211.1。
在冰冷却下，分别将三乙胺(4.8g，0.0476mol)和甲磺酰氯(3.0g，0.0261mol)慢慢滴加到化合物c-4(5.0g，0.0238mol)的EtOAc(100mL)溶液中。在0℃下搅拌反应1小时。反应完全后向反应混合物中加入水，并用二氯甲烷萃取。有机层用饱和盐水洗涤，无水硫酸镁干燥。真空除去溶剂，得到黄色油状化合物c-5，化合物无需纯化可直接用于下一步反应。
向化合物c-5(6.0g，0.0208mol)的DMF(60mL)溶液中加入叠氮化钠(2.7g，0.0416mol)。在50℃下搅拌混合物搅拌16小时。反应完全后，冷却到室温，将反应液倒入水中，用乙酸乙酯萃取，合并有机相。有机层用饱和盐水洗涤，无水硫酸镁干燥，减压浓缩，得到棕色油状化合物c-6(6.0g，98.0％收率)，化合物无需纯化可直接用于下一步反应。
将三苯基膦(13.4g，0.051mol)加入到化合物c-6(6.0g，0.0255mol)的四氢呋喃(20mL)和水(12mL)的溶液中。在N2保护下室温搅拌24小时，LCMS显示检测到所需的MS。减压除去溶剂，得到粗产物，该粗产物通过快速色谱法(DCM/MeOH在30分钟内从100/0至90/10来洗脱)得到黄色油状化合物c-7(3.5g，52.5％收率)。LCMS(ESI)：C12H20NO2[M+H]+m/z，计算值210.1，实测210.1。
将化合物c-7(3.5g，0.0167mol)，1-氟-2硝基苯c-8(2.8g，0.0200mol)和二异丙基乙胺(DIEA)(4.3g，0.0334mol)溶于DMSO溶液(50ml)。在80℃下搅拌反应混合物16小时，LCMS显示检测到所需的MS。将反应 冷却至25℃。加入100mL水，用EtOAc萃取，饱和盐水洗涤，NaSO4干燥并浓缩。残余物通过快速色谱法(PE/EtOAc在30分钟内从100/0至0/100洗脱)纯化得到化合物c-9(2.0g，34.7％收率)。LCMS(ESI)：C18H23N2O4[M+Na]+m/z，计算值353.1，实测353.1。
向化合物c-9(2.0g，0.0061mol)的MeOH(100ml)和乙酸(0.5ml)溶液中加入Pd/C(2.0g，0.0183mol)。在H2(1atm)氛围下25℃搅拌2天。将反应混合物过滤并浓缩，得到棕色固体化合物c-10(1.0g，68.8％产率)。LCMS(ESI)：C11H19N2O2[M+H]+m/z，计算值211.1，实测211.2。
将BrCN(503.7mg，4.7558mmol)加入到化合物c-10(500.0mg，2.3779mmol)在甲醇(10ml)和H2O(10ml)溶液中。在50℃下搅拌反应混合物1小时。浓缩反应混合物，得到黄色油状化合物c-11(500.0mg，84.9％收率)。LCMS(ESI)：C12H18N3O2[M+H]+m/z，计算值236.1，实测236.1。
将化合物c-11(500.0mg，2.1251mmol)、叔丁基(氯代)二甲基硅烷(960.9mg，6.3753mmol)和咪唑(434.0mg，6.3753mmol)溶于DMF(10ml)中。在25℃下搅拌反应混合物16小时，LCMS显示检测到所需的MS。用水(70mL)淬灭并用EtOAc萃取，有机层用盐水洗涤，无水NaSO4干燥，过滤并浓缩得到产物。粗品通过快速色谱法(DCM/MeOH在30分钟内从100/0到0/10)纯化得到化合物c-12(300.0mg，47.5％产率)。LCMS(ESI)：C18H32N3O2Si[M+H]+m/z，计算值350.2，实测350.1。
向化合物c-12(220.4mg，0.6307mmol)的DMF(10ml)溶液中加入化合物b-6(200.0mg，0.5256mmol)、TCFH(589.9mg，2.1024mmol)和NMI(172.6mg，2.1024mmol)。在25℃下搅拌反应混合物16小时，LCMS显示检测到所需的MS。用水(50mL)淬灭反应，用EtOAc(3×30mL)萃取并用盐水(100mL)洗涤，无水NaSO4干燥，过滤并浓缩得到棕色油状化合物c-13(100.0mg，31.8％收率)。化合物无需纯化，可直接用于下一 步反应。LCMS(ESI)：C35H55N6O6Si2[M+H]+m/z，计算值711.3，实测711.8。
化合物c-13(100.0mg，0.1404mmol)在盐酸二氧六环(5ml)的溶液中。25℃下搅拌反应混合物3小时，LCMS显示检测到所需的MS。在。浓缩混合物并通过C18反向快速色谱法(H2O(NH3.H2O)/MeCN在30分钟内从80/20至40/60来洗脱)纯化得到黄色固体化合物c-14(50.0mg，64.9％收率)。LCMS(ESI)：C23H27N6O5[M+H]+m/z，计算值467.2，实测467.3。
在N2保护下，化合物c-14(30.0mg，0.0643mmol)、PPh3(67.5mg，0.2572mmol)溶于THF(2ml)中。室温搅拌30分钟后，将偶氮二甲酸二异丙酯(DIAD)(52.0mg，0.2572mmol)的THF(1ml)溶液慢慢滴入上述反应液中。25℃下搅拌反应混合物3小时，LCMS显示检测到所需的MS。浓缩混合物并通过C18反向快速色谱法(H2O(FA)/MeCN在30分钟内从80/20至40/60来洗脱)纯化得到白色固体化合物3(3.2mg，99.6％纯度，11.0％收率)。
LCMS(ESI)：C23H26N6O4[M+H]+m/z，计算值449.1，实测449.3。1H NMR(400MHz，DMSO-d6，ppm)12.73(s,1H),8.47(s,1H),7.96(s,1H),7.62(d,J＝8.0Hz,1H),7.53(d,J＝7.2Hz,1H),7.31-7.20(m,2H),7.06(s,1H),4.51(t,J＝8.4Hz,1H),4.42-4.22(m,3H),4.17-4.04(m,1H),3.95(s,4H),3.87-3.77(m,1H),3.75(s,3H),1.11(d,J＝5.2Hz,3H)。HPLC纯度：254nm(99.6％),214nm(97.2％)。
实施例4：化合物4的制备
化合物4(黄色固体，6.25mg，99.4％纯度，15.6％收率，100％ee)和化合物2(黄色固体，6.75mg，99.7％纯度，16.9％收率，100％ee)由化合 物3(40.0mg，0.0892mmol)的拆分而来，拆分条件：chiral-prep-SFC(色谱柱：Daicel CHIRALPAK OJ-H，250mm×20mm I.D.，5μmm，流动相：CO2/MeOH(0.1％FA)，梯度:60-40，8min)(40.0mg，0.0892mmol)。
1H NMR(400MHz，DMSO-d6，ppm)(化合物4)：12.73(s,1H),8.47(s,1H),7.96(s,1H),7.62(d,J＝7.2Hz,1H),7.53(d,J＝7.2Hz,1H),7.31-7.20(m,2H),7.06(s,1H),4.58-4.46(m,1H),4.42-4.22(m,3H),4.21-4.03(m,1H),3.95(s,4H),3.81(d,J＝12.4Hz,1H),3.75(s,3H),1.10(d,J＝3.2Hz,3H)。HPLC(化合物4)纯度：254nm(99.4％),214nm(98.9％)。LCMS(ESI)(化合物4)：C23H25N6O4[M+H]+m/z，计算值449.2，实测449.3。
EGFR检测
如下测试本申请公开的化合物的EGFR抑制活性。
将本申请的化合物溶解在DMSO中。制备了1x激酶缓冲液。EGFR L858R/T790M/C797S购自Invitrogen(Cat.A33556)，EGFR(d746-750/T790M C797S)购自Carna(Cat.08-565)，酶用激酶缓冲液稀释至2.5x终浓度。使用的激酶底物22来自GL China(Cat.112393)。使用ATP和激酶底物在激酶缓冲液中的最终浓度为1.67x的底物混合物。在存在底物混合物的情况下，混合酶和化合物并使用终止缓冲液终止。使用Caliper EZ Reader(PerkinElmer model 122919/E)读取转化率并评估化合物的EGFR抑制活性IC50值(如下表2所示)。在10种不同浓度下以高达30μM的浓度测试化合物。
表2，本申请化合物的IC50值

通过猪脑磷脂人工膜测定来评估化合物的渗透性
用十二烷配置2％的猪脑磷脂提取物溶液，吸取该溶液接收板中，每孔5μL，静置10min形成人工脂质膜。每个受体板孔添加300μL的PBS(pH7.4)，每个供体板孔加入300μL含终浓度为10μM的测试化合物溶液。将接收板放入供体板中，25℃孵育16h。从受体板和供体板的每个孔中取50μL孵育液至96孔板中，加入200μL含内标(Alprazolam，Labetalol，Caffeine和Ketoprofen)的甲醇淬灭。750rpm涡旋100秒，于离心机3,220g离心20分钟，通过LC/MS/MS检测两端测试化合物的浓度。计算化合物有效渗透值Pe(以-Log10来体现)和回收率。
表3

Claims (26)

  1. 具有式(I)、式(IA)、式(II)或式(IIA)的化合物或其药学上可接受的盐：
    其中，环A为苯环或含选自N、O和S的1、2或3个杂原子的5-或6-元杂芳环；
    X为O或N(RN)；
    Y为O、N(RN)或CH2；
    RN各自独立地为H或C1-3烷基；
    R1为H或C1-3烷基；以及
    R2为C1-3烷基、C2-4烯基、C2-4炔基、卤素、C1-3烷氧基、氰基或N(RN)2。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中环A为苯环。
  3. 根据权利要求1所述的化合物或其药学上可接受的盐，其中环A为5-或6-元杂芳环，例如环A为5元杂芳环。
  4. 根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐，其中X为O。
  5. 根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐，其中X为NRN，例如X为NH或N-CH3。
  6. 根据权利要求1至5中任一项所述的化合物或其药学上可接受的盐，其中，Y为O。
  7. 根据权利要求1至5中任一项所述的化合物或其药学上可接受的盐，其中Y为CH2。
  8. 根据权利要求1至5中任一项所述的化合物或其药学上可接受的盐，其中Y为NRN。
  9. 根据权利要求1至8中任一项所述的化合物或其药学上可接受的盐，其中R1为H。
  10. 根据权利要求1至8中任一项所述的化合物或其药学上可接受的盐，其中R1为C1-3烷基，优选为甲基。
  11. 根据权利要求1至10中任一项所述的化合物或其药学上可接受的盐，其中R2为C1-3烷基，优选为甲基。
  12. 根据权利要求1至10中任一项所述的化合物或其药学上可接受的盐，其中R2为C1-3烷氧基，优选为甲氧基。
  13. 根据权利要求1至10中任一项所述的化合物或其药学上可接受的盐，其中R2为卤素，例如为F、Cl或Br。
  14. 根据权利要求1至10中任一项所述的化合物或其药学上可接受的盐，其中R2为氰基。
  15. 根据权利要求1至10中任一项所述的化合物或其药学上可接受的盐，其中R2为N(RN)2，例如NH2、NHMe或N(Me)2。
  16. 根据权利要求1至10中任一项所述的化合物或其药学上可接受的盐，具有式(IA)或式(IIA)的结构。
  17. 根据权利要求16所述的化合物或其药学上可接受的盐，其中，当 具有式(IA)的结构时，X和Y均为O，且R1和RN为甲基；当具有式(IIA)的结构时，X为O，且R1和RN为甲基。
  18. 具有如下所示结构的化合物或其药学上可接受的盐：


  19. 根据权利要求1至18中任一项所述的化合物或其药学上可接受的盐，具有至少一个氘。
  20. 一种药物组合物，包括权利要求1至19中任一项所述的化合物或其药学上可接受的盐，以及药学上可接受的载体。
  21. 一种抑制EGFR，尤其是突变EGFR的方法，包括使EGFR，尤其是突变EGFR与权利要求1至19中任一项所述的化合物或其药学上可接受的盐或者根据权利要求20所述的药物组合物接触。
  22. 一种治疗患有与突变EGFR相关的癌症的受试者的方法，包括向所述受试者施用权利要求1至19中任一项所述的化合物或其药学上可接受的盐或者根据权利要求20所述的药物组合物。
  23. 根据权利要求21或22所述的方法，其中，EGFR的突变是del 19、L858R、T790M和C797S中的一种或多种，优选所述突变EGFR是EGFR del 19 T790M C797S。
  24. 根据权利要求22或23所述的方法，其中，所述癌症选自非小细胞肺癌、脑癌、结直肠癌、膀胱癌、尿路上皮癌、乳腺癌、***癌、卵巢癌、头颈癌、胰腺癌、胃癌或间皮瘤，优选地所述癌症是非小细胞肺癌。
  25. 根据权利要求22至24中任一项所述的方法，其中，所述受试者患有脑转移。
  26. 根据权利要求22至24中任一项所述的方法，其中，所述受试者已经施用过奥希替尼。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114007698A (zh) * 2019-06-24 2022-02-01 勃林格殷格翰国际有限公司 作为egfr抑制剂的新型大环化合物和衍生物
CN114057771A (zh) * 2020-12-03 2022-02-18 北京鞍石生物科技有限责任公司 大环化合物及其制备方法和应用
CN114163454A (zh) * 2020-09-11 2022-03-11 上海翰森生物医药科技有限公司 含吡啶多环类衍生物抑制剂、其制备方法和应用
WO2022204544A1 (en) * 2021-03-26 2022-09-29 Theseus Pharmaceuticals, Inc. Macrocyclic egfr inhibitors for the treatment of cancer

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114007698A (zh) * 2019-06-24 2022-02-01 勃林格殷格翰国际有限公司 作为egfr抑制剂的新型大环化合物和衍生物
CN114163454A (zh) * 2020-09-11 2022-03-11 上海翰森生物医药科技有限公司 含吡啶多环类衍生物抑制剂、其制备方法和应用
CN114057771A (zh) * 2020-12-03 2022-02-18 北京鞍石生物科技有限责任公司 大环化合物及其制备方法和应用
WO2022204544A1 (en) * 2021-03-26 2022-09-29 Theseus Pharmaceuticals, Inc. Macrocyclic egfr inhibitors for the treatment of cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ENGELHARDT, H. ET AL.: "Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 62, 5 November 2019 (2019-11-05), XP055821569, DOI: 10.1021/acs.jmedchem.9b01169 *

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