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CN117024443A - EGFR inhibitors and uses thereof - Google Patents

EGFR inhibitors and uses thereof Download PDF

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Publication number
CN117024443A
CN117024443A CN202310420133.3A CN202310420133A CN117024443A CN 117024443 A CN117024443 A CN 117024443A CN 202310420133 A CN202310420133 A CN 202310420133A CN 117024443 A CN117024443 A CN 117024443A
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pharmaceutically acceptable
acceptable salt
compound
cancer
compound according
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陈金山
瑞吉屋·乔布拉
顾家敏
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Yuanqi Suzhou Biopharmaceutical Co ltd
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Yuanqi Suzhou Biopharmaceutical Co ltd
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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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present application provides compounds having the structure of formula (I), (IA), (II) or (IIA), or pharmaceutically acceptable salts thereof, and the use of such compounds or salts thereof for inhibiting EGFR, including mutant EGFR, including for the treatment of cancers associated with, for example, aberrant EGFR activity.

Description

EGFR inhibitors and uses thereof
Technical Field
The present application relates to novel EGFR inhibitors and their use, for example, in the treatment of a variety of cancers.
Background
The epidermal growth factor receptor (Epidermal Growth Factor Receptor, EGFR) is a receptor tyrosine kinase that transduces mitotic signals. EGFR gene mutations are found in approximately 12% to 47% of non-small cell lung Cancer (NSCLC) tumors with adenocarcinoma histology (Midha, A.et al.Am J Cancer Res.2015;5 (9): 2892-2911).
There is an urgent need for effective and clinically relevant EGFR inhibitors that can inhibit EGFR mutants, but exhibit selectivity for wild-type EGFR.
Disclosure of Invention
The present application provides compounds having the structure of formula (I), (IA), (II) or (IIA), or a pharmaceutically acceptable salt thereof:
wherein 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 ) The method comprises the steps of carrying out a first treatment on the surface of the Y is O, N (R) N ) Or CH (CH) 2 ；R N Each independently is H or C 1-3 An alkyl group; r is R 1 Is H or C 1-3 An alkyl group; r is as follows 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 also provides compounds shown in table 1 below, or pharmaceutically acceptable salts thereof:
TABLE 1 exemplary Compounds of the application
The application further provides methods of inhibiting EGFR comprising contacting EGFR with a compound of the present application or a salt thereof. Furthermore, the present application provides a method of treating a subject having a cancer associated with mutant EGFR comprising administering to the subject a compound of the application or a salt thereof.
In another aspect, the application relates to the use of the above compound in the manufacture of a medicament for preventing, inhibiting or treating cancer associated with mutant EGFR.
Detailed Description
There is a medical need for new EGFR Tyrosine Kinase Inhibitors (TKIs) that can treat lung cancer that is resistant to current EGFR treatment regimens, such as EGFR C797S mutation-related cancers that occur in current standard of care austinib (osimerinib) treatment. To facilitate effective dosing and reduce EGFR-mediated targeting toxicity, the next-generation EGFR TKI should not inhibit wild-type EGFR. High selectivity across the human kinase group will reduce off-target toxicity of the compounds. Another desirable feature of the next-generation EGFR TKI is its ability to effectively penetrate into the brain (blood brain barrier penetration) to be able to treat brain metastases and pia mater diseases. Furthermore, the next generation EGFR TKI should exhibit reduced resistance compared to existing EGFR TKIs to increase the duration of response in patients.
The above-described properties of the next generation EGFR TKI will enable the use of third generation TKIs, such as octenib, to treat patients with advanced secondary therapies (e.g., genotype EGFR del 19/L858R T790M C797S) who currently have no targeted therapy options. Furthermore, these properties also make it possible for the next generation EGFR TKI to provide treatment options for patients undergoing first-line treatment progression for EGFR C797S mutant. The activity of the next generation EGFR TKI against resistance mutations such as T790M, C797X (x= S, G, N) and L792X (x= F, H, Y) is likely to delay the development of resistance by EGFR intra-target mutations in NSCLC tumors.
The present application includes compounds for treating cancers that express mutant EGFR, wherein the mutant EGFR includes various oncogenic and resistant 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):
wherein 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 (CH) 2 ；
R N Each independently is H or C 1-3 An alkyl group;
R 1 is H or C 1-3 An alkyl group; and
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 。
As used herein, the term "alkyl" refers to straight and branched chain saturated hydrocarbon groups. Term C n Meaning that the alkyl group has "n" carbon atoms. For example, C 4 Alkyl refers to an alkyl group having 4 carbon atoms. C (C) 1-6 Alkyl refers to an alkyl group having a 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) of carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2-methylpropyl) and tert-butyl (1, 1-dimethylethyl). Unless otherwise indicated, 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. Alkynyl groups are alkyl groups having at least one triple bond.
As used herein, the term "alkoxy" or "alkoxy" refers to an "-O-alkyl" group.
As used herein, the term "heteroaryl ring" refers to a heterocycle 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 (i.e., 2, 3, 4, or 5 ring carbon atoms). Specifically contemplated rings include pyrazolyl, thienyl, furanyl, pyridyl, pyrrolyl, oxazolyl, quinolinyl, thienyl, isoquinolinyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.
In many cases, ring a is a benzene ring. In many cases, ring a is a 5-or 6-membered heteroaryl ring. In certain instances, ring a is a 5 membered heteroaryl ring.
In many cases, X is O. In some cases, X is NR N . In some cases, X is NH. In many cases, R N Is C 1-3 Alkyl, e.g. X is N (C) 1-3 Alkyl), for example NMe. In many cases, Y is CH 2 . In some cases, Y is O. In some cases, Y is N (R N ) For example NH or N (C) 1-3 Alkyl), for example NMe.
In many cases, R 1 Is H. In many cases, R 1 Is C 1-3 An alkyl group. In some cases, R 1 Is Me. In many cases, R 2 Is C 1-3 An alkyl group. In some cases, R 2 Is Me. In many cases, R 2 Is C 1-3 An alkoxy group. In some cases, R 2 Is OMe. In many cases, R 2 Is halogen. In some cases, R 2 Is F, cl or Br. In many cases, R 2 Is cyano. In some cases, R 2 Is C 2-4 Alkenyl or C 2-4 Alkynyl groups. In some cases, R 2 Is N (R) N ) 2 For example NH 2 NH (Me) or N (Me) 2 。
In many cases, the compounds described herein, or pharmaceutically acceptable salts thereof, have the structures shown in table 1 above.
The compounds of the application include all pharmaceutically acceptable isotopically-labelled compounds in which one or more atoms in a compound of the application may be replaced by the same atom Atomic substitution of atomic numbers other than atomic mass or mass number, which is usually less found in nature, examples of which include isotopes of hydrogen, e.g 2 H and 3 H. in some cases, one or more hydrogen atoms in the compounds of the application are in particular deuterium 2 H) A. The application relates to a method for producing a fibre-reinforced plastic composite In some cases, the compounds of the present application have at least one deuterium therein.
The term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic acid addition salt of a compound 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 formed thereby. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, and amino acid salts and the like (see, e.g., berge et al (1977) "Pharmaceutical Salts", j.pharm. Sci. 66:1-19.).
In some embodiments, the compounds provided herein may contain one or more acidic functionalities and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic base addition salt of a compound provided herein. These salts can likewise be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in the free acid form with a suitable base, such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, or ammonia, or a pharmaceutically acceptable primary, secondary or tertiary organic amine. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, aluminum salts, and the like. Representative organic amines useful in forming the base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, e.g., berge et al, supra).
Therapeutic targets
The compounds of the application are useful in methods of inhibiting EGFR in a cell. In various aspects, the methods comprise contacting EGFR with a compound disclosed herein, or a salt thereof. In some cases, the EGFR is mutant EGFR. Contemplated mutant EGFR include, but are not limited to: EGFR del19T790M, EGFR del19C797S, EGFR del19C 797X (X G or N), EGFR del19T790M C797S, EGFR del T790M C797X (X G or N), EGFR del 19L792X (X F, H, or Y), EGFR del19T790M L792X (X F, H, or Y), EGFR L858R, EGFR L858R R790M, EGFR L858RC797S, EGFR L858R C797X (X G or N), EGFR L858R T790M C797S, EGFR L858R T790M C797X (X G or N), EGFR L858R L792X (X F, H or Y) and EGFR L858R T790M L792X (X F, H or Y), wherein del19 represents exon 19 deletion. In various cases, the mutant of EGFR comprises one or more of del19, L858R, T790M and C797S. In some cases, the mutant EGFR is EGFR del19t790m c797s. Inhibition of EGFR may be assessed using any known technique, including, for example, assays described in the examples below.
The compounds of the application are useful in methods of treating cancer, particularly cancer associated with aberrant EGFR activity, in a subject suffering from cancer. In various cases, the cancer expresses EGFR mutations. In some cases, the mutant of EGFR comprises one or more of del 19, L858R, T790M and C797S. In some cases, the mutant EGFR is EGFR del 19t790m c797s.
In some cases, the subject has previously received cancer therapy (i.e., the EGFR inhibitor is two-line or higher line therapy). In certain instances, the previous cancer treatment is one or more of gefitinib (gefitinib), erlotinib (erlotinib), afatinib (afatinib), dactinib (dacominib), octtinib, ibrutinib (olimbinib), nazatinib (nazartinib), or AC 0010. In many cases, previous therapies involved octreotide.
Cancers of particular concern 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. In some cases, the cancer is non-small cell lung cancer. In certain instances, the subject has brain metastasis.
Pharmaceutical composition
The application also includes the pharmaceutical composition itself. The pharmaceutical composition generally includes a pharmaceutically acceptable carrier. Accordingly, the present application also provides pharmaceutical compositions comprising a compound of the present application (e.g., 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.
As used herein, the phrase "pharmaceutically acceptable" refers to those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, 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. As used herein, the term "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the patient. Some examples of materials that may be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) Starches such as corn starch, potato starch, substituted or unsubstituted cyclodextrin; (3) Cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter, suppository waxes; (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; (12) esters such as ethyl oleate, ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide, aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances for use in pharmaceutical compositions. In certain embodiments, the pharmaceutical compositions provided herein are non-caloric, i.e., do not cause significant temperature increases when administered to a patient.
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preserving and antioxidant agents, may also be present in the composition.
Examples of pharmaceutically acceptable antioxidants include: (1) Water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) Oil-soluble antioxidants such as ascorbyl palmitate, butyl Hydroxy Anisole (BHA), butyl Hydroxy Toluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; (3) Metal chelators such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.
The pharmaceutical composition may further comprise adjuvants such as preserving, wetting, emulsifying and dispersing agents. By adding various antibacterial and antifungal agents, such as parahydroxybenzoate, chlorobutanol, phenol sorbic acid, and the like, the prevention of the action of microorganisms can be ensured. It may also be desirable to include tonicity adjusting agents, such as sugars and the like, in the composition. In addition, absorption of the injectable pharmaceutical dosage form may be prolonged by the inclusion of delayed absorbents such as aluminum monostearate and gelatin.
As is well known in the art, the compositions prepared according to the present application may be administered in a variety of forms, depending on the condition to be treated and the age, condition and weight of the patient. For example, when the compositions are orally administered, they may be formulated as tablets, capsules, granules, powders or syrups; alternatively, for parenteral administration, they may be formulated as injections (intravenous, intramuscular or subcutaneous), instillation preparations or suppositories. For administration via the ocular mucosa route, they may be formulated as eye drops or eye ointments. These compositions may be prepared in conventional manner in connection with the methods described herein, and if desired, the active ingredient may be admixed with any conventional additives or excipients, such as binders, disintegrants, lubricants, flavoring agents, solubilizers, suspending aids, emulsifiers or coating agents.
Compositions suitable for oral administration may be in the form of capsules (e.g., gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, typically sucrose and acacia or tragacanth), powders, lozenges, granules, or as a solution, a suspension in an aqueous or non-aqueous liquid, an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, lozenges (using an inert base such as gelatin and glycerin or sucrose and acacia) and/or as a mouthwash or the like, each containing a predetermined amount of a compound provided herein as the active ingredient. The composition may also be administered in the form of a pill, granule or paste. Oral compositions typically include an inert diluent or an edible carrier.
Pharmaceutically compatible binders and/or adjuvant materials may be included as part of the oral composition. In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient may be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or with any of the following: (1) Fillers or extenders such as starch, cyclodextrin, lactose, sucrose, saccharin, glucose, mannitol, and/or silicic acid; (2) Binders such as carboxymethyl cellulose, microcrystalline cellulose, gum tragacanth, alginates, gelatin, polyvinylpyrrolidone, sucrose, and/or acacia; (3) humectants, such as glycerin; (4) Disintegrants, such as agar-agar, calcium carbonate, potato starch, corn starch or tapioca starch, alginic acid, primogel, certain silicates and sodium carbonate; (5) solution retarders such as paraffin; (6) absorption enhancers such as quaternary ammonium compounds; (7) Wetting agents such as acetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin, bentonite; (9) Lubricants such as talc, calcium stearate, magnesium stearate, steroids, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) glidants such as colloidal silicon dioxide; (11) a colorant; and (12) flavoring agents such as peppermint, methyl salicylate, orange flavoring. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also use excipients such as lactose or milk sugar, high molecular weight polyethylene glycols and the like as fillers in soft and hard-filled gelatin capsules.
Tablets may optionally be prepared by compression or molding using one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., 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 otherwise prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation arts. They may also be formulated so as to provide slow or controlled release of the active ingredient therein, for example using hydroxypropylmethyl cellulose in varying proportions 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 adding a sterilizing agent in the form of a sterile solid composition which is soluble in sterile water or some other sterile injectable medium immediately prior to use. These compositions may also optionally contain opacifying agents and may be compositions which they release the active ingredient(s) in a delayed manner, optionally only or preferably in a specific part of the gastrointestinal tract. Examples of embedding compositions that may be used include polymers and waxes. The active ingredient may 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. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycols and fatty acid esters of sorbitan esters, and mixtures thereof.
In addition to inert diluents, the oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.
Suspensions, in addition to the active compounds, may contain suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
Pharmaceutical compositions suitable for parenteral administration may comprise one or more compounds provided herein in combination with one or more pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted as sterile injectable solutions or dispersions just prior to use which may contain antioxidants, buffers, bacteriostats, solutes which render the composition isotonic with the blood of the intended recipient or suspending or thickening agents.
Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions provided herein include water for injection (e.g., sterile water for injection), bacteriostatic water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycols such as liquid polyethylene glycols, and the like), sterile buffers (such as citrate buffers), and suitable mixtures thereof, vegetable oils (such as olive oil), injectable organic esters (e.g., olive oil)Ethyl oleate) and Cremophor EL TM (BASF, parsippany, N.J.). In all cases, the composition must be sterile and should be fluid to the extent that easy injection is possible. Proper fluidity can be maintained, for example, by the use of a coating material, such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
The composition should be stable under the conditions of manufacture and storage and must be preserved against contamination by 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, and the like. In many cases, it is preferred to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Absorption of the injectable composition may be prolonged by including in the composition agents which delay absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions may be prepared by incorporating the active compound in the required amount in combination with one or more of the ingredients enumerated above, as required, with an appropriate solvent, followed by filtered sterilization. Generally, 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. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation method is freeze-drying (lyophilization) which yields a powder of the active ingredient plus any additional desired ingredient in a previously sterile-filtered solution thereof.
Injectable depot forms (Injectable depot form) can be prepared by forming a microencapsulated or nanocapsule matrix of the compounds of the application in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of agent to polymer, and the nature of the particular 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 embedding the agent in liposomes, microemulsions or nanoemulsions that are compatible with body tissues.
For administration by inhalation, the compounds may be delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant (e.g., a gas such as carbon dioxide) or from a nebulizer. Such methods include those described in U.S. patent No.6,468,798. In addition, intranasal delivery may be accomplished, as described, inter alia, in Hamajima et al, clin. Immunol. Immunopathol, 88 (2), 205-10 (1998). Liposomes (e.g., as described in U.S. patent No.6,472,375, incorporated herein by reference in its entirety), microcapsules, and nanocapsules may also be used. Biodegradable, targetable microparticle delivery systems or biodegradable, targetable nanoparticle delivery systems (e.g., as described in U.S. patent No.6,471,996, which is incorporated herein by reference in its entirety) may also be used.
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 may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated 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. For transdermal administration, the active compounds may be formulated into ointments, salves, gels, or creams as known in the art.
Ointments, pastes, creams and gels may contain, in addition to one or more compounds provided herein, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
In addition to the compounds provided by the present application, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. The spray may also contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.
The compounds provided herein may be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal formulation, or solid particles containing a compound or composition provided herein. Non-aqueous (e.g., fluorocarbon propellant) suspensions may be used. In some embodiments, sonic atomizers may also be used because they minimize the likelihood of the agent being exposed to shear forces that can lead to degradation of the compound.
Generally, aqueous aerosols may be prepared by formulating an aqueous solution or suspension of the agent with conventional pharmaceutically acceptable carriers and stabilizers. The carrier and stabilizer will vary with the requirements of the particular composition but will typically include nonionic surfactants @(polysorbate), ->(poloxamer), sorbitan esters, lecithin,>(polyethoxylates)), a pharmaceutically acceptable co-solvent (such as polyethylene glycol), a non-harmful protein (such as serum albumin), sorbitan esters, oleic acid, lecithin, amino acids (such as glycine), buffers, salts, sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions.
Transdermal patches have the additional advantage of controlled delivery of the compounds provided by the present application to the body. Such dosage forms may be prepared by dissolving or dispersing the agent in a suitable medium. Absorption enhancers may also be used to increase the flux of a compound across the skin. The rate of such flux may be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
The pharmaceutical compositions may also be formulated for rectal and/or vaginal delivery in the form of suppositories or retention enemas. 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 rectum or vaginal cavity and release the active agent. Compositions suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray compositions containing such carriers as are known in the art to be appropriate.
The therapeutic compounds may also be prepared with carriers that protect the therapeutic compounds from rapid elimination from the body, such as controlled release compositions, including implants and microencapsulated delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid may be used. Such compositions may be prepared using standard techniques or commercially available from, for example, alza Corporation and Nova Pharmaceuticals, inc. Liposomal suspensions (including liposomes targeted to selected cells having monoclonal antibodies to cellular antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. 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 orally, nasally (e.g., by spraying), rectally, intravaginally, parenterally, intracisternally and topically (e.g., by powder, ointment or drops), and include orally and sublingually. Regardless of the route of administration selected, the compounds provided herein and/or the pharmaceutical compositions provided herein, which may be used in a suitable hydrated form, may be formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art. In another embodiment, the pharmaceutical composition is an oral solution or a parenteral solution. Another embodiment is a lyophilized formulation that can be reconstituted prior to administration. As a solid, the composition may also include a tablet, capsule or powder.
The actual dosage level of the active ingredient in the pharmaceutical compositions provided herein can be varied to achieve a "therapeutically effective amount," which is the amount of active ingredient that achieves the desired therapeutic response for a particular patient, composition, and mode of administration without toxicity to the patient.
The concentration of the compounds provided herein in a pharmaceutically acceptable mixture will vary depending on factors including: the dose of the compound to be administered, the pharmacokinetic profile of the compound used and the route of administration. In some embodiments, the compositions provided herein may be provided in aqueous solutions containing about 0.1% to 10% (w/v) of the compounds disclosed herein, as well as other substances, for parenteral administration. Typical dosages may range from about 0.01 to about 50mg/kg body weight per day, administered in 1-4 divided doses. Each separate dose may contain the same or different compounds. The dosage will be a therapeutically effective amount, depending on several factors, including the overall health of the patient, as well as the composition and route of administration of the selected compound.
Dosage forms or compositions containing from 0.005% to 100% of the compounds of the application may be prepared, with the remainder consisting of a non-toxic carrier. Methods of preparing these compositions are known to those skilled in the art. Contemplated compositions may comprise 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 the dosage will vary depending on the symptoms, age and weight of the patient, the nature and severity of the disease to be treated or prevented, the route of administration and the pharmaceutical form, the daily dosage is usually 0.01mg to 2000mg of the compound recommended for adult patients, and may be administered in single or divided doses. The amount of active ingredient that can be combined with the carrier material to produce a single dosage form is typically the amount of the compound that produces a therapeutic effect.
In jurisdictions where patenting methods practiced on humans are prohibited, the meaning of "administering" a composition to a human subject should be limited to a controlled substance (e.g., oral, inhaled, topical application, injection, insertion, etc.) that prescribes that the human subject be self-administered by any technique. Is intended to be the broadest reasonable interpretation consistent with laws or regulations defining patentable subject matter. In jurisdictions where patenting methods for implementation on the human body is not prohibited, "administration" of a composition includes methods implemented on the human body and the activities described above.
It is to be understood that the foregoing description, while read in conjunction with the detailed description thereof, is intended to illustrate and not limit the scope of the application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the claims.
Synthesis of the Compounds of the application
The compounds of the application may be prepared in the manner described in the examples below, or using other synthetic techniques, and using common laboratory techniques, within the skill of the organic chemist.
Examples
The compounds of the application are prepared according to the following examples.
Example 1: preparation of Compound 1
To a solution of methyl 2-chloro-6-methyliisonicotinate (2.0 g,10.8 mmol) in 1, 4-dioxane (40 ml) was added Me 6 Sn 2 (3.7 g,11.3 mmol) and Pd (PPh) 3 ) 4 (622.0 mg,0.53 mmol). At N 2 The reaction was stirred at 100℃for 2 hours under protection. LCMS monitored reaction was complete and concentrated in vacuo. The residue was dissolved in acetonitrile (40 mL) and the compound of formula a-3 (1.37 g,5.4 mmol) and PdCamphos (381.0 mg,0.53 mmol) were added. At N 2 Stirring is carried out for 2 hours at 100 ℃ under protection. LCMS monitored reaction was complete and concentrated directly in vacuo. Purification of the residue by column chromatography (PE/etoac=100:0 to 3:2) afforded yellow compound a-4 (500.0 m)g,12.5% yield). LCMS (ESI): c (C) 18 H 28 N 3 O 4 Si[M+H] + ms/z, calculated 378.2, found 378.2.
LiOH (63.5 mg,2.64 mmol) was added to tetrahydrofuran (5 mL) and H of compound a-4 (500.0 mg,1.32 mmol) 2 O (5 ml) solution. The reaction was stirred at room temperature for 4 hours. LCMS showed detection of the desired MS. After concentration in vacuo, ph=5 was adjusted with 3N HCl and extracted with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford brown compound a-5 (300 mg,62.4% yield). LCMS (ESI): C17H26N3O4Si [ M+H ]] + ms/z calculated 364.2, found 364.2.
To a solution of compound a-5 (300.0 mg, 0.823mmol) in DMF (10 ml) were added N-methylimidazole (NMI) (135.3 mg,1.65 mmol) and chloro-N, N, N ', N' -tetramethylformamidine hexafluorophosphate (TCFH) (347.4 mg,1.24 mmol). After stirring for 30 minutes, 1- [ (2S) -2- {2- [ (tert-butyldimethylsilyl) oxy ]Ethoxy } propyl radical]-1, 3-Benzodiazol-2-amine a-6 (230.8 mg,0.66 mmol) was added to the above mixture. Stirring at room temperature for 16 hours. LCMS showed detection of the desired MS. Then quenched with water, extracted with EtOAc, washed with saturated brine and dried over NaSO 4 Dried, filtered, and concentrated in vacuo. Compound a-7 (500.0 mg,54.9% yield) was obtained as a brown oil. The product was used directly in the next step without purification. LCMS (ESI): c (C) 35 H 55 N 6 O 5 Si 2 [M+H] + ms/z, calculated 695.7, found 695.7.
Compound a-7 (180.0 mg,0.26 mmol) was stirred in dioxane hydrochloride (5 ml) for 16 hours. LCMS showed detection of the desired MS. Concentration in vacuo afforded the crude product which was passed through a C18 reverse phase column (H 2 Purification of O (0.1% Formic Acid (FA)/mecn=90/10 to 50/50) afforded compound a-8 (60.0 mg,51.7% yield) as an off-white solid. LCMS (ESI): c (C) 23 H 27 N 6 O 4 [M+H] + ms/z, calculated 451.3, found 451.3.
To a toluene solution of compound a-8 (60.0 mg,0.13 mmol) was added (cyanomethylene) tributyl phosphorane (CMBP) (63.4 mg,0.26 mmol). The mixture is inStirring at 120℃for 2 hours, and removing the organic solvent under reduced pressure after the completion of the reaction. The residue was purified by preparative prep-HPLC (column: gemini 5um C18150x 21.2mm, mobile phase: ACN.about.H) 2 O (0.1% FA), gradient: 40-90, 7.6 min) to give compound 1 (10.49 mg,97.8% purity, 17.8% yield, 100% ee) as an off-white solid.
LCMS(ESI)：C 23 H 25 N 6 O 3 [M+H] + ms/z calculated 433.2, found 433.2. 1 H NMR(400MHz,DMSO-d 6 ,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％)。
Example 2: preparation of Compound 2
To a solution of methyl 2-chloro-6-methoxyisonicotinate (1.0 g,4.96 mmol) in 1, 4-dioxane (20 ml) was added PCy3 (139.1 mg,0.50 mmol), KOAc (973.5 mg,9.92 mmol), compound b-2 (1.89 g,7.44 mmol) and Pd 2 (dba) 3 (285.2 mg,0.50 mmol). At N 2 The reaction was stirred at 80℃for 2 hours under protection. The reaction was monitored by LCMS and compound b-4 (878.6 mg,2.48 mmol), K was added 3 PO 4 (1.1g，4.96mmol)、Pd(dppf)Cl 2 (181.5 mg,2.48 mmol) and H 2 O (2 ml). Continuing at N 2 The reaction was stirred for a further 2 hours at 80℃under protection. After completion of the reaction by LCMS, the solvent was removed by vacuum concentration. The residue was purified by flash chromatography (DCM/meoh=100/0 to 70/30) to give compound b-5 (600.0 mg,30.7% yield) as a brown oil. LCMS (ESI): c (C) 18 H 27 N 3 O 5 Si[M+H] + ms/z, calculated 394.2, found 394.2.
LiOH (73.1 mg,3.05 mmol) was dissolved in H 2 O (5 ml) and added dropwise to the compoundIn a solution of b-5 (600.0 mg,1.52 mmol) in THF (5 mL). The reaction was stirred at room temperature for 4 hours. LCMS showed detection of the desired MS. The solvent was removed by vacuum concentration, the resultant was adjusted to ph=5 with 2N HCl and extracted with EtOAc, naSO 4 Drying, filtration and spin-drying gave compound b-6 (200 mg,34.6% yield) as a brown solid. LCMS (ESI): c (C) 17 H 25 N 3 O 5 Si[M+H] + ms/z, calculated 380.2, found 380.2.
To a solution of compound b-6 (200.0 mg, 0.227 mmol) in DMF (10 ml) was added NMI (86.0 mg,1.05 mmol) and TCFH (295.8 mg,1.05 mmol). After stirring at room temperature for 30 minutes, compound a-6 (276.4 mg,0.79 mmol) was added to the above mixture. The reaction was stirred at 25℃for 16 hours. LCMS showed detection of the desired MS. The reaction was quenched with water, extracted with EtOAc, the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound b-7 as a brown oil, which was used in the next step without purification. LCMS (ESI): c (C) 35 H 54 N 6 O 6 Si 2 [M+H] + ms/z, calculated 711.4, found 711.4.
Compound b-7 (50.0 mg,0.13 mmol) was stirred in dioxane hydrochloride solution for 16 h. LCMS showed detection of the desired MS. The solvent was removed in vacuo to give the crude product which was passed through C18 reverse phase column H 2 O (0.1% Formic Acid (FA)/mecn=100/0 to 0/100 elution) afforded compound b-8 (15.0 mg,43.5% yield) as an off-white solid. LCMS (ESI): c (C) 23 H 26 N 6 O 5 [M+H] + ms/z, calculated 467.1, found 467.1.
To a toluene solution of compound b-8 (10.0 mg,0.02 mmol) was added CMBP (10.3 mg,0.04 mmol). The mixture was stirred at 120℃for 2 hours. LCMS showed removal of the organic solvent under reduced pressure after completion of the reaction. The residue was purified by preparative prep-HPLC (column: gemini 5um C18 150x 21.2mm, mobile phase: ACN.about.H) 2 O (0.1% FA), gradient: 40-90, 8.1 min) to give compound 2 (1 mg,10.0% yield).
1 H NMR(400MHz,DMSO-d 6 ,ppm):12.73(s,1H),8.47(s,1H),7.96(s,1H),7.62(d,J＝7.2Hz1H), 7.53 (d, j=7.2 hz, 1H), 7.31-7.20 (m, 2H), 7.07 (s, 1H), 4.51 (t, j=8.0 hz, 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=5.2 hz, 3H). HPLC (compound 2) purity: 254nm (99.7%), 214nm (99.7%). LCMS (ESI) (compound 2): c (C) 23 H 24 N 6 O 4 [M+H] + ms/z, calculated 449.3, found 449.3.
Example 3: preparation of Compound 3
50% aqueous sodium hydroxide (25 mL) and tetra-n-butyl ammonium bisulfate (16.8 g,0.0493 mol) were added to toluene (100 mL) solutions of compound c-2 (6.5 g,0.0301 mol) and compound c-1 (5.0 g,0.0274 mol), respectively, and stirred at 40℃for 17 hours, and LCMS showed the detection of the desired MS. Water was added to the reaction mixture and the mixture was extracted with toluene. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: etoac=100/0 to 0/100) to give c-3 (7.0 g,80.6% yield) as a colorless oil. LCMS (ESI): c (C) 19 H 25 O 4 [M+H] + m/z, calculated 317.1, found 317.3.
Cerium diammonium nitrate (19.1 g,0.0884 mol) was added to a mixed solution of acetonitrile (200 mL) of compound c-3 (7.0 g,0.0221 mol) and water (50 mL) under ice-cooling, and stirred at 25 ℃ 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. The residue was separated and purified by silica gel column chromatography (PE: etoac=100/0 to 0/100) to give compound c-4 (5.0 g,96.8% yield). LCMS (ESI): c (C) 12 H 19 O 3 [M+H] + m/z, calculated 211.1, found 211.1.
Triethylamine (4.8 g,0.0476 mol) and methanesulfonyl chloride (3.0 g,0.0261 mol) were slowly added dropwise to a solution of compound c-4 (5.0 g, 0.02328 mol) in EtOAc (100 mL) under ice-cooling, respectively. The reaction was stirred at 0deg.C for 1 hour. After completion of the reaction, water was added to the reaction mixture, and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give compound c-5 as a yellow oil, which was used in the next reaction without purification.
To a solution of compound c-5 (6.0 g,0.0208 mol) in DMF (60 mL) was added sodium azide (2.7 g,0.0416 mol). The mixture was stirred at 50℃for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into water, extracted with ethyl acetate, and the organic phases were combined. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give compound c-6 (6.0 g,98.0% yield) as a brown oil, which was used in the next reaction without purification.
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). At N 2 Stirring was performed for 24 hours at room temperature under protection, LCMS showed detection of the desired MS. The solvent was removed under reduced pressure to give the crude product, which was eluted with flash chromatography (DCM/MeOH from 100/0 to 90/10 in 30 min) to give compound c-7 (3.5 g,52.5% yield) as a yellow oil. LCMS (ESI): c (C) 12 H 20 NO 2 [M+H] + m/z, calculated 210.1, found 210.1.
Compound c-7 (3.5 g,0.0167 mol), 1-fluoro-2-nitrobenzoic-8 (2.8 g,0.0200 mol) and Diisopropylethylamine (DIEA) (4.3 g,0.0334 mol) were dissolved in DMSO solution (50 ml). The reaction mixture was stirred at 80 ℃ for 16 hours, LCMS showed the detection of the desired MS. The reaction was cooled to 25 ℃. 100mL of water was added, extracted with EtOAc, washed with saturated brine and NaSO 4 Drying and concentrating. The residue was purified by flash chromatography (PE/EtOAc eluting from 100/0 to 0/100 over 30 minutes) to give compound c-9 (2.0 g,34.7% yield). LCMS (ESI): c (C) 18 H 23 N 2 O 4 [M+Na] + m/z, calculated 353.1, found 353.1.
To compound c-9 (2.0 g,0.0061 mol) in MeOH (100 ml) and acetic acid (0.5 ml)Pd/C (2.0 g,0.0183 mol) was added to the solution. At H 2 (1 atm) atmosphere at 25℃for 2 days. The reaction mixture was filtered and concentrated to give compound c-10 (1.0 g,68.8% yield) as a brown solid. LCMS (ESI): c (C) 11 H 19 N 2 O 2 [M+H] + m/z, calculated 211.1, found 211.2.
BrCN (503.7 mg,4.7558 mmol) was added to compound c-10 (500.0 mg,2.3779 mmol) in methanol (10 ml) and H 2 O (10 ml) solution. The reaction mixture was stirred at 50℃for 1 hour. The reaction mixture was concentrated to give compound c-11 (500.0 mg,84.9% yield) as a yellow oil. LCMS (ESI): c (C) 12 H 18 N 3 O 2 [M+H] + m/z, calculated 236.1, found 236.1.
Compound c-11 (500.0 mg,2.1251 mmol), tert-butyl (chloro) dimethylsilane (960.9 mg,6.3753 mmol) and imidazole (434.0 mg,6.3753 mmol) were dissolved in DMF (10 ml). The reaction mixture was stirred at 25 ℃ for 16 hours, LCMS showed the detection of the desired MS. Quench with water (70 mL) and extract with EtOAc, wash the organic layer with brine, anhydrous NaSO 4 Drying, filtering and concentrating to obtain the product. The crude product was purified by flash chromatography (DCM/MeOH from 100/0 to 0/10 in 30 min) to give compound c-12 (300.0 mg,47.5% yield). LCMS (ESI): c (C) 18 H 32 N 3 O 2 Si[M+H] + m/z, calculated 350.2, found 350.1.
To a solution of compound c-12 (220.4 mg,0.6307 mmol) in DMF (10 ml) were added compound b-6 (200.0 mg,0.5256 mmol), TCFH (589.9 mg, 2.284 mmol) and NMI (172.6 mg, 2.284 mmol). The reaction mixture was stirred at 25 ℃ for 16 hours, LCMS showed the detection of the desired MS. The reaction was quenched with water (50 mL), extracted with EtOAc (3X 30 mL) and washed with brine (100 mL), anhydrous NaSO 4 Drying, filtration and concentration gave compound c-13 (100.0 mg,31.8% yield) as a brown oil. The compound was used directly in the next reaction without purification. LCMS (ESI): c (C) 35 H 55 N 6 O 6 Si 2 [M+H] + m/z, calculated 711.3, found 711.8.
Compound c-13 (100.0 mg,0.1404 mmol) inDioxane hydrochloride (5 ml). The reaction mixture was stirred at 25 ℃ for 3 hours, LCMS showed the desired MS was detected. At the point. The mixture was concentrated and purified by C18 reverse direction flash chromatography (H 2 O(NH 3 .H 2 O)/MeCN was purified over 30 minutes from 80/20 to 40/60 to give compound c-14 (50.0 mg,64.9% yield) as a yellow solid. LCMS (ESI): c (C) 23 H 27 N 6 O 5 [M+H] + m/z, calculated 467.2, found 467.3.
At N 2 Under protection, compound c-14 (30.0 mg,0.0643 mmol), PPh 3 (67.5 mg,0.2572 mmol) was dissolved in THF (2 ml). After stirring at room temperature for 30 minutes, a solution of diisopropyl azodicarboxylate (DIAD) (52.0 mg,0.2572 mmol) in THF (1 ml) was slowly dropped into the reaction solution. The reaction mixture was stirred at 25 ℃ for 3 hours, LCMS showed the desired MS was detected. The mixture was concentrated and purified by C18 reverse direction flash chromatography (H 2 O (FA)/MeCN eluted from 80/20 to 40/60 in 30 min) to give compound 3 (3.2 mg,99.6% purity, 11.0% yield) as a white solid.
LCMS(ESI)：C 23 H 26 N 6 O 4 [M+H] + m/z, calculated 449.1, found 449.3. 1 H NMR(400MHz，DMSO-d 6 Ppm) 12.73 (s, 1H), 8.47 (s, 1H), 7.96 (s, 1H), 7.62 (d, j=8.0 hz, 1H), 7.53 (d, j=7.2 hz, 1H), 7.31-7.20 (m, 2H), 7.06 (s, 1H), 4.51 (t, j=8.4 hz, 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=5.2 hz, 3H). HPLC purity: 254nm (99.6%), 214nm (97.2%).
Example 4: preparation of Compound 4
Compound 4 (yellow solid, 6.25mg,99.4% purity, 15.6% yield, 100% ee) and compound 2 (yellow solid, 6.75mg,99.7% purity, 16.9% yield, 100% ee) were resolved from compound 3 (40.0 mg,0.0892 mmol) under the following conditions: chiral-prep-SFC (chromatographic column: daicel CHIRALPAK OJ-H,250 mm. Times.20 mm I.D., 5. Mu.mm, mobile phase: CO2/MeOH (0.1% FA), gradient: 60-40,8 min) (40.0 mg,0.0892 mmol).
1 H NMR(400MHz，DMSO-d 6 Ppm) (compound 4): 12.73 (s, 1H), 8.47 (s, 1H), 7.96 (s, 1H), 7.62 (d, j=7.2 hz, 1H), 7.53 (d, j=7.2 hz, 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=12.4 hz, 1H), 3.75 (s, 3H), 1.10 (d, j=3.2 hz, 3H). HPLC (compound 4) purity: 254nm (99.4%), 214nm (98.9%). LCMS (ESI) (compound 4): c (C) 23 H 25 N 6 O 4 [M+H] + m/z, calculated 449.2, found 449.3.
EGFR detection
The compounds disclosed herein were tested for EGFR inhibition activity as follows.
The compounds of the application were dissolved in DMSO. 1x kinase buffer was prepared. EGFR L858R/T790M/C797S was purchased from Invitrogen (Cat. A33556), EGFR (d 746-750/T790MC 797S) was purchased from Carna (Cat. 08-565), and the enzyme was diluted to a final concentration of 2.5 Xwith kinase buffer. Kinase substrate 22 used was from GL China (Cat. 112393). A substrate mixture of ATP and kinase substrate was used at a final concentration of 1.67x in kinase buffer. In the presence of the substrate mixture, the enzyme and compound are mixed and stopped using a stop buffer. Conversion was read using Caliper EZ Reader (PerkinElmer model 122919/E) and compounds were evaluated for EGFR inhibitory activity IC 50 Values (as shown in table 2 below). Compounds were tested at concentrations up to 30 μm at 10 different concentrations.
TABLE 2 IC of the compounds of the application 50 Value of
Compound permeability assessment by porcine cephalin artificial membrane assay
2% of pig cephalin extract solution was prepared with dodecane, and 5. Mu.L of the solution was pipetted into each well of the solution receiving plate and allowed to stand for 10min to form an artificial lipid membrane. 300. Mu.L of PBS (pH 7.4) was added to each of the acceptor plate wells, and each of the donor plate wells was added300. Mu.L of the test compound solution was added at a final concentration of 10. Mu.M. The receiving plate was placed in the donor plate and incubated for 16h at 25 ℃. mu.L of the incubation solution was taken from each well of the acceptor plate and the donor plate into a 96-well plate, and 200. Mu.L of methanol containing an internal standard (Alprazolam, labetalol, caffeine and Ketoprofen) was added for quenching. Vortex at 750rpm for 100 seconds, centrifuge 3,220g for 20 minutes and check the concentration of the compound tested at both ends by LC/MS. Calculating the effective permeation value Pe (in-Log 10 To reflect) and recovery.
TABLE 3 Table 3
Numbering of compounds BBB PAMPA (parallel artificial membrane permeability measurement)
BI-4020 5.0
TQB3804 6.0
CH7233163 6.9
1 4.6
2 4.9
3 4.9
4 4.9

Claims (26)

1. A compound having formula (I), formula (IA), formula (II) or formula (IIA) or a pharmaceutically acceptable salt thereof:
wherein 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 (CH) 2 ；
R N Each independently is H or C 1-3 An alkyl group;
R 1 is H or C 1-3 An alkyl group; and
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 。
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring a is a benzene ring.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring a is a 5-or 6-membered heteroaryl ring, e.g., ring a is a 5-membered heteroaryl ring.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X is O.
5. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X is NR N For example X is NH or N-CH 3 。
6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Y is O.
7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Y is CH 2 。
8. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Y is NR N 。
9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 1 H.
10. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 1 Is C 1-3 Alkyl is preferably methyl.
11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2 Is C 1-3 Alkyl is preferably methyl.
12. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2 Is C 1-3 Alkoxy is preferably methoxy.
13. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2 Halogen, for example F, cl or Br.
14. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2 Is cyano.
15. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2 Is N (R) N ) 2 For example NH 2 NHMe or N (Me) 2 。
16. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, having the structure of formula (IA) or formula (IIA).
17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein, when having the structure of formula (IA), X and Y are both O, and R 1 And R is N Is methyl; when having the structure of formula (IIA), X is O, and R 1 And R is N Is methyl.
18. A compound having the structure shown below or a pharmaceutically acceptable salt thereof:
。
19. the compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, having at least one deuterium.
20. A pharmaceutical composition comprising a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
21. A method of inhibiting EGFR, particularly mutant EGFR, comprising contacting EGFR, particularly mutant EGFR, with a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20.
22. A method of treating a subject having a cancer associated with mutant EGFR, comprising administering to the subject a compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20.
23. The method of claim 21 or 22, wherein the mutation of EGFR is one or more of del 19, L858R, T790M and C797S, preferably the mutant EGFR is EGFR del 19t790m C797S.
24. The method of claim 22 or 23, wherein the cancer is selected from 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, preferably the cancer is non-small cell lung cancer.
25. The method of any one of claims 22 to 24, wherein the subject has brain metastasis.
26. The method of any one of claims 22 to 24, wherein the subject has been administered octreotide.
CN202310420133.3A 2022-05-09 2023-04-19 EGFR inhibitors and uses thereof Pending CN117024443A (en)

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US20220380382A1 (en) * 2019-06-24 2022-12-01 Boehringer Ingelheim International Gmbh New macrocyclic compounds and derivatives as egfr inhibitors
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