WO2021008441A1 - Inhibiteur de btk contenant du 5-azaspiroheptane - Google Patents

Inhibiteur de btk contenant du 5-azaspiroheptane Download PDF

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WO2021008441A1
WO2021008441A1 PCT/CN2020/101200 CN2020101200W WO2021008441A1 WO 2021008441 A1 WO2021008441 A1 WO 2021008441A1 CN 2020101200 W CN2020101200 W CN 2020101200W WO 2021008441 A1 WO2021008441 A1 WO 2021008441A1
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compound
pharmaceutically acceptable
formula
alkyl
acceptable salt
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PCT/CN2020/101200
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English (en)
Chinese (zh)
Inventor
张寅生
任景
徐胜
王庆璘
邓力
刘戌时
施伟
宋伟
张旻澄
张颖
徐宏江
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正大天晴药业集团股份有限公司
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Priority to CN202080043175.4A priority Critical patent/CN113993871B/zh
Publication of WO2021008441A1 publication Critical patent/WO2021008441A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • C07D487/02—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 two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • This application relates to a compound containing 5-azaspiroheptane as a BTK inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound, and its use in the treatment of BTK-related diseases.
  • BTK Bruton's tyrosine kinase
  • B-cell tumors such as leukemia, multiple myeloma and B-cell immune diseases.
  • the irreversible inhibitors currently on the market, such as ibrutinib often have mutations in the BTK binding site, resulting in decreased drug activity and drug resistance. Therefore, more BTK inhibitors are needed clinically, and they have a higher resistance to BTK. Selectivity to avoid the side effects caused by off-target effects.
  • the application provides a compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof,
  • Ring A is selected from 5-10 membered heteroaryl or C 6-10 aryl
  • R 1 is independently selected from halogen, hydroxy, amino, cyano, C 1-6 alkoxy or C 1-6 alkyl, the C 1-6 alkoxy or C 1-6 alkyl is optionally Halogen substitution;
  • n is selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 2 is selected from hydrogen, R a S (O) 2 -, (R a O) 2 P (O) - , or R a C (O) -;
  • R a is independently selected from a C 2-6 alkynyl group, C 2-6 alkenyl, C 1-6 alkyl, C 3-6 cycloalkyl, (C 1-6 alkyl) NH -, (C 1 -6 alkyl) 2 N-, 3-6 membered heterocycloalkyl, 5-10 membered heteroaryl, or C 6-10 aryl group, the above R a is optionally substituted (C 1-6 alkyl) 2 N -, (C 1-6 alkyl)NH-, hydroxyl, amino, halogen or cyano substitution.
  • the present application provides a pharmaceutical composition, which comprises the compound of formula (I) described in the present application, its stereoisomer or a pharmaceutically acceptable salt thereof.
  • the present application provides a method for preventing or treating BTK-related diseases in mammals, including administering a therapeutically effective amount of the compound of formula (I) described in the present application, and its stereoisomers to mammals in need of such prevention or treatment Or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in this application.
  • this application provides that the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in this application are prepared for prevention or treatment with BTK Use in medicine for related diseases.
  • this application provides that the compound of formula (I) described in this application, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in this application are used in the prevention or treatment of diseases related to BTK the use of.
  • this application provides the compound of formula (I) described in this application, its stereoisomers or pharmaceutically acceptable salts thereof, or the drug combination described in this application for preventing or treating diseases related to BTK Things.
  • This application relates to a compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof,
  • Ring A is selected from 5-10 membered heteroaryl or C 6-10 aryl
  • R 1 is independently selected from halogen, hydroxy, amino, cyano, C 1-6 alkoxy or C 1-6 alkyl, the C 1-6 alkoxy or C 1-6 alkyl is optionally Halogen substitution;
  • n is selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 2 is selected from hydrogen, R a S (O) 2 -, (R a O) 2 P (O) - , or R a C (O) -;
  • R a is independently selected from a C 2-6 alkynyl group, C 2-6 alkenyl, C 1-6 alkyl, C 3-6 cycloalkyl, (C 1-6 alkyl) NH -, (C 1 -6 alkyl) 2 N-, 3-6 membered heterocycloalkyl, 5-10 membered heteroaryl, or C 6-10 aryl group, the above R a is optionally substituted (C 1-6 alkyl) 2 N -, (C 1-6 alkyl)NH-, hydroxyl, amino, halogen or cyano substitution.
  • ring A is selected from 5-6 membered heteroaryl; in some embodiments, ring A is selected from 6-membered heteroaryl; in some embodiments, ring A is selected from 6-membered nitrogen-containing heteroaryl In some embodiments, ring A is selected from pyridyl. In some embodiments, Ring A is pyridin-2-yl. In some embodiments, ring A is phenyl.
  • R 1 is independently selected from halogen, cyano, C 1-3 alkyl or C 1-3 alkoxy, the C 1-3 alkyl or C 1-3 alkoxy optionally Ground is substituted by halogen (e.g., fluorine).
  • halogen e.g., fluorine
  • R 1 is independently selected from halogen, cyano, C 1-3 alkoxy, or C 1-3 alkyl optionally substituted with halogen; in some embodiments, R 1 is independently Is selected from fluorine, chlorine, bromine, iodine, cyano, methoxy, or methyl optionally substituted by halogen; in some embodiments, R 1 is independently selected from chlorine, bromine, cyano, -CHF 2 or methyl Oxy; In some embodiments, R 1 is independently selected from bromo.
  • n is selected from 0, 1, 2, 3, or 4; in some embodiments, m is selected from 0, 1, or 2; in some embodiments, m is selected from 1.
  • R 2 is selected from R a C (O) -.
  • R a is selected from C 2-6 alkynyl group, C 2-6 alkenyl, C 1-6 alkyl, C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl; in some embodiments, R a is selected from C 2-3 alkynyl or C 3-4 cycloalkyl; in some embodiments, R a is selected from propynyl.
  • R 2 is selected from R a C (O) -, wherein R a is selected from C 2-6 alkynyl group, C 2-6 alkenyl, C 1-6 alkyl, C 3-6 cycloalkyl R a is selected from C 2-3 alkynyl or C 3-4 cycloalkyl; or R a is propynyl.
  • R 2 is selected from
  • the compound of formula (I), its stereoisomer, or pharmaceutically acceptable salt thereof of the present application is selected from the group of formula (I-1), its stereoisomer or its pharmaceutically acceptable salt salt,
  • ring A, R 1 , R 2 , and m are as defined above.
  • the compound of formula (I) of the present application its stereoisomers or pharmaceutically acceptable salts thereof are selected from compounds of formula (II) or formula (II-1) or formula (II-2), Or a stereoisomer or a pharmaceutically acceptable salt thereof,
  • R 1 and m are as defined above.
  • the compound of formula (I) of the present application is selected from the following compounds or their pharmaceutically acceptable salts:
  • the present application relates to a pharmaceutical composition, which comprises the compound of formula (I) of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.
  • the present application relates to a method for preventing or treating BTK-related diseases in mammals, including administering a therapeutically effective amount of a compound of formula (I), its stereoisomers or a mammal in need of such prevention or treatment, preferably a human Its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • this application relates to the use of a compound of formula (I), its stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof in the preparation of drugs for preventing or treating BTK-related diseases.
  • the present application relates to the use of a compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the prevention or treatment of BTK-related diseases.
  • the present application relates to a compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition for preventing or treating BTK-related diseases.
  • the aforementioned BTK-related diseases are BTK-mediated diseases.
  • the above-mentioned BTK-related diseases are selected from autoimmune diseases, inflammatory diseases or cancer.
  • the above-mentioned BTK-related diseases are selected from B lymphoma. In some specific embodiments, the above-mentioned BTK-related diseases are selected from diffuse large B-cell lymphoma.
  • substituted means that any one or more hydrogen atoms on a specific group are replaced by a substituent, as long as the valence of the specific group is normal and the compound after substitution is stable.
  • it means that two hydrogen atoms are replaced, and the oxo will not occur on the aromatic group.
  • the term “optional” or “optionally” means that the event or situation described later can occur or not occur, and the description includes occurrence of said event or situation and non-occurrence of said event or situation.
  • the ethyl group is "optionally" substituted by halogen, meaning that the ethyl group can be unsubstituted (CH 2 CH 3 ), monosubstituted (such as CH 2 CH 2 F), or polysubstituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ).
  • CH 2 CH 3 unsubstituted
  • monosubstituted such as CH 2 CH 2 F
  • polysubstituted such as CHFCH 2 F, CH 2 CHF 2 etc.
  • CF 2 CF 3 completely substituted
  • C mn in this context means that the part has an integer number of carbon atoms in a given range.
  • C 1-6 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • any variable such as R
  • its definition in each case is independent. For example, if a group contains 2 Rs, each R has independent options.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxy refers to the -OH group.
  • amino refers to the -NH 2 group.
  • cyano refers to the -CN group.
  • alkyl refers to a hydrocarbon of the formula C n H 2n + 1, for example, C 1 - 6 alkyl, C 1 - 3 alkyl.
  • the alkyl group may be linear or branched.
  • C 1 - 6 alkyl refers to (e.g., methyl, ethyl, n-propyl, isopropyl, alkyl containing 1 to 6 carbon atoms, n-butyl, isobutyl, sec-butyl, Tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • the alkyl moiety (ie, alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio have the same definition as above.
  • alkoxy refers to -O- alkyl, e.g., -OC 1 - 6 alkyl, -OC 1 - 3 alkyl.
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group having at least one double bond of carbon atoms and hydrogen atoms, straight-chain or branched-chain, e.g., C 2 - 6 alkenyl, C 2 - 3 alkenyl group.
  • alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkynyl refers to an unsaturated aliphatic hydrocarbon group having at least one triple bond in a straight or branched chain of carbon atoms and hydrogen atoms, e.g., C 2 - 6 alkynyl, C 2 - 3 alkynyl group.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), 2-propynyl (-CH 2 -C ⁇ CH), 1,3-Butadiynyl (-C ⁇ CC ⁇ CH) and so on.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the carbocyclic ring is usually a 3 to 10 membered ring, or a 3 to 6 membered ring.
  • Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantane Alkyl and so on.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the heterocyclic ring is generally a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • the heterocycloalkyl group may be a 3 to 6 membered ring containing 1 or 2 heteroatoms independently selected from oxygen and/or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxirane, sulfiethane, and azathione groups.
  • Non-limiting examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetane
  • Examples of cyclic groups, thiabutanyl, and 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine
  • 6-membered heterocycloalkyl include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, Examples of 4-thiaxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, and 7-membered heterocycloalkyl include But
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group with a conjugated ⁇ -electron system.
  • the aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, 1,2,3,4-tetralin and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one (for example, 1, 2 or 3) ring atoms selected from N, O and/or S, and the remaining ring atoms are C, And has at least one aromatic ring.
  • Preferred heteroaryl groups have a single 4- to 8-membered ring, or 5- to 8-membered ring, or 6-membered ring (for example, a 6-membered heteroaryl containing 1 or 2 N and/or O), or 6 to 14 One, especially multiple fused polycyclic rings of 6 to 10 ring atoms.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , Tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc.
  • treatment means administering the compound or formulation described in this application to ameliorate or eliminate a disease or one or more symptoms related to the disease, and includes:
  • prevention means administering the compound or formulation described in this application to prevent a disease or one or more symptoms related to the disease, including: preventing the occurrence of a disease or disease state in a mammal, especially when this When mammals are susceptible to this disease state, but have not been diagnosed as having this disease state.
  • terapéuticaally effective amount means (i) treating or preventing a specific disease, condition or disorder, (ii) reducing, ameliorating or eliminating one or more symptoms of a specific disease, condition or disorder, or (iii) preventing or delaying The amount of the compound of the present application for the onset of one or more symptoms of a specific disease, condition, or disorder described herein.
  • the amount of the compound of the present application that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. Determined by its own knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • Examples of pharmaceutically acceptable salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • pharmaceutical composition refers to a mixture of one or more of the compounds of the application or their salts and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application to the organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not damage the biological activity and performance of the active compound.
  • Suitable auxiliary materials are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • tautomer or "tautomeric form” refers to structural isomers of different energy that can interconvert via a low energy barrier.
  • proton tautomers also called proton transfer tautomers
  • proton migration such as keto-enol and imine-enamine isomerization.
  • a specific example of a proton tautomer is the imidazole moiety, where protons can migrate between two ring nitrogens.
  • Valence tautomers include interconversion through the recombination of some bonding electrons.
  • the present application also includes compounds of the present application that are the same as those described herein, but with one or more atoms replaced by an isotope-labeled atom having an atomic weight or mass number different from those generally found in nature.
  • isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • Certain isotope-labeled compounds of the application can be used in the analysis of compound and/or substrate tissue distribution. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are especially preferred due to their ease of preparation and detectability.
  • Positron emission isotopes, such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • PET positron emission tomography
  • the isotope-labeled compounds of the present application can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by replacing non-isotopically-labeled reagents with isotope-labeled reagents.
  • substitution with heavier isotopes can provide certain therapeutic advantages resulting from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations
  • deuterium substitution can be partial or complete
  • partial deuterium substitution refers to the substitution of at least one hydrogen with at least one deuterium.
  • the compounds of the application may be asymmetric, for example, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compound containing asymmetric carbon atoms of the present application can be isolated in an optically pure form or a racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.
  • the pharmaceutical composition of the application can be prepared by combining the compound of the application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes for administering the compound of the application or a pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, etc.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These auxiliary materials enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • the solid oral composition can be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and processing the mixture into granules to obtain tablets Or the core of the dragee.
  • suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as a sterile solution, suspension or lyophilized product in a suitable unit dosage form.
  • the daily dose is 0.01 to 200 mg/kg body weight, in the form of single or divided doses.
  • the compound of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent replacement manners, preferred implementation manners include but are not limited to the embodiments of the present application.
  • PE petroleum ether
  • EA ethyl acetate
  • DMSO dimethyl sulfoxide
  • DMF N,N-dimethylformamide
  • DCM dichloromethane
  • MeOH stands for methanol
  • EDTA ethylenediaminetetraacetic acid
  • DTT Represents dithiothreitol
  • EGTA represents ethylene glycol bis(2-aminoethyl ether) tetraacetic acid
  • ATP represents adenosine triphosphate
  • HATU 2-(7-oxybenzotriazole)-N,N, N',N'-tetramethylurea hexafluorophosphate
  • ACN stands for acetonitrile
  • Et 3 N stands for triethylamine
  • NIS stands for N-iodosuccinimide
  • Cbz- stands for benzyloxycarbonyl
  • Boc- stands for tertiary Butoxycarbonyl
  • Step 1 (S)-6-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-5-azaspiro[2.4]heptane-5-carboxylic acid benzyl ester (1- 2)
  • Step 2 (S)-6-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-5-azaspiro[2.4]heptane-5-carboxylic acid benzyl ester (1- 3)
  • Step 1 Add 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (24.54 g), 4-bromopyridin-2-amine (13.3g) and triethylamine (31.1g), dissolved in DCM (300mL), stirred at room temperature for 20 minutes, added HATU (35.1g), heated to 70 After reacting at °C for 6 hours, the reaction is complete. The reaction solution is added to water (500ml) for liquid separation. The organic phase is spin-dried under reduced pressure and re-dissolved in DMF (50ml). Add 1M HCl aqueous solution (500ml), stir well and filter.
  • Step 1 (S)-6-(1-iodo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-5-azaspiro[2.4]heptane-5-carboxylic acid benzyl Esters (1-4)
  • Step 2 (S)-6-(8-Amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)-5-azaspiro[2.4]heptane-5-carboxylic acid benzyl Ester (Intermediate 1-5)
  • Step 3 (S)-6-(8-amino-1-(4-((4-bromopyridin-2-yl)carbamoyl)-2-fluorophenyl)imidazole[1,5-a]pyridine (Azin-3-yl)-5-azaspirocyclo[2.4]heptane-5-carboxylic acid benzyl ester (Intermediate 1-6)
  • Step 4 (S)-4-(8-amino-3-(5-azaspiro[2.4]heptane-6-yl)imidazo[1,5-a]pyrazin-1-yl)-N -(4-Bromopyridin-2-yl)-3-fluorobenzamide (Intermediate 1-7)
  • Step 5 (S)-4-(8-amino-3-(5-but-2-ynyl)-5-azaspiro[2.4]heptane-6-yl)imidazo[1,5-a ]Pyrazin-1-yl)-N-(4-bromopyridin-2-yl)-3-fluorobenzamide (Compound I-1)
  • Step 1 (S)-6-(((3-chloropyrazin-2-yl)methyl)carbamoyl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (2 -2)
  • Step 2 (S)-6-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-5-azaspiro[2.4]heptane-5--carboxylic acid tert-butyl ester ( 2-3)
  • Step 1 (S)-6-(1-iodo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert Butyl ester (2-4)
  • Step 2 (S)-6-(8-Amino-1-iodoimidazo[1,5-a]pyrazin-3-yl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert Butyl ester (Intermediate 2-5)
  • Step 3 (S)-6-(8-amino-1-(4-((4-chloropyridin-2-yl)carbamoyl)-2-fluorophenyl)imidazole[1,5-a]pyridine (Azin-3-yl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (Intermediate 2-6)
  • Step 4 (S)-4-(8-amino-3-(5-but-2-ynyl)-5-azaspiro[2.4]heptane-6-yl)imidazo[1,5-a ]Pyrazin-1-yl)-N-(4-chloropyridin-2-yl)-3-fluorobenzamide (Compound I-2)
  • Step 1 Add 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (5g ), 4-cyanopyridin-2-amine (2.69g) and triethylamine (5.7g), and dissolved in DMF (20mL), add HATU (7.86g), heat to 60°C and react for 6 hours, the reaction is complete The reaction solution was added to saturated brine (200 mL), ethyl acetate (200 mL) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and spin-dried under reduced pressure to obtain Intermediate L (5.12 g).
  • Step 1 (S)-6-(8-amino-1-(4-((4-cyanopyridin-2-yl)carbamoyl)-2-fluorophenyl)imidazole [1,5-a] Pyrazin-3-yl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (Intermediate 3-6)
  • Step 2 (S)-4-(8-amino-3-(5-but-2-ynyl)-5-azaspiro[2.4]heptane-6-yl)imidazo[1,5-a ]Pyrazin-1-yl)-N-(4-cyanopyridin-2-yl)-3-fluorobenzamide (Compound I-3)
  • Step 1 Add 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (5g ), 4-difluoromethylpyridin-2-amine (2.84g) and triethylamine (5.7g), dissolved in DMF (20mL), HATU (7.86g) was added, heated to 60°C for 6 hours, After the reaction was completed, the reaction solution was added to saturated brine (200 mL), ethyl acetate (200 mL) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and spin-dried under reduced pressure to obtain Intermediate M (4.45 g).
  • Step 1 (S)-6-(8-amino-1-(4-((4-difluoromethylpyridin-2-yl)carbamoyl)-2-fluorophenyl)imidazole [1,5- a]Pyrazin-3-yl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (Intermediate 4-6)
  • Step 2 (S)-4-(8-amino-3-(5-but-2-ynyl)-5-azaspiro[2.4]heptane-6-yl)imidazo[1,5-a ]Pyrazin-1-yl)-N-(4-difluoromethylpyridin-2-yl)-3-fluorobenzamide (Compound I-4)
  • Step 1 Add 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (5.14 g), 4-methoxypyridine-2-amine (2g) and triethylamine (4.89g), dissolved in DMF (30mL), stirred at room temperature for 20 minutes, added HATU (7.35g), heated to The reaction was reacted at 60°C for 3 hours. The reaction was completed. The reaction solution was extracted with water (200ml) and ethyl acetate. The organic phase was washed with water and saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, filtered, and concentrated intermediate N (2.8g) ).
  • Step 1 (S)-6-(8-amino-1-(4-((4-methoxypyridin-2-yl)carbamoyl)-2-fluorophenyl)imidazole [1,5-a ]Pyrazin-3-yl)-5-azaspiro[2.4]heptane-5-carboxylic acid tert-butyl ester (Intermediate 6-6)
  • Step 2 (S)-4-(8-amino-3-(5-but-2-ynyl)-5-azaspiro[2.4]heptane-6-yl)imidazo[1,5-a ]Pyrazin-1-yl)-N-(4-methoxypyridin-2-yl)-3-fluorobenzamide (Compound I-5)
  • Test Example 1 In vitro activity
  • ⁇ 8nM detection reagent (final concentration 2nM, Ab), incubated for 1 hour at room temperature; PE Envision multifunctional microplate reader reads the plate (excitation 620nm, emission 665nm), using four-parameter fitting to calculate IC50.
  • ⁇ 8nM detection reagent final concentration of 2nM, Eu-anti-phospho-tyrosine antibody
  • PE Envision multi-functional microplate reader reads the plate (excitation 320nm, emission 665nm), using four-parameter fitting, Calculate IC50.
  • TEC stock solution Dilute the 50ng/ ⁇ L TEC stock solution with kinase buffer (50mM HEPES, 10mM MgCl 2 , 2mM DTT, 1mM EGTA, 0.01% Tween 20), and add 6 ⁇ L 1.67 ⁇ 0.01336g/ ⁇ L working solution (final The concentration is 0.008ng/ ⁇ L), the different compounds dissolved in DMSO are added to the wells with a nanoliter sampler to make the final compound concentration of 1000nM-0.24nM, a 4-fold gradient, a total of 7 concentrations, and a blank control empty ( Without enzyme) and negative control wells (containing enzyme, plus solvent DMSO).
  • kinase buffer 50mM HEPES, 10mM MgCl 2 , 2mM DTT, 1mM EGTA, 0.01% Tween 20
  • 6 ⁇ L 1.67 ⁇ 0.01336g/ ⁇ L working solution final The concentration is 0.008ng/ ⁇ L
  • ⁇ 8nM detection reagent final concentration of 2nM, Eu-anti-phospho-tyrosine antibody, incubate at room temperature for 1 hour; PE Envision multi-functional microplate reader reads the plate (excitation 320nm, emission 665nm), using four-parameter fitting, Calculate IC50.
  • ITK Interleukin-2-inducible T-cellkinase inhibitory activity screening
  • kinase buffer 50mM HEPES, 10mM MgCl 2, 2mM DTT, 1mM EGTA, 0.01% Tween 20
  • 50ng / ⁇ L of diluted mother liquor ITK is added per well of fluid 6 ⁇ L 1.67 ⁇ 0.0835g / ⁇ L (final The concentration is 0.05ng/ ⁇ L)
  • the different compounds dissolved in DMSO are added to the wells with a nanoliter sampler to make the final compound concentration of 1000nM-0.24nM, a 4-fold gradient, a total of 7 concentrations, and a blank control empty ( Without enzyme) and negative control wells (containing enzyme, plus solvent DMSO).
  • ⁇ 8nM detection reagent final concentration of 2nM, Eu-anti-phospho-tyrosine antibody, incubate at room temperature for 1 hour; PE Envision multi-functional microplate reader reads the plate (excitation 320nm, emission 665nm), using four-parameter fitting, Calculate IC50.
  • PV sodium pervanadate
  • the base is diluted to 6mM, ready to use.
  • TMD-8 cells in good exponential growth phase, collect the cells into a centrifuge tube, low-speed benchtop centrifuge, 1500 rpm, centrifuge for 3 minutes, discard the supernatant, and add 2mL seed plate medium (RPMI basic medium + 5% FBS+0.05mM 2-mercaptoethanol) to resuspend the cells.
  • 2mL seed plate medium RPMI basic medium + 5% FBS+0.05mM 2-mercaptoethanol
  • Use a cell counter to count take the required amount of cells to adjust the density to 5 ⁇ 10 4 cells/mL, use a row gun to inoculate the 96-well plate, 100 ⁇ L/well, and place the cells at 37°C and 5% CO 2 saturated humidity Cultivate in an incubator. After culturing for 24 hours, use a nanoliter sampler to add compound samples. Set 2 replicate wells for each concentration.
  • ICR mice weighing 18-22g, were adapted for 3 to 5 days, and then randomly divided into groups, 9 mice in each group, and the related compounds were intragastrically administered at a dose of 10 mg/kg, and the related compounds were injected intravenously at a dose of 1 mg/kg.
  • the test animals (ICR mice) were fasted for 12 hours before administration, and were given food 4 hours after administration. They were free to drink water before and after the experiment and during the experiment.
  • each mouse collected 3 to 4 time points, each time point 3 mice, collect whole blood In a centrifuge tube containing EDTA-K2 and sodium fluoride, transfer to 4°C within 30 minutes and centrifuge at 4000 rpm ⁇ 10 minutes to separate plasma. After collecting all plasma, store it at -20°C for testing.
  • ig gavage
  • iv intravenous injection
  • MRT mean residence time
  • Vz apparent volume of distribution
  • CLz clearance rate
  • Model group vehicle 6; compound I-1: 50mg/kg, bid, i.g 6.
  • the vehicle or drug was administered by intragastric administration at a volume of 10ml/kg, twice a day, for 23 consecutive days. Measure the tumor volume 2-3 times a week, weigh the mouse at the same time, and record the data; observe the animal performance daily. After all the administration was finished, the animals were sacrificed and the tumors were stripped and weighed.
  • Tumor volume (TV) (length ⁇ width 2) / 2.
  • Tumor growth inhibition (1-tumor weight in the treatment group / tumor weight in the model group) ⁇ 100%.

Abstract

La présente invention concerne un inhibiteur de BTK contenant du 5-azaspiroheptane, et concerne spécifiquement un composé de formule (I), un stéréoisomère de celui-ci ou un sel pharmaceutiquement acceptable de celui-ci, un procédé de préparation de celui-ci, une composition pharmaceutique contenant le composé, et l'utilisation de celui-ci dans le traitement de maladies associées à BTK.
PCT/CN2020/101200 2019-07-12 2020-07-10 Inhibiteur de btk contenant du 5-azaspiroheptane WO2021008441A1 (fr)

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CN106831787A (zh) * 2017-01-20 2017-06-13 成都倍特药业有限公司 用作布鲁顿酪氨酸激酶抑制剂的化合物及其制备方法和应用
CN108602827A (zh) * 2015-11-06 2018-09-28 安塞塔制药公司 Bruton酪氨酸激酶的咪唑并吡嗪抑制剂
WO2020015735A1 (fr) * 2018-07-20 2020-01-23 正大天晴药业集团股份有限公司 Inhibiteurs de la tyrosine kinase de bruton
WO2020052628A1 (fr) * 2018-09-14 2020-03-19 正大天晴药业集团股份有限公司 Inhibiteur de btk contenant du furo[3,4-b]pyrrole
CN111471048A (zh) * 2020-04-30 2020-07-31 成都海博为药业有限公司 一种具有含氮桥环、螺环或并环结构的化合物及其用途

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EP2548877A1 (fr) * 2011-07-19 2013-01-23 MSD Oss B.V. Dérivés de 4-(pyridine condensée à 5 chaînons)benzamide comme inhibiteurs de BTK
CN105837576B (zh) * 2015-01-14 2019-03-26 湖北生物医药产业技术研究院有限公司 Btk抑制剂

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WO2016109223A1 (fr) * 2014-12-31 2016-07-07 Merck Sharp & Dohme Corp. Inhibiteurs de la btk de type benzamide imidazopyrazines
CN108602827A (zh) * 2015-11-06 2018-09-28 安塞塔制药公司 Bruton酪氨酸激酶的咪唑并吡嗪抑制剂
CN106831789A (zh) * 2016-12-21 2017-06-13 南京亘泰医药技术有限公司 布鲁顿酪氨酸激酶抑制剂
CN106831787A (zh) * 2017-01-20 2017-06-13 成都倍特药业有限公司 用作布鲁顿酪氨酸激酶抑制剂的化合物及其制备方法和应用
WO2020015735A1 (fr) * 2018-07-20 2020-01-23 正大天晴药业集团股份有限公司 Inhibiteurs de la tyrosine kinase de bruton
WO2020052628A1 (fr) * 2018-09-14 2020-03-19 正大天晴药业集团股份有限公司 Inhibiteur de btk contenant du furo[3,4-b]pyrrole
CN111471048A (zh) * 2020-04-30 2020-07-31 成都海博为药业有限公司 一种具有含氮桥环、螺环或并环结构的化合物及其用途

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