WO2022253313A1 - 三氟甲基取代的磺酰胺类化合物的磷酸酯 - Google Patents

三氟甲基取代的磺酰胺类化合物的磷酸酯 Download PDF

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WO2022253313A1
WO2022253313A1 PCT/CN2022/096845 CN2022096845W WO2022253313A1 WO 2022253313 A1 WO2022253313 A1 WO 2022253313A1 CN 2022096845 W CN2022096845 W CN 2022096845W WO 2022253313 A1 WO2022253313 A1 WO 2022253313A1
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alkyl
compound
coch
pharmaceutically acceptable
alternatively
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PCT/CN2022/096845
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English (en)
French (fr)
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王斌
刘飞
丰巍伟
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正大天晴药业集团股份有限公司
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Priority to EP22815353.2A priority Critical patent/EP4353722A1/en
Priority to CN202280037317.5A priority patent/CN117377672A/zh
Publication of WO2022253313A1 publication Critical patent/WO2022253313A1/zh

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    • 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
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This application relates to a phosphate ester compound of a trifluoromethyl-substituted sulfonamide compound selectively inhibiting the anti-apoptotic protein BCL-2, its preparation method, a pharmaceutical composition containing these compounds, and its therapeutic effect on anti-apoptotic protein Use in BCL-2 related diseases such as cancer.
  • BCL-2 protein is divided into three families: BCL-2 family (its family members include BCL-2, BCL-XL, etc.), BAX family and BH3-only family, among which BCL-2 family plays an anti-apoptotic role , members of the latter two families play a pro-apoptotic role.
  • Anti-apoptotic BCL-2 family proteins are associated with many diseases and are being investigated as potential therapeutic drug targets. Such targets for interventional therapy include, for example, the BCL-2 family proteins BCL-2 and BCL-XL, among others. Recently, inhibitors of BCL-2 family proteins have been reported in WO2012071374, WO2010138588, WO2010065865. Although inhibitors with high binding to the target protein are taught therein, compound binding affinity is only one of many parameters to be considered. One goal is to generate compounds that bind preferentially, ie, selectivity, to one protein over another. To demonstrate this selectivity, compounds are known to exhibit high binding affinity for a particular protein, and lower binding affinity for another member.
  • This application includes a series of compounds, which show higher selectivity compared to anti-apoptotic BCL-2 protein and anti-apoptotic BCL-XL protein, and also have the ability to inhibit the activity of anti-apoptotic BCL-2 protein better performance. At the same time, it also has better stability of liver microsomes and optimized pharmacokinetic parameters.
  • the present application relates to a compound of formula I, its stereoisomer or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from hydrogen, halogen, or C 1-3 alkyl
  • R 2 is selected from -R 3 or -C 1-6 alkylene-R 3 ;
  • R 3 is selected from 5-6 membered heterocycloalkyl, which is optionally substituted by one or two groups selected from the following groups: 4-6 membered heterocycloalkyl, C 3 -6 cycloalkyl, -COR a , -SO 2 R b , -COOC 1-6 alkyl, or C 1-6 alkyl optionally substituted by halogen;
  • R a or R b are independently selected from H, 4-6 membered heterocycloalkyl, C 3-6 cycloalkyl, or C 1-6 alkyl, and the C 1-6 alkyl is optionally replaced by halogen , -CN, -N(C 1-6 alkyl) 2 , -NHC 1-6 alkyl, or -OC 1-6 alkyl substitution;
  • G 1 is selected from C 1-10 alkyl substituted by OP(O)(OH) 2 .
  • R 1 is selected from hydrogen, fluoro, chloro, or C 1-3 alkyl. In some embodiments, R 1 is selected from hydrogen, chloro or methyl.
  • R 2 is selected from -R 3 or -C 1-4 alkylene-R 3 .
  • R 2 is selected from -R 3 or -C 1-3 alkylene-R 3 .
  • R 2 is selected from -R 3 or -CH 2 R 3 , -(CH 2 ) 2 R 3 , or -(CH 2 ) 3 R 3 .
  • R is selected from 5-6 membered heterocycloalkyl
  • the heteroatoms in the 5-6 membered heterocycloalkyl are selected from N or O
  • the number of heteroatoms is selected from 1 or 2.
  • R is selected from 5-6 membered heterocycloalkyl groups optionally substituted by one or two groups at the N atom on the ring .
  • R is selected from 5-6 membered heterocycloalkyl optionally substituted with one or two groups selected from: 4-5 heterocyclo Alkyl, C 4-5 alkyl, -COR a , -SO 2 R b , -COOC 1-3 alkyl, or C 1-3 alkyl optionally substituted with halogen.
  • R is selected from 5-6 membered heterocycloalkyl optionally substituted with one or two groups selected from: -COR a or SO 2 R b .
  • R a or R b are independently selected from 4-6 membered heterocycloalkyl, C 3-5 cycloalkyl, or C 1-5 alkyl, and the C 1-5 alkyl is any Optionally substituted with halogen, -CN, -N(C 1-3 alkyl) 2 , -NHC 1-3 alkyl, or -OC 1-3 alkyl.
  • R a or R b are independently selected from C 3-4 cycloalkyl, or C 1-4 alkyl, and the C 1-4 alkyl is optionally replaced by fluorine, chlorine, -CN , -N(C 1-3 alkyl) 2 , or -OC 1-3 alkyl.
  • R a or R b are independently selected from methyl, ethyl, -CH 2 CN, cyclopropyl, cyclobutyl, tert-butyl, -CF 3 , isopropyl, -CH 2 OCH 3 , or -CH 2 N(CH 3 ) 2 .
  • Ra is selected from -CH 2 CN, cyclopropyl, tert-butyl, -CF 3 , isopropyl, -CH 2 OCH 3 , -CH 2 N(CH 3 ) 2 , or methyl .
  • Rb is selected from methyl, ethyl, cyclopropyl, or cyclobutyl.
  • R 3 is selected from 5-6 membered heterocycloalkyl optionally substituted by: -COCH 2 CN, -CO-cyclopropane, - COC(CH 3 ) 3 , -COCF 3 , -COCH(CH 3 ) 2 , -COCH 2 OCH 3 , -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -SO 2 -cyclopropane, -SO 2 - Cyclobutane, -COCH 2 N(CH 3 ) 2 , or -COCH 3 .
  • R is selected from tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, or dioxane -COCH 2 CN, -CO-cyclopropane, -COC(CH 3 ) 3 , -COCF 3 , -COCH(CH 3 ) 2 , -COCH 2 OCH3 , -SO2CH3 , -SO2CH2CH3 , -SO2 - cyclopropane , -SO2 - cyclobutane, -COCH2N ( CH3 ) 2 or -COCH3 .
  • R is selected from tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl.
  • R 3 is selected from dioxanyl.
  • R 3 is selected from piperidinyl or morpholinyl optionally substituted by: -COCH 2 CN, -CO-cyclopropane, -COC( CH 3 ) 3 , -COCF 3 , -COCH(CH 3 ) 2 , -COCH 2 OCH 3 , -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -SO 2 -cyclopropane, -SO 2 -cyclobutane Alkane, -COCH 2 N(CH 3 ) 2 or -COCH 3 .
  • R is selected from
  • R is selected from
  • the heteroatoms in the 5-6 membered heterocycloalkyl group are selected from N or O, and the number of heteroatoms is selected from 1 or 2.
  • the 5-6 membered heterocycloalkyl group is selected from dioxanyl, tetrahydropyranyl, morpholinyl, piperidinyl, or tetrahydrofuranyl.
  • the 5-6 membered heterocycloalkyl group is selected from 6 membered heterocycloalkyl groups.
  • the 5-6 membered heterocycloalkyl group is selected from dioxanyl, morpholinyl, tetrahydropyranyl, or piperidinyl.
  • the 5-6 membered heterocycloalkyl group is selected from dioxanyl.
  • the 5-6 membered heterocycloalkyl group is selected from morpholinyl.
  • the 5-6 membered heterocycloalkyl is selected from tetrahydropyranyl.
  • the heteroatoms in the 4-6 membered heterocycloalkyl are selected from N or O, and the number of heteroatoms is selected from 1 or 2. In some embodiments, the heteroatoms in the 4-6 membered heterocycloalkyl group are selected from O, and the number of heteroatoms is 1 or 2. In some embodiments, the 4-6 membered heterocycloalkyl is selected from 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl.
  • G 1 is selected from C 1-6 alkyl substituted with OP(O)(OH) 2 .
  • G 1 is selected from C 1-4 alkyl substituted with OP(O)(OH) 2 .
  • G 1 is selected from C 1-3 alkyl substituted with OP(O)(OH) 2 .
  • G 1 is selected from —CH 2 OP(O)(OH) 2 .
  • the present application relates to a compound of formula II or formula III, its stereoisomer or a pharmaceutically acceptable salt thereof:
  • R is the same as that of the compound of formula I; m is selected from 1, 2, 3 or 4.
  • the present application relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof,
  • the present application relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof,
  • the present application relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof,
  • the present application relates to the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof,
  • the present application relates to a pharmaceutical composition, which comprises the above-mentioned compound of formula I of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof.
  • the present application relates to a pharmaceutical composition, which comprises the above-mentioned compound of formula II or formula III of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present application further comprises pharmaceutically acceptable excipients.
  • the present application describes a method for treating diseases related to the anti-apoptotic protein BCL-2 in mammals, comprising administering a therapeutically effective amount of the compound of the present application, its stereoisomers to a mammal (preferably a human) in need of such treatment body or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the application describes the application of the compound of formula I, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation for the prevention or treatment of anti-apoptotic protein BCL-2 related Use in medicine for disease.
  • the application describes the use of the compound of formula I, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the prevention or treatment of diseases related to anti-apoptotic protein BCL-2 .
  • the present application describes the compound of formula I, its stereoisomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition for preventing or treating diseases related to anti-apoptotic protein BCL-2.
  • the disease related to the anti-apoptotic protein BCL-2 is selected from cancer.
  • the cancer is selected from acute lymphoblastic leukemia.
  • the compounds of the present application selectively inhibit BCL-2/BAK enzymes at the level of enzymes, and have lower BCL-XL/BAK enzyme inhibitory activity than BCL-XL/BAK enzymes. Moreover, it has good physical and chemical properties such as high solubility in water, good in vivo and in vitro pharmacokinetic properties (such as high bioavailability, high stability before entering plasma), and good in vivo pharmacodynamic properties.
  • substituted means that any one or more hydrogen atoms on the specified atom are replaced by a substituent, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • an ethyl group is "optionally" substituted with halogen, meaning that the ethyl group can be unsubstituted (-CH 2 CH 3 ), mono-substituted (such as -CH 2 CH 2 F), polysubstituted (such as -CHFCH 2 F, -CH 2 CHF 2 , etc.) or fully substituted (-CF 2 CF 3 ). It will be appreciated by those skilled in the art that for any group containing one or more substituents, no sterically impossible and/or synthetically impossible substitution or substitution pattern is introduced.
  • C mn herein, is that the moiety has an integer number of carbon atoms in the 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.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 .
  • the alkyl group may be linear or branched.
  • C 1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n - butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkyl portion ie, alkyl group
  • alkoxy, alkylamino, dialkylamino, alkylsulfonyl and alkylthio has the same definition as above.
  • C 1-4 alkyl refers to an alkyl group containing 1 to 4 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.).
  • alkylene refers to a divalent group formed by removing one hydrogen from any position of an alkyl group.
  • C 1-6 alkylene include, but are not limited to, methylene, ethylene, methylmethylene, dimethylmethylene, 1,3-propylene, etc. .
  • 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, preferably a 3 to 6 membered ring, eg a 3 to 5 membered ring or a 3 to 4 membered ring.
  • Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, Adamantyl, etc.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged, or spiro ring. Unless otherwise indicated, the heterocycle is typically a 3 to 7 membered ring, such as a 4 to 6 membered ring or 5 to 6 membered ring.
  • 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, thioethyl, cycloazaethyl
  • 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetyl, Cyclic, thiabutanyl
  • 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine , imidazolidinyl, tetrahydropyrazolyl
  • 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazin
  • treating means administering a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes: preventing a disease or disease state from occurring in a mammal, especially when Such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state.
  • the term "effective amount” means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying the The amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder described in .
  • the amount of a compound of the present application that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art according to its own knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without Excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. .
  • composition refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable auxiliary materials.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients 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 energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens.
  • Valence tautomers include interconversions through recombination of some of the bonding electrons.
  • the present application also includes isotopically labeled compounds of the present application that are identical to those described herein, but wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may 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 isotopically labeled compounds of the present application are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (ie3H ) and carbon-14 (ie14C ) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron-emitting 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.
  • Isotopically labeled compounds of the present application can generally be prepared by following procedures similar to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • substitution with heavier isotopes such as deuterium may confer certain therapeutic advantages resulting from greater metabolic stability (e.g. increased in vivo half-life or reduced dosage requirements), and thus in some cases
  • deuterium substitution may be partial or complete, partial deuterium substitution meaning at least one hydrogen is replaced by at least one deuterium.
  • Compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers are included in this application, such as enantiomers and diastereomers.
  • the compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable auxiliary materials, for example, it 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, etc.
  • Typical routes of administering a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, dragee-making methods, pulverizing methods, emulsifying methods, freeze-drying methods and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets Or the core of the sugar coating.
  • Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • the pharmaceutical composition can also be adapted for parenteral administration, such as a suitable unit dosage form of sterile solution, suspension or freeze-dried product and the like.
  • the daily dose administered is 0.01 mg/kg body weight to 200 mg/kg body weight, in single or divided doses.
  • the compounds 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 equivalents well known to those skilled in the art Alternatives, preferred implementations include but are not limited to the examples of this application.
  • the chemical reactions in the specific embodiments of the present application are completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes on the basis of existing embodiments.
  • tBu represents t-butyl
  • compound 1-a was replaced with compound 2-a (prepared according to Example 3 of WO2020238785) to obtain compound 2-1.
  • ESI-MS: m/z 1084.9 [M+H] + .
  • dilution buffer in the kit (manufacturer: Cisbio, product number: 63ADK000CB01PEH) to dilute the 500nM Tag1-BCL-2 protein stock solution to 5nM, and at the same time dilute the 20 ⁇ M Tag2-BAK protein stock solution to 120nM, first add 5 ⁇ L of Tag1-BCL-2 protein dilution, and then add different compounds dissolved in DMSO to the wells with a nanoliter sampler, so that the final concentration of the compound is 200nM-0.0488nM, 4 times gradient, a total of 7 concentrations, and a blank control is set at the same time Wells (without enzyme) and negative control wells (with enzyme, plus solvent DMSO) were set up in duplicate, and finally 5 ⁇ L of Tag2-BAK protein dilution was added to each well, centrifuged to mix, and incubated at 25°C for 15 minutes.
  • the detection buffer in the kit uses the detection buffer in the kit to dilute 100X anti-Tag1-Eu 3+ to a 1X usage concentration, and at the same time dilute 100X anti-Tag2-XL665 to a 1X usage concentration.
  • PE Envision multifunctional microplate reader was used to read the plate (excitation 620nm, emission 665nm), and four-parameter fitting was used to calculate IC 50 (shown in Table 1).
  • the dilution buffer in the kit (manufacturer: Cisbio, product number: 63ADK000CB04PEH) to dilute the 300nM Tag1-BCL-XL protein stock solution to 2nM, and at the same time dilute the 10 ⁇ M Tag2-BAK protein stock solution to 80nM, first add 5 ⁇ L of Tag1-BCL-XL protein dilution, and then use a nanoliter sampler to add different compounds dissolved in DMSO to the wells, so that the final concentration of the compound is 2000nM-0.488nM, 4-fold gradient, a total of 7 concentrations, and set a blank control at the same time Wells (without enzyme) and negative control wells (with enzyme, plus solvent DMSO) were set up in duplicate, and finally 5 ⁇ L of Tag2-BAK protein dilution was added to each well, centrifuged to mix, and incubated at 25°C for 15 minutes.
  • the detection buffer in the kit uses the detection buffer in the kit to dilute 100X anti-Tag1-Eu 3+ to a 1X usage concentration, and at the same time dilute 100X anti-Tag2-XL665 to a 1X usage concentration.
  • PE Envision multifunctional microplate reader was used to read the plate (excitation 620nm, emission 665nm), and four-parameter fitting was used to calculate IC 50 (shown in Table 1).
  • Test example 2 compound to RS4; 11 cell proliferation inhibitory effect
  • RS4;11 cells in good exponential growth phase collect the cells into a centrifuge tube, centrifuge at 1500 rpm for 3 min in a low-speed desktop centrifuge, discard the supernatant, and add 5 mL of complete medium (RPMI basal medium) with a pipette +10% FBS) for cell resuspension.
  • complete medium RPMI basal medium
  • FBS pipette +10% FBS
  • Inoculate on a 96-well plate with a discharge gun, 100 ⁇ L/well, and culture in a cell culture incubator at 37°C with 5% CO2 saturated humidity. After culturing for 24 hours, add the compound (500-0.1 nM) using a nanoliter sampler, set up 2 replicate wells for each concentration, and use the cells without compound as the negative control, add CCK-8 after 72 hours, 10 ⁇ L/ Well, after 4 hours, the Envision microplate reader detects its absorbance at 450nm, and calculates the inhibition rate, inhibition rate (%) (negative control group average value—experimental group average value)/(negative control group average value—blank group average value ) ⁇ 100%, taking the logarithm of the compound concentration as the abscissa, and the inhibition rate as the ordinate, four-parameter analysis, fitting the dose-effect curve, and calculating the IC 50 (see Table 2).
  • Intestinal S9 (species: human, monkey, dog, rat and mouse) incubation samples were prepared by mixing PBS buffer (pH7.4), intestinal S9 solution (1mg/mL), test compound and NADPH+MgCl 2 solution, and incubated at 37°C and 300rpm for 2 hours.
  • the 0-hour sample was prepared by mixing PBS buffer (pH 7.4), enteric S9 solution (1 mg/mL) and the test compound.
  • the sample was added to an acetonitrile solution containing an internal standard, and the supernatant was prepared by protein precipitation, which was diluted for LC/MS/MS determination.
  • SD rats with a body weight of 200-220 g were randomly divided into groups after 3-5 days of adaptation, 3 rats in each group, and were given the compound to be tested by intragastric administration at a dose of 10 mg/kg (calculated as the original drug).
  • Blood collection time points were 0.25 (15min), 0.5 (30min), 1, 2, 3, 5, 7, 10, and 24h, and blood was collected from the orbit to prepare plasma samples to be tested.
  • Non-compartmental models were used to fit pharmacokinetic parameters (see Table 3).
  • Reagents used 0.2M NaOH, Sinopharm batch number 20180223; and 0.2M phosphate, Sinopharm 20180910, pH 7.4.
  • the instruments/equipment used include balance: HPLC Dionex U3000, Mettler XPE105DR; pipette: Tianbo 0.5mL, 0.1mL; constant temperature numerical control shaker: ZWY-240, set at 25°C and 200rpm.
  • Example compounds were tested in aqueous media at 25°C. An excess of the example compound was weighed out and mixed with an aliquot of the target medium in a clear glass vial. The vial was capped and sealed, and then shaken in a shaker at 25°C as appropriate. When equilibration is complete, remove the sample from the shaker and measure the final pH. The suspension was filtered through a syringe filter of 13 mm, 0.22 ⁇ m Syring Filter (hydrophilic PTFE-SA membrane, batch number HKS13SATQ2B). Use each filter for one sample only. The assay was performed after appropriate dilution of the filtrate with the same solvent as that used for the stock solution. Calculate the sample concentration from the calibration curve for the compound. The results are shown in Table 4.
  • Test Example 6 Pharmacodynamic evaluation of the test substance in the subcutaneous transplantation model of RS4;11 human B-cell leukemia
  • NOD/SCID mice female, 9-10 weeks (the age of mice at the time of tumor cell inoculation), body weight 16.3-22.0 g. Purchased from Ankai Yibo Biotechnology Co., Ltd., production license number: SCXK (Beijing) 2017-0006, animal certificate number: 11402400013155. Breeding environment: SPF grade. 1 ⁇ 10 7 RS4;11 cells were subcutaneously inoculated on the right front back of the mouse. The day of inoculation was defined as day 0. When the average volume of the tumor reached 240mm 3 , they were randomly divided into groups according to the size of the tumor. Dosing was performed according to Table 5.
  • Table 5 The route of administration, dosage and scheme in the subcutaneous animal model of human B-cell leukemia RS4;11
  • n number of animals; administration volume is 10 ⁇ L/g.
  • StudyDirector TM version number 3.1.399.19, supplier Studylog System, Inc., S. San Francisco, CA, USA
  • T/C% Relative tumor proliferation rate
  • T and C are the relative tumor volume (RTV) or tumor weight (TW) of the treatment group and the control group at a specific time point, respectively).
  • the compounds of the present application can obtain good pharmacodynamic results in vivo.

Abstract

一种选择性抑制抗凋亡蛋白BCL-2的三氟甲基取代的磺酰胺类化合物的磷酸酯化合物、其制备方法、含有这些化合物的药物组合物、以及其在治疗与抗凋亡蛋白BCL-2相关疾病例如癌症中的用途。

Description

三氟甲基取代的磺酰胺类化合物的磷酸酯
相关申请的引用
本申请要求于2021年06月04日向中华人民共和国国家知识产权局提交的第202110623940.6号中国专利申请的优先权和权益，在此将其全部内容以援引的方式整体并入文本中。
技术领域
本申请涉及选择性抑制抗凋亡蛋白BCL-2的三氟甲基取代的磺酰胺类化合物的磷酸酯化合物、其制备方法、含有这些化合物的药物组合物、以及其在治疗与抗凋亡蛋白BCL-2相关疾病例如癌症中的用途。
背景技术
BCL-2蛋白分为三个家族：BCL-2家族(其家族成员包括BCL-2、BCL-XL等)、BAX家族和BH3-only家族，其中BCL-2家族起着抗细胞凋亡的作用，后两个家族的成员起着促细胞凋亡的作用。
抗细胞凋亡BCL-2家族蛋白与许多疾病有关并且正被研究作为潜在的治疗药物目标。用于介入疗法的这类目标包括，例如，BCL-2家族蛋白BCL-2和BCL-XL等。最近，BCL-2家族蛋白的抑制剂已经报道于WO2012071374、WO2010138588、WO2010065865。虽然其中教导了具有对靶蛋白高结合的抑制剂，但化合物结合亲合力仅仅是许多待考虑的参数之一。一个目标是产生如下这样的化合物：其相对于另一种蛋白，优先地结合到一种蛋白，即对其的选择性。为显示这种选择性，周知的是化合物显示对特定的蛋白的高结合亲合力，以及对另一成员的较低的结合亲合力。
本申请包括一系列化合物，相对于抗细胞凋亡BCL-2蛋白及抗细胞凋亡BCL-XL蛋白，其显示出较高的选择性，且抑制抗细胞凋亡BCL-2蛋白活性方面也具有较好性能。同时，还具有较好的肝微粒体稳定性，以及优化的药代动力学参数。
发明内容
一方面，本申请涉及式I化合物、其立体异构体或其药学上可接受的盐，
Figure PCTCN2022096845-appb-000001
其中，
R 1选自氢、卤素、或C 1-3烷基；
R 2选自-R 3或-C 1-6亚烷基-R 3；
R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个选自以下的基团取代：4-6元杂环烷基、C 3-6环烷基、-COR a、-SO 2R b、-COOC 1-6烷基、或任选地被卤素取代的C 1-6烷基；
R a或R b分别独立地选自H、4-6元杂环烷基、C 3-6环烷基、或C 1-6烷基，所述C 1-6烷基任选地被卤素、-CN、-N(C 1-6烷基) 2、-NHC 1-6烷基、或-OC 1-6烷基取代；
G 1选自被OP(O)(OH) 2取代的C 1-10烷基。
在一些实施方案中，结构片段
Figure PCTCN2022096845-appb-000002
选自
Figure PCTCN2022096845-appb-000003
在一些实施方案中，结构片段
Figure PCTCN2022096845-appb-000004
选自
Figure PCTCN2022096845-appb-000005
在一些实施方案中，结构片段
Figure PCTCN2022096845-appb-000006
选自
Figure PCTCN2022096845-appb-000007
Figure PCTCN2022096845-appb-000008
在一些实施方案中，R 1选自氢、氟、氯或C 1-3烷基。在一些实施方案中，R 1选自氢、氯或甲基。
在一些实施方案中，R 2选自-R 3或-C 1-4亚烷基-R 3。
在一些实施方案中，R 2选自-R 3或-C 1-3亚烷基-R 3。
在一些实施方案中，R 2选自-R 3或-CH 2R 3、-(CH 2) 2R 3、或-(CH 2) 3R 3。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基中的杂原子选自N或O，杂原子个数选自1或2。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个基团取代，取代位点为环上的N原子。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个选自以下的基团取代：4-5杂环烷基、C 4-5烷基、-COR a、-SO 2R b、-COOC 1-3烷基、或任选地被卤素取代的C 1-3烷基。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个选自以下的基团取代：-COR a或SO 2R b。
在一些实施方案中，R a或R b分别独立地选自4-6元杂环烷基、C 3-5环烷基、或C 1-5烷基，所述C 1-5烷基任选地被卤素、-CN、-N(C 1-3烷基) 2、-NHC 1-3烷基、或-OC 1-3烷基取代。
在一些实施方案中，R a或R b分别独立地选自C 3-4环烷基、或C 1-4烷基，所述C 1-4烷基任选地被氟、氯、-CN、-N(C 1-3烷基) 2、或-OC 1-3烷基取代。
在一些实施方案中，R a或R b分别独立地选自甲基、乙基、-CH 2CN、环丙基、环丁基、叔丁基、-CF 3、异丙基、-CH 2OCH 3、或-CH 2N(CH 3) 2。
在一些实施方案中，R a选自-CH 2CN、环丙基、叔丁基、-CF 3、异丙基、-CH 2OCH 3、-CH 2N(CH 3) 2、或甲基。
在一些实施方案中，R b选自甲基、乙基、环丙基、或环丁基。
在一些实施方案中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被以下基团取代：-COCH 2CN、-CO-环丙烷、-COC(CH 3) 3、-COCF 3、-COCH(CH 3) 2、-COCH 2OCH 3、-SO 2CH 3、-SO 2CH 2CH 3、-SO 2-环丙烷、-SO 2-环丁烷、-COCH 2N(CH 3) 2、或-COCH 3。
在一些实施方案中，R 3选自四氢呋喃基、四氢吡喃基、哌啶基、吗啉基或二氧六环基，所述四氢呋喃基、四氢吡喃基、哌啶基、吗啉基或二氧六环基任选地被以下基团取代：-COCH 2CN、-CO-环丙烷、-COC(CH 3) 3、-COCF 3、-COCH(CH 3) 2、-COCH 2OCH 3、-SO 2CH 3、-SO 2CH 2CH 3、-SO 2-环丙烷、-SO 2-环丁烷、-COCH 2N(CH 3) 2或-COCH 3。
在一些实施方案中，R 3选自四氢呋喃基、四氢吡喃基或二氧六环基。
在一些实施方案中，R 3选自二氧六环基。
在一些实施方案中，R 3选自哌啶基或吗啉基，所述哌啶基或吗啉基任选地被以下基团取代：-COCH 2CN、-CO-环丙烷、-COC(CH 3) 3、-COCF 3、-COCH(CH 3) 2、-COCH 2OCH 3、-SO 2CH 3、-SO 2CH 2CH 3、-SO 2-环丙烷、-SO 2-环丁烷、-COCH 2N(CH 3) 2或-COCH 3。
在一些实施方案中，R 3选自
Figure PCTCN2022096845-appb-000009
Figure PCTCN2022096845-appb-000010
Figure PCTCN2022096845-appb-000011
在一些实施方案中，R 3选自
Figure PCTCN2022096845-appb-000012
Figure PCTCN2022096845-appb-000013
在一些实施方案中，所述5-6元杂环烷基中的杂原子选自N或O，杂原子个数选自1或2。
在一些实施方案中，所述5-6元杂环烷基选自二氧六环基、四氢吡喃基、吗啉基、哌啶基、或四氢呋喃基。
在一些实施方案中，所述5-6元杂环烷基选自6元杂环烷基。
在一些实施方案中，所述5-6元杂环烷基选自二氧六环基、吗啉基、四氢吡喃基、或哌啶基。
在一些实施方案中，所述5-6元杂环烷基选自二氧六环基。
在一些实施方案中，所述5-6元杂环烷基选自吗啉基。
在一些实施方案中，所述5-6元杂环烷基选自四氢吡喃基。
在一些实施方案中，所述4-6元杂环烷基中杂原子选自N或O，杂原子个数选自1或2。在一些实施方案中，所述4-6元杂环烷基中杂原子选自O，杂原子个数为1或2。在一些实施方案中，所述4-6元杂环烷基选自4元杂环烷基、5元杂环烷基、或6元杂环烷基。
在一些实施方案中，G 1选自被OP(O)(OH) 2取代的C 1-6烷基。
在一些实施方案中，G 1选自被OP(O)(OH) 2取代的C 1-4烷基。
在一些实施方案中，G 1选自被OP(O)(OH) 2取代的C 1-3烷基。
在一些实施方案中，G 1选自-CH 2OP(O)(OH) 2。
另一方面，本申请涉及式II或式III化合物、其立体异构体或其药学上可接受的盐：
Figure PCTCN2022096845-appb-000014
其中，R 2的定义同式I化合物；m选自1、2、3或4。
本申请涉及以下化合物、其立体异构体或其药学上可接受的盐，
Figure PCTCN2022096845-appb-000015
或者，
Figure PCTCN2022096845-appb-000016
Figure PCTCN2022096845-appb-000017
Figure PCTCN2022096845-appb-000018
本申请涉及以下化合物、其立体异构体或其药学上可接受的盐，
Figure PCTCN2022096845-appb-000019
或者，
Figure PCTCN2022096845-appb-000020
Figure PCTCN2022096845-appb-000021
Figure PCTCN2022096845-appb-000022
本申请涉及以下化合物、其立体异构体或其药学上可接受的盐，
Figure PCTCN2022096845-appb-000023
Figure PCTCN2022096845-appb-000024
优选
Figure PCTCN2022096845-appb-000025
Figure PCTCN2022096845-appb-000026
本申请涉及以下化合物、其立体异构体或其药学上可接受的盐，
Figure PCTCN2022096845-appb-000027
优选
Figure PCTCN2022096845-appb-000028
Figure PCTCN2022096845-appb-000029
另一方面，本申请涉及一种药物组合物，其包含本申请的上述式I化合物、其立体异构体或其药学上可接受的盐。在一些实施方案中，本申请涉及一种药物组合物，其包含本申请的上述式II化合物或式III化合物、其立体异构体或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包含药学上可接受的辅料。
另一方面，本申请描述了治疗哺乳动物与抗凋亡蛋白BCL-2相关疾病的方法，包括对需要该治疗的哺乳动物(优选人类)给予治疗有效量的本申请的化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。
另一方面，本申请描述了本申请的式I化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在制备用于预防或者治疗与抗凋亡蛋白BCL-2相关疾病的药物中的用途。
另一方面，本申请描述了本申请的式I化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在预防或者治疗与抗凋亡蛋白BCL-2相关疾病的用途。
另一方面，本申请描述了用于预防或者治疗与抗凋亡蛋白BCL-2相关疾病的式I化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。
其中，所述与抗凋亡蛋白BCL-2相关疾病选自癌症。所述癌症选自急性淋巴细胞白血病。
本申请化合物(优选具体化合物)，在酶的层面，相对于BCL-XL/BAK酶，选择性抑制BCL-2/BAK酶，具有更低的BCL-XL/BAK酶抑制活性。并且，具有较好的理化性质例如在水中的溶解度高，具有良好的体内外药代性质(例如生物利用度高、进入血浆前稳定性高)，以及良好的体内药效学性质。
定义
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(-CH 2CH 3)、单取代的(如-CH 2CH 2F)、多取代的(如-CHFCH 2F、-CH 2CHF 2等)或完全被取代的(-CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文中的C m-n，是该部分具有给定范围中的整数个碳原子。例如“C 1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“烷基”是指通式为C nH 2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C 1- 6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。再例如术语“C 1- 4烷基”指含有1至4个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等)。
术语“亚烷基”是指烷基的任意位置除去1个氢而形成的二价基团。例如，术语“C 1-6亚烷基”的非限制性实例包括但不限于亚甲基、亚乙基、甲基亚甲基、二甲基亚甲基、1,3-亚丙基等。
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至10元环、优选3至6元环，例如3至5元环或3至4元环。环烷基的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基(双环[2.2.1]庚基)、双环[2.2.2]辛基、金刚烷基等。
术语“杂环烷基”是指完全饱和的并且可以以单环、桥环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至3个(优选1或2个)独立地选自硫、氧和/或氮的杂原子的3至7元环，例如4至6元环或5至6元环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，7元杂环烷基的实例包括但不限于氮杂 环庚烷基、氧杂环庚烷基、硫杂环庚烷基。优选为具有5或6个环原子的单环杂环烷基。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“药学上可接受的”，是指针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising等应理解为开放的、非排他性的意义，即“包括但不限于”。
本申请的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
某些同位素标记的本申请化合物(例如用 3H及 14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素由于其易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括在本申请中，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品等。
本文所述的式I化合物的所有施用方法中，每天给药的剂量为0.01mg/kg体重到200mg/kg体重，以单独或分开剂量的形式。
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其它化学合成方法的结合所形成的实施方式以及本领域技术人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本领域合成路线规划中的一个重要考量因素是为反应性官能团(如本申请中的羟基)选择合适的保护基，例如，可参考Greene's Protective Groups in Organic Synthesis(4th Ed).Hoboken,New Jersey:John Wiley & Sons,Inc.
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本申请。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
具体实施方式
为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。
tBu代表叔丁基。
实施例1
1)化合物1-1的制备
Figure PCTCN2022096845-appb-000030
将化合物1-a(2g，根据WO2020088442实施例8制备)、二叔丁基氯甲基磷酸酯(1.65g)、1,8-双二甲基萘(0.50g)加入乙腈(10mL)中搅拌混合，加热至80℃搅拌6h，自然降至室温并搅拌12h，减压浓缩得到化合物1-1。ESI-MS:m/z＝1104.8[M+H] +。
2)化合物1的制备
Figure PCTCN2022096845-appb-000031
将化合物1-1(1.9g)加入二氯甲烷(5mL)，滴加三氟乙酸(5mL)，室温搅拌12h，减压浓缩后经制备液相纯化得到化合物1(340mg)。
1H NMR(500MHz,DMSO-d6),δ:8.75(1H,d),8.60(1H,t,),8.55(1H,d),8.52(1H,d),7.99(1H,d),7.89(1H,m),7.86(1H,dd),7.70(1H,d),7.57(1H,d),7.39(1H,d),7.19(1H,d),6.88(1H,d),6.81(1H,dd),6.43(1H,d),6.36(1H,s),6.33(1H,s),3.81(1H,m),3.81(1H,m),3.79(1H,m),3.67(1H,m),3.61(1H,m),3.58(1H,m),3.53(1H,m),3.49(1H,m),3.42(1H,m),3.41(1H,m),3.33(1H,m),3.06(4H,brs),2.28(1H,m),2.19(1H,m),2.15(4H,m),1.96(2H,m),1.49(2H,m),0.97(3H,s),0.96(3H,s)。ESI-MS:m/z＝1048.8[M+H] +。
实施例2
1)化合物2-1的制备
Figure PCTCN2022096845-appb-000032
参照化合物1-1的制备方法，将化合物1-a换成化合物2-a(根据WO2020238785实施例3制备)，得到化合物2-1。ESI-MS:m/z＝1084.9[M+H] +。
2)化合物2的制备
Figure PCTCN2022096845-appb-000033
参照化合物1的制备方法，将化合物1-1换成化合物2-1，得到化合物2。
1H NMR(500MHz,DMSO-d6),δ:8.75(1H,d),8.60(1H,t,),8.54(1H,d),8.51(1H,d),7.99(1H,d),7.86(1H,dd),7.84(1H,d),7.57(1H,d),7.50(1H,d),7.19(1H,d),7.17(1H,d),6.87(1H,d),6.79(1H,dd),6.43(1H,d),6.34(1H,s),6.32(1H,s),3.79(4H,m),3.64(4H,m),3.49(2H,m),3.41(1H,m),3.29(4H,m),3.02(2H,brs),2.91(1H,brs),2.64(1H,m),2.29(1H,m),2.18(1H,m),2.16(3H,s),1.91(2H,m),1.49(2H,m),0.97(3H,s), 0.96(3H,s)。ESI-MS:m/z＝1028.6[M+H] +。
试验例1.体外蛋白结合抑制活性
1.1 BCL-2/BAK结合抑制活性筛选
用试剂盒(厂家：Cisbio，货号：63ADK000CB01PEH)中的稀释缓冲液将500nM的Tag1-BCL-2蛋白母液稀释成5nM，同时将20μM的Tag2-BAK蛋白母液稀释成120nM，先每孔加入5μL的Tag1-BCL-2蛋白稀释液，然后用纳升加样仪将DMSO溶解的不同化合物加入到孔中，使化合物终浓度为200nM-0.0488nM，4倍梯度，共7个浓度，同时设空白对照孔(不含酶)与阴性对照孔(含酶，加溶媒DMSO)，设2个复孔，最后再每孔加入5μL的Tag2-BAK蛋白稀释液，离心混匀，25℃孵育15min。用试剂盒中的检测缓冲液将100X的anti-Tag1-Eu 3+稀释成1X的使用浓度，同时将100X的anti-Tag2-XL665稀释成1X的使用浓度。将anti-Tag1-Eu 3+和anti-Tag2-XL665按1：1混匀，每孔加入5μL的混合液，25℃反应2h及以上。PE Envision多功能酶标仪进行读板(激发620nm，发射665nm)，采用四参数拟合，计算IC 50(表1所示)。
1.2 BCL-XL/BAK结合抑制活性筛选
用试剂盒(厂家：Cisbio，货号：63ADK000CB04PEH)中的稀释缓冲液将300nM的Tag1-BCL-XL蛋白母液稀释成2nM，同时将10μM的Tag2-BAK蛋白母液稀释成80nM，先每孔加入5μL的Tag1-BCL-XL蛋白稀释液，然后用纳升加样仪将DMSO溶解的不同化合物加入到孔中，使化合物终浓度为2000nM-0.488nM，4倍梯度，共7个浓度，同时设空白对照孔(不含酶)与阴性对照孔(含酶，加溶媒DMSO)，设2个复孔，最后再每孔加入5μL的Tag2-BAK蛋白稀释液，离心混匀，25℃孵育15min。用试剂盒中的检测缓冲液将100X的anti-Tag1-Eu 3+稀释成1X的使用浓度，同时将100X的anti-Tag2-XL665稀释成1X的使用浓度。将anti-Tag1-Eu 3+和anti-Tag2-XL665按1：1混匀，每孔加入5μL的混合液，25℃反应2h及以上。PE Envision多功能酶标仪进行读板(激发620nm，发射665nm)，采用四参数拟合，计算IC 50(表1所示)。
表1 化合物抑制BCL-2/BAK和BCL-XL/BAK结合的活性
Figure PCTCN2022096845-appb-000034
试验例2.化合物对RS4；11细胞的增殖抑制作用
取处于指数生长期状态良好的RS4；11细胞，收集细胞至离心管，低速台式离心机，1500转/min，离心3min，弃上清，用移液器加入5mL完全培养基(RPMI基础培养基+10％FBS)进行细胞重悬。使用细胞计数仪计数，完全培养基进行稀释，调整细胞密度至2*10 5个/mL，再加入等量的RPMI基础培养基调整血清浓度为5％，细胞密度为1*10 5个/mL用于种板。使用排枪接种于96孔板上，100μL/孔，置于37℃、含5％CO 2饱和湿度的细胞培养箱中培养。培养24h后，使用纳升加样仪进行化合物加样(500-0.1nM)，每一浓度设置2个复孔，以不加化合物的细胞作为阴性对照，72小时后加CCK-8，10μL/孔，4小时后Envision酶标仪450nm处检测其吸光值，计算抑制率，抑制率(％)＝(阴性对照组平均值—实验组平均值)/(阴性对照组平均值—空白组平均值)×100％，以化合物浓度对数为横坐标，抑制率为纵坐标，四参数分析，拟合量效曲线，计算IC 50(见表2)。
表2 化合物对RS4；11细胞的增殖抑制作用
Figure PCTCN2022096845-appb-000035
试验例3.体外肠S9稳定性
肠S9(种属：人、猴、犬、大鼠及小鼠)温孵样本制备为混合PBS缓冲液(pH7.4)、肠S9溶液(1mg/mL)、受试化合物及NADPH+MgCl 2溶液，并于37℃及300rpm孵育2小时。0小时样本制备为混合PBS缓冲液(pH7.4)、肠S9溶液(1mg/mL)及受试化合物。样本加入含内标的乙腈溶液，经蛋白沉淀制备上清液，稀释后用于LC/MS/MS测定。
结果：本申请受试化合物体外肠S9代谢稳定。
试验例4.大鼠体内药代动力学评价
SD大鼠，体重200-220g，适应3～5天后，随机分组，每组3只，按10mg/kg(以原药计)剂量灌胃分别给予待测化合物。
采血时间点0.25(15min)、0.5(30min)、1、2、3、5、7、10、24h，于眼眶取血制备待测血浆样品。
吸取50μL待测血浆样品和标曲样品，加入含内标的乙腈溶液经蛋白沉淀得到上清液，稀释后用于LC/MS/MS测定。
采用非房室模型拟合药代参数(见表3)。
表3 化合物的药代参数
Figure PCTCN2022096845-appb-000036
试验例5.溶解度测定
所用试剂：0.2M NaOH，国药批号20180223；及0.2M磷酸盐，国药20180910，pH 7.4。所用仪器/设备包括天平：HPLC Dionex U3000，Mettler XPE105DR；移液管：天玻0.5mL、0.1mL；恒温数控摇床：ZWY-240，设定在25℃及200rpm。
在25℃于水性介质中测试实施例化合物。称过量的实施例化合物并在透明玻璃小瓶中与目标介质的等分部分混合。将小瓶加盖密封，随后视情况将其在25℃摇床中震荡摇晃。当完成平衡时，从摇床中取出样品并测量最终pH值。将混悬液滤过针头式过滤器13mm，0.22μm Syring Filter针式过滤器(亲水性PTFE-SA膜，批号HKS13SATQ2B)。每个过滤器仅用于一个样品。在用与储备溶液所用的相同的溶剂将滤液适当稀释后进行测定。依据化合物的校准曲线计算样品浓度。结果见表4。
表4.pH 7.4条件下水溶解度
实施例 水溶解度(pH7.4,μg/mL)
1 19390
2 2230
试验例6.受试物在RS4；11人类B细胞白血病皮下移植模型中的药效学评价
NOD/SCID小鼠，雌性，9-10周(肿瘤细胞接种时的小鼠周龄)，体重16.3-22.0g。购自安凯毅博生物技术有限公司，生产许可证号：SCXK(京)2017-0006，动物合格证编号：11402400013155。饲养环境：SPF级。小鼠右侧前背部皮下接种1×10 7个RS4；11细胞。接种当天定义为第0天。待肿瘤平均体积达到240mm 3时，根据肿瘤大小随机分组。按下表5进行给药。
表5 人源B细胞白血病RS4；11皮下动物模型中的给药途径、剂量及方案
Figure PCTCN2022096845-appb-000037
注：n：动物只数；给药体积为10μL/g。
实验过程中观察到的临床症状均记录在原始数据中。肿瘤体积计算公式：肿瘤体积(mm 3)＝1/2×(a×b 2)(其中a表示长径，b表示短径)。实验中使用StudyDirector TM(版本号3.1.399.19，供应商Studylog System,Inc.,S.San Francisco,CA,USA)软件收集数据，包括肿瘤的长短径的测量和动物体重的称量。原始数据由 天平和游标卡尺测量后直接导入软件，数据的任何变动都将被记录在此软件中。相对肿瘤增殖率，T/C％，即在某一时间点，治疗组和对照组相对肿瘤体积或瘤重的百分比值。计算公式如下：
T/C％＝T RTV/C RTV×100％(T RTV：治疗组平均RTV；C RTV：溶媒对照组平均RTV；RTV＝V t/V 0，V 0为分组时该动物的瘤体积，V t为治疗后该动物的瘤体积)。
相对肿瘤抑制率，TGI(％)，计算公式如下：TGI％＝(1-T/C)×100％。(T和C分别为治疗组和对照组在某一特定时间点的相对肿瘤体积(RTV)或瘤重(TW))。
所有实验结果以平均瘤体积±SEM(平均标准误差)表示。用独立样本T检验方法比较治疗组相对肿瘤体积与对照组相比有无显著性差异。所有的数据均用SPSS 18.0进行分析。p<0.05为具有显著性差异。
本申请的化合物可以获得良好的体内药效结果。

Claims (13)

  1. 式I化合物、其立体异构体或其药学上可接受的盐，
    Figure PCTCN2022096845-appb-100001
    其中，
    R 1选自氢、卤素、或C 1-3烷基；
    R 2选自-R 3或-C 1-6亚烷基-R 3；
    R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个选自以下的基团取代：4-6元杂环烷基、C 3-6环烷基、-COR a、-SO 2R b、-COOC 1-6烷基、或任选地被卤素取代的C 1-6烷基；
    R a或R b分别独立地选自H、4-6元杂环烷基、C 3-6环烷基、或C 1-6烷基，所述C 1-6烷基任选地被卤素、-CN、-N(C 1-6烷基) 2、-NHC 1-6烷基、或-OC 1-6烷基取代；
    G 1选自被OP(O)(OH) 2取代的C 1-10烷基。
  2. 根据权利要求1所述的式I化合物、其立体异构体或其药学上可接受的盐，其中，结构片段
    Figure PCTCN2022096845-appb-100002
    为
    Figure PCTCN2022096845-appb-100003
    或者，结构片段
    Figure PCTCN2022096845-appb-100004
    为
    Figure PCTCN2022096845-appb-100005
    或者，结构片段
    Figure PCTCN2022096845-appb-100006
    选自
    Figure PCTCN2022096845-appb-100007
  3. 根据权利要求1或2所述的式I化合物、其立体异构体或其药学上可接受的盐，其中，R 1选自氢、氟、氯或C 1-3烷基；
    或者，R 1选自氢、氯或甲基。
  4. 根据权利要求1-3任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中，R 2选自-R 3或-C 1-4亚烷基-R 3；
    或者，R 2选自-R 3或-C 1-3亚烷基-R 3；
    或者，R 2选自-R 3或-CH 2R 3、-(CH 2) 2R 3、或-(CH 2) 3R 3。
  5. 根据权利要求1-4任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个基团取代，取代位点为环上的N原子；
    或者，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个选自以下的基团取代：4-5杂环烷基、C 4-5烷基、-COR a、-SO 2R b、-COOC 1-3烷基、或任选地被卤素取代的C 1-3烷基；
    或者，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被一个或两个选自以下的基团取代：-COR a或SO 2R b。
  6. 根据权利要求1-5任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中，R a或R b分别独立地选自4-6元杂环烷基、C 3-5环烷基、或C 1-5烷基，所述C 1-5烷基任选地被卤素、-CN、 -N(C 1-3烷基) 2、-NHC 1-3烷基、或-OC 1-3烷基取代；
    或者，R a或R b分别独立地选自C 3-4环烷基、或C 1-4烷基，所述C 1-4烷基任选地被氟、氯、-CN、-N(C 1-3烷基) 2、或-OC 1-3烷基取代；
    或者，R a或R b分别独立地选自甲基、乙基、-CH 2CN、环丙基、环丁基、叔丁基、-CF 3、异丙基、-CH 2OCH 3、或-CH 2N(CH 3) 2；
    或者，R a选自-CH 2CN、环丙基、叔丁基、-CF 3、异丙基、-CH 2OCH 3、-CH 2N(CH 3) 2、或甲基；
    或者，R b选自甲基、乙基、环丙基、或环丁基。
  7. 根据权利要求1-6任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中，R 3选自5-6元杂环烷基，所述5-6元杂环烷基任选地被以下基团取代：-COCH 2CN、-CO-环丙烷、-COC(CH 3) 3、-COCF 3、-COCH(CH 3) 2、-COCH 2OCH 3、-SO 2CH 3、-SO 2CH 2CH 3、-SO 2-环丙烷、-SO 2-环丁烷、-COCH 2N(CH 3) 2、或-COCH 3；
    或者，R 3选自四氢呋喃基、四氢吡喃基、哌啶基、吗啉基或二氧六环基，所述四氢呋喃基、四氢吡喃基、哌啶基、吗啉基或二氧六环基任选地被以下基团取代：-COCH 2CN、-CO-环丙烷、-COC(CH 3) 3、-COCF 3、-COCH(CH 3) 2、-COCH 2OCH 3、-SO 2CH 3、-SO 2CH 2CH 3、-SO 2-环丙烷、-SO 2-环丁烷、-COCH 2N(CH 3) 2或-COCH 3；
    或者，R 3选自四氢呋喃基、四氢吡喃基或二氧六环基；
    或者，R 3选自哌啶基或吗啉基，所述哌啶基或吗啉基任选地被以下基团取代：-COCH 2CN、-CO-环丙烷、-COC(CH 3) 3、-COCF 3、-COCH(CH 3) 2、-COCH 2OCH 3、-SO 2CH 3、-SO 2CH 2CH 3、-SO 2-环丙烷、-SO 2-环丁烷、-COCH 2N(CH 3) 2或-COCH 3；
    优选地，R 3选自
    Figure PCTCN2022096845-appb-100008
    Figure PCTCN2022096845-appb-100009
    优选地，R 3选自
    Figure PCTCN2022096845-appb-100010
    Figure PCTCN2022096845-appb-100011
    Figure PCTCN2022096845-appb-100012
  8. 根据权利要求1-7任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，其中，G 1选自被OP(O)(OH) 2取代的C 1-6烷基；
    或者，G 1选自被OP(O)(OH) 2取代的C 1-4烷基；
    或者，G 1选自被OP(O)(OH) 2取代的C 1-3烷基；
    或者，G 1选自-CH 2OP(O)(OH) 2。
  9. 根据权利要求1-8任一项所述的式I化合物、其立体异构体或其药学上可接受的盐，选自式II或式III化合物、其立体异构体或其药学上可接受的盐：
    Figure PCTCN2022096845-appb-100013
    其中，R 2的定义如权利要求1和4-7任一项所述；m选自1、2、3或4。
  10. 以下化合物、其立体异构体或其药学上可接受的盐，
    Figure PCTCN2022096845-appb-100014
    或者，
    Figure PCTCN2022096845-appb-100015
    Figure PCTCN2022096845-appb-100016
  11. 根据权利要求10所述的化合物、其立体异构体或其药学上可接受的盐，选自以下化合物、其立体异构体或其药学上可接受的盐，
    Figure PCTCN2022096845-appb-100017
    Figure PCTCN2022096845-appb-100018
    或者，
    Figure PCTCN2022096845-appb-100019
    Figure PCTCN2022096845-appb-100020
  12. 一种药物组合物，其包含权利要求1-11任一项所述的化合物、其立体异构体或其药学上可接受的盐。
  13. 权利要求1-11任一项所述的化合物、其立体异构体或其药学上可接受的盐、或权利要求12所述的药物组合物在制备用于预防或者治疗与抗凋亡蛋白BCL-2相关疾病的药物中的用途；
    优选地，所述与抗凋亡蛋白BCL-2相关疾病为癌症；
    优选地，所述癌症为急性淋巴细胞白血病。
PCT/CN2022/096845 2021-06-04 2022-06-02 三氟甲基取代的磺酰胺类化合物的磷酸酯 WO2022253313A1 (zh)

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