WO2022148439A1 - Composé hétérocyclique utilisé en tant qu'inhibiteur de bcl-2 - Google Patents

Composé hétérocyclique utilisé en tant qu'inhibiteur de bcl-2 Download PDF

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WO2022148439A1
WO2022148439A1 PCT/CN2022/070756 CN2022070756W WO2022148439A1 WO 2022148439 A1 WO2022148439 A1 WO 2022148439A1 CN 2022070756 W CN2022070756 W CN 2022070756W WO 2022148439 A1 WO2022148439 A1 WO 2022148439A1
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optionally substituted
hydrogen
compound
alkyl
methyl
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PCT/CN2022/070756
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English (en)
Chinese (zh)
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孔祥龙
周超
郑之祥
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南京天印健华医药科技有限公司
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    • 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
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • 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

Definitions

  • the present invention relates to heterocyclic compounds, pharmaceutical compositions containing them and their use as B-cell lymphoma-2 (BCL-2) inhibitors. More specifically, the present invention provides novel heterocyclic compounds as BCL-2 inhibitors, pharmaceutical compositions containing such heterocyclic compounds, and application of the heterocyclic compounds to treat or prevent BCL-2-mediated related diseases and functional disorders, such as tumors.
  • BCL-2 B-cell lymphoma-2
  • the present invention also relates to a method for preparing the heterocyclic compound.
  • the BCL-2 protein family is one of the core regulatory mechanisms of apoptosis (also called programmed cell death), which can receive and transmit internal intracellular signals or external environmental stress signals, such as nutritional or hypoxic stress, DNA damage, carcinogenesis Excessive activation of genes, endoplasmic reticulum stress, etc., mainly play a leading role in the intrinsic apoptosis pathway.
  • BCL-2 B-cell lymphoma-22
  • the BCL-2 gene is a proto-oncogene, and the proteins it expresses are called BCL-2 family proteins.
  • There are 27 BCL-2 family proteins in the human body which can be divided into 3 subclasses according to function and sequence analysis.
  • the first subclass is anti-apoptotic, including BCL-XL, BCL-2, BCL-W, MCL -1, BFL-1, they are mainly localized on mitochondria and protect mitochondria from adversity damage; the other two subclasses are apoptosis-promoting, and one subclass is the ultimate executor of mitochondrial damage, including BAX and BAK.
  • the rest belong to the BH3 subclass, which can directly sense various cellular stress signals.
  • BCL-2 protein which antagonizes apoptosis, is closely related to tumors.
  • BCL-2 family proteins bind to BCL-2 family proteins.
  • Multiple signaling pathways such as JAK-STAT, NFkB, and UPS (ubiquitin-proteasome system), can cause the overexpression of BCL-2 protein that antagonizes apoptosis.
  • BCL-2 family anti-apoptotic proteins The high expression of BCL-2 family anti-apoptotic proteins is related to the drug resistance of various tumors.
  • the overexpression of BCL-2 anti-apoptotic proteins can enable tumor cells to escape apoptosis caused by anti-tumor drugs, thereby causing drug resistance. medicine.
  • inhibition of BCL-2 family proteins can inhibit the formation of tumor angiogenesis, thereby inhibiting tumor metastasis (Benjamin, D.; Isaac, J. et al. J. Clin. Oncol. 2008, 26(25), 4180 ). Therefore, targeted inhibition of BCL-2 family anti-apoptotic proteins can inhibit the occurrence, development and drug resistance of tumors.
  • Venetoclax (ABT-199) jointly developed by AbbVie and Roche is a highly selective BCL-2 inhibitor (Andrew, J.; Joel, D. et al. Nature Medicine, 2013, 19(2), 202 ), in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), multiple myeloma (MM), etc., through combination therapy with Ibrutinib, etc., the objective response rate (ORR) and The complete remission rate (CR) has been greatly improved (Valentin, R.; Grablow, S. et al.
  • CLL chronic lymphocytic leukemia
  • MCL mantle cell lymphoma
  • MM multiple myeloma
  • ORR objective response rate
  • CR complete remission rate
  • the present invention relates to compounds of formula (I), isomers, prodrugs, solvates, stable isotope derivatives or pharmaceutically acceptable salts thereof,
  • X 1 is selected from optionally substituted C3-C6 cycloalkyl or optionally substituted 3-6 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, wherein said any The selected substituent is selected from hydroxyl, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S; preferably , X 1 is selected from optionally substituted C5-C6 cycloalkyl or optionally substituted 5-6-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, wherein the Optional substituents are selected from hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, 4- or 5-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S; further preferably , X 1 is selected from optionally substituted cyclohexyl
  • X 2 is selected from 5-6 membered heterocycloalkylene containing 1 or 2 heteroatoms selected from N, O, S, wherein the heterocycloalkylene is optionally surrounded by 1 or 2 C1-C4 alkyl groups or halogen substitution; preferably, X 2 is selected from a 6-membered heterocycloalkylene group containing 2 N atoms, wherein the heterocycloalkylene group is optionally substituted with 1 or 2 C1-C4 alkyl groups; further preferably , X 2 is selected from wherein the piperazinide group is optionally substituted by 1 C1-C4 alkyl group; further preferably, X 2 is selected from wherein the piperazinylene group is optionally substituted with 1 methyl; most preferably, X is selected from 5-6 membered heterocycloalkylene containing 1 or 2 heteroatoms selected from N, O, S, wherein the heterocycloalkylene is optionally surrounded by 1 or 2 C1-C4 alkyl groups or
  • R 0 is selected from hydrogen, halogen; preferably, R 0 is selected from hydrogen, fluorine, chlorine; most preferably, R 0 is selected from hydrogen, fluorine;
  • R 1 and R 2 are each independently selected from hydrogen and C1-C6 alkyl; preferably, R 1 and R 2 are each independently selected from hydrogen and C1-C4 alkyl; more preferably, R 1 and R 2 are each independently is selected from hydrogen, methyl, ethyl; most preferably, R 1 , R 2 are each independently selected from hydrogen, methyl;
  • n is selected from 1-4; preferably, n is selected from 1, 3 or 4.
  • the present invention relates to compounds of formula (I) as hereinbefore described, isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts thereof, wherein:
  • X 1 is selected from optionally substituted C5-C6 cycloalkyl or optionally substituted 5-6 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S, wherein any of said The selected substituent is selected from hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, 4- or 5-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S;
  • X 2 is selected from a 6-membered heterocycloalkylene group containing 2 N atoms, wherein the heterocycloalkylene group is optionally substituted with 1 or 2 C1-C4 alkyl groups;
  • R 0 is selected from hydrogen, halogen
  • R 1 and R 2 are each independently selected from hydrogen, C1-C6 alkyl
  • n is selected from 1-4.
  • the present invention relates to compounds of formula (I) as hereinbefore described, isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts thereof, wherein:
  • X 1 is selected from optionally substituted cyclohexyl or optionally substituted tetrahydropyranyl, 1,4-dioxanyl, piperidinyl, morpholinyl, wherein the optionally substituted group is selected from hydroxyl, C1-C4 alkyl, oxetanyl or tetrahydrofuranyl;
  • X 2 is selected from wherein the piperazinylene group is optionally substituted by 1 C1-C4 alkyl group;
  • R 0 is selected from hydrogen, halogen
  • R 1 and R 2 are each independently selected from hydrogen, C1-C4 alkyl
  • n is selected from 1-4.
  • the present invention relates to a compound of formula (I) as hereinbefore described, its isomer, prodrug, solvate, stable isotopic derivative or pharmaceutically acceptable salt, wherein:
  • X 1 is selected from optionally substituted cyclohexyl or optionally substituted tetrahydropyranyl, 1,4-dioxanyl, piperidinyl, morpholinyl, wherein the optionally substituted group is selected from hydroxyl, C1-C4 alkyl, oxetanyl or tetrahydrofuranyl;
  • X 2 is selected from wherein the piperazinylene group is optionally substituted by 1 C1-C4 alkyl group;
  • R 0 is selected from hydrogen, fluorine, chlorine
  • R 1 and R 2 are each independently selected from hydrogen, C1-C4 alkyl
  • n is selected from 1, 3 or 4.
  • the present invention relates to a compound of formula (I) as hereinbefore described, its isomer, prodrug, solvate, stable isotopic derivative or pharmaceutically acceptable salt, wherein:
  • X 1 is selected from (1r,4r)-1-hydroxy-1-methylcyclohexane-4-yl, (S)-1,4-dioxan-2-yl, (R)-1,4 -Dioxan-2-yl, tetrahydropyran-4-yl, 1-(oxetan-3-yl)piperidin-4-yl, (S)-4-(oxetane alk-3-yl)morpholin-2-yl;
  • X 2 is selected from wherein the piperazinylene group is optionally substituted with 1 methyl;
  • R 0 is selected from hydrogen, fluorine
  • R 1 and R 2 are each independently selected from hydrogen, methyl, and ethyl
  • n is selected from 1, 3 or 4.
  • the present invention relates to a compound of formula (I) as hereinbefore described, its isomer, prodrug, solvate, stable isotopic derivative or pharmaceutically acceptable salt, wherein:
  • X 1 is selected from (1r,4r)-1-hydroxy-1-methylcyclohexane-4-yl, (S)-1,4-dioxan-2-yl, (R)-1,4 -Dioxan-2-yl, tetrahydropyran-4-yl, 1-(oxetan-3-yl)piperidin-4-yl, (S)-4-(oxetane alk-3-yl)morpholin-2-yl;
  • X 2 is selected from
  • R 0 is selected from hydrogen, fluorine
  • R 1 and R 2 are each independently selected from hydrogen and methyl
  • n is selected from 1, 3 or 4.
  • the present invention relates to a compound of formula (I) as described above, its isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts thereof, selected from the group consisting of:
  • the present invention also relates to compounds of formula (I), isomers, prodrugs, solvates, stable isotope derivatives or pharmaceutically acceptable salts thereof according to any one of the embodiments of the present invention for use in the preparation of Use of a BCL-2 inhibitor in medicine.
  • the present invention also relates to a compound of formula (I) or an isomer, prodrug, solvate, stable isotope derivative or a pharmaceutically acceptable salt thereof according to any one of the embodiments of the present invention in the manufacture of a medicament for the treatment or prevention of related diseases mediated by BCL-2, such as tumors selected from hematological malignancies including acute lymphoblastic leukemia, lung cancer, breast cancer, ovarian cancer , rectal cancer, prostate cancer, pancreatic cancer, glioma.
  • related diseases mediated by BCL-2 such as tumors selected from hematological malignancies including acute lymphoblastic leukemia, lung cancer, breast cancer, ovarian cancer , rectal cancer, prostate cancer, pancreatic cancer, glioma.
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or an isomer, prodrug, solvate, stable isotopic derivative or A pharmaceutically acceptable salt thereof, optionally one or more other BCL-2 inhibitors, and one or more pharmaceutically acceptable carriers, diluents and excipients.
  • the present invention also relates to the use of the pharmaceutical composition according to the present invention in the preparation of a medicament, wherein the medicament is used for the treatment or prevention of BCL-2-mediated related diseases, such as tumors, which are selected from From hematological malignancies including acute lymphoblastic leukemia, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, glioma.
  • BCL-2-mediated related diseases such as tumors, which are selected from From hematological malignancies including acute lymphoblastic leukemia, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, glioma.
  • the present invention also relates to a method of treating or preventing related diseases mediated by BCL-2, comprising administering to a patient in need thereof a therapeutically effective amount of the compound described in any one of the embodiments of the present invention or an isomer, pro- Drugs, solvates, stable isotope derivatives or pharmaceutically acceptable salts thereof; or pharmaceutical compositions of the present invention, said related diseases such as tumors selected from hematological malignancies including acute lymphoblastic leukemia disease, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, glioma.
  • related diseases such as tumors selected from hematological malignancies including acute lymphoblastic leukemia disease, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, glioma.
  • Another aspect of the present invention pertains to a compound described in any one of the embodiments of the present invention, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, for use in therapy or Prevention of related diseases mediated by BCL-2, such as tumors selected from hematological malignancies including acute lymphoblastic leukemia, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, Glioma.
  • related diseases mediated by BCL-2 such as tumors selected from hematological malignancies including acute lymphoblastic leukemia, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, Glioma.
  • Another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or an isomer, prodrug, solvate, stable isotope thereof, as described in any one of the embodiments of the present invention
  • Derivatives or pharmaceutically acceptable salts thereof optionally one or more other BCL-2 inhibitors, and one or more pharmaceutically acceptable carriers, diluents and excipients for use in therapy Or prevent related diseases mediated by BCL-2, such as tumors selected from hematological malignancies including acute lymphoblastic leukemia, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer ,Glioma.
  • Another aspect of the present invention pertains to a compound of formula (I) or an isomer, prodrug, solvate thereof as described in any one of the embodiments of the present invention for the treatment and/or prophylaxis of BCL-2-mediated related diseases , a stable isotope derivative or a pharmaceutically acceptable salt thereof.
  • Said BCL-2 mediated related disease such as tumor, said related disease such as tumor selected from hematological malignancies including acute lymphoblastic leukemia, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreas Cancer, glioma.
  • the drug can be in any pharmaceutical dosage form, including but not limited to tablets, capsules, solutions, freeze-dried preparations, and injections.
  • the pharmaceutical formulations of the present invention may be administered in dosage unit form containing a predetermined amount of active ingredient per dosage unit.
  • a unit may contain, for example, from 0.5 mg to 1 gram, preferably from 1 mg to 700 mg, particularly preferably from 5 mg to 300 mg, of a compound of the invention, or drug, depending on the condition to be treated, the method of administration and the age, weight and condition of the patient.
  • the formulations can be administered in dosage unit form containing a predetermined quantity of active ingredient per dosage unit.
  • Preferred dosage unit formulations are those containing a daily dose or sub-dose, as indicated above, or a corresponding fraction thereof, of the active ingredient.
  • pharmaceutical formulations of this type can be prepared using methods well known in the pharmaceutical art.
  • the pharmaceutical formulations of the present invention may be suitable for administration by any desired suitable method, such as oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods of administration.
  • suitable method such as oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods of administration.
  • Such formulations can be prepared, for example, by combining the active ingredient with one or more excipients or one or more adjuvants, using all methods known in the art of pharmacy.
  • the present invention also provides methods for preparing the compounds.
  • R 0 and X 1 are as described above;
  • R 1 , R 2 and n are as defined above;
  • compound (V) Under nitrogen protection, compound (V), p-chlorobenzeneboronic acid, alkali such as potassium carbonate, phase-transfer catalyst such as tetra-n-butylammonium bromide and catalyst such as palladium acetate are added to a solvent such as water, the system is evacuated and replaced with nitrogen three times, and heated to 40 °C. React at ⁇ 100°C for 2 to 10 hours to obtain compound (VI);
  • R 0 , R 1 , R 2 , n and X 1 are as defined above;
  • R 3 is selected from H or methyl;
  • Cx-Cy used in the present invention represents a range of carbon atoms, where x and y are both integers, for example C3-C8 cycloalkyl represents a cycloalkyl having 3-8 carbon atoms, C0- C2 alkyl refers to an alkyl group having 0-2 carbon atoms, wherein C0 alkyl refers to a chemical single bond.
  • alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms, for example, may be 1 to 18 carbon atoms, 1 to 12 carbon atoms , straight and branched chain groups of 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, and various branched isomers thereof, etc.
  • Alkyl groups can be optionally substituted or unsubstituted.
  • cycloalkyl refers to a saturated monocyclic or polycyclic cyclic hydrocarbon group comprising 3 to 12 ring atoms, such as 3 to 12, 3 to 10, 3 to 8 or 3 to 6 ring atoms, or can be a 3, 4, 5, or 6 membered ring.
  • monocyclic cyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • Cycloalkyl groups can be optionally substituted or unsubstituted.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group comprising 3 to 20 ring atoms, such as 3 to 16, 3 to 12, 3 to 16 10, 3 to 8, or 3 to 6 ring atoms, one or more of which is selected from nitrogen, oxygen, or a heteroatom of S(O)m (where m is an integer from 0 to 2), excluding- The ring moiety of O-O-, -O-S- or -S-S-, the remaining ring atoms being carbon.
  • the heterocyclyl ring contains 3 to 10 ring atoms, more preferably 3 to 8 ring atoms, most preferably a 5- or 6-membered ring A ring of which 1-4 are heteroatoms, more preferably 1-3 are heteroatoms, and most preferably 1-2 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, piperidinyl, 4-piperidinyl, piperazinyl, 1,4-dioxanyl, morpholinyl, 2-morpholinyl, 4-morpholinyl, thiomorpholinyl, pyranyl, tetrahydropyranyl, 4-tetrahydropyranyl, homopiperazinyl, dioxanyl, 2-dioxanyl Alkyl, tetrahydrofuranyl, etc.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls. Heterocyclyl groups can be optionally substituted or unsubstituted.
  • heterocyclylene refers to a substituted or unsubstituted heterocyclyl having a core of two terminal monovalent groups obtained by removing one hydrogen atom from each of the two terminal atoms. produced; the heterocyclyl group has the meanings set forth above.
  • Non-limiting examples of “heterocyclylene” include pyrrolidylene, piperidinylene, piperazinylene, morpholinylene, and the like.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, are substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.
  • the substituents include, but are not limited to, the various groups described above.
  • the compounds claimed in the present invention include not only the compounds themselves, but also isomers, prodrugs, solvates, stable isotope derivatives or pharmaceutically acceptable salts thereof.
  • the "pharmaceutical composition” of the present invention refers to containing one or more isomers, prodrugs, solvates, stable isotope derivatives or pharmaceutically acceptable salts thereof and other chemical components of the compounds of the present invention mixture. Other components such as pharmaceutically acceptable pharmaceutically acceptable carriers, diluents and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • room temperature in the present invention refers to 15-30°C.
  • stable isotopic derivatives include: isotopically substituted derivatives obtained by replacing any hydrogen atom in formula (I) with 1-5 deuterium atoms, and any carbon atom in formula (I) by 1-3 Isotopically substituted derivatives obtained by substituting one carbon 14 atom or isotopically substituted derivatives obtained by substituting 1-3 oxygen 18 atoms in the formula (I) for any oxygen atom.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by general chemical methods.
  • salts can be prepared by reacting the free base or acid with an equivalent or an excess of acid (inorganic or organic) or base in a suitable solvent or solvent composition.
  • prodrug in the present invention refers to the conversion of the compound into the original active compound after metabolism in the body.
  • a prodrug is an inactive substance, or is less active than the active parent compound, but can provide ease of manipulation, administration, or improved metabolic properties.
  • the "isomers” in the present invention refer to the tautomers, mesomers, racemates, enantiomers, diastereomers, and other isomers of the compound of formula (I) of the present invention. Mixture form, etc. All of these isomers, including stereoisomers and geometric isomers, are included in the present invention.
  • the geometric isomers include cis-trans isomers.
  • solvents refers to the association of one or more solvent molecules with a compound of the present invention or a salt thereof.
  • solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, ethyl acetate, acetic acid, and the like.
  • the present invention includes any polymorphs of the compounds or salts thereof, as well as any hydrates or other solvates.
  • the term "patient” generally refers to mammals, especially humans.
  • tumor includes benign tumors and malignant tumors, such as cancer.
  • cancer includes various tumors mediated by BCL-2, including but not limited to hematological malignancies including acute lymphoblastic leukemia, lung, breast, ovarian, prostate, rectal, pancreatic Cancer, glioma.
  • the term "therapeutically effective amount” is meant to include an amount of the compound of the present invention effective to treat or prevent related diseases mediated by BCL-2.
  • the structures of all compounds of the present invention can be identified by nuclear magnetic resonance (1H NMR) and/or mass spectrometry (MS).
  • MS mass spectra
  • Thin-layer silica gel plate is generally selected from Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • Column chromatography generally uses Yantai Yellow Sea 100-200 or 200-300 mesh silica gel as a carrier.
  • Preparative liquid chromatography uses Waters SQD2 mass spectrometry-oriented high-pressure liquid chromatography, XBridge-C18; 30 ⁇ 150mm preparative column, 5 ⁇ m;
  • Method 1 acetonitrile-water (0.2% formic acid), flow rate 25mL/min;
  • Method 2 acetonitrile-water (0.8% ammonium bicarbonate), flow rate 25mL/min;
  • the known starting materials of the present invention can be synthesized by adopting or according to methods known in the art, or can be purchased from Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Shanghai Bide Medicine, Shanghai Accela Latin Chemical, Shanghai Merrill Chemical, Bailingwei Chemical, Annagy Chemical and other companies.
  • the solvents used in the reaction are all anhydrous solvents.
  • the anhydrous tetrahydrofuran was obtained by using commercially available tetrahydrofuran, using sodium block as water-removing agent and benzophenone as indicator, refluxed to a blue-purple solution under argon protection, collected by distillation, and stored at room temperature under argon protection.
  • Other anhydrous solvents were purchased from Annagy Chemical and Bailingwei Chemical. All the transfer and use of anhydrous solvents should be carried out under the protection of argon unless otherwise specified.
  • Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • reaction temperature is room temperature, and the temperature range is 15°C-30°C.
  • the monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC), and the systems of the developing solvents used in the reaction are A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system.
  • TLC thin layer chromatography
  • A dichloromethane and methanol system
  • B petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound.
  • the eluent system for column chromatography and the developing solvent system for thin layer chromatography used to purify the compound include A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of triethylamine and an acidic or basic reagent.
  • 1,2-Difluoro-3-nitrobenzene (10.00 g, 62.89 mmol) was dissolved in chlorosulfonic acid (21 mL), heated to 150° C. and stirred under reflux for 10 hours. After cooling to room temperature, a saturated aqueous sodium bicarbonate solution was added to the reaction solution under an ice bath to adjust the pH to about 7. Extract with dichloromethane (100 mL ⁇ 3), wash the organic phase with saturated brine (100 mL ⁇ 2), dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude product 3,4-difluoro-5-nitrobenzenesulfonyl chloride.
  • intermediate 2 refers to intermediate 1, wherein (S)-1,4-dioxane-2-methylamine is used instead of (tetrahydro-2H-pyran-4-yl)methanamine in the second step .
  • N,N-dimethylformamide (8.76g, 0.12mol) and anhydrous dichloromethane (300mL) were mixed, the ice bath was lowered to 0°C, and phosphorus oxychloride (13.86g, 0.09mol) was slowly added dropwise. After the dropwise addition, the mixture was stirred at 0 °C for 30 minutes, then returned to room temperature and stirred for 3 hours. The ice bath was lowered to 0 °C, and the compound (3aS, 7aR)-7a-methyloctahydro-5H-inden-5-one was slowly added dropwise.
  • intermediate 5 refers to the synthesis steps of intermediate 4, wherein the first step uses (3aR, 7aS)-7a-methyloctahydro-5H-inden-5-one (synthetic reference: Tetrahedron Letters, 35(1), 171-174; 1994) in place of (3aS,7aR)-7a-methyloctahydro-5H-inden-5-one.
  • intermediate 7 refers to the synthesis steps of intermediate 6, wherein the first step uses (1S,6S)-1-methylbicyclo[4.1.0]heptan-3-one (synthetic reference: Tetrahedron Letters, 60(11) , 785-788; 2019) in place of (1R,6R)-1-methylbicyclo[4.1.0]heptan-3-one.
  • reaction solution was diluted with water (500 mL), the mixture was extracted with ethyl acetate (150 mL ⁇ 3), the organic phases were combined and washed with water (200 mL) and saturated brine (200 mL) respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentration under reduced pressure gave the product (4aS,8aR)-4a-methyloctahydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane] (2.90 g, colorless oil). Yield: 92%.
  • Phosphorus oxychloride (5.50 g, 36.00 mmol) was added dropwise to a dichloromethane solution (50 mL) of N,N-dimethylformamide (5.30 g, 72.00 mmol) in an ice bath under nitrogen protection. , warmed to room temperature and stirred for 0.5 h. It was cooled to 0° C. again, compound (4aS, 8aR)-4a-methyloctahydronaphthalene-2-(1H)one (2.00 g, 12.00 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. A 40% aqueous sodium acetate solution (20 mL) was added, and the mixture was stirred at room temperature for 0.5 hour.
  • the synthesis of intermediate 9 refers to the synthesis of intermediate 8, in which the first step uses (4aR,8aS)-4a-methylhexahydro-1H-spiro[naphthalene-2,2'-[1,3]dioxolane ]-5(3H)-one (Synthetic reference: Organic Letters, 20(1), 130-133; 2018) instead of (4aS,8aR)-4a-methylhexahydro-1H-spiro[naphthalene-2,2' -[1,3]dioxolane]-5(3H)-one.
  • the mixture was quenched with water (25 mL) and ethyl acetate (25 mL), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (25 mL x 2).
  • the combined organic phases were washed with saturated brine (50 mL ⁇ 2).
  • the organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was de-solubilized under reduced pressure to obtain the crude product.
  • the mixture was quenched with water (25 mL) and ethyl acetate (25 mL), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (25 mL x 2).
  • the combined organic phases were washed with saturated brine (50 mL ⁇ 2).
  • the organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was de-solubilized under reduced pressure to obtain the crude product.
  • the experimental method is outlined as follows:
  • the effect of compounds on the biological activity of BCL-2 was evaluated by detecting the effect of the compounds on the binding activity of BCL-2 and leukemia pro-apoptotic protein (BIM) using an affinity assay method based on the principle of fluorescence polarization.
  • the reaction buffer contains the following components: PBS (pH 7.4, 3 mM Na 2 HPO 4 , 155 mM NaCl, 1 mM KH 2 PO 4 ), 1 mM DTT; human recombinant Bcl-2 protein (Cat. No.
  • Y is the percentage of inhibition
  • X is the logarithm of the concentration of the compound to be tested
  • Bottom is the maximum percentage of inhibition
  • Top is the minimum percentage of inhibition
  • slope factor is the slope coefficient of the curve.
  • the experimental method is outlined as follows:
  • the effect of compounds on the biological activity of BCL-XL was evaluated by detecting the effect of the compounds on the binding activity of BCL-XL and BIM using an affinity assay method based on the principle of fluorescence polarization.
  • the reaction buffer contains the following components: PBS (pH 7.4, 3 mM Na 2 HPO 4 , 155 mM NaCl, 1 mM KH 2 PO 4 ), 1 mM DTT; human recombinant Bcl-XL protein (Cat. No.
  • 10455-H08E was purchased from Beijing Yiqiao Shenzhou Biotechnology Co., Ltd., diluted to 10 nM with reaction buffer;
  • FITC-labeled BIM polypeptide was purchased from Nanjing GenScript Biotechnology Co., Ltd. and diluted to 10 nM with reaction buffer.
  • Y is the percentage of inhibition
  • X is the logarithm of the concentration of the compound to be tested
  • Bottom is the maximum percentage of inhibition
  • Top is the minimum percentage of inhibition
  • slope factor is the slope coefficient of the curve.
  • the effect of the compounds of the present invention on the proliferation of RS4;11 cells was evaluated using a luminescence cell viability assay.
  • the experimental method is outlined as follows:
  • CellTilter-Glo reagent (Promega, G7572) is composed of CellTilter-Glo lyophilized powder and CellTilter-Glo buffer. When using, the lyophilized powder can be dissolved in the buffer.
  • RS4;11 cells were cultured in RPMI1640 complete medium (Thermofisher, 72400-047) containing 10% FBS (GBICO, 10099-141) and 100 units/ml penicillin-streptomycin (Thermofisher, 15140122) ), when the cells covered 80-90% in the culture vessel, they were digested with 0.25% trypsin (containing EDTA) (Thermofisher, Cat. No. 25200056), and then planted in a white 384-well plate (Thermofisher, Cat. No. 164610), and then The 384-well plate was incubated overnight in a 37°C, 5% CO2 incubator.
  • the percent inhibition of RS4;11 cell proliferation by a compound can be calculated using the following formula:
  • Y Bottom+(Top-Bottom)/(1+10 ⁇ ((LogIC 50 -X)*slope factor)) where Y is the inhibition percentage, Bottom is the bottom plateau of the curve (the bottom plateau value of the S-shaped curve), Top is the top plateau of the curve (the top plateau value of the S-shaped curve), and X is the logarithm of the concentration of the tested compound.
  • the compounds of the examples of the present invention can effectively and selectively inhibit the activity of BCL-2, and the inhibition of BCL-XL is weak. It can be used to treat various cancers caused by abnormal overexpression of BCL-2 family proteins: especially hematological malignancies including acute lymphoblastic leukemia, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, brain glial tumor etc. And avoid toxic side effects caused by BCL-XL inhibition, such as thrombocytopenia. Some compounds can also effectively inhibit RS4;11 acute lymphocyte proliferation. It has a strong inhibitory effect on malignant blood diseases such as acute lymphoblastic leukemia.

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Abstract

La présente invention concerne un composé hétérocyclique en tant qu'inhibiteur de BCL-2 tel que représenté par la formule (I), une composition pharmaceutique contenant le composé hétérocyclique, et l'utilisation du composé hétérocyclique pour traiter ou prévenir des maladies et un dysfonctionnement associés médiés par BCL-2, comme des tumeurs. La présente invention concerne également un procédé de préparation du composé hétérocyclique.
PCT/CN2022/070756 2021-01-07 2022-01-07 Composé hétérocyclique utilisé en tant qu'inhibiteur de bcl-2 WO2022148439A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN115260191A (zh) * 2022-09-29 2022-11-01 上海睿跃生物科技有限公司 哌啶类化合物及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102307622A (zh) * 2008-12-04 2012-01-04 雅培制药有限公司 用于治疗癌症和免疫和自身免疫疾病的诱发细胞凋亡的药剂
CN102448959A (zh) * 2009-05-26 2012-05-09 雅培制药有限公司 用于治疗癌症和免疫和自身免疫疾病的细胞程序死亡诱导药剂
CN102939009A (zh) * 2010-05-26 2013-02-20 Abbvie公司 用于治疗癌症以及免疫与自身免疫疾病的细胞凋亡诱导剂
CN111214471A (zh) * 2018-11-23 2020-06-02 苏州亚盛药业有限公司 药物组合物及其用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102307622A (zh) * 2008-12-04 2012-01-04 雅培制药有限公司 用于治疗癌症和免疫和自身免疫疾病的诱发细胞凋亡的药剂
CN102448959A (zh) * 2009-05-26 2012-05-09 雅培制药有限公司 用于治疗癌症和免疫和自身免疫疾病的细胞程序死亡诱导药剂
CN102939009A (zh) * 2010-05-26 2013-02-20 Abbvie公司 用于治疗癌症以及免疫与自身免疫疾病的细胞凋亡诱导剂
CN111214471A (zh) * 2018-11-23 2020-06-02 苏州亚盛药业有限公司 药物组合物及其用途

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115260191A (zh) * 2022-09-29 2022-11-01 上海睿跃生物科技有限公司 哌啶类化合物及其制备方法和应用

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