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WO2022148439A1 - 作为bcl-2抑制剂的杂环化合物 - Google Patents

作为bcl-2抑制剂的杂环化合物 Download PDF

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Publication number
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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Prior art keywords
optionally substituted
hydrogen
compound
alkyl
methyl
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PCT/CN2022/070756
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English (en)
French (fr)
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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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Publication of WO2022148439A1 publication Critical patent/WO2022148439A1/zh

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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

本发明提供了如式(I)所示的作为BCL-2抑制剂的杂环化合物、含有这种杂环化合物的药物组合物和应用所述杂环化合物治疗或预防由BCL-2介导的相关疾病和功能障碍的用途，所述相关疾病例如肿瘤。本发明还涉及制备所述的杂环化合物的方法。

Description

作为BCL-2抑制剂的杂环化合物 技术领域
本发明涉及杂环化合物、含有其的药物组合物和其作为B细胞淋巴瘤-2(BCL-2)抑制剂的用途。更具体说，本发明提供了新的作为BCL-2抑制剂的杂环化合物、含有这种杂环化合物的药物组合物和应用所述杂环化合物治疗或预防由BCL-2介导的相关疾病和功能障碍的用途，所述相关疾病例如肿瘤。本发明还涉及制备所述杂环化合物的方法。
背景技术
BCL-2蛋白家族是细胞凋亡(也叫程序性细胞死亡)的核心调节机制之一，可以接收和传递内在胞内信号或外部环境应激信号，如营养或缺氧胁迫、DNA损伤、致癌基因过量激活、内质网应激胁迫等，主要在内在凋亡途径(Intrinsic pathway)中起主导作用。BCL-2(B-cell lymphoma-2)蛋白在1986年首次被发现，由BCL-2基因表达。BCL-2基因是一种原癌基因，其表达的蛋白称为BCL-2家族蛋白。人体中共有27个BCL-2家族的蛋白，按照功能和序列分析可分为3个亚类，第一亚类是拮抗细胞凋亡的，包括BCL-XL、BCL-2、BCL-W、MCL-1、BFL-1,它们主要定位于线粒体上，保护线粒体免于逆境损伤；另两个亚类是促进细胞凋亡的，一亚类是线粒体损伤的最终执行者，包括BAX和BAK。其余都归于BH3亚类，可以直接感应各种不同细胞逆境胁迫信号。拮抗和促进细胞凋亡的蛋白之间相互作用的动态平衡以决定细胞的生死命运。拮抗细胞凋亡的BCL-2蛋白与肿瘤密切相关，约有50％的肿瘤(如白血病、直肠癌、前列腺癌等)存在BCL-2家族蛋白异常过量表达，其中BCL-2活性异常在血液肿瘤中广泛存在。JAK-STAT、NFkB、UPS(ubiquitin-proteasome system)等多个信号通路可以引起拮抗凋亡的BCL-2蛋白的过表达。
BCL-2家族拮抗凋亡蛋白的高表达与多种肿瘤的药物耐药性相关，如BCL-2拮抗凋亡蛋白的过表达能使肿瘤细胞逃避抗肿瘤药物引起的凋亡，从而引起药物耐药。有研究表明，抑制BCL-2家族蛋白可以抑制肿瘤新生血管的形成，从而抑制肿瘤的转移(Benjamin,D.； Isaac,J.et al.J.Clin.Oncol.2008,26(25),4180)。因此，靶向抑制BCL-2家族抗凋亡蛋白能抑制肿瘤的发生、发展和耐药。
尽管已经有20多种靶向BCL-2家族的小分子抑制剂的报导，但进入临床实验的寥寥无几，梯瓦的Obatoclax在26例接受治疗的慢性淋巴细胞白血病(CLL)中只有1例获得部分应答，且有较强的神经毒性，于2013年终止了开发；艾伯维研发的Navitoclax(ABT-263)尽管在复发或难治性淋巴恶性肿瘤患者的I期剂量爬坡实验中，表现出50％的良好反应率，但同时也表现出非常强的BCL-XL的靶向毒性：如血小板降低和严重贫血。艾伯维与罗氏联合开发的Venetoclax(ABT-199)是一种高选择性的BCL-2抑制剂(Andrew,J.；Joel,D.et al.Nature Medicine,2013,19(2),202)，在复发/难治性慢性淋巴细胞白血病(CLL)、套细胞淋巴瘤(MCL)、多发性骨髓瘤(MM)等的治疗中通过与Ibrutinib等的联合用药，客观缓解率(ORR)与完全缓解率(CR)都得到了极大提升(Valentin,R.；Grablow,S.et al.Blood,2018,132(12),1248)，但依然有白细胞与血小板减少、贫血、腹泻、头晕、疲劳、易感染等毒副作用，严重的毒副作用还包括肺炎、贫血、高烧等。因此有必要研发高活性，低毒副作用的选择性BCL-2抑制剂。
发明内容
本发明涉及如下式(I)化合物，其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐，
Figure PCTCN2022070756-appb-000001
其中：
X 1选自任选被取代的C3-C6环烷基或任选被取代的含有1或2个 选自N、O、S的杂原子的3-6元饱和杂环基，其中所述任选的取代基选自羟基、卤素、C1-C6烷基、C1-C6烷氧基、含有1或2个选自N、O、S的杂原子的3-6元饱和杂环基；优选地，X 1选自任选被取代的C5-C6环烷基或任选被取代的含有1或2个选自N、O、S的杂原子的5-6元饱和杂环基，其中所述任选的取代基选自羟基、C1-C4烷基、C1-C4烷氧基、含有1或2个选自N、O、S的杂原子的4或5元饱和杂环基；进一步优选地，X 1选自任选被取代的环己烷基或任选被取代的四氢吡喃基、1，4-二氧六环基、哌啶基、吗啉基，其中所述任选的取代基选自羟基、C1-C4烷基、氧杂环丁烷基或四氢呋喃基；最优选地，X 1选自(1r,4r)-1-羟基-1-甲基环己烷-4-基、(S)-1，4-二氧六环-2-基、(R)-1，4-二氧六环-2-基、四氢吡喃-4-基、1-(氧杂环丁烷-3-基)哌啶-4-基、(S)-4-(氧杂环丁烷-3-基)吗啉-2-基；
X 2选自含有1或2个选自N、O、S的杂原子的5-6元亚杂环烷基，其中所述亚杂环烷基任选被1或2个C1-C4烷基或卤素取代；优选地，X 2选自含有2个N原子的6元亚杂环烷基，其中所述亚杂环烷基任选被1或2个C1-C4烷基取代；进一步优选地，X 2选自
Figure PCTCN2022070756-appb-000002
其中所述亚哌嗪基任选被1个C1-C4烷基取代；再进一步优选地，X 2选自
Figure PCTCN2022070756-appb-000003
其中所述亚哌嗪基任选被1个甲基取代；最优选地，X 2选自
Figure PCTCN2022070756-appb-000004
R 0选自氢、卤素；优选地，R 0选自氢、氟、氯；最优选地，R 0选自氢、氟；
R 1、R 2各自独立地选自氢、C1-C6烷基；优选地，R 1、R 2各自独立地选自氢、C1-C4烷基；进一步优选地，R 1、R 2各自独立地选自氢、甲基、乙基；最优选地，R 1、R 2各自独立地选自氢、甲基；
n选自1-4；优选地，n选自1、3或4。
优选地，本发明涉及如上文所述的式(I)化合物，其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐，其中：
X 1选自任选被取代的C5-C6环烷基或任选被取代的含有1或2个选自N、O、S的杂原子的5-6元饱和杂环基，其中所述任选的取代基选自羟基、C1-C4烷基、C1-C4烷氧基、含有1或2个选自N、O、S的杂原子的4或5元饱和杂环基；
X 2选自含有2个N原子的6元亚杂环烷基，其中所述亚杂环烷基任选被1或2个C1-C4烷基取代；
R 0选自氢、卤素；
R 1、R 2各自独立地选自氢、C1-C6烷基；
n选自1-4。
进一步优选地，本发明涉及如上文所述的式(I)化合物，其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐，其中：
X 1选自任选被取代的环己烷基或任选被取代的四氢吡喃基、1，4-二氧六环基、哌啶基、吗啉基，其中所述任选的取代基选自羟基、C1-C4烷基、氧杂环丁烷基或四氢呋喃基；
X 2选自
Figure PCTCN2022070756-appb-000005
其中所述亚哌嗪基任选被1个C1-C4烷基取代；
R 0选自氢、卤素；
R 1、R 2各自独立地选自氢、C1-C4烷基；
n选自1-4。
再进一步优选地，本发明涉及如上文所述的式(I)化合物，其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐，其中：
X 1选自任选被取代的环己烷基或任选被取代的四氢吡喃基、1，4-二氧六环基、哌啶基、吗啉基，其中所述任选的取代基选自羟基、C1-C4烷基、氧杂环丁烷基或四氢呋喃基；
X 2选自
Figure PCTCN2022070756-appb-000006
其中所述亚哌嗪基任选被1个C1-C4烷基取代；
R 0选自氢、氟、氯；
R 1、R 2各自独立地选自氢、C1-C4烷基；
n选自1、3或4。
更优选地，本发明涉及如上文所述的式(I)化合物，其异 构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐，其中：
X 1选自(1r,4r)-1-羟基-1-甲基环己烷-4-基、(S)-1，4-二氧六环-2-基、(R)-1，4-二氧六环-2-基、四氢吡喃-4-基、1-(氧杂环丁烷-3-基)哌啶-4-基、(S)-4-(氧杂环丁烷-3-基)吗啉-2-基；
X 2选自
Figure PCTCN2022070756-appb-000007
其中所述亚哌嗪基任选被1个甲基取代；
R 0选自氢、氟；
R 1、R 2各自独立地选自氢、甲基、乙基；
n选自1、3或4。
更进一步优选地，本发明涉及如上文所述的式(I)化合物，其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐，其中：
X 1选自(1r,4r)-1-羟基-1-甲基环己烷-4-基、(S)-1，4-二氧六环-2-基、(R)-1，4-二氧六环-2-基、四氢吡喃-4-基、1-(氧杂环丁烷-3-基)哌啶-4-基、(S)-4-(氧杂环丁烷-3-基)吗啉-2-基；
X 2选自
Figure PCTCN2022070756-appb-000008
R 0选自氢、氟；
R 1、R 2各自独立地选自氢、甲基；
n选自1、3或4。
再更进一步优选地，本发明涉及如上文所述的式(I)化合物，其异构体、前药、溶剂合物、稳定的同位素衍生物或其药学上可接受的盐，其选自：
Figure PCTCN2022070756-appb-000009
Figure PCTCN2022070756-appb-000010
Figure PCTCN2022070756-appb-000011
Figure PCTCN2022070756-appb-000012
本发明还涉及根据本发明任意一个实施方案中所述的式(I)化合物、其异构体、前药、溶剂合物、稳定的同位素衍生物或其药学上可接受的盐在制备用作BCL-2抑制剂的药物中的用途。
本发明还涉及根据本发明任意一个实施方案中所述的式(I)化合物或其异构体、前药、溶剂合物、稳定的同位素衍生物或其药学上可接受的盐在制备药物中的用途，所述药物用于治疗或预防由BCL-2介导的相关疾病，所述相关疾病例如肿瘤，所述肿瘤选自包括急性淋巴性白血病的恶性血液病、肺癌、乳腺癌、卵巢癌、直肠癌、前列腺癌、胰腺癌、脑胶质瘤。
本发明进一步涉及一种药物组合物，所述药物组合物包括本发明任意一个实施方案中所述的式(I)化合物或其异构体、前药、溶剂合物、稳定的同位素衍生物或其药学上可接受的盐，任选的一种或多种其它BCL-2抑制剂，以及一种或多种药学上可接受的载体、稀释剂和赋形剂。
本发明还涉及根据本发明所述的药物组合物在制备药物中的用途，其中所述药物用于治疗或者预防由BCL-2介导的相关疾病，所述相关疾病例如肿瘤，所述肿瘤选自包括急性淋巴性白血病的恶性血液病、肺癌、乳腺癌、卵巢癌、直肠癌、前列腺癌、胰腺癌、脑胶质瘤。
本发明还涉及一种治疗或者预防由BCL-2介导的相关疾病的方法，其包括给予有需要的患者治疗有效量的本发明任意一个实施方案中所述的化合物或其异构体、前药、溶剂合物、稳定的同位素衍生物或其药学上可接受的盐；或本发明所述的药物组合物，所述相关疾病例如肿瘤，所述肿瘤选自包括急性淋巴性白血病的恶性血液病、肺癌、乳腺癌、卵巢癌、直肠癌、前列腺癌、胰腺癌、脑胶质瘤。
本发明的另一方面涉及本发明任意一个实施方案中所述的化合物、或其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐，其用于治疗或者预防由BCL-2介导的相关疾病，所述相关疾病例如肿瘤，所述肿瘤选自包括急性淋巴性白血病的恶性血液病、肺癌、乳腺癌、卵巢癌、直肠癌、前列腺癌、胰腺癌、脑胶质瘤。
本发明的另一方面涉及一种药物组合物，所述药物组合物包括本发明任意一个实施方案中所述的式(I)化合物或其异构体、前药、溶剂合物、稳定的同位素衍生物或其药学上可接受的盐，任选的一种或多种其它BCL-2抑制剂，以及一种或多种药学上可接受的载体、稀释剂和赋形剂，其用于治疗或者预防由BCL-2介导的相关疾病，所述相关疾病例如肿瘤，所述肿瘤选自包括急性淋巴性白血病的恶性血液病、肺癌、乳腺癌、卵巢癌、直肠癌、前列腺癌、胰腺癌、脑胶质瘤。
本发明的另一方面涉及作为治疗和/或预防由BCL-2介导的相关疾病的本发明任意一个实施方案中所述的式(I)化合物或其异构体、前药、溶剂合物、稳定的同位素衍生物或其药学上可接受的盐。所述BCL-2介导的相关疾病例如肿瘤，所述相关疾病例如肿瘤，所述肿瘤选自包括急性淋巴性白血病的恶性血液病、肺癌、乳腺癌、卵巢癌、直肠癌、前列腺癌、胰腺癌、脑胶质瘤。
根据本发明，所述药物可以是任何药物剂型，包括但不限于片剂、胶囊剂、溶液剂、冻干制剂、注射剂。
本发明的药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式给药。这种单位可根据治疗的病症、给药方法和患者的年龄、体重和状况包含例如0.5毫克至1克，优选1毫克至700毫克，特别优选5毫克至300毫克的本发明的化合物，或药物制剂可以以每剂量单位包含预定量的活性成分的剂量单位形式给药。优选剂量 单位制剂是包含如上指示的日剂量或分剂量或其相应分数的活性成分的那些。此外，可以使用制药领域中公知的方法制备这种类型的药物制剂。
本发明药物制剂可适于通过任何所需的合适方法给药，例如通过经口(包括口腔或舌下)、直肠、经鼻、局部(包括口腔、舌下或经皮)、阴道或肠胃外(包括皮下、肌内、静脉内或皮内)方法给药。可以使用制药领域中已知的所有方法通过例如将活性成分与一种或多种赋形剂或一种或多种辅助剂合并来制备这样的制剂。
制备流程
本发明还提供制备所述化合物的方法。
流程1
Figure PCTCN2022070756-appb-000013
R 0与X 1的定义如前文所述；
第一步：
化合物(I)溶解在氯磺酸中，在油浴加热(120～150℃)下反应10～20小时，冷却到室温，用冰水淬灭，乙酸乙酯萃取，有机相干燥浓缩得到的粗品溶于无水四氢呋喃中，低温(-80～-60℃)下滴加氨水，并继续搅拌1～5小时，用酸如盐酸酸化，得到化合物(II)；
第二步：
化合物(II)与相应的胺溶于溶剂(如乙腈)中，加入碱(如三乙胺或者二异丙基乙基胺等)，在惰性气体(如氮气或氩气)保护下，在温度为25～60℃下搅拌10～20小时，得到化合物(III)。
流程2
Figure PCTCN2022070756-appb-000014
R 1、R 2和n的定义如前文所述；
第一步：
氮气保护下将三氯氧磷滴加入冰浴下的N,N-二甲基甲酰胺的二氯甲烷溶液，滴加完后，室温搅拌30分钟，降温至0℃，滴加化合物(IV)的二氯甲烷溶液，室温～60℃反应10～24小时，得到化合物(V)；
第二步：
氮气保护下将化合物(V)，对氯苯硼酸，碱如碳酸钾，相转移催化剂如四正丁基溴化铵以及催化剂如醋酸钯加入溶剂如水中，体系抽真空氮气置换三次，加热至40～100℃反应2～10小时，得到化合物(VI)；
第三步：
将化合物(VI)溶于溶剂如四氢呋喃或甲醇，加入还原剂如硼氢化钠，室温搅拌1～5小时，得到化合物(VII)；
第四步：
将化合物(VII)溶于溶剂如二氯甲烷中，加入氯代试剂如氯化亚砜，室温搅拌10～24小时，得到化合物(VIII)。
流程3
Figure PCTCN2022070756-appb-000015
R 0、R 1、R 2、n与X 1的定义如前文所述；R 3选自H或者甲基；
第一步：
将化合物(IX)(合成参考：Journal of Organic Chemistry,84(8),4814-4829,2019)和相应的哌嗪或者甲基哌嗪(X)溶解在溶剂(如二甲基亚砜)中，室温下加入碱如N,N-二异丙基乙胺，在温度为50～100℃下搅拌12～24小时，得到化合物(XI)；
第二步：
将化合物(XI)和化合物(VIII)溶解在溶剂如乙腈中，加入碱如N,N-二异丙基乙胺，加热到50～90℃搅拌8～24小时，得到化合物(XII)；
第三步：
将化合物(XII)溶解在溶剂如水、乙醇中，加入碱如氢氧化锂，加热到50～90℃搅拌1～5小时，再以酸如盐酸酸化，得到化合物(XIII)；
第四步：
将化合物(XIII)、化合物(III)、缩合剂如1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、碱如4-二甲氨基吡啶溶解在溶剂如二氯甲烷中，室温搅拌12～36小时，得到化合物(XIV)。
具体实施方式
定义
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。在本发明中未具体定义的基团具有本领域技术人员公知的本领域通常代表的含义。
在本发明中使用的表示方式“Cx-Cy”表示碳原子数的范围，其中x和y均为整数，例如C3-C8环烷基表示具有3-8个碳原子的环烷基，C0-C2烷基表示具有0-2个碳原子的烷基，其中C0烷基是指化学单键。
在本发明中,术语“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团，例如可以是1至18个碳原子、1至12个碳原子、1至8个碳原子、1至6个碳原子或1至4个碳原子的直链和支链基团。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、及其各种支链异构体等。烷基可以是任选取代的或未取代的。
在本发明中,术语“环烷基”指饱和单环或多环环状烃基，其包括3至12个环原子，例如可以是3至12个、3至10个、3至8个或3至6个环原子，或者可以是3、4、5、6元环。单环环基的非限制性实例包含环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。环烷基可以是任选取代的或未取代的。
在本发明中,术语“杂环基”指饱和或部分不饱和单环或多环环状烃基，其包括3至20个环原子，例如可以是3至16个、3至12个、3至10个、3至8个或3至6个环原子，其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包括3至12个环原子，其中1～4个是杂原子，更优选杂环基环包含3至10个环原子、更优选包括3至8个环原子，最优选5元环或6元环，其中1～4个是杂原子，更优选1～3个是杂原子，最优选1～2个是杂原子。单环杂环基的非限制性实例包含氧杂环丁烷基、吡咯烷基、哌啶基、4-哌啶基、哌嗪基、1,4-二氧六环基、吗啉基、2-吗啉基、4-吗啉基、硫代吗啉基、吡喃基、四氢吡喃基、4-四氢吡喃基、高哌嗪基、二噁烷基、2-二噁烷 基、四氢呋喃基等。多环杂环基包括螺环、稠环和桥环的杂环基。杂环基可以是任选取代的或未取代的。
在本发明中,术语“亚杂环基”指具有两个端部单价基团核心的取代或未取代的杂环基，其是从两个端部原子的每个原子上除去一个氢原子所产生的；所述杂环基具有前文所述的含义。“亚杂环基”的非限制性实例包含亚吡咯烷基、亚哌啶基、亚哌嗪基、亚吗啉基等。
在本发明中,术语“卤素”指氟、氯、溴或碘。
在本发明中,“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
在本发明中,“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
所述取代基包括但不限于前文所述的各种基团。
本发明要求保护的化合物不仅包括所述化合物本身，还包括所述化合物的异构体、前药、溶剂合物、稳定的同位素衍生物或其药学上可接受的盐。
本发明所述“药物组合物”表示含有一种或多种本发明所述化合物异构体、前药、溶剂合物、稳定的同位素衍生物或其药学上可接受的盐及其他化学组分的混合物。其他组分例如药学上可接受的药学可接受的载体、稀释剂和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
当在说明书中使用时，术语“包含”包括“由…组成”。
本发明所述“室温”是指15-30℃。
本发明所述“稳定的同位素衍生物”包括：式(I)中任意的氢原子被1-5个氘原子取代得到的同位素取代衍生物、式(I)中任意的碳原子被1-3个碳14原子取代得到的同位素取代衍生物或式(I) 中任意的氧原子被1-3个氧18原子取代得到的同位素取代衍生物。
本发明所述“药学上可接受的盐”在Berge，et al.，“Pharmaceutically acceptable salts”，J.Pharm.Sci.,66,1-19(1977)中有讨论，并对药物化学家来说是显而易见，所述的盐是基本上无毒性的，并能提供所需的药代动力学性质、适口性、吸收、分布、代谢或排泄等。
本发明药学上可接受的盐可通过一般的化学方法合成。
一般情况下，盐的制备可以通过游离碱或酸与等化学当量或者过量酸(无机酸或有机酸)或碱在合适的溶剂或溶剂组合物中反应制得。
本发明所述“前药”是指化合物在体内代谢后转换成原始活性化合物。代表性地讲，前药为非活性物质，或者比活性母体化合物活性小，但可以提供方便的操作、给药或者改善代谢特性。
本发明所述“异构体”是指本发明的式(I)化合物的互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、其混合物形式等。所有这些异构体，包括立体异构体、几何异构体均包含在本发明中。所述几何异构体包括顺反异构体。
本发明所述“溶剂合物”指一种或多种溶剂分子与本发明的化合物或其盐的缔合。形成药学上可接受的溶剂化物的溶剂的实例包括但不限于水、异丙醇、乙醇、甲醇、乙酸乙酯、乙酸等。
本发明包括所述化合物或其盐的任何多晶型物以及任何水合物或其它溶剂合物。
在本发明中，术语“患者”通常指哺乳动物，尤其是人。
在本发明中，术语“肿瘤”包括良性肿瘤和恶性肿瘤，例如癌症。
在本发明中，术语“癌症”包括由BCL-2介导的各种肿瘤，包括但不限于包括急性淋巴性白血病的恶性血液病、肺癌、乳腺癌、卵巢癌、前列腺癌、直肠癌、胰腺癌、脑胶质瘤。
在本发明中，术语“治疗有效量”是指包括可有效治疗或预防由BCL-2介导的相关疾病的本发明化合物的量。
实施例
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
本发明所有化合物的结构可通过核磁共振(1H NMR)和/或质谱检测(MS)鉴定。
1H NMR化学位移(δ)以PPM(parts per million，百万分之几)记录。NMR通过Bruker AVANCE III-400MHz光谱仪进行。合适的溶剂选自氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)、氘代二甲亚砜(DMSO-d 6)等，四甲基硅烷作为内标(TMS)。
低分辨率质谱(MS)由Agilent 1260 HPLC/6120质谱仪测定，使用Agilent ZORBAX XDB-C18，4.6×50mm，3.5μm。
梯度洗脱条件一：0-1分钟：95％溶剂A1和5％溶剂B1,1-2分钟：5％溶剂A1和95％溶剂B1；2.01-2.50分钟：95％溶剂A1和5％溶剂B1。百分数为某一溶剂占总溶剂体积的体积百分数。溶剂A1：0.01％甲酸水溶液；溶剂B1：0.01％甲酸的乙腈溶液；百分数为溶质占溶液的体积百分数。
薄层硅胶板是一般选自烟台黄海HSGF254或青岛GF254硅胶板。柱层析一般使用烟台黄海100-200或200-300目硅胶作为载体。
制备液相色谱(prep-HPLC)使用Waters SQD2质谱导向高压液相色谱分离仪,XBridge-C18；30 X 150mm制备柱，5μm；
方法一：乙腈-水(0.2％甲酸),流速25mL/分钟；方法二：乙腈-水(0.8％碳酸氢铵),流速25mL/分钟；
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、上海毕得医药、上海阿拉丁化学、上海迈瑞尔化学、百灵威化学、安耐吉化学等公司。
实施例中如无特殊说明，反应所用溶剂均为无水溶剂。其中无水四氢呋喃使用市售四氢呋喃，以钠块为除水剂，以二苯甲酮作为指示剂，氩气保护下回流至溶液呈蓝紫色，蒸馏收集，氩气保护下室温储存。其他无水溶剂购自安耐吉化学及百灵威化学。所有无水溶剂的转移和使用如无特殊说明，均需在氩气保护下进行。
实施例中如无特殊说明，反应均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
氢化反应通常抽真空，充入氢气，反复操作3次。
实施例中如无特殊说明，反应的温度为室温，温度范围是15℃-30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有A：二氯甲烷和甲醇体系；B：石油醚和乙酸乙酯体系。溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂的体系包括A：二氯甲烷和甲醇体系；B：石油醚和乙酸乙酯体系。溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和酸性或碱性试剂等进行调节。
中间体1
3-氟-5-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯磺酰胺
Figure PCTCN2022070756-appb-000016
第一步
3,4-二氟-5-硝基苯磺酰胺
将1,2-二氟-3-硝基苯(10.00g，62.89mmol)溶解在氯磺酸(21mL)中，加热至150℃回流搅拌10小时。冷却至室温，在冰浴下向反应液中加入饱和碳酸氢钠水溶液，调节pH值大约为7。用二氯甲烷(100mL×3)萃取，有机相用饱和食盐水(100mL×2)洗，无水硫酸钠干燥，过滤浓缩得到粗产品3,4-二氟-5-硝基苯磺酰氯。在1000mL三口瓶中加入异丙醇(200mL)和氨水(5mL，37％)于-78℃下搅拌10分钟。将所得的粗产品3,4-二氟-5-硝基苯磺酰氯溶于异丙醇中(30mL)，在-78℃缓慢滴入到上面的异丙醇和氨水混合物中，滴加完毕后在-78℃搅拌两小时，加入稀盐酸(1N)调制体系pH值大约为6。然后反应混合物升至室温，减压浓缩去除大部分异丙醇溶剂，向其中加入纯水， 固体析出，过滤得固体粗品。粗品用二氯甲烷打浆纯化得到目标产物3,4-二氟-5-硝基苯磺酰胺(4.90g，黄色固体)。产率：33％。
1H NMR(400MHz,DMSO-d 6)δ8.38-8.36(m,1H),8.29-8.26(m,1H),7.84(s,2H)。
第二步
3-氟-5-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯磺酰胺
将化合物3,4-二氟-5-硝基苯磺酰胺(1.55g，6.51mmol)、(四氢-2H-吡喃-4-基)甲胺(0.89g，7.73mmol)、N,N-二异丙基乙胺(3.91g，30.31mmol)和乙腈(20.0mL)混合。40℃下搅拌2小时。旋干溶剂，此混合物用50mL水淬灭，用乙酸乙酯(60mL×2)萃取。合并有机相用饱和食盐水(50mL×3)洗涤。分出有机相用无水硫酸钠干燥，过滤除去干燥剂，减压脱溶得粗品。柱层析纯化(石油醚/乙酸乙酯＝1：1)得到目标产物3-氟-5-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯磺酰胺(1.66g，黄色固体)。产率：76％。
MS m/z(ESI):334[M+1]；
1H NMR(400MHz,DMSO-d 6)δ8.33-8.30(m,2H),7.76-7.74(m,1H),7.45(s,2H),3.86-3.84(m,2H),3.50-3.45(m,2H),3.29-3.23(m,3H),1.59-1.57(m,2H),1.25-1.20(m,2H)。
中间体2的合成步骤参考中间体1，其中第二步用(S)-1,4-二氧己环烷-2-甲胺代替(四氢-2H-吡喃-4-基)甲胺。
Figure PCTCN2022070756-appb-000017
中间体3
3-氟-5-硝基-4-(((1-(3-氧杂环丁烷基)哌啶-4-基)甲基)氨基)苯磺酰胺
Figure PCTCN2022070756-appb-000018
第一步
4-(((2-氟-6-硝基-4-氨磺酰苯基)氨基)甲基)哌啶-1-甲酸叔丁酯
将化合物3,4-二氟-5-硝基苯磺酰胺(0.30g，1.26mmol)和4-(氨基甲基)哌啶-1-甲酸叔丁酯(0.28g，1.28mmol)、N,N-二异丙基乙胺(0.47g，3.63mmol)和乙腈(8mL)混合，40℃下搅拌2小时。此混合物用水(10mL)淬灭，用乙酸乙酯(10mL×2)萃取。合并有机相用饱和食盐水(10mL)洗涤。将有机相用无水硫酸钠干燥，过滤除去干燥剂，滤液旋干，残余物用柱层析纯化(石油醚/乙酸＝3：2)得到目标产物4-(((2-氟-6-硝基-4-氨磺酰苯基)氨基)甲基)哌啶-1-甲酸叔丁酯(0.49g，黄色固体)。产率：89％。
MS m/z(ESI):433[M+1]；
1H NMR(400MHz,CD 3OD)δ8.41-8.37(m,1H),7.64-7.60(m,1H),4.02-4.00(m,2H),3.47-3.44(m,2H),2.67-2.64(m,2H),1.75-1.66(m,3H),1.35(s,9H),1.14-1.03(m,2H)。
第二步
3-氟-5-硝基-4-((哌啶-4-基甲基)氨基)苯磺酰胺
将化合物4-(((2-氟-6-硝基-4-氨磺酰苯基)氨基)甲基)哌啶-1-甲酸叔丁酯(0.49g，1.12mmol)和三氟乙酸(3mL)、二氯甲烷(9mL)混合，常温下搅拌0.5小时。旋干溶剂，此混合物用三乙胺调节pH值为中性，再次旋干溶剂，得到粗品3-氟-5-硝基-4-((哌啶-4-基甲基)氨基)苯磺酰胺(0.35g，黄色油)。此混合物不经纯化直接用于下一步反应。MS m/z(ESI):333[M+1]；
第三步
3-氟-5-硝基-4-(((1-(3-氧杂环丁烷基)哌啶-4-基)甲基)氨基)苯磺酰胺
将化合物3-氟-5-硝基-4-((哌啶-4-基甲基)氨基)苯磺酰胺(0.35g，1.05mmol)和氧杂环丁烷基-3-酮(0.23g，3.15mmol)、氰基硼氢化 钠(0.23g，5.23mmol)和甲醇(8mL)混合，常温下搅拌1.5小时。此混合物用水(10mL)淬灭，用乙酸乙酯(10mL×2)萃取。合并有机相并用饱和食盐水(10mL)洗涤。将有机相用无水硫酸钠干燥，过滤除去干燥剂，旋干，残余物用柱层析纯化(石油醚/乙酸乙酯＝3：1)纯化得到目标产物3-氟-5-硝基-4-(((1-(3-氧杂环丁烷基)哌啶-4-基)甲基)氨基)苯磺酰胺(0.32g，黄色固体)。产率：78％。
MS m/z(ESI):389[M+1]；
1H NMR(400MHz,CD 3OD)δ8.47-8.46(m,1H),7.72-7.70(m,1H),4.68-4.65(m,2H),4.60-4.59(m,2H),3.57-3.55(m,2H),3.49-3.45(m,1H),2.83-2.80(m,2H),1.89-1.78(m,3H),1.42-1.20(m,4H)。
中间体4
(3aR,7aS)-5-(氯甲基)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚
Figure PCTCN2022070756-appb-000019
第一步
(3aR,7aS)-6-氯-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-甲醛
将N,N-二甲基甲酰胺(8.76g，0.12mol)和无水二氯甲烷(300mL)混合，冰浴降至0℃，缓慢滴加三氯氧磷(13.86g，0.09mol)。滴加完毕后0℃下搅拌30分钟，然后恢复至室温搅拌3小时，冰浴降至0℃，缓慢滴加化合物(3aS,7aR)-7a-甲基八氢-5H-茚-5-酮(合成参考：Tetrahedron Letters,35(1),171-174；1994)(9.00g，0.06mol)和无水二氯甲烷(50mL)的混合物，滴加完毕后恢复至室温搅拌48小时。此混合物用饱和氯化铵溶液(300mL)淬灭，分出有机相，减压脱溶，残余物和水相混合，用甲基叔丁基醚(150mL×3)萃取。合并有机相用饱和食盐水(150mL×2)洗涤，用无水硫酸钠干燥，过滤除去干燥剂，滤液减压脱溶得到目标产物((3aR,7aS)-6-氯-3a-甲基 -2,3,3a,4,7,7a-六氢-1H-茚-5-甲醛(10.30g，黄色液体)，产率：88％。MS m/z(ESI)：199&201[M+1]；
第二步
(3aR,7aS)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-甲醛
将化合物((3aR,7aS)-6-氯-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-甲醛(10.30g，0.05mol)、4-氯苯硼酸(7.80g，0.05mol)和水(300mL)混合，氩气保护条件下加入醋酸钯(1.13g，5.00mmol)，碳酸钾(20.70g，0.15mol)和四丁基溴化铵(16.10g，0.05mol)，氩气保护下50℃搅拌6小时。此混合物用水(100mL)和甲基叔丁基醚(200mL)淬灭。分出有机相，水相用甲基叔丁基醚(150mL×2)萃取。合并有机相用饱和食盐水(150mL×2)洗涤，用无水硫酸钠干燥，过滤除去干燥剂。滤液减压脱溶得粗品，粗品通过快速柱层析纯化(石油醚/乙酸乙酯＝95:5)，得到目标产物(3aR,7aS)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-甲醛(4.00g，黄色液体)。产率：28％。
MS m/z(ESI):275&277[M+1]；
1H NMR(400MHz,CDCl 3)δ9.52(s,1H),7.44-7.30(m,2H),7.20-7.02(m,2H),2.72-2.33(m,3H),2.11-1.74(m,4H),1.72-1.22(m,4H),1.02(s,3H)。
第三步
((3aR,7aS)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-基)甲醇
将化合物(3aR,7aS)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-甲醛(1.00g，3.65mmol)和四氢呋喃(40mL)混合，加入硼氢化钠(0.28g，7.30mmol)，室温下搅拌1小时。此混合物用饱和氯化铵溶液(60mL)和二氯甲烷(60mL)淬灭。分出有机相，水相用二氯甲烷(30mL×3)萃取。合并有机相用饱和食盐水(80mL×2)洗涤，用无水硫酸钠干燥，过滤除去干燥剂。滤液减压脱溶得目标产物((3aR,7aS)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-基)甲醇(0.95g，淡黄色液体)。产率：94％。MS m/z(ESI):259&261[M-17]；
第四步
(3aR,7aS)-5-(氯甲基)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H- 茚
将化合物((3aR,7aS)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-基)甲醇(0.95g，3.44mmol)，氯化亚砜(3.0mL)和二氯甲烷(30mL)混合，室温下搅拌1小时。减压脱溶得到目标产物(3aR,7aS)-5-(氯甲基)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚(1.01g，淡黄色液体)。粗品。MS m/z(ESI):295,297&299[M+1]。
中间体5的合成参考中间体4的合成步骤，其中第一步用(3aR,7aS)-7a-甲基八氢-5H-茚-5-酮(合成参考：Tetrahedron Letters,35(1),171-174；1994)代替(3aS,7aR)-7a-甲基八氢-5H-茚-5-酮。
Figure PCTCN2022070756-appb-000020
中间体6
(1R,6S)-4-(氯甲基)-3-(4-氯苯基)-1-甲基双环[4.1.0]庚-3-烯
Figure PCTCN2022070756-appb-000021
第一步
(1S,6R)-4-氯-6-甲基双环[4.1.0]庚-3-烯-3-甲醛
将干燥N,N-二甲基甲酰胺(4.66g，63.83mmol)加入到干燥二氯甲烷(160mL)中，室温下慢慢滴加三氯氧磷(9.76g，63.83mmol)，搅拌3小时。将(1R,6R)-1-甲基双环[4.1.0]庚-3-酮(3.96g，31.92mmol)(合成参考：Tetrahedron Letters,60(11),785-788；2019)溶于干燥二氯甲烷(80mL)，慢慢滴加到反应液中，室温搅拌过夜。TLC点板检测反应结束，将反应液慢慢滴加到冰冷的饱和氯化铵水溶液中，分离有机相，水相用二氯甲烷萃取(200mL×2)，合并有机相用饱和食盐 水(200mL×2)洗涤，用无水硫酸钠干燥有机相，过滤，滤液减压除去溶剂得到粗产物(1S,6R)-4-氯-6-甲基双环[4.1.0]庚-3-烯-3-甲醛(4.25g，淡黄色油状)。产率：28％。
1H NMR(400MHz,CDCl 3)δ10.18(s,1H),2.9-2.69(m,3H),2.47-2.40(m,1H),1.15(s,3H),1.02-0.97(m,1H),0.43-0.40(m,1H),0.33-0.31(m,1H)。
第二步
(1R,6S)-4-(4-氯苯基)-6-甲基双环[4.1.0]庚-3-烯-3-甲醛
将(1S,6R)-4-氯-6-甲基双环[4.1.0]庚-3-烯-3-甲醛(0.45g，2.68mmol)，对氯苯硼酸(0.50g，3.20mmol)，四丁基溴化铵(1.30g，4.00mmol)溶于水(10mL)，加入碳酸钾(1.10g，8.00mmol)和醋酸钯(0.06g，0.27mmol)。在氮气保护下，于45℃搅拌3小时。冷却至室温，用乙酸乙酯萃取(30mL×3)，合并有机相用饱和食盐水(30mL×2)洗涤，用无水硫酸钠干燥，过滤，滤液浓缩。残余物用硅胶柱层析纯化(乙酸乙酯：石油醚＝1：10)得到目标产物(1R,6S)-4-(4-氯苯基)-6-甲基双环[4.1.0]庚-3-烯-3-甲醛(0.23g，黄色油)。
MS m/z(ESI)：247&249[M+1]；
1H NMR(400MHz,CDCl 3)δ9.47(s,1H),7.35(d,J＝8.0Hz,2H),7.12(d,J＝8.0Hz,2H),2.95-2.90(m,1H),2.80-2.66(m,2H),2.50-2.42(m,1H),1.18(s,3H),1.08-1.03(m,1H),0.43-0.36(m,2H)。
第三步
((1S,6R)-4-(4-氯苯基)-6-甲基双环[4.1.0]庚-3-烯-3-基甲醇
将(1R,6S)-4-(4-氯苯基)-6-甲基双环[4.1.0]庚-3-烯-3-甲醛(3.24g，13.10mmol)加入到四氢呋喃(50mL)和甲醇(10mL)中，0℃下分批加入硼氢化钠(0.71g，19.70mmol)。室温搅拌1小时。加入饱和氯化铵溶液(100mL)淬灭，用乙酸乙酯(50mL×3)萃取，合并有机相用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗产物((1S,6R)-4-(4-氯苯基)-6-甲基双环[4.1.0]庚-3-烯-3-基)甲醇(3.43g，黄色油状物)。MS m/z(ESI)：249&251[M+1]。
第四步
(1R,6S)-4-(氯甲基)-3-(4-氯苯基)-1-甲基双环[4.1.0]庚-3-烯
将((1S,6R)-4-(4-氯苯基)-6-甲基双环[4.1.0]庚-3-烯-3-基)甲醇(3.43 g，13.10mmol)溶于干燥二氯甲烷(100mL)，加入N,N-二甲基甲酰胺(48mg，0.66mmol)。将二氯亚砜(3.12g，26.2mmol)溶于二氯甲烷(50mL)，在冰浴下慢慢滴加到反应液中，室温搅拌3小时。TLC硅胶板检测反应结束，减压去除溶剂，得到的粗品溶于二氯甲烷，加入N,N-二异丙基乙胺(5mL)，搅拌10分钟，旋蒸浓缩得到粗品(1R,6S)-4-(氯甲基)-3-(4-氯苯基)-1-甲基双环[4.1.0]庚-3-烯(3.50g，黄色油状)。
1H NMR(400MHz,CDCl 3)δ7.36(d,J＝8.0Hz,2H),7.20(d,J＝8.0,2H),3.86(s,2H),2.62-2.60(m,1H),2.56-2.49(m,2H),2.42-2.40(m,1H),1.13(s,3H),1.00-0.96(m,1H),0.49-0.47(m,1H),0.34-0.32(m,1H)。
中间体7的合成参考中间体6的合成步骤，其中第一步用(1S,6S)-1-甲基双环[4.1.0]庚-3-酮(合成参考：Tetrahedron Letters,60(11),785-788；2019)代替(1R,6R)-1-甲基双环[4.1.0]庚-3-酮。
Figure PCTCN2022070756-appb-000022
中间体8
(4aS,8aR)-6-(氯甲基)-7-(4-氯苯基)-4a-甲基-1,2,3,4,4a,5,8,8a-八氢萘
Figure PCTCN2022070756-appb-000023
第一步
(4aS,8aR)-4a-甲基八氢-1H-螺[萘-2,2'-[1,3]二氧戊环]
将化合物(4aS,8aR)-4a-甲基六氢-1H-螺[萘-2,2'-[1,3]二氧戊环]-5(3H)-酮(合成参考：Organic Letters,20(1),130-133；2018)(3.36g，15.00mmol)、水合肼(10.00g，0.18mmol)、氢氧化钾(8.40g，0.15mmol)加入二乙二醇(120mL)，升温至240℃搅拌2小时后冷却至室温。用水(500mL)稀释反应液，混合物用乙酸乙酯萃取(150mL×3)，有机相合并后分别用水(200mL)和饱和食盐水(200mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物(4aS,8aR)-4a-甲基八氢-1H-螺[萘-2,2'-[1,3]二氧戊环](2.90g，无色油状物)。产率：92％。
1H NMR(400MHz,CDCl 3)δ3.95-3.91(m,4H),1.75-1.62(m,5H),1.53-1.45(m,5H),1.44-1.33(m,5H),0.99(s,3H)。
第二步
(4aS,8aR)-4a-甲基八氢萘-2-(1H)酮
将化合物(4aS,8aR)-4a-甲基八氢-1H-螺[萘-2,2'-[1,3]二氧戊环](2.90g，13.80mmol)溶于四氢呋喃(20mL)，加入浓盐酸(37％，10mL)，室温搅拌1小时后加入水(100mL)稀释，浓缩除去四氢呋喃。水相用甲基叔丁基醚萃取(50mL×3)，有机相合并后用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物(4aS,8aR)-4a-甲基八氢萘-2-(1H)酮(2.00g，无色油状物)。产率：87.2％。MS m/z(ESI):167[M+1]；
第三步
(4aR,8aS)-3-氯-8a-甲基-1,4,4a,5,6,7,8,8a-八氢萘-2-甲醛
氮气保护下将三氯氧磷(5.50g，36.00mmol)滴加入冰浴的N,N-二甲基甲酰胺(5.30g，72.00mmol)的二氯甲烷溶液(50mL)中，滴加完毕后，升温至室温搅拌0.5小时。再次冷却至0℃，滴加入化合物(4aS,8aR)-4a-甲基八氢萘-2-(1H)酮(2.00g，12.00mmol)，室温搅拌过夜。加入40％乙酸钠水溶液(20mL)，室温搅拌0.5小时。分离有机相，水相用乙酸乙酯(30mL×2)萃取，合并有机相用水(30mL×2)和饱和食盐水(30mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物(4aR,8aS)-3-氯-8a-甲基-1,4,4a,5,6,7,8,8a-八氢萘-2-甲醛(2.30g，黄色油状物)。产率：90％。MS m/z(ESI):213&215[M+1]；
第四步
(4aR,8aS)-3-(4-氯苯基)-8a-甲基-1,4,4a,5,6,7,8,8a-八氢萘-2-甲醛
将(4aR,8aS)-3-氯-8a-甲基-1,4,4a,5,6,7,8,8a-八氢萘-2-甲醛(2.30g，粗产品，10.80mmol)、对氯苯硼酸(2.00g，13.00mmol)、碳酸钾(4.50g，32.40mmol)、四正丁基溴化铵(3.50g，10.80mmol)和醋酸钯(0.49g，2.20mmol)加入水(60mL)，体系抽真空用氮气置换三次，升温至50℃搅拌4小时。冷却至室温，反应液用乙酸乙酯(50mL×2)萃取，合并有机相用饱和食盐水(50mL)洗涤，分出有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物用硅胶柱分离纯化(0-5％乙酸乙酯/石油醚)得到(4aR,8aS)-3-(4-氯苯基)-8a-甲基-1,4,4a,5,6,7,8,8a-八氢萘-2-甲醛(0.90g，淡黄色油状物)。产率：33.1％。
MS m/z(ESI):289&291[M+1]；
1H NMR(400MHz,CDCl 3)δ9.43(s,1H),7.39-7.32(m,2H),7.18-7.11(m,2H),2.61-2.52(m,1H),2.45-2.35(m,1H),2.23-2.13(m,1H),1.86-1.78(m,1H),1.78-1.65(m,1H),1.50-1.37(m,3H),1.33-1.04(m,5H),0.89(s,3H)。
第五步
(4aR,8aS)-3-(4-氯苯基)-8a-甲基-1,4,4a,5,6,7,8,8a-八氢萘-2-甲醇
将(4aR,8aS)-3-(4-氯苯基)-8a-甲基-1,4,4a,5,6,7,8,8a-八氢萘-2-甲醛(0.90g，3.10mmol)溶于四氢呋喃/甲醇混合溶液(v/v＝10/1，11mL)，加入硼氢化钠(0.24g，6.20mmol)，室温搅拌2小时。加入饱和氯化铵溶液(30mL)淬灭反应。反应液用乙酸乙酯(30mL×2)萃取，合并有机相用饱和食盐水(30mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到(4aR,8aS)-3-(4-氯苯基)-8a-甲基-1,4,4a,5,6,7,8,8a-八氢萘-2-甲醇(0.63g，黄色油状物)。产率：69.5％。MS m/z(ESI):273&275[M-17]；
第六步
(4aS,8aR)-6-(氯甲基)-7-(4-氯苯基)-4a-甲基-1,2,3,4,4a,5,8,8a-八氢萘
将(4aR,8aS)-3-(4-氯苯基)-8a-甲基-1,4,4a,5,6,7,8,8a-八氢萘-2-甲醇(0.63g，2.17mmol)溶于二氯甲烷(20mL)，加入氯化亚砜(0.77g，6.51mmol)室温搅拌过夜。反应液减压浓缩得到(4aS,8aR)-6-(氯甲 基)-7-(4-氯苯基)-4a-甲基-1,2,3,4,4a,5,8,8a-八氢萘(0.67g，黄色油状物)。粗品。
1H NMR(400MHz,CDCl 3)δ7.34-7.28(m,2H),7.17-7.11(m,2H),4.00-3.84(m,2H),2.36-2.26(m,2H),2.09-1.98(m,2H),1.86-1.80(m,1H),1.73-1.65(m,2H),1.49-1.30(m,6H),0.97(s,3H)。
中间体9的合成参考中间体8的合成，其中第一步用(4aR,8aS)-4a-甲基六氢-1H-螺[萘-2,2'-[1,3]二氧戊环]-5(3H)-酮(合成参考：Organic Letters,20(1),130-133；2018)代替(4aS,8aR)-4a-甲基六氢-1H-螺[萘-2,2'-[1,3]二氧戊环]-5(3H)-酮。
Figure PCTCN2022070756-appb-000024
中间体11
5-(氯甲基)-6-(4-氯苯基)-2,3,3a,4,7,7a-六氢-1H-茚
Figure PCTCN2022070756-appb-000025
第一步
6-羰基八氢-1H-茚-5-甲酸甲酯
将化合物碳酸二甲酯(0.45g，5.00mol)和四氢呋喃(10mL)混合，氩气保护下，分批加入氢化钠(0.08g，2.00mol，60％矿物油分散)，在50℃搅拌5分钟。然后加入八氢-5H-茚-5-酮(合成参考：Advanced Synthesis&Catalysis,360(20),3924-3929；2018)(0.14g，1.00mol)，在70℃搅拌2小时。此混合物用水(25mL)和乙酸乙酯(25mL)淬灭，分出有机相，水相用乙酸乙酯(25mL×2)萃取。合并 有机相用饱和食盐水(50mL×2)洗涤。将有机相用无水硫酸钠干燥，过滤除去干燥剂，滤液减压脱溶得粗品。粗品用制备薄层色谱板纯化(石油醚/乙酸乙酯＝30：1)得到目标产物6-羰基八氢-1H-茚-5-甲酸甲酯(0.07g，黄色液体)。产率：37％。
1H NMR(400MHz,CDCl 3)δ3.76(s,3H),2.61-2.57(m,1H),2.22-2.18(m,2H),2.02-1.97(m,2H),1.76-1.70(m,3H),1.45-1.40(m,3H),1.18-1.12(m,2H)。
第二步
6-(((三氟甲基)磺酰)氧代)-2,3,3a,4,7,7a-六氢-1H-茚-5-甲酸甲酯
将化合物6-羰基八氢-1H-茚-5-甲酸甲酯(0.07g，0.37mmol)、1,1,1-三氟-N-苯基-N-((三氟甲基)磺酰)甲磺酰胺(0.21g，0.6mmol)、碳酸钾(0.14g，1.0mmol)、N,N-二甲基甲酰胺(3mL)和四氢呋喃(3mL)混合，氩气保护下于45℃搅拌15小时。冷却至室温，此混合物用水(25mL)和乙酸乙酯(25mL)淬灭，分出有机相，水相用乙酸乙酯(25mL×2)萃取。合并有机相用饱和食盐水(50mL×2)洗涤。将有机相用无水硫酸钠干燥，过滤除去干燥剂，滤液减压脱溶得粗品。粗品用制备薄层色谱板纯化(石油醚/乙酸乙酯＝30：1)得到目标产物6-(((三氟甲基)磺酰)氧代)-2,3,3a,4,7,7a-六氢-1H-茚-5-甲酸甲酯(37mg，黄色液体)。产率：57％。MS m/z(ESI)：329[M+1]；
第三步
6-(4-氯苯基)-2,3,3a,4,7,7a-六氢-1H-茚-5-甲酸甲酯
将化合物(6-(((三氟甲基)磺酰)氧代)-2,3,3a,4,7,7a-六氢-1H-茚-5-甲酸甲酯(37mg，0.20mmol)、4-氯苯硼酸(50mg，0.30mmol)和乙二醇二甲醚(4mL)、甲醇(2mL)混合，氩气保护条件下加入四(三苯基膦)钯(20mg，0.02mmol)，氟化铯(80mg，0.50mmol)，氩气保护下70℃反应15小时。冷却至室温，此混合物用水(25mL)和乙酸乙酯(25mL)淬灭。分出有机相，水相用乙酸乙酯(25mL×2)萃取。合并有机相用饱和食盐水(50mL×2)洗涤。用无水硫酸钠干燥，过滤除去干燥剂，滤液减压脱溶得粗品，粗品通过硅胶柱(石油醚/乙酸乙酯＝30：1)纯化得到目标产物6-(4-氯苯基)-2,3,3a,4,7,7a-六氢-1H-茚-5-甲酸甲酯(40mg，黄色液体)。产率：65％。
MS m/z(ESI)：291&293[M+1]；
1H NMR(400MHz,CDCl 3)δ7.26(d,J＝8.0Hz,2H),7.06(d,J＝8.0Hz,2H),3.45(s,3H),2.89-2.85(m,1H),2.41-2.38(m,1H),2.27-2.23(m,1H),2.16-2.12(m,1H),2.00-1.96(m,2H),1.73-1.68(m,3H),1.47-1.39(m,3H)。
第四步
(6-(4-氯苯基)-2,3,3a,4,7,7a-六氢-1H-茚-5-基)甲醇
将化合物6-(4-氯苯基)-2,3,3a,4,7,7a-六氢-1H-茚-5-羧酸甲酯(40mg，0.17mmol)和四氢呋喃(3mL)混合，在冰盐浴下降至-15℃，分批缓慢加入氢化铝锂(10mg，0.30mmol)，加完后自然升至室温，搅拌3小时。加入盐酸(1M，0.30mmol，0.3mL)淬灭。以二氯甲烷(25mL×3)萃取，合并有机相用饱和食盐水(25mL×3)洗涤。用无水硫酸钠干燥，过滤除去干燥剂。滤液减压脱溶得到目标产物(6-(4-氯苯基)-2,3,3a,4,7,7a-六氢-1H-茚-5-基)甲醇(40mg，淡黄色液体)，产率：98％。MS m/z(ESI):245&247[M-17]。
第五步
5-(氯甲基)-6-(4-氯苯基)-2,3,3a,4,7,7a-六氢-1H-茚
将化合物(6-(4-氯苯基)-2,3,3a,4,7,7a-六氢-1H-茚-5-基)甲醇(40mg，0.13mmol)，氯化亚砜(0.1mL)和二氯甲烷(3mL)混合，室温下搅拌1小时。减压脱溶得到目标产物5-(氯甲基)-6-(4-氯苯基)-2,3,3a,4,7,7a-六氢-1H-茚(40mg，淡黄色液体)，粗品。MS m/z(ESI):281,283&285[M+1]。
中间体12
(R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧代)-4-(3-甲基哌嗪-1-基)苯甲酸甲酯
Figure PCTCN2022070756-appb-000026
(R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧代)-4-(3-甲基哌嗪-1-基)苯甲 酸甲酯
将化合物2-((1H-吡咯并[2,3-b]吡啶-5-基)氧代)-4-氟苯甲酸甲酯(合成参考：Journal of Organic Chemistry,84(8),4814-4829；2019)(2.86g，10.00mmol)、(R)-2-甲基哌嗪(3.00g，30.00mmol)、N,N-二异丙基乙胺(3.12g，24.18mmol)和二甲基亚砜(20mL)混合。60℃下搅拌16小时。此混合物用水(50mL)稀释，用乙酸乙酯(60mL×2)萃取。合并有机相用饱和食盐水(50mL×3)洗涤。将有机相用无水硫酸钠干燥，过滤除去干燥剂，减压脱溶得粗品。柱层析纯化(二氯甲烷/甲醇＝90：10)得到目标产物(R)-2-((1H-吡咯并[2,3-b]吡啶-5-基)氧代)-4-(3-甲基哌嗪-1-基)苯甲酸甲酯(2.55g，黄色固体)。产率：70％。
MS m/z(ESI):367[M+1]；
1H NMR(400MHz,CDCl 3)δ9.92(s,1H),8.19(d,J＝2.4Hz,1H),7.91(d,J＝9.2Hz,1H),7.52(d,J＝2.4Hz,1H),7.36-7.35(m,1H),6.66-6.63(m,1H),6.43(d,J＝1.6Hz,1H),6.34(d,J＝2.4Hz,1H),3.79(s,3H),3.54-3.48(m,2H),3.05-3.02(m,1H),2.93-2.84(m,2H),2.77-2.71(m,1H),2.42-2.37(m,1H),1.08(d,J＝6.4Hz,3H)。
实施例1
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧代)-4-(4-(((3aR,7aS)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-基)甲基)哌嗪-1-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺
Figure PCTCN2022070756-appb-000027
第一步
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧代)-4-(4-(((3aR,7aS)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-基)甲基)哌嗪-1-基)苯甲酸甲酯
将化合物(3aR,7aS)-5-(氯甲基)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚(中间体4)(1.01g，3.44mmol)，2-((1H-吡咯并[2,3-b]吡啶-5-基)氧代)-4-(哌嗪-1-基)苯甲酸甲酯(合成参考：WO2010138588A2)(1.21g，3.44mmol)，N,N-二异丙基乙胺(1.80g，13.76mmol)和乙腈(30mL)混合，75℃下搅拌16小时。冷却室温，加水(100mL)稀释，用乙酸乙酯(100mL×2)萃取，合并有机相用饱和食盐水(100mL)洗。有机相用无水硫酸钠干燥，过滤除去干燥剂，滤液减压脱溶得粗品，粗品通过快速柱层析纯化(石油醚/乙酸乙酯＝1:1)，得到目标产物2-((1H-吡咯并[2,3-b]吡啶-5-基)氧代)-4-(4-(((3aR,7aS)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-基)甲基)哌嗪-1-基)苯甲酸甲酯(0.95g，白色固体)。产率：45％。
MS m/z(ESI):611&613[M+1]；
1H NMR(400MHz,CDCl 3)δ9.74(s,1H),8.16(d,J＝2.4Hz,1H),7.88(d,J＝8.9Hz,1H),7.52(d,J＝2.4Hz,1H),7.39-7.33(m,1H),7.25-7.21(m,2H),6.99-6.90(m,2H),6.60-6.58(m,1H),6.45-6.43(m,1H),6.27(s,1H),3.78(s,3H),3.24-3.02(m,4H),2.90-2.65(m,2H),2.45-1.88(m,6H),1.83-1.50(m,6H),1.46-1.19(m,3H),1.00(s,3H)。
第二步
(2-((1H-吡咯并[2,3-b]吡啶-5-基)氧代)-4-(4-(((3aR,7aS)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-基)甲基)哌嗪-1-基)苯甲酸
将2-((1H-吡咯并[2,3-b]吡啶-5-基)氧代)-4-(4-(((3aR,7aS)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-基)甲基)哌嗪-1-基)苯甲酸甲酯(0.95g，1.56mmol)，氢氧化钠(0.30g，7.50mmol)，乙醇(20mL)和水(1mL)混合，80℃下搅拌1小时。减压脱溶，残余物加入水(30mL)和盐酸(1M，15mL)。用二氯甲烷(30mL×3)萃取，有机相用饱和食盐水(50mL)洗，用无水硫酸钠干燥，过滤除去干燥剂。减压脱溶得到目标产物(2-((1H-吡咯并[2,3-b]吡啶-5-基)氧代)-4-(4-(((3aR,7aS)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-基)甲基)哌嗪-1-基)苯甲酸(0.90g，白色固体)，产率：97％。MS m/z(ESI):597&599[M+1]；
第三步
2-((1H-吡咯并[2,3-b]吡啶-5-基)氧代)-4-(4-(((3aR,7aS)-6-(4-氯苯 基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-基)甲基)哌嗪-1-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺
将(2-((1H-吡咯并[2,3-b]吡啶-5-基)氧代)-4-(4-(((3aR,7aS)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-基)甲基)哌嗪-1-基)苯甲酸(0.50g，1.00mmol)，3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯磺酰胺(0.44g，1.40mmol)(合成参考：WO 2018041248 A1)，1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(0.38g，2.00mmol)，4-二甲胺基吡啶(0.12g，1.00mmol)，三乙胺(0.20g，2.00mmol)和二氯甲烷(60mL)混合，室温下搅拌16小时。加水(50mL)稀释，分离有机相，水相用二氯甲烷(50mL×2)萃取，合并有机相用饱和食盐水(50mL)洗涤。用无水硫酸钠干燥，过滤，滤液减压脱溶得粗品，残余物通过快速柱层析纯化(二氯甲烷/甲醇＝97：3)，得到目标产物2-((1H-吡咯并[2,3-b]吡啶-5-基)氧代)-4-(4-(((3aR,7aS)-6-(4-氯苯基)-3a-甲基-2,3,3a,4,7,7a-六氢-1H-茚-5-基)甲基)哌嗪-1-基)-N-((3-硝基-4-(((四氢-2H-吡喃-4-基)甲基)氨基)苯基)磺酰基)苯甲酰胺1(0.27g，淡黄色固体)，产率：30％。
MS m/z(ESI):894&896[M+1]；
1H NMR(400MHz,CDCl 3)δ10.35-9.99(m,2H),8.89(s,1H),8.52(s,1H),8.31-8.11(m,2H),8.00-7.86(m,1H),7.71(s,1H),7.50(s,1H),7.31-7.14(m,2H),6.99-6.78(m,3H),6.64-6.39(m,2H),5.99(s,1H),4.19-3.91(m,2H),3.53-3.37(m,2H),3.33-3.21(m,2H),3.16-3.01(m,4H),2.96-2.65(m,2H),2.47-2.13(m,5H),2.10-1.87(m,3H),1.83-1.69(m,4H),1.67-1.49(m,3H),1.46-1.21(m,5H),0.98(s,3H)。
实施例2到31的合成步骤参考实施例1的过程。
Figure PCTCN2022070756-appb-000028
Figure PCTCN2022070756-appb-000029
Figure PCTCN2022070756-appb-000030
Figure PCTCN2022070756-appb-000031
Figure PCTCN2022070756-appb-000032
Figure PCTCN2022070756-appb-000033
Figure PCTCN2022070756-appb-000034
Figure PCTCN2022070756-appb-000035
Figure PCTCN2022070756-appb-000036
Figure PCTCN2022070756-appb-000037
Figure PCTCN2022070756-appb-000038
Figure PCTCN2022070756-appb-000039
Figure PCTCN2022070756-appb-000040
Figure PCTCN2022070756-appb-000041
Figure PCTCN2022070756-appb-000042
生物学实验
BCL-2生物活性抑制的测试
使用荧光偏振实验评估本发明的化合物对BCL-2生物活性的影响
实验方法概述如下：
使用荧光偏振原理的亲和性测定方法，通过检测化合物对BCL-2和白血病促凋亡蛋白(BIM)的结合活性的影响，从而评估化合物对BCL-2生物活性的影响。反应缓冲液包含以下组分：PBS(pH 7.4,3mM  Na 2HPO 4、155mM NaCl、1mM KH 2PO 4)、1mM DTT；人源重组Bcl-2蛋白(货号10195-H08E)购自北京义翘神州生物技术有限公司，用反应缓冲液稀释成5nM；FITC标记的BIM多肽购自南京金斯瑞生物科技有限公司，用反应缓冲液稀释成5nM。
将化合物在100％DMSO中溶解稀释至0.1、1、10μM，然后用DMSO进行4倍的系列稀释至最低浓度为0.0061、0.061、0.61nM，每个浓度点再使用反应缓冲液稀释50倍。
向黑色384孔检测板中添加3μL化合物溶液和12μL BCL-2溶液，混合均匀后室温孵育15分钟。随后加入15μL FITC-BIM溶液，将反应混合物在室温避光孵育30分钟后，立即在Envision多功能酶标仪(Perkin Elmer)上进行荧光偏振的检测，480nm为激发波长，535nm为发射波长。该实验中，未加BCL-2蛋白组作为阴性对照(100％抑制)，加BCL-2蛋白但未加化合物组作为阳性对照(0％抑制)。化合物对BCL-2亲和性的抑制百分比可以用以下公式计算：
化合物IC 50值由8个浓度点用XLfit(ID Business Solutions Ltd.,UK)软件通过以下公式计算：
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50-X)*slope factor))
其中Y为抑制百分比，X为待测化合物浓度的对数值，Bottom为最大抑制百分比，Top为最小抑制百分比，slope factor为曲线斜率系数。
BCL-XL生物活性抑制的测试
使用荧光偏振实验评估本发明的化合物对BCL-XL生物活性的影响
实验方法概述如下：
使用荧光偏振原理的亲和性测定方法，通过检测化合物对BCL-XL和BIM的结合活性的影响，从而评估化合物对BCL-XL生物活性的影响。反应缓冲液包含以下组分：PBS(pH 7.4,3mM Na 2HPO 4、155mM NaCl、1mM KH 2PO 4)、1mM DTT；人源重组Bcl-XL蛋白(货号10455-H08E)购自北京义翘神州生物技术有限公司，用反应缓冲液稀释成10nM；FITC标记的BIM多肽购自南京金斯瑞生物科技有限公司，用反应缓冲液稀释成10nM。
将化合物在100％DMSO中溶解稀释至1μM，然后用DMSO进行4倍的系列稀释至最低浓度为0.061nM，每个浓度点再使 用反应缓冲液稀释50倍。
向黑色384孔检测板中添加3μL化合物溶液和12μL BCL-XL溶液，混合均匀后室温孵育15分钟。随后加入15μL FITC-BIM溶液，将反应混合物在室温避光孵育30分钟后，立即在Envision多功能酶标仪(Perkin Elmer)上进行荧光偏振的检测，480nm为激发波长，535nm为发射波长。该实验中，未加BCL-XL蛋白组作为阴性对照(100％抑制)，加BCL-XL蛋白但未加化合物组作为阳性对照(0％抑制)。化合物对BCL-XL亲和性的抑制百分比可以用以下公式计算：
化合物IC 50值由8个浓度点用XLfit(ID Business Solutions Ltd.,UK)软件通过以下公式计算：
Y＝Bottom+(Top-Bottom)/(1+10^((logIC 50-X)*slope factor))
其中Y为抑制百分比，X为待测化合物浓度的对数值，Bottom为最大抑制百分比，Top为最小抑制百分比，slope factor为曲线斜率系数。
RS4；11细胞(急性淋巴白血病细胞)半数有效抑制浓度IC 50的测定
使用发光法细胞活力检测实验评估本发明的化合物对RS4；11细胞增殖的影响。
实验方法概述如下：
使用CellTilter-Glo(CTG)检测试剂盒，通过采用一种独特的、高灵敏度且稳定性的荧光素酶检测活细胞新陈代谢的关键指标ATP，试验中产生的发光信号和培养基中的有活力细胞数呈正比，从而检测RS4；11的细胞增殖状况。
CellTilter-Glo试剂(Promega,G7572)由CellTilter-Glo冻干粉和CellTilter-Glo缓冲液组成，使用时将冻干粉溶解到缓冲液中即可。
RS4；11细胞(ATCC，CRL-1873)培养在RPMI1640完全培养基(Thermofisher，72400-047)中含10％FBS(GBICO,10099-141)和100units/ml青链霉素混合液(Thermofisher，15140122)，当细胞在培养容器中覆盖率达80-90％时，用0.25％胰酶(含EDTA)(Thermofisher,货号25200056)消化吹散后种植于白色384孔板(Thermofisher,货号164610),然后384孔板置于37℃，5％CO 2的培养箱中培养过夜。将化合物在100％DMSO中溶解稀释至5mM，然后 用DMSO进行4倍的系列稀释至最低浓度为0.061μM，每个浓度点再使用FBS-free的RPMI1640培养基稀释50倍。如果化合物IC 50值非常低，可以降低化合物的起始浓度。过夜后每孔加入3μL培养基稀释后的化合物，轻轻离心混匀，其中，不加细胞组作为阴性对照(100％抑制)，加0.2％DMSO组作为阳性对照(0％抑制)。该384孔板置于37℃，5％CO 2的培养箱中继续培养，48小时后取出平衡至室温，每孔加15μL CTG试剂，置于摇床上轻轻摇动3分钟以确保细胞裂解充分，放置10分钟使冷光信号稳定，然后用EnVision(Perkin Elmer)读取冷光信号。
化合物对RS4；11细胞增殖抑制的百分比可以用以下公式计算：
抑制百分比＝100-100*(signal化合物-signal阴性对照)/(signal阳性对照-signal阴性对照)
化合物IC 50值由8个浓度点用XLfit(ID Business Solutions Ltd.,UK)软件通过以下公式计算：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC 50-X)*slope factor))其中Y为抑制百分比，Bottom为the bottom plateau of the curve(S型曲线的底部平台值)，Top为the top plateau of the curve(S型曲线的顶部平台值)，X为待测化合物浓度的对数值。
上述体外BCL-2和BCL-XL蛋白活性检测实验的结果见下表1，细胞实验的结果见表2。
表1：BCL-2和BCL-XL蛋白活性检测结果
化合物编号 FP BCL-2 IC 50(nM) FP BCL-XL IC 50(nM)
1 6.14 >1000
2 9.13 >1000
3 2.62 >1000
4 4.01 >1000
5 2.46 >1000
6 3.53 >1000
7 1.7 >1000
8 12.15 >1000
9 8.25 >1000
10 14.51 >1000
11 7.37 >1000
12 7.14 >1000
13 3.28 >1000
14 7.03 >1000
15 3.49 >1000
16 2.9 >1000
17 5.39 >1000
18 17.68 >1000
19 9.22 >1000
20 15.04 >1000
21 19.53 >1000
22 7.14 >1000
23 2.11 >1000
24 4.99 >1000
25 10.13 >1000
26 0.58 >1000
27 0.85 >1000
28 3.99 >1000
29 2.89 >1000
30 1.5 >1000
31 1.2 >1000
。
表2：RS4；11细胞活性检测结果
化合物编号 RS4；11 IC 50(nM)
1 19.5
3 9.0
5 4.75
6 10.77
7 2.8
8 83
9 29
10 30
11 41
12 37
13 12
14 19
15 37
16 11
17 15
23 14
24 16
25 37
26 4.5
27 16
28 5.8
29 6
30 26
31 13
Venetoclax 5.5
。
由上述实验结果可知，本发明的实施例化合物能够有效选择性的抑制BCL-2的活性，对BCL-XL抑制较弱。可以用于治疗BCL-2家族蛋白异常过量表达导致的多种癌症：尤其是包括急性淋巴性白血病的恶性血液病、肺癌、乳腺癌、卵巢癌、直肠癌、前列腺癌、胰腺癌、脑胶质瘤等。并且避免由BCL-XL抑制引起的毒副作用，如血小板降低。部分化合物也能有效抑制RS4；11急性淋巴细胞增殖。对急性淋巴性白血病等恶性血液病有较强的抑制疗效。
对于本领域技术人员来说，很明显，本公开不局限于上述说明性的实施例，并且在不背离本公开实质特性的条件下，其可以通过其它具体形式来具体实施。因此，期望在各方面都认为这些实施例是说明性的和非限制性的，应参照的是附加的权利要求，而不是上述实施例，且由此在权利要求的等效含义和范围内的所有变化都被包括在其中。

Claims (10)

  1. 式(I)化合物，其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐，
    Figure PCTCN2022070756-appb-100001
    其中：
    X 1选自任选被取代的C3-C6环烷基或任选被取代的含有1或2个选自N、O、S的杂原子的3-6元饱和杂环基，其中所述任选的取代基选自羟基、卤素、C1-C6烷基、C1-C6烷氧基、含有1或2个选自N、O、S的杂原子的3-6元饱和杂环基；优选地，X 1选自任选被取代的C5-C6环烷基或任选被取代的含有1或2个选自N、O、S的杂原子的5-6元饱和杂环基，其中所述任选的取代基选自羟基、C1-C4烷基、C1-C4烷氧基、含有1或2个选自N、O、S的杂原子的4或5元饱和杂环基；进一步优选地，X 1选自任选被取代的环己烷基或任选被取代的四氢吡喃基、1，4-二氧六环基、哌啶基、吗啉基，其中所述任选的取代基选自羟基、C1-C4烷基、氧杂环丁烷基或四氢呋喃基；最优选地，X 1选自(1r,4r)-1-羟基-1-甲基环己烷-4-基、(S)-1，4-二氧六环-2-基、(R)-1，4-二氧六环-2-基、四氢吡喃-4-基、1-(氧杂环丁烷-3-基)哌啶-4-基、(S)-4-(氧杂环丁烷-3-基)吗啉-2-基；
    X 2选自含有1或2个选自N、O、S的杂原子的5-6元亚杂环烷基，其中所述亚杂环烷基任选被1或2个C1-C4烷基或卤素取代；优选地，X 2选自含有2个N原子的6元亚杂环烷基，其中所述亚杂环烷基任选被1或2个C1-C4烷基取代；进一步优选地，X 2选自
    Figure PCTCN2022070756-appb-100002
    其中 所述亚哌嗪基任选被1个C1-C4烷基取代；再进一步优选地，X 2选自
    Figure PCTCN2022070756-appb-100003
    其中所述亚哌嗪基任选被1个甲基取代；最优选地，X 2选自
    Figure PCTCN2022070756-appb-100004
    R 0选自氢、卤素；优选地，R 0选自氢、氟、氯；最优选地，R 0选自氢、氟；
    R 1、R 2各自独立地选自氢、C1-C6烷基；优选地，R 1、R 2各自独立地选自氢、C1-C4烷基；进一步优选地，R 1、R 2各自独立地选自氢、甲基、乙基；最优选地，R 1、R 2各自独立地选自氢、甲基；
    n选自1-4；优选地，n选自1、3或4。
  2. 根据权利要求1的式(I)化合物，其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐，其中：
    X 1选自任选被取代的C5-C6环烷基或任选被取代的含有1或2个选自N、O、S的杂原子的5-6元饱和杂环基，其中所述任选的取代基选自羟基、C1-C4烷基、C1-C4烷氧基、含有1或2个选自N、O、S的杂原子的4或5元饱和杂环基；
    X 2选自含有2个N原子的6元亚杂环烷基，其中所述亚杂环烷基任选被1或2个C1-C4烷基取代；
    R 0选自氢、卤素；
    R 1、R 2各自独立地选自氢、C1-C6烷基；
    n选自1-4。
  3. 根据权利要求1的式(I)化合物，其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐，其中：
    X 1选自任选被取代的环己烷基或任选被取代的四氢吡喃基、1，4-二氧六环基、哌啶基、吗啉基，其中所述任选的取代基选自羟基、C1-C4烷基、氧杂环丁烷基或四氢呋喃基；
    X 2选自
    Figure PCTCN2022070756-appb-100005
    其中所述亚哌嗪基任选被1个C1-C4烷基取代；
    R 0选自氢、卤素；
    R 1、R 2各自独立地选自氢、C1-C4烷基；
    n选自1-4。
  4. 根据权利要求1的式(I)化合物，其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐，其中：
    X 1选自任选被取代的环己烷基或任选被取代的四氢吡喃基、1，4-二氧六环基、哌啶基、吗啉基，其中所述任选的取代基选自羟基、C1-C4烷基、氧杂环丁烷基或四氢呋喃基；
    X 2选自
    Figure PCTCN2022070756-appb-100006
    其中所述亚哌嗪基任选被1个C1-C4烷基取代；
    R 0选自氢、氟、氯；
    R 1、R 2各自独立地选自氢、C1-C4烷基；
    n选自1、3或4。
  5. 根据权利要求1的式(I)化合物，其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐，其中：
    X 1选自(1r,4r)-1-羟基-1-甲基环己烷-4-基、(S)-1，4-二氧六环-2-基、(R)-1，4-二氧六环-2-基、四氢吡喃-4-基、1-(氧杂环丁烷-3-基)哌啶-4-基、(S)-4-(氧杂环丁烷-3-基)吗啉-2-基；
    X 2选自
    Figure PCTCN2022070756-appb-100007
    其中所述亚哌嗪基任选被1个甲基取代；
    R 0选自氢、氟；
    R 1、R 2各自独立地选自氢、甲基、乙基；
    n选自1、3或4。
  6. 根据权利要求1的式(I)化合物，其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐，其中：
    X 1选自(1r,4r)-1-羟基-1-甲基环己烷-4-基、(S)-1，4-二氧六环-2-基、(R)-1，4-二氧六环-2-基、四氢吡喃-4-基、1-(氧杂环丁烷-3-基)哌啶-4-基、(S)-4-(氧杂环丁烷-3-基)吗啉-2-基；
    X 2选自
    Figure PCTCN2022070756-appb-100008
    R 0选自氢、氟；
    R 1、R 2各自独立地选自氢、甲基；
    n选自1、3或4。
  7. 根据权利要求1的式(I)化合物，其异构体、前药、溶剂合物、稳定的同位素衍生物或其药学上可接受的盐，其选自：
    Figure PCTCN2022070756-appb-100009
    Figure PCTCN2022070756-appb-100010
    Figure PCTCN2022070756-appb-100011
    Figure PCTCN2022070756-appb-100012
  8. 根据权利要求1-7任一项的化合物或其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐在制备用作BCL-2抑制剂的药物中的用途。
  9. 根据权利要求1-7任一项的化合物或其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐在制备用于治疗或预防由BCL-2介导的相关疾病的药物中的用途，所述相关疾病例如肿瘤，所述肿瘤选自包括急性淋巴性白血病的恶性血液病、肺癌、乳腺癌、卵巢癌、直肠癌、前列腺癌、胰腺癌、脑胶质瘤。
  10. 药物组合物，其含有根据权利要求1-7任一项的化合物或其异构体、前药、溶剂合物、稳定的同位素衍生物或药学上可接受的盐，任选的一种或多种其它BCL-2抑制剂，以及一种或多种药学上可接受的载体、稀释剂和赋形剂。
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