WO2020187188A1 - 喹啉衍生物及免疫调节剂联合在制备抗肿瘤药物中的应用 - Google Patents

喹啉衍生物及免疫调节剂联合在制备抗肿瘤药物中的应用 Download PDF

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WO2020187188A1
WO2020187188A1 PCT/CN2020/079540 CN2020079540W WO2020187188A1 WO 2020187188 A1 WO2020187188 A1 WO 2020187188A1 CN 2020079540 W CN2020079540 W CN 2020079540W WO 2020187188 A1 WO2020187188 A1 WO 2020187188A1
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immunomodulator
compound
pharmaceutically acceptable
formula
acceptable salt
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PCT/CN2020/079540
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English (en)
French (fr)
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张杨
陈正霞
黎健
陈曙辉
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南京明德新药研发有限公司
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Priority to JP2021555080A priority Critical patent/JP2022524629A/ja
Priority to EP20772991.4A priority patent/EP3939592A4/en
Priority to US17/437,428 priority patent/US20220175756A1/en
Publication of WO2020187188A1 publication Critical patent/WO2020187188A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule

Definitions

  • the invention relates to the application of a class of quinoline derivatives and immunomodulators in the preparation of anti-tumor drugs.
  • PTK Protein tyrosine kinase
  • HGF hepatocyte growth factor
  • PDGF platelet-derived growth factor
  • FGF and VEGF kinases
  • Acid kinases which include LCK, ABL, etc.
  • c-Met protein also known as hepatocyte growth factor (HGF) receptor
  • HGF hepatocyte growth factor
  • c-Met signaling pathway demonstrates various cellular responses, including mitogenic activity, proliferative activity, morphogenetic activity, and angiogenic activity.
  • Inhibitors of the HGF/c-Met pathway have significant potential to treat cancer.
  • ABL is a tyrosine kinase encoded by a proto-oncogene.
  • the activated ABL can promote cell proliferation, differentiation and EMT. In hematoma, it is mainly activated through gene fusion such as BCR-ABL. In solid tumors, it is mainly through gene amplification, overexpression and activation of upstream receptor tyrosine kinases such as PDGFR and EGFR.
  • TNIK is a serine/threonine kinase that can bind to ⁇ -catenin/TCF in the wnt signaling pathway to activate downstream target genes of wnt signaling and promote tumor growth.
  • MINK is a member of the STE20 protein kinase family. It is highly expressed in the central nervous system and can activate the JNK and p38 signaling pathways.
  • FGFR Fibroblast growth factor receptor
  • FGF fibroblast growth factor
  • the FGFRs family includes the following types: FGFR1b, FGFR1c, FGFR2b, FGFR2c, FGFR3b, FGFR3c, FGFR4 .
  • Different subtypes of FGFRs bind to different FGFs. The combination of FGFs and FGFRs leads to autophosphorylation of multiple tyrosine residues in the cell.
  • FGFR4 is highly expressed in liver cancer, colon cancer, gastric cancer, esophageal cancer, and testicular cancer
  • FGF19 which specifically binds to FGFR4
  • the signal abnormalities that FGFR4 specifically binds to FGF19 are various An important factor in tumor occurrence and metastasis.
  • VEGF Vascular endothelial cell growth factor
  • PDGF platelet-derived growth factor
  • targets such as ABL, C-Met, TNIK, FGFR1-4, VEGFR (FLT1, KDR, FLT4), PDGFR in the treatment of tumor cells, from the perspective of molecular mechanism of action, the targets can complement each other and reduce The escape of tumor cells reduces drug resistance and improves therapeutic effects. Therefore, drugs that simultaneously act on these targets are very much expected.
  • the present invention provides an application of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an immunomodulator in the preparation of a drug for treating tumors.
  • R 1 is selected from C 1-6 alkoxy optionally substituted with 1, 2 or 3 R;
  • Ring B is selected from C 3-6 cycloalkyl
  • R is selected from F, Cl, Br, I, OH, and NH 2 .
  • the present invention provides an application of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating tumors in combination with an immunomodulator.
  • the present invention provides the application of an immunomodulator in the preparation of a drug for treating tumors in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the aforementioned ring B is selected from cyclopropyl.
  • R 1 is selected from
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from
  • R 1 and R 2 are as defined in the present invention.
  • the compound of formula (I) has the following structure or a pharmaceutically acceptable salt thereof
  • the aforementioned immunomodulator is selected from PD-1 inhibitors or PDL-1 inhibitors.
  • the aforementioned immunomodulator is selected from PD-1 antibody or PDL-1 antibody.
  • the aforementioned immunomodulator is selected from PD-1 antibodies.
  • the above-mentioned PD-1 antibody is selected from the group consisting of pembrolizumab, nivolizumab, sintilizumab, teriplizumab, RMP1-14, camrelizumab, tislelizumab and Cemiplimab.
  • the above-mentioned PD-1 antibody is selected from the group consisting of pembrolizumab, nivolizumab, sintilizumab, teriplizumab, RMP1-14, camrelizumab, tislelizumab, spartalizumab, relatlimab +nivolumab(solid tumors), Bristol-Myers Squibb, BCD-100, Biocad, genolimzumab, durvalumab+MEDI-0680(solid tumor), MedImmune/AstraZeneca pazopanib+pembrolizumab(renalANT cell cancer), MerHepa/Novartis cellular, N, dovartis Carcinoma Vaccine, BAT-1306, AGEN-2034, JNJ-63723283, GLS-010, MGA-012, AK-104, AK-103, JTX-4014, PF-06801591, HLX-10
  • the above-mentioned immunomodulator is selected from PDL-1 antibody.
  • the above-mentioned PDL-1 antibody is selected from Avelumab, Atelizumab and Durvalumab.
  • the aforementioned PDL-1 antibody is selected from the group consisting of durvalumab, avelumab, atezolizumab, KN-035, durvalumab+tremelimumab (solid tumor), AstraZeneca/MedImmune, CS-1001, bintrafusp alfa, durvalumab+AZD-5069 (SCCHN ), AstraZeneca, durvalumab+MEDI-0680(solid tumor), MedImmune/AstraZeneca, durvalumab+dabrafenib+trametinib(cancer), MedImmune/AstraZeneca, CX-072, BGB-A333, BMS-936559, NANTaldVoraccine containing Cancer NANT Hepatocellular Carcinoma Vaccine, NANT Squamous Cell Carcinoma Vaccine, NANT Triple Negative Breast Cancer Vaccine, NANT Merkel Cell Carcinoma Vaccine,
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and the immunomodulator are administered separately.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof and the immunomodulator are administered concurrently.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered before the aforementioned immunomodulator.
  • the administration of the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt thereof occurs 24 hours (1 day), 2 days, 3 days, 4 days or before the administration of the immunomodulator 5 days.
  • the compound of formula (I) or its pharmaceutically acceptable salt or the immunomodulator compared with the compound of formula (I) or its pharmaceutically acceptable salt or the immunomodulator alone, the compound of formula (I) or its pharmaceutically acceptable salt and the above Immunomodulators treat tumors in a synergistic manner.
  • the present invention also provides a composition comprising the compound represented by formula (I), its isomers or pharmaceutically acceptable salts thereof, and an immunomodulator.
  • the compound of formula (I) has the following structure or a pharmaceutically acceptable salt thereof
  • the aforementioned immunomodulator is selected from PD-1 antibodies.
  • the above composition is used in the preparation of drugs for treating tumor diseases.
  • the above-mentioned tumor is selected from hepatocellular carcinoma, renal cell carcinoma, endometrial cancer, gastric cancer, cholangiocarcinoma, non-small cell lung cancer, melanoma, urinary epithelial cell carcinoma, malignant glioma, and esophageal cancer , Pancreatic cancer, breast cancer, bowel cancer, lymphoma, cervical cancer and brain cancer.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included in the scope of the present invention.
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution will not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent is absent. For example, when X in A-X is vacant, it means that the structure is actually A.
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond between the site and other groups can be a straight solid bond Straight dotted key Or wavy line Said.
  • the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms.
  • the number of atoms in a ring is generally defined as the number of ring members.
  • “5-7 membered ring” refers to a “ring” in which 5-7 atoms are arranged around.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Example C 1- 3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n- propyl and isopropyl) and the like.
  • C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy etc. .
  • C 1-6 alkoxy examples include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) Oxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy and the like.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system.
  • the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4, C 5, C 6, C 7, C 8, C 9, C 10, C 11, and C 12, also including any one of n + m to n ranges, for example C 1- 3 comprises a C 1-12 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; in the same way, from n to n +m means the number of atoms in the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring , 10-membered ring, 11-member
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, a nucleophilic substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes but is not limited to "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethyls
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (P
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations: aq stands for water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent amount; CDI stands for Carbonyl diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate Esters; EtOH stands for ethanol; MeOH stands for methanol; CB
  • the compound of the present invention shows obvious anti-tumor activity in combination with PD-1 antibody on a mouse CT26 tumor model, and the compound of the present invention significantly enhances the anti-tumor effect of PD-1 antibody.
  • Figure 1 The effect of Example 1 on the tumor volume of a mouse CT26 colon cancer tumor model.
  • Example 1A (6.05g) was added to a three-necked flask containing NMP (60mL), pyridine (1.32g) and phenyl chloroformate (5.20g) were added to the reaction system, and the reaction system was at room temperature (25-30°C). ) After stirring for 1 hour, the reaction was complete. Cyclopropylamine (2.84g) was also added to the reaction system. The reaction solution was stirred at room temperature (25-30°C) for 0.5 hours. The reaction was completed. Add 20 mL of ethanol to the reaction system and stir.
  • Example 1B This compound is obtained by adding 1 equivalent of hydrochloric acid, sulfuric acid or methanesulfonic acid in acetone or ethanol solution to obtain the corresponding salt.
  • Example 1B (1.5g, 3.37mmol) was added to EtOH (45mL), the reaction temperature was raised to 60°C, at this temperature, CH 3 SO 3 H (324.07mg, 3.37mmol, 240.05 ⁇ L) was added dropwise to the reaction In the solution, after the dripping is completed, the reaction solution is dissolved, and the temperature of the reaction solution is naturally cooled to 15-20°C under stirring, and the reaction solution is stirred at this temperature for 2 hours. A large amount of brown solid precipitated, filtered, and the filter cake was rinsed with absolute ethanol (5 mL), and the obtained filter cake was spin-dried under reduced pressure at 50° C. without purification, and Example 1 was obtained.
  • Experimental example 1 Anti-tumor activity test of the compound of the present invention on an animal tumor model in vivo
  • the anti-tumor effect of the compound to be tested in combination with mouse anti-PD-1 antibody was investigated on the CT26 in vivo tumor model of mouse colon cancer.
  • mice Female Balb/c mice were subcutaneously inoculated with CT26 mouse colon cancer cell lines, and after the inoculation, they were randomly grouped according to body weight, and the administration was carried out as described below.
  • Group 1 (control group): The administration started in the afternoon of the day of inoculation, and vehicle 1 (10% DMSO + 10% Solutol + 80% DDH2O) was administered intragastrically at a dose of 0.1 mL/10 g body weight twice a day. After the inoculation, the administration was started when the tumor volume had grown to about 60 mm 3, and the vehicle 2 (DPBS) was given by intraperitoneal injection at a dose of 0.1 mL/10 g body weight twice a week.
  • vehicle 1 10% DMSO + 10% Solutol + 80% DDH2O
  • Group 2 After inoculation, the drug will be administered when the tumor volume has grown to about 60mm 3.
  • Anti-mouse PD-1 antibody (RMP1-14, provided by BioXcell) will be given intraperitoneally at a dose of 3 mg/kg body weight twice a week .
  • Group 3 Administration was started in the afternoon on the day of inoculation, and Example 1 (suspended in 0.5% MC+0.2% Tween 80) was administered intragastrically at a dose of 10 mg/kg body weight once a day. After the inoculation, the administration was started when the tumor volume had grown to about 60 mm 3, and the anti-mouse PD-1 antibody (RMP1-14, provided by BioXcell) was administered by intraperitoneal injection at a dose of 3 mg/kg body weight twice a week.
  • RMP1-14 anti-mouse PD-1 antibody
  • tumor proliferation rate tumor volume in the treatment group/tumor volume in the control group ⁇ 100%
  • Example 1 significantly enhanced the anti-tumor effect of PD-1 antibody.

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Abstract

提供一类喹啉衍生物与免疫调节剂联合在制备抗肿瘤的药物中的应用。

Description

喹啉衍生物及免疫调节剂联合在制备抗肿瘤药物中的应用
本申请主张如下优先权
CN201910198729.7，申请日：2019-03-15。
技术领域
本发明涉及一类喹啉衍生物与免疫调节剂联合在制备抗肿瘤的药物中的应用。
背景技术
蛋白酪氨酸激酶(PTK)是一种酶，它与作为底物的ATP一起，将肽和蛋白质中的酪氨酸残基磷酸化。这些酶在细胞信号传导的调控中是关键因素，如细胞增值、分化等。PTK特别还包括受体酪氨酸激酶，它包括肝细胞生长因子(HGF)，血小板衍生生长因子(PDGF)和在血管形成中起作用的激酶(FGF和VEGF)；此外还包括非受体酪氨酸激酶，这包括LCK，ABL等。
c-Met蛋白(也称为肝细胞生长因子(HGF)受体)是具有酪氨酸激酶活性的跨膜190kDa异源二聚体，其有c-Met癌基因编码。已经显示，HGF/c-Met信号途径证明各种细胞反应，包括促有丝分裂活性、增值活性、形态发生活性和血管生成活性。HGF/c-Met途径的抑制剂具有显著的治疗癌症的潜力。
ABL是一个原癌基因编码的酪氨酸激酶，激活的ABL能促进细胞增殖、分化以及EMT等。在血液瘤中主要通过BCR-ABL等基因融合的方式被激活。在实体瘤中主要通过基因扩增，过表达以及上游受体酪氨酸激酶如PDGFR，EGFR等激活。TNIK是一个丝氨酸/苏氨酸激酶，能与wnt信号通路中的β-catenin/TCF结合，激活wnt信号下游靶基因，促进肿瘤生长。MINK是STE20蛋白激酶家族的成员，在中枢神经系统中有较高的表达，能够激活JNK以及p38信号通路。
FGFR是一类具有传导生物信号、调节细胞生长、参与组织修复等功能的生物活性物质，近年来，已有多个FGFR家族成员被发现在肿瘤发生、发展过程中起重要作用。成纤维细胞生长因子受体(FGFR)是一类可与成纤维细胞生长因子(FGF)特异性结合的受体蛋白，FGFRs家族包括以下类型：FGFR1b、FGFR1c、FGFR2b、FGFR2c、FGFR3b、FGFR3c、FGFR4。不同亚型的FGFR与之结合的FGF不一样，FGFs与FGFRs结合后导致胞内多个酪氨酸残基的自身磷酸化，磷酸化的FGFRs激活下游的信号通路包括MEK/MAPK、PLCy/PKC、PI3K/AKT、STATS等。其中FGFR4在肝癌、结肠癌、胃癌、食道癌、睾丸癌中高表达，而与FGFR4特异性结合的FGF19在人结肠癌、肝癌和肺癌细胞高表达，FGFR4与FGF19特异性结合的信号异常是多种肿瘤发生及转移的重要因素。
血管内皮细胞生长因子(VEGF)和血小板衍生生长因子(PDGF)对肿瘤新生血管的生成发挥重要的作用，它们与其受体VEGFR，PDGFR结合，将信号传递到胞内区，进而发生磷酸化二聚体，激活这一信号通路，并将能量向下游传递，从而导致肿瘤细胞生长、转移、增殖等不受控制。
如上几个靶点如ABL，C-Met，TNIK，FGFR1-4，VEGFR(FLT1,KDR,FLT4)，PDGFR对肿瘤细胞的治疗中，从分子作用机制上来看，靶点间能够协同互补，减少肿瘤细胞的逃逸，减少药物耐药性，提高治疗效果，因此同时作用于这些靶点的药物是非常期待。
发明内容
本发明提供了一种式(Ⅰ)化合物或其药学上可接受的盐和免疫调节剂联合在制备治疗肿瘤的药物中的应用。
Figure PCTCN2020079540-appb-000001
其中，
R 1选自任选被1、2或3个R取代的C 1-6烷氧基；
R 2选自-C(＝O)NH 2和-C(＝O)NH-C 1-3烷基；
环B选自C 3-6环烷基；
R选自F、Cl、Br、I、OH和NH 2。
本发明提供了一种式(Ⅰ)化合物或其药学上可接受的盐在制备和免疫调节剂联合治疗肿瘤的药物中的应用。
本发明提供了一种免疫调节剂在制备与式(Ⅰ)化合物或其药学上可接受的盐联合治疗肿瘤的药物中的应用。
本发明的一些方案中，上述环B选自环丙烷基。
本发明的一些方案中，上述R 1选自
Figure PCTCN2020079540-appb-000002
本发明的一些方案中，上述R 2选自-C(＝O)NH 2。
本发明的一些方案中，上述式(Ⅰ)化合物或其药学上可接受的盐选自
Figure PCTCN2020079540-appb-000003
其中，R 1、R 2如本发明所定义。
本发明的一些方案中，上述式(Ⅰ)化合物具有下式结构或其药学上可接受的盐
Figure PCTCN2020079540-appb-000004
本发明的一些方案中，上述免疫调节剂选自PD-1抑制剂或PDL-1抑制剂。
本发明的一些方案中，上述免疫调节剂选自PD-1抗体或PDL-1抗体。
本发明的一些方案中，上述免疫调节剂选自PD-1抗体。
本发明的一些方案中，上述PD-1抗体选自帕博利珠单抗、纳武利尤单抗、信迪利单抗、特瑞普利单抗、RMP1-14、camrelizumab、tislelizumab和Cemiplimab。
本发明的一些方案中，上述PD-1抗体选自帕博利珠单抗、纳武利尤单抗、信迪利单抗、特瑞普利单抗、RMP1-14、camrelizumab、tislelizumab、spartalizumab、relatlimab+nivolumab(solid tumors),Bristol-Myers Squibb、BCD-100,Biocad、genolimzumab、durvalumab+MEDI-0680(solid tumor),MedImmune/AstraZeneca pazopanib+pembrolizumab(renal cell cancer),Merck/Novartis、dostarlimab、NANT Hepatocellular Carcinoma Vaccine、BAT-1306、AGEN-2034、JNJ-63723283、GLS-010、MGA-012、AK-104、AK-103、JTX-4014、PF-06801591、HLX-10、RG-7769、PF-06936308、MEDI-5752、PD-1checkpoint inhibitor(cancer),Sinocelltech、CS-1003、Sym-021、LZM-009、MGD-019、REGN-1979+REGN-2810、BI-754091、XmAb-20717、ABBV-181、PF-06753512、anti-PD1mAb,Fujian Haixi Pharmaceuticals、IBI-318、nivolumab biosimilar,BioXpress Therapeutics、pembrolizumab biosimilar,BioXpress Therapeutics、PD-1checkpoint inhibitor(cancer),Harvard/Zateras、PD-1checkpoint inhibitor+A2aR checkpoint inhibitor(cancer),Domain Therapeutics/Merck KGaA、PD-1checkpoint inhibitor(cancer),Waterstone Pharmaceuticals、dual targeting anti-PD-1/LAG-3mAbs(cancer),TESARO、dual targeting anti-PD-1/TIM-3mAbs(cancer),TESARO、STI-1110、ADU-1503和Cemiplimab。
本发明的一些方案中，上述免疫调节剂选自PDL-1抗体。
本发明的一些方案中，上述PDL-1抗体选自Avelumab、阿替利珠单抗和Durvalumab。
本发明的一些方案中，上述PDL-1抗体选自durvalumab、avelumab、atezolizumab、KN-035、durvalumab+tremelimumab(solid tumor),AstraZeneca/MedImmune、CS-1001、bintrafusp alfa、durvalumab+AZD-5069(SCCHN),AstraZeneca、durvalumab+MEDI-0680(solid tumor),MedImmune/AstraZeneca、durvalumab+dabrafenib+trametinib(cancer),MedImmune/AstraZeneca、CX-072、BGB-A333、BMS-936559、NANT Colorectal Cancer Vaccine containing aldoxorubicin、NANT Hepatocellular Carcinoma Vaccine、NANT Squamous  Cell Carcinoma Vaccine、NANT Triple Negative Breast Cancer Vaccine、NANT Merkel Cell Carcinoma Vaccine、NANT Pancreatic Cancer Vaccine、KL-A167、durvalumab+oleclumab(solid tumor/NSCLC),Medimmune/AstraZeneca、durvalumab+monalizumab(solid tumor/NSCLC),Medimmune/Astrazeneca、SHR-1316、durvalumab+danvatirsen(SCCHN/solid tumor/NSCLC),MedImmune/Astrazeneca、TQB-2450、CK-301、STI-A1014、durvalumab+gefitinib(NSCLC),MedImmune/AstraZeneca、BCD-135、KN-046、INBRX-105、IMC-001、HLX-20、trabectedin+durvalumab(iv,ovarian cancer/soft tissue sarcoma),AstraZeneca/PharmaMar、FAZ-053、durvalumab+AZD-1775(solid tumor),Medimmune/AstraZeneca、selumetinib+durvalumab(solid tumors),AstraZeneca、FS-118和LY-3300054。
本发明的一些方案中，上述式(Ⅰ)化合物或其药学上可接受的盐和所述免疫调节剂分开施用。
本发明的一些方案中，上述式(Ⅰ)化合物或其药学上可接受的盐和所述免疫调节剂并行施用。
本发明的一些方案中，在上述免疫调节剂之后，施用所述式(Ⅰ)化合物或其药学上可接受的盐。
本发明的一些方案中，在上述免疫调节剂之前，施用所述式(Ⅰ)化合物或其药学上可接受的盐。
本发明的一些方案中，上述式(Ⅰ)化合物或其药学上可接受的盐的给药发生在所述免疫调节剂给药之前24小时(1天)、2天、3天、4天或5天。
本发明的一些方案中，与单独的式(Ⅰ)化合物或其药学上可接受的盐或单独的所述免疫调节剂相比，上述式(Ⅰ)化合物或其药学上可接受的盐和上述免疫调节剂以协同作用方式治疗肿瘤。
本发明还提供了一种组合物，包括式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐和免疫调节剂。
本发明的一些方案中，上述式(Ⅰ)化合物具有下式结构或其药学上可接受的盐
Figure PCTCN2020079540-appb-000005
本发明的一些方案中，上述免疫调节剂选自PD-1抗体。
本发明的一些方案中，上述组合物在制备治疗肿瘤疾病药物中的应用。
本发明的一些方案中，上述的肿瘤选自肝细胞癌、肾细胞癌、子宫内膜癌、胃癌、胆管癌、非小细胞肺癌、黑色素瘤、泌尿上皮细胞癌、恶性胶质瘤、食道癌、胰腺癌、乳腺癌、肠癌、淋巴瘤、子宫颈癌和脑癌。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定 义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用 放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2020079540-appb-000006
直形虚线键
Figure PCTCN2020079540-appb-000007
或波浪线
Figure PCTCN2020079540-appb-000008
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2020079540-appb-000009
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2020079540-appb-000010
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连。
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳 原子的烷基基团。所述C 1-6烷氧基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、C 4和C 3烷氧基等。C 1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。
除非另有规定，“C 3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 3-6环烷基包括C 3-5、C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜； EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2020079540-appb-000011
软件命名，市售化合物采用供应商目录名称。
技术效果
本发明化合物在小鼠CT26肿瘤模型上与PD-1抗体联用表现出了明显的抗肿瘤活性，本发明化合物显著增强了PD-1抗体的抗肿瘤效果。
附图说明
图1：实施例1对小鼠CT26结肠癌肿瘤模型瘤体积的影响。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
流程A
Figure PCTCN2020079540-appb-000012
实施例1A
Figure PCTCN2020079540-appb-000013
在20-30℃，将4-氯-7-甲氧基喹啉-6-甲酰胺(550.0g)加入到反应釜中。在20-30℃，将DMSO(16.5L)加入到反应釜中。在20-30℃，将2-氟-3氯-4-氨基苯酚加入到反应釜中。在20-35℃，在搅拌下10-15分钟内将叔丁醇钠(229g)缓慢加入到反应釜中。反应釜经过1.5小时加热到96℃(内温)。反应在96-100℃搅拌6.5小时，4-氨基-3-氯-2氟苯酚无剩余。反应冷却至20-30℃。搅拌下，向反应液中缓慢加入23.1L水，过程中有深褐色固体析出，保持内温低于40℃。在30-40℃搅拌0.5小时。冷却至20-30℃，过滤。在20-30℃，将滤饼和3.5L水加入反应釜。在20-30℃，搅拌0.5小时。过滤。在20-30℃，将滤饼和4.0L水加入反应釜。在20-30℃，搅拌0.5小时。过滤，滤饼在真空干燥器中40℃干燥18小时(五氧化二磷做干燥剂，油泵抽真空)。将固体研碎，得758g灰白色固体并将其在40℃继续干燥18小时(五氧化二磷做干燥剂，油泵抽真空)，得到实施例1A。
LCMS(ESI)m/z:362.0[M+1] +
1H NMR(400MHz,DMSO-d 6)δppm 8.68(br s,2H),7.82-7.96(m,1H),7.67-7.82(m,1H),7.46-7.59(m,1H),7.12-7.26(m,1H),6.67-6.80(m,1H),6.43-6.58(m,1H),5.84(s,2H),4.04(s,3H).
实施例1B
Figure PCTCN2020079540-appb-000014
实施例1A(6.05g)加入到盛有NMP(60mL)的三口瓶中，吡啶(1.32g)，氯甲酸苯酯(5.20g)加入到反应体系中，反应体系在室温下(25～30℃)搅拌1小时，生成中间体反应完全，环丙胺(2.84g)也加入到反应体系中，反应液在室温下(25～30℃)搅拌0.5小时，反应完成，反应体系中加入20mL乙醇，搅拌下向反应体系中加入自来水(500mL)，有固体析出，过滤，滤饼减压旋干，得到粗品(土黄色固体，5.26g)；粗品通过层析柱(DCM：MeOH＝20/1～10/1)纯化，得到产物(土黄色固体，3.12g)，产物中加入4mL无水乙醇常温搅拌18h，过滤，滤饼用1mL乙醇洗涤，减压干燥，得到实施例1B。此化合物通过在丙酮或乙醇溶液中加入1个当量的盐酸或硫酸或甲磺酸得到对应的盐。
LCMS(ESI)m/z:445.0[M+1] +
1H NMR(400MHz,DMSO-d 6)ppm 8.66-8.71(m,2H),8.12-8.20(m,2H),7.72-7.93(m,2H),7.45(t,J＝9.16Hz,1H),7.28(d,J＝2.76Hz,1H),6.58(d,J＝5.02Hz,1H),4.05(s,3H),2.56-2.64(m,1H),0.38-0.77(m,4H)
实施例1
Figure PCTCN2020079540-appb-000015
实施例1B(1.5g,3.37mmol)加入到EtOH(45mL)中，反应温度升至60℃，在该温度下，将CH 3SO 3H(324.07mg,3.37mmol,240.05μL)滴加到反应液中，滴加完毕，反应液溶清，搅拌下反应液自然降温至15～20℃，在该温度下搅拌2h。有大量棕色固体析出，过滤，滤饼用无水乙醇(5mL)淋洗，得到的滤饼50℃减压旋干，不纯化，得到实施例1。
LCMS(ESI)m/z:445.0[M+1] +
1H NMR(400MHz,DMSO-d 6)δppm 9.02(d,J＝6.53Hz,1H)8.72(s,1H)8.18-8.27(m,2H)7.87-8.03(m,2H)7.65(s,1H)7.53(t,J＝9.03Hz,1H)7.32(br s,1H)7.11(d,J＝6.27Hz,1H)4.08(s,3H)2.55-2.62(m,1H)2.35(s,3H)0.34-0.75(m,4H)
生物测试数据：
实验例1：本发明化合物的在体内动物肿瘤模型上的抗肿瘤活性测试
实验目的
在小鼠结肠癌CT26体内肿瘤模型上考察待测化合物的与小鼠抗PD-1抗体联用的抑瘤效果。
实验方法：
在雌性Balb/c小鼠皮下接种CT26小鼠结肠癌细胞株，接种后按照体重随机分组，并且按照下列描述进行给药处理。
第1组(对照组)：接种当天下午开始给药，每天两次按照0.1mL/10g体重的剂量灌胃给药溶媒1(10％DMSO+10％Solutol+80％DDH2O)。接种后待肿瘤体积生长到60mm 3左右时开始给药，每周两次按照0.1mL/10g体重的剂量腹腔注射给予溶媒2(DPBS)一次。
第2组：接种后待肿瘤体积生长到60mm 3左右时开始给药，每周两次按照3mg/kg体重的剂量腹腔注射给予抗小鼠PD-1抗体(RMP1-14，由BioXcell提供)一次。
第3组：接种当天下午开始给药，每天一次按照10mg/kg体重的剂量灌胃给药实施例1(混悬于0.5％MC+0.2％Tween 80)。接种后待肿瘤体积生长到60mm 3左右时开始给药，每周两次按照3mg/kg体重的剂量 腹腔注射给予抗小鼠PD-1抗体(RMP1-14，由BioXcell提供)一次。
实验期间每周三次称量小鼠体重，肿瘤成瘤后，与体重同步每周三次测量瘤体积，按照长×宽 2/2的公式计算瘤体积。按照公式计算肿瘤增殖率：肿瘤增殖率＝治疗组瘤体积/对照组瘤体积×100％
组间用Student’s t-test进行统计学分析，p<0.05为有显著性差异。
实验结果：
在小鼠CT26肿瘤模型上(如图1所示)，实施例1与PD-1抗体联用表现出了明显的抗肿瘤活性，第25天的肿瘤增殖率为：15.38％(p<0.01)，明显高于抗体单用药组(抗体单用药组的肿瘤增殖率为59.44％。在第25天的时候联用组瘤体积与抗体单用组相比有显著性差异(p<0.05)，说明在本次实验中，实施例1显著增强了PD-1抗体的抗肿瘤效果。

Claims (25)

  1. 一种式(Ⅰ)化合物或其药学上可接受的盐和免疫调节剂联合在制备治疗肿瘤的药物中的应用。
    Figure PCTCN2020079540-appb-100001
    其中，
    R 1选自任选被1、2或3个R取代的C 1-6烷氧基；
    R 2选自-C(＝O)NH 2和-C(＝O)NH-C 1-3烷基；
    环B选自C 3-6环烷基；
    R选自F、Cl、Br、I、OH和NH 2。
  2. 一种式(Ⅰ)化合物或其药学上可接受的盐在制备和免疫调节剂联合治疗肿瘤的药物中的应用。
  3. 一种免疫调节剂在制备与式(Ⅰ)化合物或其药学上可接受的盐联合治疗肿瘤的药物中的应用。
  4. 根据权利要求1～3任意一项所述的应用，其中，环B选自环丙烷基。
  5. 根据权利要求1～3任意一项所述的应用，其中，R 1选自
    Figure PCTCN2020079540-appb-100002
  6. 根据权利要求1～3任意一项所述的应用，其中，R 2选自-C(＝O)NH 2。
  7. 根据权利要求1～6任意一项所述的应用，其中，所述式(Ⅰ)化合物或其药学上可接受的盐选自
    Figure PCTCN2020079540-appb-100003
    其中，R 1、R 2如权利要求1～3任意一项所定义。
  8. 根据权利要求1～3任意一项所述的应用，所述式(Ⅰ)化合物具有下式结构或其药学上可接受的盐
    Figure PCTCN2020079540-appb-100004
  9. 根据权利要求1～3任意一项所述的应用，其中，所述免疫调节剂选自PD-1抑制剂和PDL-1抑制剂。
  10. 根据权利要求9所述的应用，其中，所述免疫调节剂选自PD-1抗体和PDL-1抗体。
  11. 根据权利要求10所述的应用，其中，所述免疫调节剂选自PD-1抗体。
  12. 根据权利要求11所述的应用，其中，所述PD-1抗体选自帕博利珠单抗、纳武利尤单抗、信迪利单抗、特瑞普利单抗、RMP1-14、camrelizumab、tislelizumab和Cemiplimab。
  13. 根据权利要求1～3任意一项所述的应用，其中，所述免疫调节剂选自PDL-1抗体。
  14. 根据权利要求13所述的应用，其中，所述PDL-1抗体选自Avelumab、阿替利珠单抗和Durvalumab。
  15. 根据权利要求1～14任一项所述的应用，其中，将所述式(Ⅰ)化合物或其药学上可接受的盐和所述免疫调节剂分开施用。
  16. 根据权利要求1～14任一项所述的应用，其中，将所述式(Ⅰ)化合物或其药学上可接受的盐和所述免疫调节剂并行施用。
  17. 根据权利要求16所述的应用，其中，在所述免疫调节剂之后，施用所述式(Ⅰ)化合物或其药学上可接受的盐。
  18. 根据权利要求16所述的应用，其中，在所述免疫调节剂之前，施用所述式(Ⅰ)化合物或其药学上可接受的盐。
  19. 根据权利要求18所述的应用，其中，所述式(Ⅰ)化合物或其药学上可接受的盐的给药发生在所述免疫调节剂给药之前24小时(1天)、2天、3天、4天或5天。
  20. 根据权利要求1～14任一项所述的应用，其中，所述式(Ⅰ)化合物或其药学上可接受的盐和所述免疫调节剂以协同作用方式治疗肿瘤。
  21. 一种组合物，包括式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐和免疫调节剂。
  22. 根据权利要求21所述的组合物，其中，所述式(Ⅰ)化合物具有下式结构或其药学上可接受的盐
    Figure PCTCN2020079540-appb-100005
  23. 根据权利要求21所述的组合物，其中，所述免疫调节剂选自PD-1抗体。
  24. 根据权利要求21～23所述的组合物在制备治疗肿瘤疾病药物中的应用。
  25. 根据权利要求1～20所述的应用、权利要求21～23所述的组合物或权利要求24所述的应用，其中，所述的肿瘤选自肝细胞癌、肾细胞癌、子宫内膜癌、胃癌、胆管癌、非小细胞肺癌、黑色素瘤、泌尿上皮细胞癌、恶性胶质瘤、食道癌、胰腺癌、乳腺癌、肠癌、淋巴瘤、子宫颈癌和脑癌。
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