WO2022247881A1 - 治疗肿瘤的联合疗法 - Google Patents

治疗肿瘤的联合疗法 Download PDF

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WO2022247881A1
WO2022247881A1 PCT/CN2022/095115 CN2022095115W WO2022247881A1 WO 2022247881 A1 WO2022247881 A1 WO 2022247881A1 CN 2022095115 W CN2022095115 W CN 2022095115W WO 2022247881 A1 WO2022247881 A1 WO 2022247881A1
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days
cancer
alkyl
pharmaceutically acceptable
atom
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PCT/CN2022/095115
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English (en)
French (fr)
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邓永奇
贾岩林
田元
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凯复(苏州)生物医药有限公司
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Priority to CN202280037849.9A priority Critical patent/CN117377471A/zh
Publication of WO2022247881A1 publication Critical patent/WO2022247881A1/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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention is in the field of biomedicine, and in particular relates to methods of treating, containing, reducing the severity, reducing the risk, or inhibiting metastasis of cancer in an individual, or enhancing a cell-mediated immune response against cancer, comprising adding The subject is administered a therapeutically effective dose of an EP4 receptor antagonist and a therapeutically effective dose of lenvatinib or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a pharmaceutical composition or kit comprising an EP4 receptor antagonist and lenvatinib or a pharmaceutically acceptable salt thereof.
  • VEGF vascular endothelial growth factor
  • VEGFR vascular endothelial growth factor receptor
  • fibroblast growth factor activates various signaling pathways through fibroblast growth factor receptor (FGFR), participates in the regulation of cell proliferation, and promotes cell growth.
  • FGF fibroblast growth factor
  • FGFR fibroblast growth factor receptor
  • Lenvatinib is a multi-kinase inhibitor that can potently inhibit VEGFR 1-3, FGFR 1-4, PDGFR ⁇ , RET and KIT. Lenvatinib blocks these signaling pathways that promote tumor angiogenesis and tumor growth, thereby inhibiting tumor growth and metastasis. Clinical trials have shown that lenvatinib has a significant inhibitory effect on tumors. Lenvatinib is currently approved for the treatment of hepatocellular carcinoma and thyroid cancer.
  • E-type prostaglandin 2 (PGE2), an arachidonic acid derivative, has increased levels in some tumor tissues.
  • EP4 is the main PGE2 receptor in tumor tissue. PGE2 in tumor tissue inhibits the function of immune cells in the tumor microenvironment through the EP4 receptor, so that tumor cells escape the anti-tumor immune system and accelerate tumor growth and metastasis. In addition, PGE2 can also promote tumor angiogenesis and tumor cell growth by activating EP4 receptors. EP4 receptor antagonists can block these effects of PGE2, thereby enhancing anti-tumor immune function and inhibiting tumor growth. Evidence shows that EP4 receptor antagonists can enhance the response of immune cells and show the effect of inhibiting tumor growth in multiple tumor models. At present, EP4 receptor antagonists are still in the early stage of clinical research, and there is no clinically approved drug for tumor treatment.
  • the invention adopts EP4 receptor antagonist and lenvatinib or its pharmaceutically acceptable salt in combination to treat malignant tumor and cancer.
  • the inventors unexpectedly found that the combination of an EP4 receptor antagonist and lenvatinib or a pharmaceutically acceptable salt thereof has achieved a synergistic effect in the treatment of cancer.
  • the invention provides a method of treating, suppressing, reducing the severity, reducing the risk, or inhibiting metastasis of cancer in an individual, or enhancing a cell-mediated immune response to cancer, comprising administering to said individual A therapeutically effective amount of EP4 receptor antagonist and a therapeutically effective amount of lenvatinib or a pharmaceutically acceptable salt thereof are administered.
  • the present invention provides an EP4 receptor antagonist in the preparation for use in combination with lenvatinib or a pharmaceutically acceptable salt thereof to treat, curb, reduce the severity, reduce the risk or inhibit the cancer in an individual its metastasis, or use in drugs that enhance cell-mediated immune responses against cancer.
  • the present invention provides an EP4 receptor antagonist for use in combination with lenvatinib or a pharmaceutically acceptable salt thereof to treat, curb, reduce the severity, reduce the risk or inhibit cancer in an individual It metastasizes, or enhances cell-mediated immune responses against cancer.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an EP4 receptor antagonist, lenvatinib or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the invention provides a kit comprising:
  • Figure 1 The effect of compound 6 combined with lenvatinib mesylate in CT26 tumor model.
  • Figure 2 The effect of the combination of compound 6, lenvatinib mesylate and anti-PD-1 antibody in the CT26 tumor model.
  • Figure 3 The effect of the combination of compound 6, lenvatinib mesylate and anti-PD-1 antibody in the H22 tumor model.
  • Figure 4 The effect of the combination of compound 6, lenvatinib mesylate and anti-PD-1 antibody on the survival of mice in the H22 tumor model.
  • Stepoisomers within the meaning of the present invention refer to geometric isomers (or configurational isomers) or optical isomers.
  • “Geometric isomers” result from substituents at different positions on the double bond, which can then have the Z or E configuration, also known as cis or trans.
  • Optical isomers result in particular from substituents at different steric positions on a carbon atom containing four different substituents. This carbon atom then constitutes a chiral center or an asymmetric center.
  • Optical isomers include diastereomers and enantiomers.
  • Optical isomers that are non-superimposable mirror images of each other are termed “enantiomers”.
  • Optical isomers that are not superimposable mirror images of each other are termed "diastereomers”.
  • racemic mixture A mixture containing equal amounts of two individual enantiomeric forms of opposite chirality is termed a "racemic mixture”.
  • tautomers refer to structural isomers of compounds obtained by prototropie , ie by migration of a hydrogen atom and change in the position of the double bond.
  • the different tautomers of a compound are generally interconvertible and exist in solution in equilibrium in proportions which may vary depending on the solvent used, temperature or pH.
  • pharmaceutically acceptable is understood to mean its use in the preparation of pharmaceutical compositions which are generally safe, non-toxic, biologically or otherwise satisfactory and which are substances are acceptable for veterinary and human pharmaceutical use.
  • a "pharmaceutically acceptable salt” of a compound is understood to mean a salt which is pharmaceutically acceptable (as defined herein) and which possesses the intended pharmacological activity of the parent compound.
  • Such salts include:
  • Acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid , Fumaric Acid, Glucoheptonic Acid, Gluconic Acid, Glutamic Acid, Glycolic Acid, Xinaphthoic Acid, 2-Hydroxyethanesulfonic Acid, Lactic Acid, Maleic Acid, Malic Acid, Mandelic Acid, Methanesulfonic Acid, Muconic Acid acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid, etc.; and
  • alkali metal ions for example, Na + , K + or Li +
  • alkaline earth metal ions such as Ca 2+ or Mg 2+
  • aluminum ions or a salt formed when coordinating with an organic base or an inorganic base.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • halogen means a fluorine, bromine, chlorine or iodine atom.
  • C 1-4 alkyl refers to a saturated straight or branched hydrocarbon chain containing 1 to 4 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl groups.
  • C 1-4 alkylene refers to a divalent hydrocarbon chain containing 1 to 4 carbon atoms. Representative examples include, but are not limited to, CH2- , -CH2 - CH2- , -CH2- CH2 - CH2- , -CH2- CH2 - CH2 - CH2- , and the like.
  • C 1-4 alkoxy refers to -O-(C 1-4 alkyl), wherein C 1-4 alkyl is as defined above.
  • Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like.
  • halogenated C 1-4 alkyl refers to a C 1-4 alkyl substituted by one or more halogens, wherein the definitions of C 1-4 alkyl and halogen are as above.
  • halogenated C 1-4 alkoxy means that C 1-4 alkoxy is substituted by one or more halogens, wherein the definitions of C 1-4 alkoxy and halogen are as above.
  • hydroxyC 1-4 alkyl refers to C 1-4 alkyl substituted by hydroxy, wherein alkyl is as defined above.
  • C 3-6 cycloalkyl refers to a saturated or partially unsaturated monocyclic hydrocarbon system containing 3 to 6 carbon atoms, representative examples include, but are not limited to, cyclohexyl, cyclopentyl, cyclobutyl, Cyclopropyl, cyclohexenyl, etc.
  • 3-6 membered heteroalkyl refers to a heteroalkyl group containing 3 to 6 ring atoms, of which 1-3 ring atoms are selected from nitrogen, oxygen, or S(O) m (where m is 0, 1 or 2).
  • Atoms of saturated or partially unsaturated monocyclic hydrocarbon systems representative examples include, but are not limited to, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, di Hydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, etc.
  • C6-10 aryl refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group having a conjugated ⁇ -electron system, such as phenyl and naphthalene base. Phenyl is more preferred.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen, preferably containing 1 to 2 heteroatoms 5-membered or 6-membered heteroaryl, such as quinolinyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, Pyrimidinyl, thiadiazole, pyrazinyl, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • hydroxyl refers to a -OH group.
  • nitro refers to -NO2 .
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • a bond refers to a covalent bond represented by "-”.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle 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 are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • antibody as used herein includes all classes of immunoglobulins, including IgG, IgM, IgA, IgD and IgE, or fragments thereof, which may be suitable for use in medicine as used herein.
  • Antibodies can be monoclonal or polyclonal and can be of any species of origin including, for example, mouse, rat, rabbit, horse or human.
  • Antibody fragments that retain the specificity found for a protein or epitope, such as CTLA4, PD-L1 or PD-1, that bind to the antibodies used in the present invention are also included within the scope of the term "antibody". These fragments can be produced by known techniques.
  • Antibodies can be chimeric or humanized, especially when they are used for therapeutic purposes.
  • Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions or kits of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, Soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol etc.
  • the pharmaceutical composition can also optionally contain small amounts of wetting agents, emulsifying agents or pH buffering agents.
  • Oral formulations can contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • compositions and kits of the invention may act systemically and/or locally.
  • they may be administered by a suitable route, for example by injection (e.g. intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, transdermal Nasally, transmucosally, topically, in the form of ophthalmic formulations or by inhalation.
  • the pharmaceutical composition of the present invention and each component in the kit can be administered in an appropriate dosage form.
  • the dosage forms include but are not limited to tablets, capsules, lozenges, hard lozenges, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions , Injectable solutions, elixirs, syrups.
  • container is a container for containing pharmaceutical components. This container may be used for preparation, storage, transport and/or individual/bulk sale, and it is intended to cover bottles, jars, vials, flasks, syringes, tubes (for example for cream preparations), or for preparation, containment, storage or distribution Any other containers for pharmaceutical products.
  • the term "instructions" as used herein is an insert, label, label, etc., which recites information pertaining to the pharmaceutical components located within the container.
  • the information listed is generally at the discretion of regulatory agencies (eg, the United States Food and Drug Administration) having jurisdiction in the territories in which the article is to be marketed.
  • the package insert specifically lists the indications for which the pharmaceutical composition is approved.
  • the package insert may be made of any material from which the information contained therein or thereon can be read.
  • the package insert is a printable material (eg, paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information can be formed (eg, printed or applied).
  • an effective amount refers to the amount of the active ingredient which, when administered, alleviates to some extent one or more symptoms of the condition being treated.
  • “Individual” as used herein includes a human or non-human animal.
  • Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • cancer metastasis refers to cancer that has spread (metastasized) from its original site to another area of the body. Almost all cancers have the potential to spread. Whether metastasis occurs depends on a complex interplay of several tumor cell factors, including the type of cancer, how mature (differentiated) the tumor cells are, their location and how long the cancer has been present, and other factors that are not fully understood . Metastasis spreads in three ways—local extension from the tumor to surrounding tissue, via the bloodstream to distant sites, or via the lymphatic system to nearby or distant lymph nodes. Each cancer can have a representative pathway of spread. Tumors are named according to where they originated (for example, breast cancer that has spread to the brain is called metastatic breast cancer that has spread to the brain).
  • drug resistance refers to cancer cells that have acquired resistance to chemotherapy. Cancer cells can acquire resistance to chemotherapy through a range of mechanisms, including mutation or overexpression of drug targets, inactivation of drugs, or elimination of drugs from cells.
  • the present invention provides a method of treating, suppressing, reducing the severity, reducing the risk, or inhibiting metastasis of cancer in an individual, or enhancing a cell-mediated immune response against cancer, the method comprising adding to the The subject is administered a therapeutically effective amount of an EP4 receptor antagonist and a therapeutically effective amount of lenvatinib or a pharmaceutically acceptable salt thereof.
  • the method of the present invention also includes administering other anti-tumor drugs to the individual; preferably, administering to the individual any member of the PD-1 signaling pathway (preferably targeting PD-1 , PD-L1 or PD-L2) PD-1 pathway inhibitors.
  • the present invention provides an EP4 receptor antagonist in the preparation for use in combination with lenvatinib or a pharmaceutically acceptable salt thereof to treat, curb, reduce the severity of, reduce the risk of, or Use in a drug that inhibits its metastasis, or enhances a cell-mediated immune response against cancer.
  • the present invention provides an EP4 receptor antagonist for use in combination with lenvatinib or a pharmaceutically acceptable salt thereof and a PD-1 pathway inhibitor to treat, curb individual cancer, reduce its use in drugs that reduce the severity, reduce the risk, or inhibit metastasis, or enhance the cell-mediated immune response against cancer.
  • the present invention provides lenvatinib or a pharmaceutically acceptable salt thereof in the preparation for use in combination with an EP4 receptor antagonist to treat, curb, reduce the severity of, reduce the risk of, or Use in a drug that inhibits its metastasis, or enhances a cell-mediated immune response against cancer.
  • the present invention provides EP4 receptor antagonists for use in the manufacture of treatment, suppression, and reduction of the severity of cancer in an individual being treated with a cancer therapy comprising lenvatinib or a pharmaceutically acceptable salt thereof. use in drugs to reduce the risk of, or inhibit metastasis of, cancer, or to enhance cell-mediated immune responses against cancer.
  • the present invention provides EP4 receptor antagonists for use in the preparation of cancer therapy comprising lenvatinib or a pharmaceutically acceptable salt thereof and/or comprising PD-1 pathway inhibitors
  • EP4 receptor antagonists for use in the preparation of cancer therapy comprising lenvatinib or a pharmaceutically acceptable salt thereof and/or comprising PD-1 pathway inhibitors
  • the present invention provides an EP4 receptor antagonist for use in combination with lenvatinib or a pharmaceutically acceptable salt thereof to treat, curb, reduce the severity of, reduce the risk of, or Inhibit its metastasis, or enhance the cell-mediated immune response against cancer.
  • the present invention provides an EP4 receptor antagonist for use in combination with lenvatinib or a pharmaceutically acceptable salt thereof and a PD-1 pathway inhibitor to treat, suppress cancer, reduce its severity, reduce its risk, or inhibit its metastasis, or enhance cell-mediated immune responses against cancer.
  • the present invention provides lenvatinib, or a pharmaceutically acceptable salt thereof, for use in combination with an EP4 receptor antagonist to treat, curb, reduce the severity, reduce the risk, or Inhibit its metastasis, or enhance the cell-mediated immune response against cancer.
  • the present invention provides an EP4 receptor antagonist for use in the treatment, suppression, reduction of the severity of cancer in an individual being treated with a cancer therapy comprising lenvatinib or a pharmaceutically acceptable salt thereof. sex, reduce its risk, or inhibit its metastasis, or enhance cell-mediated immune responses against cancer.
  • the present invention provides an EP4 receptor antagonist for use in the treatment, suppression of cancer therapy comprising lenvatinib or a pharmaceutically acceptable salt thereof and/or comprising a PD-1 pathway inhibitor Treating, reducing the severity, reducing the risk, or inhibiting metastasis of cancer in an individual treated with a cancer therapy, or enhancing a cell-mediated immune response against the cancer.
  • the EP4 receptor antagonist is an antibody or small molecule that blocks the action of prostaglandin E2 receptor 4 (EP4) encoded by the PTGER4 gene.
  • the EP4 receptor antagonists include, but are not limited to, those disclosed in Drug Discovery Today, Vol. 22, No. 1, pp. 57-71 (January 2017), which is incorporated by reference in its entirety Join this article.
  • the EP4 receptor antagonist may be a compound having the following formula or a pharmaceutically acceptable salt thereof,
  • the EP4 receptor antagonist may be a compound having the following formula or a pharmaceutically acceptable salt thereof,
  • the EP4 receptor antagonist may be a compound having the following formula or a pharmaceutically acceptable salt thereof,
  • the EP4 receptor antagonist may be a compound having the following formula or a pharmaceutically acceptable salt thereof,
  • the EP4 receptor antagonist may be a compound having the following formula or a pharmaceutically acceptable salt thereof,
  • the EP4 receptor antagonist may be a compound having the following formula or a pharmaceutically acceptable salt thereof,
  • the EP4 receptor antagonist can be any compound disclosed in WO 2020/012305 A1, which is incorporated herein by reference in its entirety.
  • the EP4 receptor antagonist may be a compound having the following formula or a pharmaceutically acceptable salt thereof,
  • the EP4 receptor antagonist may be a compound having the following formula or a pharmaceutically acceptable salt thereof,
  • the EP4 receptor antagonist may be a compound having the following formula or a pharmaceutically acceptable salt thereof,
  • the EP4 receptor antagonist can be any compound disclosed in WO 2020/014465 A1, which is incorporated herein by reference in its entirety.
  • the EP4 receptor antagonist may be a compound having the following formula or a pharmaceutically acceptable salt thereof,
  • the EP4 receptor antagonist may be a compound having the following formula or a pharmaceutically acceptable salt thereof,
  • the EP4 receptor antagonist may be a compound having the following formula or a pharmaceutically acceptable salt thereof,
  • the EP4 receptor antagonist may be a compound having the following formula or a pharmaceutically acceptable salt thereof,
  • the EP4 receptor antagonist may be a compound having the following formula or a pharmaceutically acceptable salt thereof,
  • the EP4 receptor antagonist can be Discovery of AAT-008, a novel, potent, and selective prostaglandin EP4 receptor antagonist (Bioorg Med Chem Lett. 2017 Mar 1; 27 (5): 1186- 1192), which is incorporated herein by reference in its entirety.
  • the EP4 receptor antagonist may be a compound having the following formula or a pharmaceutically acceptable salt thereof,
  • the EP4 receptor antagonist may also be a cyclooxygenase (COX) inhibitor, such as an inhibitor of COX-1, COX-2, or both.
  • COX inhibitor is a COX-2 selective inhibitor.
  • the COX inhibitor is selected from the group consisting of celecoxib, deracoxib, deracoxib, valdecoxib, rofecoxib, lumicoxib, etoricoxib, meloxicam and its mixture.
  • the EP4 receptor antagonist may be a phospholipase A2 inhibitor, and preferably an inhibitor of cytosolic phospholipase A2.
  • the EP4 receptor antagonist may be a compound of formula (I):
  • M 1 , M 2 , M 3 , M 5 , M 6 and M 7 are each independently N atom or CR 4 ;
  • M 4 is selected from N atom and C atom
  • Ring A is selected from C 6-10 aryl, C 3-6 cycloalkyl, 5-10 membered heteroaryl and 3-6 membered heterocyclic group;
  • Y is selected from a bond, C 1-4 alkylene, -CR 5 R 6 -, -O-, -OC 1-4 alkylene-, -NR 9 C 1-4 alkylene-, and -NR 9 -, the C 1-4 alkylene is optionally selected from H atom, D atom, halogen, hydroxyl, cyano, amino, nitro, C 1-4 alkyl, C 1-4 alkoxy, halogen Substituted C 1-4 alkyl, halogenated C 1-4 alkoxy, hydroxy C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl and 5 -One or more substituents in 10-membered heteroaryl;
  • R 1 and R 2 are the same or different, and each independently selected from H atom, D atom, cyano group, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 Membered heterocyclyl, -C(O)OR 4 , C(O)NR 7 R 8 , -COR 4 , -S(O) m R 4 , -NR 7 R 8 , C 6-10 aryl and 5- 10-membered heteroaryl, the C 1-4 alkyl and C 1-4 alkoxy are each independently selected from H atom, D atom, halogen, hydroxyl, cyano, amino, nitro, C 1 -4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl , halogenated C 1-4 alkoxy, hydroxy C 1-4 alkyl, C 3-6 cycloalkyl, 3- 6-membered heterocyclyl, -C(O)OR 4 , C(O)NR 7 R
  • R 3 are the same or different, and each independently selected from hydrogen H atom, D atom, halogen, hydroxyl, cyano, amino, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C(O)R 4 , -C(O)OR 4 , -OC(O)NR 7 R 8 , -NR 7 C(O)OR 4 , -S(O) m R 4 , -NR 7 R 8 and -C(O)NR 7 R 8 , wherein the C 1-4 alkyl, C 1 -4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl are each independently selected from C 1-4 alkyl One of , hydroxy C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4
  • R 4 is selected from H atom, D atom, halogen, hydroxyl, amino, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6- 10 aryl and 5-10 membered heteroaryl, wherein said C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl are each independently selected from C 1-4 alkyl, hydroxy C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, One or more substituents in halogenated C 1-4 alkoxy, halogen, hydroxyl, cyano, amino and nitro;
  • R 5 and R 6 are each independently selected from H atom, D atom, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl and 5-10 membered Heteroaryl, wherein said C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl and 5-10 membered heteroaryl are each independently optionally Selected from C 1-4 alkyl, hydroxy C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, halogen, hydroxyl, cyano , one or more substituents in amino and nitro; or R 5 and R 6 form C 3-6 cycloalkyl or 3-6 membered heterocyclic group together with the atoms they are connected to, wherein the C 3 -6 cycloalkyl or 3-6 membered heterocyclic groups are each independently optionally selected from
  • R 7 and R 8 are each independently selected from H atom, D atom, C 1-4 alkyl, halogenated C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6 -10 aryl and 5-10 membered heteroaryl, wherein said C 1-4 alkyl, halogenated C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6 -10 aryl and 5-10 membered heteroaryl are each independently selected from C 1-4 alkyl, hydroxy C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkane One or more substituents in radical, halogenated C 1-4 alkoxy, halogen, hydroxyl, cyano, amino and nitro;
  • R 9 is selected from H atom, D atom and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally selected from hydroxy C 1-4 alkyl, C 1-4 alkoxy, halogenated C One or more substituents in 1-4 alkyl, halogenated C 1-4 alkoxy, halogen, hydroxyl, cyano, amino and nitro;
  • n 0, 1 or 2;
  • n 0, 1, 2, 3 or 4.
  • the compound of the formula (I) is a compound shown in the formula (II):
  • M 1 , M 3 , M 5 and M 6 are each independently CH or C-halogen
  • M 2 is CR 4 or N atom
  • M 7 is N atom
  • M 4 is C atom
  • ring A, R 1 , R 2 , R 3 , R 4 , X, Y and n are as defined in formula (I).
  • Y is C 1-4 alkylene, preferably methylene.
  • R 1 and R 2 are the same or different, and each independently selected from H atom, D atom and C 1-4 alkyl; or R 1 and R 2 forms a C 3-6 cycloalkyl group together with the atoms it is connected to, preferably a cyclopropyl group.
  • the compound of the formula (I) is a compound shown in the formula (III):
  • R 1 and R 2 are the same or different, and are each independently selected from H atom, D atom and C 1-4 alkyl; or R 1 and R 2 form a C 3-6 cycloalkyl group together with the atoms they are connected to, preferably Cyclopropyl;
  • M 2 is N atom or CR 4 ;
  • R 4 is selected from H atom, D atom and halogen
  • X, ring A, R3 and n are as defined in formula (I).
  • ring A is selected from phenyl, pyridyl, quinolinyl, benzofuryl, morpholinyl, pyrazole, cyclopropyl, isoxazole , benzoxazole and benzothiazole.
  • R 3 are the same or different, and are each independently selected from H atom, D atom, halogen, C 1-4 alkyl, fluoro C 1-4 Alkyl, phenyl, phenyl substituted by hydroxy C 1-4 alkyl, morpholinyl, pyridyl, pyrazolyl, pyrazolyl substituted by C 1-4 alkyl, hydroxy C 1-4 alkyl substituted Pyrazolyl, cyclopropyl, isoxazolyl and piperidinyl.
  • the compound of formula (I) includes but is not limited to:
  • the PD-1 pathway inhibitor may be an antibody (especially an antagonistic antibody or a nucleic acid-encoded antibody (intrabody)), siRNA, antisense RNA, a Proteins of amino acid sequences (or nucleic acids encoding them) for PD-1 signaling (e.g., fusion proteins of fragments of PD-L1 or PD-L2 and the Fc portion of immunoglobulins), membrane-bound PD-1 competitors Binding soluble proteins (or nucleic acids encoding soluble proteins) of their ligands PD-L1 and PD-L2; or small molecule inhibitors capable of inhibiting PD-1 pathway signaling.
  • an antibody especially an antagonistic antibody or a nucleic acid-encoded antibody (intrabody)
  • siRNA e.g., antisense RNA, a Proteins of amino acid sequences (or nucleic acids encoding them) for PD-1 signaling (e.g., fusion proteins of fragments of PD-L1 or
  • the PD-1 pathway inhibitor is an anti-PD-1 antibody, including but not limited to: Pembrolizumab (Pembrolizumab, Keytruda), Nivolumba (Opdivo), Simiprimumab ( Cemiplimab, Libtayo, REGN-2810), toripalimab, sintilimab, camrelizumab, tislelizumab (Tislelizumab, BeiGen), Genolizumab (Genolimzumab, GB226, Asia Sheng), JTX-4014 (Jounce), AMP-224, AMP-514, PDR-001 (Spartalizumab, Novartis), BCD-100, TSR-042, JNJ-63723283, Sasanlimab (PF-06801591), BI-754091, GLS-010, LZM009, HX008, MDX-1106, Merck 3745 and CT-011.
  • the PD-1 pathway inhibitor is an anti-PD-L1 antibody, including but not limited to: Atezolizumab, Durvalumab (Durvalumab, Imfinzi, AZ), Avi Monoclonal antibody (Avelumab, Bavencio, EMD), durvalumab (KN035), GLS-010, CS1001, M7824, CX-071, LY-3300054, CA-170, SHR-1316, ZKAB001, BAT1306, BMS1166, MAX-10181, YW243.55.S70, MPDL3280A, and MDX-1105.
  • Atezolizumab Durvalumab (Durvalumab, Imfinzi, AZ), Avi Monoclonal antibody (Avelumab, Bavencio, EMD), durvalumab (KN035), GLS-010, CS1001, M7824, CX-071, LY-3300054, CA-170, SHR-1316, Z
  • the PD-1 pathway inhibitor is a protein comprising an amino acid sequence (or a nucleic acid encoding said amino acid sequence) capable of binding PD-1 but preventing PD-1 pathway signaling, in which case Particularly preferred are fusion proteins of fragments of PD-L1 or PD-L2 ligands.
  • the cancer is selected from the group consisting of bladder cancer, breast cancer, uterine cancer, endometrial cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, Liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), urinary tract cancer, melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma Carcinoma, sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, mesothelioma, bile duct cancer, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer , salivary gland carcinoma, metasta
  • the cancer is a drug-resistant tumor (preferably a lenvatinib-resistant tumor, an EP4 receptor antagonist-resistant tumor or a PD-1 pathway inhibitor-resistant tumor).
  • a drug-resistant tumor preferably a lenvatinib-resistant tumor, an EP4 receptor antagonist-resistant tumor or a PD-1 pathway inhibitor-resistant tumor.
  • the EP4 receptor antagonist is administered in an amount of about 0.005 mg/day to about 5000 mg/day, such as about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, or 5000mg/day dose administration.
  • the EP4 receptor antagonist is administered in an amount of about 1 ng/kg to about 200 mg/kg, about 1 ⁇ g/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg of body weight per day.
  • Medicine for example, at about 1 ⁇ g/kg, about 10 ⁇ g/kg, about 25 ⁇ g/kg, about 50 ⁇ g/kg, about 75 ⁇ g/kg, about 100 ⁇ g/kg, about 125 ⁇ g/kg, about 150 ⁇ g/kg, about 175 ⁇ g/kg , about 200 ⁇ g kg, about 225 ⁇ g/kg, about 250 ⁇ g kg, about 275 ⁇ g kg, about 300 ⁇ g/kg, about 325 ⁇ g kg, about 350 ⁇ g/kg, about 375 ⁇ g/kg, about 400 ⁇ g/kg, about 425 ⁇ g/kg, about 450 ⁇ g/kg, About 475 ⁇ g/kg, about 500 ⁇ g/kg, about 525 ⁇
  • lenvatinib or a pharmaceutically acceptable salt thereof is administered in an amount of 0.005 mg/day to about 5000 mg/day, such as about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, The dosage of 4000, 4500 or 5000 mg/day is administered.
  • lenvatinib or a pharmaceutically acceptable salt thereof is administered at about 1 ng/kg to about 200 mg/kg, about 1 ⁇ g/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg per day.
  • Administration in an amount of kg body weight for example, about 1 ⁇ g/kg, about 10 ⁇ g/kg, about 25 ⁇ g/kg, about 50 ⁇ g/kg, about 75 ⁇ g/kg, about 100 ⁇ g/kg, about 125 ⁇ g/kg, about 150 ⁇ g/kg per day , About 175 ⁇ g/kg, About 200 ⁇ gkg, About 225 ⁇ g/kg, About 250 ⁇ gkg, About 275 ⁇ gkg, About 300 ⁇ g/kg, About 325 ⁇ gkg, About 350 ⁇ g/kg, About 375 ⁇ g/kg, About 400 ⁇ g/kg, About 425 ⁇ g/kg, About 450 ⁇ g /kg, about 475 ⁇ g/kg, about 500 ⁇ g/kg, about 525 ⁇ gkg, about 550 ⁇ g/kg, about 575 ⁇ gkg, about 600 ⁇ g/kg, about 625 ⁇ g/kg, about 650 ⁇ g/kg, about 675 ⁇ g/kg, about 700 ⁇ g/kg, about 725 ⁇ g/kg, about 750
  • the other anti-tumor drugs are administered in an amount of 0.005 mg/day to about 5000 mg/day, such as about 0.005, 0.05, 0.5, 5, 10, 20, 30 ,40,50,100,150,200,250,300,350,400,450,500,550,600,650,700,750,800,850,900,950,1000,1500,2000,2500,3000 , 3500, 4000, 4500 or 5000 mg/day.
  • the other anti-tumor drugs are dosed at about 1 ng/kg to about 200 mg/kg, about 1 ⁇ g/kg to about 100 mg/kg or about 1 mg/kg to about 100 mg/kg per day.
  • About 50 mg/kg of body weight is administered, for example, about 1 ⁇ g/kg, about 10 ⁇ g/kg, about 25 ⁇ g/kg, about 50 ⁇ g/kg, about 75 ⁇ g/kg, about 100 ⁇ g/kg, about 125 ⁇ g/kg, about 150 ⁇ g/kg, about 175 ⁇ g/kg, about 200 ⁇ gkg, about 225 ⁇ g/kg, about 250 ⁇ gkg, about 275 ⁇ gkg, about 300 ⁇ g/kg, about 325 ⁇ gkg, about 350 ⁇ g/kg, about 375 ⁇ g/kg, about 400 ⁇ g/kg, about 425 ⁇ g/kg , about 450 ⁇ g/kg, about 475 ⁇ g/kg, about 500 ⁇ g/kg, about 525 ⁇ g kg, about 550 ⁇ g/kg, about 575 ⁇ g kg, about 600 ⁇ g/kg, about 625 ⁇ g/kg, about 650 ⁇ g/kg, about 675 ⁇ g/kg, about 700 ⁇ g/kg, about 7
  • the EP4 receptor antagonist is combined with lenvatinib or a pharmaceutically acceptable salt thereof and optionally other antitumor drugs (preferably PD-1 pathway inhibitors) together, simultaneously, sequentially or alternatively.
  • the EP4 receptor antagonist, lenvatinib or a pharmaceutically acceptable salt thereof and/or other optional antitumor drugs are administered continuously At least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, At least 40 days, at least 45 days, or at least 50 days.
  • the EP4 receptor antagonist, lenvatinib or a pharmaceutically acceptable salt thereof and/or optionally other anti-tumor drugs are administered to one or multiple (eg 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) courses of treatment, wherein each course of treatment lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days , at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days; and every two courses of treatment 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks or four weeks in between.
  • each course of treatment lasts at least 3 days, at least 4 days
  • the EP4 receptor antagonist, lenvatinib or a pharmaceutically acceptable salt thereof and/or other antitumor drugs are the same or different.
  • the EP4 receptor antagonist, lenvatinib or a pharmaceutically acceptable salt thereof and/or other optional antitumor drugs is 1-10 times, preferably 1-5 times, such as 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5 times the amount administered in the latter course of treatment.
  • the EP4 receptor antagonist, lenvatinib or a pharmaceutically acceptable salt thereof, and optionally other antitumor drugs are administered in the same (for example, oral ) or different routes (for example, oral and parenteral (such as injection) respectively).
  • the EP4 receptor antagonist and lenvatinib or a pharmaceutically acceptable salt thereof are orally administered.
  • the PD-1 pathway inhibitor is administered by injection.
  • lenvatinib or a pharmaceutically acceptable salt thereof is administered in the same dose as when lenvatinib or a pharmaceutically acceptable salt thereof is administered alone or in the absence of administration of the EP4 receptor antagonist A lower amount than the amount administered was administered.
  • lenvatinib or a pharmaceutically acceptable salt thereof is administered alone or in the absence of Compared with the EP4 receptor antagonist, the required dose of lenvatinib or its pharmaceutically acceptable salt is reduced, for example, by at least 10%, at least 15%, at least 20%, at least 30%, At least 40%, at least 50%, or at least 75%.
  • other anti-tumor drugs are administered at the same rate as when the other anti-tumor drugs (preferably PD-1 pathway inhibitors) are administered alone or without administration of the EP4 In the case of receptor antagonists, the amount administered is lower.
  • the other anti-tumor drug preferably a PD-1 pathway inhibitor
  • the required dosage of other anti-tumor drugs is reduced, for example, reduced by at least 10%, at least 15%, at least 20% %, at least 30%, at least 40%, at least 50%, or at least 75%.
  • the EP4 receptor antagonist enhances the efficacy of lenvatinib or a pharmaceutically acceptable salt thereof in the treatment of cancer and/or reduces the efficacy of lenvatinib or a pharmaceutically acceptable salt thereof in the treatment of cancer. Side effects in cancer.
  • the EP4 receptor antagonist enhances the efficacy of lenvatinib or a pharmaceutically acceptable salt thereof in the treatment of cancer (for example, by at least 30%, 50%, 75% or 100%, or by enhancing At least 2 times, 5 times, 10 times, 20 times, 40 times or 50 times) and/or reduce the side effects of lenvatinib or a pharmaceutically acceptable salt thereof in the treatment of cancer (for example, reduce at least 30%, 50% , 75% or 100%, or at least a 2-fold, 5-fold, 10-fold, 20-fold, 40-fold or 50-fold reduction).
  • the present invention provides EP4 receptor antagonists in preparation for enhancing the efficacy of lenvatinib or a pharmaceutically acceptable salt thereof in the treatment of cancer and/or reducing the efficacy of lenvatinib or a pharmaceutically acceptable salt thereof.
  • EP4 receptor antagonists in preparation for enhancing the efficacy of lenvatinib or a pharmaceutically acceptable salt thereof in the treatment of cancer and/or reducing the efficacy of lenvatinib or a pharmaceutically acceptable salt thereof.
  • the EP4 receptor antagonist enhances the efficacy of the other anti-tumor drugs (preferably PD-1 pathway inhibitors) in the treatment of cancer and/or reduces the efficacy of the other anti-tumor drugs (preferably PD-1 Pathway inhibitors) side effects in the treatment of cancer.
  • the other anti-tumor drugs preferably PD-1 pathway inhibitors
  • the other anti-tumor drugs preferably PD-1 Pathway inhibitors
  • the EP4 receptor antagonist enhances the efficacy of the other anti-tumor drugs (preferably PD-1 pathway inhibitors) in the treatment of cancer (for example, at least 30%, 50%, 75% or 100% , or enhance at least 2-fold, 5-fold, 10-fold, 20-fold, 40-fold or 50-fold) and/or reduce the side effects of said other antitumor drugs (preferably PD-1 pathway inhibitors) in the treatment of cancer (for example, reduce At least 30%, 50%, 75% or 100%, or at least a 2-fold, 5-fold, 10-fold, 20-fold, 40-fold or 50-fold reduction).
  • the other anti-tumor drugs preferably PD-1 pathway inhibitors
  • the present invention provides EP4 receptor antagonists in the preparation of drugs for enhancing the efficacy of PD-1 pathway inhibitors in the treatment of cancer and/or reducing the side effects of PD-1 pathway inhibitors in the treatment of cancer the use of.
  • the individual has advanced cancer, refractory cancer, relapsed cancer or drug-resistant cancer, in particular cancer therapy comprising lenvatinib or a pharmaceutically acceptable salt thereof and and/or cancers that are resistant to cancer therapies that include PD-1 pathway inhibitors.
  • the present invention provides that the EP4 receptor antagonist is prepared for use with lenvatinib or a pharmaceutically acceptable salt thereof and optionally other antitumor drugs (preferably PD-1 pathway inhibitors) Combination for the treatment of drug-resistant cancers, particularly individuals with cancers resistant to cancer therapies comprising lenvatinib or a pharmaceutically acceptable salt thereof and/or cancer therapies comprising PD-1 pathway inhibitors use in medicines.
  • the EP4 receptor antagonist is prepared for use with lenvatinib or a pharmaceutically acceptable salt thereof and optionally other antitumor drugs (preferably PD-1 pathway inhibitors) Combination for the treatment of drug-resistant cancers, particularly individuals with cancers resistant to cancer therapies comprising lenvatinib or a pharmaceutically acceptable salt thereof and/or cancer therapies comprising PD-1 pathway inhibitors use in medicines.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an EP4 receptor antagonist, lenvatinib or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier;
  • said EP4 receptor antagonist is as defined above.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an EP4 receptor antagonist, lenvatinib or a pharmaceutically acceptable salt thereof, a PD-1 pathway inhibitor, and a pharmaceutically acceptable carrier;
  • said EP4 receptor antagonist and said PD-1 pathway inhibitor are as defined above.
  • the present invention provides a kit comprising:
  • a first component in a first container comprising an EP4 receptor antagonist (which is preferably as defined above) and optionally a pharmaceutically acceptable carrier;
  • the present invention provides a kit comprising:
  • a first component in a first container comprising an EP4 receptor antagonist (which is preferably as defined above) and optionally a pharmaceutically acceptable carrier;
  • a third component located in a third container, said third component comprising other antineoplastic agents (preferably PD-1 pathway inhibitors, said PD-1 pathway inhibitors being preferably as defined above) and optionally present a pharmaceutically acceptable carrier; and
  • Compound 6 obtained from Kaifu Pharmaceutical (Suzhou) Co., Ltd.
  • Lenvatinib mesylate Obtained from Beijing Coupling Technology Co., Ltd.
  • CT26 cells (cell number: BNCC287983) were purchased from Beijing Beina Biotechnology Co., Ltd.
  • Mus Musculus Mus Musculus, BALB/c
  • TGI Tumor growth inhibition rate
  • T/C RTV of treatment group/RTV of vehicle group
  • RTV (relative volume) tumor volume at the end of the experiment/tumor volume at the time of experiment grouping x 100%
  • CI value (combination drug index) AB (two-drug combination drug T/C)/A (single drug T/C) x B (single drug T/C); ⁇ CI value ⁇ 0.9 indicates low synergism of combined drug effect, 0.6 ⁇ CI value ⁇ 0.8 indicates moderate synergistic effect of combined drug effect, 0.4 ⁇ CI value ⁇ 0.6 indicates highly synergistic effect of combined drug effect, and 0.2 ⁇ CI value ⁇ 0.4 indicates combined drug effect Intensity synergy.
  • SPSS 16.0 statistical software was used for One-way ANOVA test, and the tumor volume was statistically analyzed between groups, and P ⁇ 0.05 was considered to have a significant difference.
  • Compound 6 obtained from Kaifu Pharmaceutical (Suzhou) Co., Ltd.
  • Lenvatinib mesylate Obtained from Beijing Coupling Technology Co., Ltd.
  • PD-1 antibody obtained from BioXcell, lot number BE0146.
  • CT26 cells were purchased from Beijing Beina Biotechnology Co., Ltd.
  • Mus Musculus Mus Musculus, BALB/c
  • mice tolerated each test drug and therapy well.
  • tumor growth inhibition rate was 81%
  • Compound 6 obtained from Kaifu Pharmaceutical (Suzhou) Co., Ltd.
  • Lenvatinib mesylate Obtained from Beijing Coupling Technology Co., Ltd.
  • PD-1 antibody obtained from BioXcell, lot number BE0146.
  • H22 cells were purchased from Beijing Beina Biotechnology Co., Ltd.
  • Mus Musculus Mus Musculus, BALB/c
  • H22 tumor cells resuspended in serum-free medium at a concentration of 1.0x10 7 /ml, 100 ⁇ l per animal, inoculated subcutaneously on the right side of the flank of the experimental animal, and administered in groups when the tumor grew to about 100-150 mm 3 , each There were 8 rats in the group, and the specific dosage regimen was shown in the table below.
  • mice tolerated each test drug and therapy well.
  • the 50% survival period of the mice was 19 days; the compound 6 alone administration group was 26 days; the PD-1 antibody alone administration group was 24 days; lenvatinib mesylate The salt alone administration group was 35 days; the 50% survival period of the mice in the PD-1 antibody combined with lenvatinib mesylate group was 49 days; the compound 6 combined with lenvatinib mesylate group The 50% survival period of the mice in the medium was 52 days; the 50% survival period of the mice in the compound 6 combined with PD-1 antibody and lenvatinib mesylate was greater than 62 days. It can be seen that the combination therapy of compound 6 with PD-1 antibody and lenvatinib mesylate can significantly prolong the survival of treated individuals.

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Abstract

一种治疗、遏制个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答的方法，所述方法包括向所述个体给药治疗有效量的EP4受体拮抗剂以及治疗有效量的乐伐替尼或其药学上可接受的盐。还涉及包含EP4受体拮抗剂以及乐伐替尼或其药学上可接受的盐的药物组合物或药盒。

Description

治疗肿瘤的联合疗法 发明领域
本发明属于生物医药领域，并具体涉及治疗、遏制个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答的方法，所述方法包括向所述个体给药治疗有效量的EP4受体拮抗剂以及治疗有效量的乐伐替尼或其药学上可接受的盐。本发明还涉及包含EP4受体拮抗剂以及乐伐替尼或其药学上可接受的盐的药物组合物或药盒。
发明背景
在恶性肿瘤的生长和转移过程中，需要不断形成新生血管，以满足肿瘤生长所需要的营养和氧气。血管生成通常与血管内皮生长因子(VEGF)相关。VEGF通过血管内皮生长因子受体(VEGFR)起作用。VEGFR有3种亚型，分别为VEGFR1、VEGFR2和VEGFR3。肿瘤组织的缺氧环境通过HIF1可以引起VEGF的释放。研究显示，VEGF和VEGFR在多种肿瘤组织中的表达增高。在肿瘤生长过程中，VEGF通过激活VEGFR，促进血管生成，提供肿瘤生长所需的营养和氧气。
另外，成纤维细胞生长因子(FGF)通过成纤维细胞生长因子受体(FGFR)激活多种信号通路，参与细胞增殖的调节，促进细胞生长。研究结果显示，FGFR在多种肿瘤中存在基因突变、表达增加或功能异常，这对肿瘤的生长起促进作用。
乐伐替尼(lenvatinib)是多激酶的抑制剂，其能够强效抑制VEGFR 1-3、FGFR 1-4、PDGFRα、RET以及KIT。乐伐替尼阻断这些促进肿瘤血管生成和肿瘤生长的信号通路，从而抑制肿瘤的生长和转移。临床试验显示乐伐替尼对肿瘤有明显抑制作用。目前，乐伐替尼已获批用于肝细胞癌和甲状腺癌的治疗。
E型前列腺素2(PGE2)是花生四烯酸衍生物，在一些肿瘤组织中水平增高。EP4是肿瘤组织中主要的PGE2受体。肿瘤组织中的PGE2通过EP4受体抑制肿瘤微环境中的免疫细胞的功能，从而使肿瘤细胞逃脱抗肿瘤免疫系统，加速肿瘤的生长和转移。另外，PGE2通过激活EP4受体，还可促进肿瘤组织的血管生成和肿瘤细胞生长。EP4受体拮抗剂可以阻断PGE2的这些作用，从而增强抗肿瘤免疫功能，抑制肿瘤生长。证据显示，EP4受体拮抗剂可以提高免疫细胞的反应，并在多个肿瘤模型中显示抑制肿瘤生长的效果。目前，EP4受体拮抗剂还在早期临床研究阶段，尚无临床获批用于肿瘤治疗的药物。
发明概述
本发明采用EP4受体拮抗剂和乐伐替尼或其药学上可接受的盐联合用药来治疗恶性肿瘤和癌症。发明人出乎意料地发现，EP4受体拮抗剂和乐伐替尼或其药学上可接受的盐的组合在治疗癌症时取得了协同效果。
在一个方面中，本发明提供治疗、遏制个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答的方法，所述方法包括向所述个体给药治疗有效量的EP4受体拮抗剂以及治疗有效量的乐伐替尼或其药学上可接受的盐。
在另一方面中，本发明提供EP4受体拮抗剂在制备用于与乐伐替尼或其药学上可接受的盐组合来治疗、遏制个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答的药物中的用途。
在另一方面中，本发明提供EP4受体拮抗剂，其用于与乐伐替尼或其药学上可接受的盐组合来治疗、遏制个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答。
在另一方面中，本发明提供药物组合物，其包含EP4受体拮抗剂和乐伐替尼或其药学上可接受的盐以及药学上可接受的载体。
在另一方面中，本发明提供药盒，其包含：
(a)位于第一容器中的第一组分，所述第一组分包含EP4受体拮抗剂和任选存在的药学上可接受的载体；
(b)位于第二容器中的第二组分，所述第二组分包含乐伐替尼或其药学上可接受的盐和任选存在的药学上可接受的载体；以及
(c)任选存在的说明书。
附图简要说明
图1.化合物6与乐伐替尼甲磺酸盐的联合用药在CT26肿瘤模型中的作用。
图2.化合物6、乐伐替尼甲磺酸盐和抗PD-1抗体的联合用药在CT26肿瘤模型中的作用。
图3.化合物6、乐伐替尼甲磺酸盐和抗PD-1抗体的联合用药在H22肿瘤模型中的作用。
图4.化合物6、乐伐替尼甲磺酸盐和抗PD-1抗体的联合用药在H22肿瘤模型中对小鼠生存期的影响。
发明详述
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
如本文中所使用，术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
在本发明的含义内，“立体异构体”是指几何异构体(或构型异构体)或旋光异构体。
“几何异构体”由双键上不同位置的取代基所导致，然后其可以具有Z或E构型，也被称作顺式或反式。
“光学异构体”特别地由碳原子上不同空间位置的取代基所导致，所述碳原子包含四个不同的取代基。这个碳原子则构成手性中心或不对称中心。光学异构体包括非对映异构体和对映异构体。彼此为不可重叠的镜像的光学异构体被称作“对映异构体”。彼此不为可重叠的镜像的光学异构体被称作“非对映异构体”。
含有等量的、相反手性的两种单独的对映异构体形式的混合物被称作“外消旋混合物”。
在本发明的含义内，“互变异构体”是指通过质子转移重排( prototropie)，即通过氢原子的迁移和双键的位置的改变而获得的化合物的结构异构体。化合物的不同互变异构体通常是可互相转化的，并且按比例平衡地存在于溶液中，所述比例可以根据所使用的溶剂、温度或pH而变化。
在本发明中，“药学上可接受的”被理解为是指其用于制备药物组合物，所述组合物一般是安全的，无毒的，在生物学或其他方面满足需要并且所述组合物可以被接受用于兽类和人类药物用途。
在本发明中，化合物的“药学上可接受的盐”被理解为指代下列盐，其是药学上可接受的(如本文所定义的)盐并且其具备预期的母体化合物的药理活性。这种盐包括：
(1)与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等形成的酸加成盐，或与有机酸如乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、羟萘酸、2-羟基乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘康酸、2-萘磺酸、丙酸、水杨酸、琥珀酸、二苯甲酰基-L-酒石酸、酒石酸、对甲苯磺酸、三甲基乙酸、三氟乙酸等形成的酸加成盐；和
(2)当母体化合物中存在的酸质子被金属离子，例如，碱金属离子(例如，Na +、K +或Li +)，碱土金属离子(如Ca 2+或Mg 2+)或铝离子代替；或者与有机碱或无机碱配位时形成的盐。可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等。可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠。
在本发明中，术语“卤素”是指氟、溴、氯或碘原子。
术语“C 1-4烷基”是指包含1至4个碳原子的饱和的直链或支链的烃链。代表性的例子包括，但不限于，甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基基团。
术语“C 1-4亚烷基”指包含1至4个碳原子的二价烃链。代表性的例子包括，但不限于，CH 2-、-CH 2-CH 2-、-CH 2-CH 2-CH 2-、-CH 2-CH 2-CH 2-CH 2-等。
术语“C 1-4烷氧基”是指-O-(C 1-4烷基)，其中C 1-4烷基的定义如上所述。非限制性实施例包括甲氧基、乙氧基、丙氧基、丁氧基等。
术语“卤代C 1-4烷基”是指C 1-4烷基被一个或多个卤素取代，其中C 1-4烷基、卤素的定义如上所述。
术语“卤代C 1-4烷氧基”是指C 1-4烷氧基被一个或多个卤素取代，其中C 1-4烷氧基、卤素的定义如上所述。
术语“羟基C 1-4烷基”指被羟基取代的C 1-4烷基，其中烷基如上所定义。
术语“C 3-6环烷基”指包含3至6个碳原子的饱和或部分不饱和单环烃系统，代表性的例子包括，但不限于，环己基、环戊基、环丁基、环丙基、环己烯基等。
术语“3-6元杂烷基”指包含3至6个环原子，其中1-3个环原子为选自氮、氧或S(O) m(其中m是0、1或2)的杂原子的饱和或部分不饱和单环烃系统，代表性的例子包括，但不限于，吡咯烷基、咪唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基等。
术语“C 6-10芳基”指具有共轭的π电子体系的6至10元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2022095115-appb-000001
术语“5-10元杂芳基”指包含1至4个杂原子、5至10个环原子的杂芳族体系，其中杂原子选自氧、硫和氮，优选含有1至2个杂原子的5元或6元杂芳基，例如喹啉基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、异噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2022095115-appb-000002
术语“羟基”是指-OH基团。
术语“硝基”指-NO 2。
术语“氨基”是指-NH 2。
术语“氰基”是指-CN。
术语“一个键”指用“-”表示的一个共价键。
“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。
“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。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。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。
如本文所用的术语“抗体”包括所有类型的免疫球蛋白，包括IgG，IgM，IgA，IgD和IgE，或其片段，其可适用于本文所用的医学。抗体可以是单克隆抗体或多克隆抗体，并且可以是任何来源的物种，包括例如小鼠、大鼠、兔、马或人。保留对蛋白质或表位特异性发现的抗体片段，例如CTLA4、 PD-L1或PD-1，与本发明中使用的抗体结合，也包括在术语“抗体”的范围内。这些片段可以通过已知的技术产生。抗体可以是嵌合的或人源化的，特别是当它们用于治疗目的时。
在本发明的药物组合物或药盒中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述药物组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。
本发明的药物组合物及药盒中的各组分可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射(如静脉内、动脉内、皮下、腹膜内、肌内注射，包括滴注)或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
对于这些给药途径，可以适合的剂型给药本发明的药物组合物及药盒中的各组分。
所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂。
本文所用的术语“容器”为用于容纳药物组分的容器。此容器可用于制备、储存、运输和/或独立/批量销售，其意图涵盖瓶、罐、小瓶、烧瓶、注射器、管(例如用于乳膏制品)，或者用于制备、容纳、储存或分配药物产品的任何其它容器。
本文所用的术语“说明书”为插页、标签、标示等，其列举了与位于所述容器内的药物组分相关的信息。所列出的信息通常由管辖待销售所述制品的区域的管理机构(例如美国食品与药品管理局)决定。优选所述包装说明书具体列出了所述药物组分获准用于的适应症。所述包装说明书可由任何材料制成，可从所述材料上读取包含于其中或其上的信息。优选所述包装说明书为可印刷材料(例如纸、塑料、卡纸板、箔、胶粘纸或塑料等)，其上可形成(例如印刷或施涂)所需信息。
如本文中所使用的术语“有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的活性成分的量。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
如本文中所使用，“癌症转移”是指从其初始部位扩散(转移)到身体另一区域的癌症。几乎所有的癌症都具有扩散的潜能。是否会发生转移取决于多个肿瘤细胞因素(包括癌症的类型、肿瘤细胞的成熟(分化)程度、所在位置和癌症已存在多长时间，以及其它未完全了解的因素)之间复杂的相互作用。转移扩散有三种方式-从肿瘤到周围组织的局部扩展、通过血流到达远处的部位或通过淋巴系统到达邻近或远处的淋巴结。每种癌症都可具有代表性的扩散途径。肿瘤是根据原发部位命名的(例如，已扩散到脑的乳腺癌被称为转移至脑的转移性乳腺癌)。
如本文中所使用，“耐药”是指对化学疗法获得耐药性的癌细胞。癌细胞可通过一系列机制获得对化学疗法的耐药性，包括药物靶点的突变或过表达、药物的失活或药物从细胞消除。
治疗方法和用途
在一个实施方案中，本发明提供治疗、遏制个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答的方法，所述方法包括向所述个体给药治疗有效量的EP4受体拮抗剂以及治疗有效量的乐伐替尼或其药学上可接受的盐。
在优选的实施方案中，本发明的方法还包括向所述个体给药其它抗肿瘤药物；优选地，向所述个体给药靶向PD-1信号传导途径任意成员(优选靶向PD-1、PD-L1或PD-L2)的PD-1途径抑制剂。
在另一实施方案中，本发明提供EP4受体拮抗剂在制备用于与乐伐替尼或其药学上可接受的盐组合来治疗、遏制个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答的药物中的用途。
在另一实施方案中，本发明提供EP4受体拮抗剂在制备用于与乐伐替尼或其药学上可接受的盐和PD-1途径抑制剂组合来治疗、遏制个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答的药物中的用途。
在另一实施方案中，本发明提供乐伐替尼或其药学上可接受的盐在制备用于与EP4受体拮抗剂组合来治疗、遏制个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答的药物中的用途。
在另一实施方案中，本发明提供EP4受体拮抗剂在制备用于治疗、遏制正在用包含乐伐替尼或其药学上可接受的盐的癌症疗法进行治疗的个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答的药物中的用途。
在另一实施方案中，本发明提供EP4受体拮抗剂在制备用于治疗、遏制正在用包含乐伐替尼或其药学上可接受的盐的癌症疗法和/或包含PD-1途径抑制剂的癌症疗法进行治疗的个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答的药物中的用途。
在另一实施方案中，本发明提供EP4受体拮抗剂，其用于与乐伐替尼或其药学上可接受的盐组合来治疗、遏制个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答。
在另一实施方案中，本发明提供EP4受体拮抗剂，其用于与乐伐替尼或其药学上可接受的盐和PD-1途径抑制剂组合来治疗、遏制个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答。
在另一实施方案中，本发明提供乐伐替尼或其药学上可接受的盐，其用于与EP4受体拮抗剂组合来治疗、遏制个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答。
在另一实施方案中，本发明提供EP4受体拮抗剂，其用于治疗、遏制正在用包含乐伐替尼或其药学上可接受的盐的癌症疗法进行治疗的个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答。
在另一实施方案中，本发明提供EP4受体拮抗剂，其用于治疗、遏制正在用包含乐伐替尼或其药学上可接受的盐的癌症疗法和/或包含PD-1途径抑制剂的癌症疗法进行治疗的个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答。
I.乐伐替尼
如本文中所使用，术语“乐伐替尼”是指具有下式结构的化合物或其药学上可接受的盐(例如甲磺酸盐)：
Figure PCTCN2022095115-appb-000003
II.EP4受体拮抗剂
在优选的实施方案中，所述EP4受体拮抗剂是阻断由PTGER4基因编码的前列腺素E2受体4(EP4)的作用的抗体或小分子。
在优选的实施方案中，所述EP4受体拮抗剂包括但不限于Drug Discovery Today，第22卷第1期第57-71页(2017年1月)中公开的那些，将其以其整体援引加入本文。
在优选的实施方案中，所述EP4受体拮抗剂可为具有下式的化合物或其药学上可接受的盐，
Figure PCTCN2022095115-appb-000004
以上通式中的各个变量如WO 2012/039972 A1中所限定，将其以其整体援引加入本文。优选地，所述EP4受体拮抗剂可为具有下式的化合物或其药学上可接受的盐，
Figure PCTCN2022095115-appb-000005
在优选的实施方案中，所述EP4受体拮抗剂可为具有下式的化合物或其药学上可接受的盐，
Figure PCTCN2022095115-appb-000006
以上通式中的各个变量如WO2018008711A1中所限定，将其以其整体援引加入本文。优选地，所述EP4受体拮抗剂可为具有下式的化合物或其药学上可接受的盐，
Figure PCTCN2022095115-appb-000007
在优选的实施方案中，所述EP4受体拮抗剂可为具有下式的化合物或其药学上可接受的盐，
Figure PCTCN2022095115-appb-000008
以上通式中的各个变量如WO 2013/004290 A1中所限定，将其以其整体援引加入本文。优选地，所述EP4受体拮抗剂可为具有下式的化合物或其药学上可接受的盐，
Figure PCTCN2022095115-appb-000009
在优选的实施方案中，所述EP4受体拮抗剂可为WO 2020/012305 A1中公开的任意化合物，将其以其整体援引加入本文。优选地，所述EP4受体拮抗剂可为具有下式的化合物或其药学上可接受的盐，
Figure PCTCN2022095115-appb-000010
在优选的实施方案中，所述EP4受体拮抗剂可为具有下式的化合物或其药学上可接受的盐，
Figure PCTCN2022095115-appb-000011
以上通式中的各个变量如WO 2018/195123 A1中所限定，将其以其整体援引加入本文。优选地，所述EP4受体拮抗剂可为具有下式的化合物或其药学上可接受的盐，
Figure PCTCN2022095115-appb-000012
在优选的实施方案中，所述EP4受体拮抗剂可为WO 2020/014465 A1中公开的任意化合物，将其以其整体援引加入本文。优选地，所述EP4受体拮抗剂可为具有下式的化合物或其药学上可接受的盐，
Figure PCTCN2022095115-appb-000013
在优选的实施方案中，所述EP4受体拮抗剂可为具有下式的化合物或其药学上可接受的盐，
Figure PCTCN2022095115-appb-000014
以上通式中的各个变量如WO 2019/149286 A1中所限定，将其以其整体援引加入本文。优选地，所述EP4受体拮抗剂可为具有下式的化合物或其药学上可接受的盐，
Figure PCTCN2022095115-appb-000015
在优选的实施方案中，所述EP4受体拮抗剂可为具有下式的化合物或其药学上可接受的盐，
Figure PCTCN2022095115-appb-000016
以上通式中的各个变量如WO 2019/101171 A1中所限定，将其以其整体援引加入本文。优选地，所述EP4受体拮抗剂可为具有下式的化合物或其药学上可接受的盐，
Figure PCTCN2022095115-appb-000017
在优选的实施方案中，所述EP4受体拮抗剂可为Discovery of AAT-008，a novel，potent，and selective prostaglandin EP4 receptor antagonist(Bioorg Med Chem Lett.2017 Mar 1；27(5)：1186-1192)中公开的任意化合物，将其以其整体援引加入本文。优选地，所述EP4受体拮抗剂可为具有下式的化合物或其药学上可接受的盐，
Figure PCTCN2022095115-appb-000018
在优选的实施方案中，所述EP4受体拮抗剂也可为环氧合酶(COX)抑制剂，例如COX-1、COX-2或二者的抑制剂。在优选的实施方案中，所述COX抑制剂为COX-2选择性抑制剂。在优选的实施方案中，所述COX抑制剂选自塞来昔布、地拉考昔、地拉考昔、伐地考昔、罗非昔布、芦米考昔、依托考昔、美洛昔康及其混合物。
在优选的实施方案中，所述EP4受体拮抗剂可为磷脂酶A2抑制剂，并且优选为胞浆型磷脂酶A2的抑制剂。
在优选的实施方案中，所述EP4受体拮抗剂可为式(I)的化合物：
Figure PCTCN2022095115-appb-000019
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其药学上可接受的盐，
其中：
M 1、M 2、M 3、M 5、M 6和M 7各自独立地为N原子或C-R 4；
M 4选自N原子和C原子；
环A选自C 6-10芳基、C 3-6环烷基、5-10元杂芳基和3-6元杂环基；
X为
Figure PCTCN2022095115-appb-000020
Y选自一个键、C 1-4亚烷基、-CR 5R 6-、-O-、-OC 1-4亚烷基-、-NR 9C 1-4亚烷基-和-NR 9-，所述C 1-4亚烷基任选被选自H原子、D原子、卤素、羟基、氰基、氨基、硝基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；
R 1和R 2相同或不同，且各自独立地选自H原子、D原子、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3-6元杂环基、-C(O)OR 4、C(O)NR 7R 8、-COR 4、-S(O) mR 4、-NR 7R 8、C 6-10芳基和5-10元杂芳基，所述C 1-4烷基和C 1-4烷氧基各自独立地任选被选自H原子、D原子、卤素、羟基、氰基、氨基、硝基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、C 3-6环烷基、3-6元杂环基、-C(O)OR 4、C(O)NR 7R 8、-COR 4、-NR 4C(O)NR 7R 8、-OC(O)NR 7R 8、-NR 7C(O)OR 4、-S(O) mR 4、-NR 7R 8、C 6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；或者R 1和R 2与其相连接的原子一起形成C 3-6环烷基或3-6元杂环基，其中所述C 3-6环烷基和3-6元杂环基各自独立地任选被选自D原子、素、羟基、氰基、氨基、硝基、-C(O)OR 4、C(O)NR 7R 8、-COR 4、-NR 4C(O)NR 7R 8、-OC(O)NR 7R 8、-NR 7C(O)OR 4、-S(O) mR 4、-NR 7R 8、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；
R 3相同或不同，且各自独立地选自氢H原子、D原子、卤素、羟基、氰基、氨基、硝基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3-6元杂环基、C 6-10芳基、5-10元杂芳基、-C(O)R 4、-C(O)OR 4、-OC(O)NR 7R 8、-NR 7C(O)OR 4、-S(O) mR 4、-NR 7R 8和-C(O)NR 7R 8，其中所述C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基各自独立地任选被选自C 1-4烷基、羟基C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤素、羟基、氰基、氨基和硝基中的一个或多个取代基所取代；
R 4选自H原子、D原子、卤素、羟基、氨基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基，其中所述C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基各自独立地任选被选自C 1-4烷基、羟基C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤素、羟基、氰基、氨基和硝基中的一个或多个取代基所取代；
R 5和R 6各自独立地选自H原子、D原子、C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基，其中所述C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基各自独立地任选被选自C 1-4烷基、羟基C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤素、羟基、氰基、氨基和硝基中的一个或多个取代基所取代；或者R 5和R 6与其相连接的原子一起形成C 3-6环烷基或3-6元杂环基，其中所述C 3-6环烷基或3-6元杂环基各自独立地任选被选自卤素、羟基、氰基、氨基、硝基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；
R 7和R 8各自独立地选自H原子、D原子、C 1-4烷基、卤代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基，其中所述C 1-4烷基、卤代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基各自独立地任选被选自C 1-4烷基、羟基C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤素、羟基、氰基、氨基和硝基中的一个或多个取代基所取代；
R 9选自H原子、D原子和C 1-4烷基，其中所述C 1-4烷基任选被选自羟基C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤素、羟基、氰基、氨基和硝基中的一个或多个取代基所取代；
m为0、1或2；以及
n为0、1、2、3或4。
在优选实施方案中，所述式(I)的化合物为式(II)所示的化合物：
Figure PCTCN2022095115-appb-000021
M 1、M 3、M 5和M 6各自独立地为CH或C-卤素，M 2为C-R 4或N原子，M 7为N原子，M 4为C原子，环A、R 1、R 2、R 3、R 4、X、Y和n如式(I)所定义。
在优选实施方案中，在所述式(I)的化合物中，Y为C 1-4亚烷基，优选亚甲基。
在优选实施方案中，在所述式(I)的化合物中，R 1和R 2相同或不同，且各自独立地选自H原子、D原子和C 1-4烷基；或者R 1和R 2与其相连接的原子一起形成C 3-6环烷基，优选环丙基。
在优选实施方案中，所述式(I)的化合物为式(III)所示的化合物：
Figure PCTCN2022095115-appb-000022
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
其中：
R 1和R 2相同或不同，且各自独立地选自H原子、D原子和C 1-4烷基；或者R 1和R 2与其相连接的原子一起形成C 3-6环烷基，优选环丙基；
M 2为N原子或C-R 4；
R 4选自H原子、D原子和卤素；
X、环A、R 3和n如式(I)中所定义。
在优选实施方案中，在所述式(I)的化合物中，环A选自苯基、吡啶基、喹啉基、苯并呋喃基、吗啉基、吡唑、环丙基、异噁唑、苯并噁唑和苯并噻唑。
在优选实施方案中，在所述式(I)的化合物中，R 3相同或不同，且各自独立地选自H原子、D原子、卤素、C 1-4烷基、氟代C 1-4烷基、苯基、羟基C 1-4烷基取代的苯基、吗啉基、吡啶基、吡唑基、C 1-4烷基取代的吡唑基、羟基C 1-4烷基取代的吡唑基、环丙基、异噁唑基和哌啶基。
在优选实施方案中，所述式(I)的化合物包括但不限于：
Figure PCTCN2022095115-appb-000023
Figure PCTCN2022095115-appb-000024
Figure PCTCN2022095115-appb-000025
Figure PCTCN2022095115-appb-000026
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其药学上可接受的盐。
III.PD-1途径抑制剂
在优选的实施方案中，所述PD-1途径抑制剂可以是抗体(特别是拮抗性抗体或核酸编码的抗体(细胞内抗体))、siRNA、反义RNA、包含能够结合PD-1但是防止PD-1信号传导的氨基酸序列(或编码其的核酸)的蛋白(例如，PD-L1或PD-L2的片段与免疫球蛋白的Fc部分的融合蛋白)、与膜结合的PD-1竞争对其配体PD-L1和PD-L2的结合的可溶性蛋白(或编码可溶性蛋白的核酸)；或能够抑制PD-1途径信号传导的小分子抑制剂。
在优选的实施方案中，所述PD-1途径抑制剂是抗PD-1抗体，其包括但不限于：派姆单抗 (Pembrolizumab，Keytruda)、Nivolumba(Opdivo)、西米普利单抗(Cemiplimab，Libtayo，REGN-2810)、特瑞普利单抗、信迪利单抗、卡瑞丽珠单抗、替雷利珠单抗(Tislelizumab，BeiGen)、杰诺单抗(Genolimzumab，GB226，亚盛)、JTX-4014(Jounce)、AMP-224、AMP-514、PDR-001(Spartalizumab，Novartis)、BCD-100、TSR-042、JNJ-63723283、Sasanlimab(PF-06801591)、BI-754091、GLS-010、LZM009、HX008、MDX-1106，Merck 3745和CT-011。
在优选的实施方案中，所述PD-1途径抑制剂是抗PD-L1抗体，其包括但不限于：阿特朱单抗(Atezolizumab)、德瓦鲁单抗(Durvalumab，Imfinzi，AZ)、阿维单抗(Avelumab，Bavencio，EMD)、度伐利尤单抗(KN035)、GLS-010、CS1001、M7824、CX-071、LY-3300054、CA-170、SHR-1316、ZKAB001、BAT1306、BMS1166、MAX-10181、YW243.55.S70、MPDL3280A和MDX-1105。
在优选的实施方案中，所述PD-1途径抑制剂是包含能够结合PD-1但是防止PD-1途径信号传导的氨基酸序列(或编码所述氨基酸序列的核酸)的蛋白，在该情形中特别优选的是PD-L1或PD-L2配体的片段的融合蛋白。
IV.癌症类型和给药方法
在优选实施方案中，所述癌症选自膀胱癌、乳腺癌、子宫癌、子宫内膜癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、尿道癌、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、胶质母细胞瘤、髓母细胞瘤，以及恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；
优选地，所述癌症为耐药性肿瘤(优选为乐伐替尼耐药性肿瘤、EP4受体拮抗剂耐药性肿瘤或PD-1途径抑制剂耐药性肿瘤)。
在优选实施方案中，将所述EP4受体拮抗剂以约0.005mg/日至约5000mg/日的量，例如约0.005、0.05、0.5、5、10、20、30、40、50、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1500、2000、2500、3000、3500、4000、4500或5000mg/日的量给药。
在优选实施方案中，将所述EP4受体拮抗剂以每日约1ng/kg至约200mg/kg、约1μg/kg至约100mg/kg或者约1mg/kg至约50mg/kg体重的量给药，例如以每日约1μg/kg、约10μg/kg、约25μg/kg、约50μg/kg、约75μg/kg、约100μg/kg、约125μg/kg、约150μg/kg、约175μg/kg、约200μg kg、约225μg/kg、约250μgkg、约275μg kg、约300μg/kg、约325μgkg、约350μg/kg、约375μg/kg、约400μg/kg、约425μg/kg、约450μg/kg、约475μg/kg、约500μg/kg、约525μgkg、约550μg/kg、约575μg kg、约600μg/kg、约625μg/kg、约650μg/kg、约675μg/kg、约700μg/kg、约725μg/kg、约750μg/kg、约775μg/kg、约800μg/kg、约825μg/kg、约850μg/kg、约875μg/kg、约900μg/kg、约925μg/kg、约950μg/kg、约975μg/kg、约1mg/kg、约5mg/kg、约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约60mg/kg、约70mg/kg、约80mg/kg、约90mg/kg、约100mg/kg、约125mg/kg、约150mg/kg、约175mg/kg、约200mg/kg体重的量给药。
在优选实施方案中，将乐伐替尼或其药学上可接受的盐以0.005mg/日至约5000mg/日的量，例如约0.005、0.05、0.5、5、10、20、30、40、50、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1500、2000、2500、3000、3500、4000、4500或5000mg/日的量给药。
在优选实施方案中，将乐伐替尼或其药学上可接受的盐以每日约1ng/kg至约200mg/kg、约1μg/kg至约100mg/kg或者约1mg/kg至约50mg/kg体重的量给药，例如以每日约1μg/kg、约10μg/kg、约25μg/kg、约50μg/kg、约75μg/kg、约100μg/kg、约125μg/kg、约150μg/kg、约175μg/kg、约200μgkg、约225μg/kg、约250μgkg、约275μgkg、约300μg/kg、约325μgkg、约350μg/kg、约375μμg/kg、约400μg/kg、约425μg/kg、约450μg/kg、约475μg/kg、约500μg/kg、约525μgkg、约550μg/kg、约575μgkg、约600μg/kg、约625μg/kg、约650μμg/kg、约675μg/kg、约700μg/kg、约725μg/kg、约750μg/kg、约775μg/kg、约800μg/kg、约825μg/kg、约850μg/kg、约875μg/kg、约900μg/kg、约925μg/kg、约950μg/kg、约975μg/kg、约1mg/kg、约5mg/kg、约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50 mg/kg、约60mg/kg、约70mg/kg、约80mg/kg、约90mg/kg、约100mg/kg、约125mg/kg、约150mg/kg、约175mg/kg、约200mg/kg体重的量给药。
在优选实施方案中，将所述其它抗肿瘤药物(优选PD-1途径抑制剂)以0.005mg/日至约5000mg/日的量，例如约0.005、0.05、0.5、5、10、20、30、40、50、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1500、2000、2500、3000、3500、4000、4500或5000mg/日的量给药。
在优选实施方案中，将所述其它抗肿瘤药物(优选PD-1途径抑制剂)以每日约1ng/kg至约200mg/kg、约1μg/kg至约100mg/kg或者约1mg/kg至约50mg/kg体重的量给药，例如以每日约1μg/kg、约10μg/kg、约25μg/kg、约50μg/kg、约75μg/kg、约100μg/kg、约125μg/kg、约150μg/kg、约175μg/kg、约200μgkg、约225μg/kg、约250μgkg、约275μgkg、约300μg/kg、约325μgkg、约350μg/kg、约375μg/kg、约400μg/kg、约425μg/kg、约450μg/kg、约475μg/kg、约500μg/kg、约525μg kg、约550μg/kg、约575μg kg、约600μg/kg、约625μg/kg、约650μg/kg、约675μg/kg、约700μg/kg、约725μg/kg、约750μg/kg、约775μg/kg、约800μg/kg、约825μg/kg、约850μg/kg、约875μg/kg、约900μg/kg、约925μg/kg、约950μg/kg、约975μg/kg、约1mg/kg、约5mg/kg、约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约60mg/kg、约70mg/kg、约80mg/kg、约90mg/kg、约100mg/kg、约125mg/kg、约150mg/kg、约175mg/kg、约200mg/kg体重的量给药。
在优选实施方案中，将所述EP4受体拮抗剂与乐伐替尼或其药学上可接受的盐以及任选存在的其它抗肿瘤药物(优选PD-1途径抑制剂)一起、同时、顺序或交替给药。
在优选实施方案中，将所述EP4受体拮抗剂、乐伐替尼或其药学上可接受的盐和/或任选存在的其它抗肿瘤药物(优选PD-1途径抑制剂)连续给药至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少30天、至少35天、至少40天、至少45天或至少50天。
在优选实施方案中，将所述EP4受体拮抗剂、乐伐替尼或其药学上可接受的盐和/或任选存在的其它抗肿瘤药物(优选PD-1途径抑制剂)给药一个或多个(例如1、2、3、4、5、6、7、8、9或10个)疗程，其中每个疗程持续至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少30天、至少35天、至少40天、至少45天或至少50天；并且每两个疗程之间间隔0、1、2、3、4、5、6、7、8、9、10天、两周、三周或四周。
在优选实施方案中，当给药多个疗程时，各疗程所给药的EP4受体拮抗剂、乐伐替尼或其药学上可接受的盐和/或任选存在的其它抗肿瘤药物(优选PD-1途径抑制剂)的量相同或不同。在更优选的实施方案中，在前一疗程中所给药的所述EP4受体拮抗剂、乐伐替尼或其药学上可接受的盐和/或任选存在的其它抗肿瘤药物(优选PD-1途径抑制剂)的量是后一疗程所给药量的1-10倍，优选1-5倍，例如1.5、2、2.5、3、3.5、4、4.5或5倍。
在优选实施方案中，将所述EP4受体拮抗剂、乐伐替尼或其药学上可接受的盐以及任选存在的其它抗肿瘤药物(优选PD-1途径抑制剂)以相同(例如口服)或不同途径(例如分别以口服及肠胃外(如注射))给药。
在优选的实施方案中，将所述EP4受体拮抗剂和乐伐替尼或其药学上可接受的盐口服给药。在优选的实施方案中，将PD-1途径抑制剂注射给药。
在优选实施方案中，将乐伐替尼或其药学上可接受的盐以比当将乐伐替尼或其药学上可接受的盐单独给药或在未给药所述EP4受体拮抗剂时所给药的量更低的量给药。
在优选实施方案中，对于取得给定的抗肿瘤效果(诸如肿瘤大小的减小百分比和/或生存率)，与将乐伐替尼或其药学上可接受的盐单独给药或在未给药所述EP4受体拮抗剂时相比，所需的乐伐替尼或其药学上可接受的盐给药量降低，例如降低至少10％、至少15％、至少20％、至少30％、至少40％、至少50％或至少75％。
在优选实施方案中，将其它抗肿瘤药物(优选PD-1途径抑制剂)以比当将所述其它抗肿瘤药物(优选PD-1途径抑制剂)单独给药或在未给药所述EP4受体拮抗剂时所给药的量更低的量给药。
在优选实施方案中，对于取得给定的抗肿瘤效果(诸如肿瘤大小的减小百分比和/或生存率)，与将所述其它抗肿瘤药物(优选PD-1途径抑制剂)单独给药或在未给药所述EP4受体拮抗剂时相比，所需的所述其它抗肿瘤药物(优选PD-1途径抑制剂)给药量降低，例如降低至少10％、至少15％、至少 20％、至少30％、至少40％、至少50％或至少75％。
在优选实施方案中，所述EP4受体拮抗剂增强乐伐替尼或其药学上可接受的盐在治疗癌症中的疗效和/或降低乐伐替尼或其药学上可接受的盐在治疗癌症中的副作用。
在优选实施方案中，所述EP4受体拮抗剂增强乐伐替尼或其药学上可接受的盐在治疗癌症中的疗效(例如增强至少30％、50％、75％或100％，或者增强至少2倍、5倍、10倍、20倍、40倍或50倍)和/或降低乐伐替尼或其药学上可接受的盐在治疗癌症中的副作用(例如降低至少30％、50％、75％或100％，或者降低至少2倍、5倍、10倍、20倍、40倍或50倍)。
在优选实施方案中，本发明提供EP4受体拮抗剂在制备用于增强乐伐替尼或其药学上可接受的盐在治疗癌症中的疗效和/或降低乐伐替尼或其药学上可接受的盐在治疗癌症中的副作用的药物中的用途。
在优选实施方案中，所述EP4受体拮抗剂增强所述其它抗肿瘤药物(优选PD-1途径抑制剂)在治疗癌症中的疗效和/或降低所述其它抗肿瘤药物(优选PD-1途径抑制剂)在治疗癌症中的副作用。
在优选实施方案中，所述EP4受体拮抗剂增强所述其它抗肿瘤药物(优选PD-1途径抑制剂)在治疗癌症中的疗效(例如增强至少30％、50％、75％或100％，或者增强至少2倍、5倍、10倍、20倍、40倍或50倍)和/或降低所述其它抗肿瘤药物(优选PD-1途径抑制剂)在治疗癌症中的副作用(例如降低至少30％、50％、75％或100％，或者降低至少2倍、5倍、10倍、20倍、40倍或50倍)。
在优选实施方案中，本发明提供EP4受体拮抗剂在制备用于增强PD-1途径抑制剂在治疗癌症中的疗效和/或降低PD-1途径抑制剂在治疗癌症中的副作用的药物中的用途。
在优选实施方案中，所述个体患有晚期癌症、难治性癌症、复发性癌症或耐药性癌症，特别是患有对于包含乐伐替尼或其药学上可接受的盐的癌症疗法和/或包含PD-1途径抑制剂的癌症疗法耐药的癌症。
在另一实施方案中，本发明提供EP4受体拮抗剂在制备用于与乐伐替尼或其药学上可接受的盐以及任选存在的其它抗肿瘤药物(优选PD-1途径抑制剂)组合来治疗患有耐药性癌症，特别是患有对于包含乐伐替尼或其药学上可接受的盐的癌症疗法和/或包含PD-1途径抑制剂的癌症疗法耐药的癌症的个体的药物中的用途。
药物组合物和药盒
在另一实施方案中，本发明提供药物组合物，其包含EP4受体拮抗剂和乐伐替尼或其药学上可接受的盐以及药学上可接受的载体；
优选地，所述EP4受体拮抗剂如上文所定义。
在另一实施方案中，本发明提供药物组合物，其包含EP4受体拮抗剂、乐伐替尼或其药学上可接受的盐和PD-1途径抑制剂以及药学上可接受的载体；
优选地，所述EP4受体拮抗剂和所述PD-1途径抑制剂如上文所定义。
在另一实施方案中，本发明提供药盒，其包含：
(a)位于第一容器中的第一组分，所述第一组分包含EP4受体拮抗剂(其优选如上文所定义)和任选存在的药学上可接受的载体；
(b)位于第二容器中的第二组分，所述第二组分包含乐伐替尼或其药学上可接受的盐和任选存在的药学上可接受的载体；以及
(c)任选存在的说明书。
在另一实施方案中，本发明提供药盒，其包含：
(a)位于第一容器中的第一组分，所述第一组分包含EP4受体拮抗剂(其优选如上文所定义)和任选存在的药学上可接受的载体；
(b)位于第二容器中的第二组分，所述第二组分包含乐伐替尼或其药学上可接受的盐和任选存在的药学上可接受的载体；
(c)位于第三容器中的第三组分，所述第三组分包含其它抗肿瘤药物(优选为PD-1途径抑制剂，所述PD-1途径抑制剂优选如上文所定义)和任选存在的药学上可接受的载体；以及
(d)任选存在的说明书。
实施例
为了使本发明的目的和技术方案更加清楚，以下结合具体实施例进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。并且，下列实施例中未提及的具体实验方法，均按照常规实验方法进行。
实施例1.
1.实验目的：验证化合物6与乐伐替尼甲磺酸盐联合使用对小鼠结直肠癌细胞(CT26细胞)的抑制作用及耐受性研究。
2.主要实验材料：
2.1供试药物
化合物6：由凯复制药(苏州)有限公司获得。
乐伐替尼甲磺酸盐：由北京偶合科技获得。
2.2移植模型所需细胞：
CT26细胞(细胞编号：BNCC287983)购自北京北纳生物科技有限公司。
2.3实验动物
种属品系：Mus Musculus，BALB/c
周龄：6-8周
性别：雌性
体重：16-18g
实验动物提供商：北京维通利华生物技术有限公司
3.实验方法
3.1药物配制：称取适量的化合物6和乐伐替尼甲磺酸盐分别加入适量0.5％MC(甲基纤维素)中，在超声仪中超声5分钟，待化合物分散成均匀混悬溶液。
Figure PCTCN2022095115-appb-000027
3.2细胞培养
用含有灭活的10％胎牛血清，100U/ml的青霉素和100μg/ml的链霉素的RPMI1640培养基在37℃、5％CO 2的培养箱中培养CT26肿瘤细胞，每隔3至4天待细胞长满后分瓶传代(约至细胞培养瓶的80％-90％)，将处于对数生长期的肿瘤细胞用于体内肿瘤的接种。
3.3肿瘤细胞接种与分组
无血清培养基重悬的CT26肿瘤细胞，浓度为0.25x10 7/ml，100μl/只，接种于实验动物的右侧胁肋部皮下，在肿瘤生长至50-100mm 3左右时(在本实施例中为肿瘤细胞接种后第8天)分组给药，共4组，每组8只，具体给药方案如下表中所示。
Figure PCTCN2022095115-appb-000028
Qd：每天一次，PO：口服灌胃。
3.4检测指标
3.4.1肿瘤体积：每周使用游标卡尺对肿瘤体积进行3次的测量，测量肿瘤的长径和短径，其体积计算公式为：体积＝0.5×长径×短径 2。
3.4.2动物给药后的反应：在进行肿瘤体积测量的同时，称量小鼠体重。记录小鼠体重的变化与给药时间的关系。同时观察小鼠的存活情况和健康状况(如给药期间动物活动、进食等一般状态)。
3.4.3药物评价指标
3.4.3.1肿瘤生长抑制率(％)
肿瘤生长抑制率(TGI)(％)＝(1-T/C)x 100％
T/C＝治疗组RTV/溶媒组RTV
RTV(相对体积)＝实验结束时的肿瘤体积/实验分组时的肿瘤体积x 100％
肿瘤生长抑制率≥60％，并经统计学处理P＜0.05为有效。
CI值(联合用药指数)＝AB(两药联合用药T/C)/A(单独用药T/C)x B(单独用药T/C)；0.9≤CI值≤1.1为联合用药作用叠加，0.8≤CI值＜0.9为联合用药作用低度协同，0.6≤CI值＜0.8为联合用药作用中度协同，0.4≤CI值＜0.6为联合用药作用高度协同，0.2≤CI值＜0.4为联合用药作用强度协同。
应用SPSS16.0统计学软件进行One-way ANOVA检验，对肿瘤体积进行组间统计学分析，P≤0.05认为有显著性差异。
4.结果
4.1.肿瘤生长抑制结果如表1和图1中所示。
Figure PCTCN2022095115-appb-000029
5.实验结果讨论：
由实验期间动物给药后的反应和动物体重变化可见，化合物6及化合物6与乐伐替尼甲磺酸盐联用在小鼠体内耐受性良好。
肿瘤细胞接种8天后，肿瘤长至65mm 3开始分组给药，肿瘤细胞接种后第28天(即开始给药后第20天)，化合物6-30mg/kg与乐伐替尼甲磺酸盐-20mg/kg联用组中，肿瘤生长抑制率为83％(P＝0.007，与溶媒组相比)，CI值为0.43，表明联合用药强度为高度协同。
实施例2.
1.实验目的：验证化合物6与乐伐替尼甲磺酸盐联合使用、化合物6与PD-1抗体联合使用、化合物6与PD-1抗体及乐伐替尼甲磺酸盐三药联合使用对小鼠结直肠癌细胞(CT26细胞)的抑制作用及耐受性研究。
2.主要实验材料：
2.1供试药物
化合物6：由凯复制药(苏州)有限公司获得。
乐伐替尼甲磺酸盐：由北京偶合科技获得。
PD-1抗体：由BioXcell获得，批号BE0146。
2.2移植模型所需细胞：
CT26细胞购自北京北纳生物科技有限公司。
2.3.实验动物
种属品系：Mus Musculus，BALB/c
周龄：6-8周
性别：雌性
体重：18-20g
实验动物提供商：北京维通利华生物技术有限公司
3.实验方法
3.1化合物配制信息：称取适量的化合物6、乐伐替尼甲磺酸盐分别加入适量0.5％MC(甲基纤维素)中，在超声仪中超声5分钟，待化合物分散成均匀混悬溶液。
移液枪吸取一定体积PD-1抗体溶液，加入一定体积的PBS溶液。
Figure PCTCN2022095115-appb-000030
3.2细胞培养
用含有灭活的10％胎牛血清，100U/ml的青霉素和100μg/ml的链霉素的RPMI1640培养基在37℃、5％CO 2的培养箱中培养CT26肿瘤细胞，每隔3至4天待细胞长满后分瓶传代(约至细胞培养瓶的80％-90％)，将处于对数生长期的肿瘤细胞用于体内肿瘤的接种。
3.3肿瘤细胞接种与分组
无血清培养基重悬的CT26肿瘤细胞，浓度为0.5x10 7/ml，100μl/只，接种于实验动物的右侧胁肋部皮下，在肿瘤生长至100-120mm 3左右时(在本实施例中为肿瘤细胞接种后第9天)分组给药，每组8只，具体给药方案如下表中所示。
Figure PCTCN2022095115-appb-000031
Figure PCTCN2022095115-appb-000032
注：Qd：每天一次，PO：口服灌胃；ip：腹腔注射；TW：一周两次。
3.4检测指标
与实施例1中相同。
4.结果
4.1.肿瘤生长抑制结果如表2和图2中所示。
表2.小鼠结直肠癌CT26模型的体内药效学研究(肿瘤体积分析)
Figure PCTCN2022095115-appb-000033
a.与溶媒组比较。
5.实验结果讨论：
由实验期间动物给药后的反应和动物体重变化可见，小鼠对各测试药物和疗法耐受性良好。
由测得的肿瘤生长抑制率可见，与目前临床上使用的PD-1抗体与乐伐替尼甲磺酸盐联用疗法(在本实施例中肿瘤生长抑制率为65％)相比，化合物6与PD-1抗体和乐伐替尼甲磺酸盐的联用疗法取得了更好的肿瘤抑制效果(肿瘤生长抑制率为81％)。
实施例3.
1.实验目的：验证化合物6、PD-1抗体、乐伐替尼甲磺酸盐单独使用及化合物6与乐伐替尼甲磺酸盐联合使用、乐伐替尼甲磺酸盐与PD-1抗体联合使用、化合物6与PD-1抗体及乐伐替尼甲磺酸盐三药联合使用对小鼠肝癌细胞(H22细胞)的抑制作用及耐受性研究。
2.主要实验材料：
2.1供试药物
化合物6：由凯复制药(苏州)有限公司获得。
乐伐替尼甲磺酸盐：由北京偶合科技获得。
PD-1抗体：由BioXcell获得，批号BE0146。
2.2移植模型所需细胞：
H22细胞购自北京北纳生物科技有限公司。
2.3.实验动物
种属品系：Mus Musculus，BALB/c
周龄：6-8周
性别：雌性
体重：16-18g
实验动物提供商：北京维通利华生物技术有限公司
3.实验方法
3.1化合物配制信息：称取适量的化合物6、乐伐替尼甲磺酸盐分别加入适量0.5％MC(甲基纤维素)中，在超声仪中超声5分钟，待化合物分散成均匀混悬溶液。
移液枪吸取一定体积PD-1抗体溶液，加入一定体积的PBS溶液。
Figure PCTCN2022095115-appb-000034
3.2细胞培养
用含有灭活的10％胎牛血清，100U/ml的青霉素和100μg/ml的链霉素的RPMI1640培养基在37℃、5％CO 2的培养箱中培养H22肿瘤细胞，每隔3至4天待细胞长满后分瓶传代(约至细胞培养瓶的80％-90％)，将处于对数生长期的肿瘤细胞用于体内肿瘤的接种。
3.3肿瘤细胞接种与分组
无血清培养基重悬的H22肿瘤细胞，浓度为1.0x10 7/ml，100μl/只，接种于实验动物的右侧胁肋部皮下，在肿瘤生长至100-150mm 3左右时分组给药，每组8只，具体给药方案如下表中所示。
Figure PCTCN2022095115-appb-000035
Figure PCTCN2022095115-appb-000036
Qd：每天一次，PO：口服灌胃；ip：腹腔注射；TW：一周两次。
3.4检测指标
与实施例1中相同。
4.结果
4.1.肿瘤生长抑制结果如表3和图3中所示。
Figure PCTCN2022095115-appb-000037
5.实验结果讨论：
由实验期间动物给药后的反应和动物体重变化可见，小鼠对各测试药物和疗法耐受性良好。
由测得的肿瘤生长抑制率可见，在H22模型中，目前临床上使用的PD-1抗体与乐伐替尼甲磺酸盐联用疗法仅取得叠加作用(CI值为1.00)，而化合物6与乐伐替尼甲磺酸盐的联用疗法取得了协同作用(CI值为0.78)。
此外，与目前临床上使用的PD-1抗体与乐伐替尼甲磺酸盐联用疗法(在本实施例中肿瘤生长抑制率为65％)相比，化合物6与PD-1抗体和乐伐替尼甲磺酸盐的联用疗法取得了更好的肿瘤抑制效果(肿瘤生长抑制率为83％)。
实施例4.
1.实验目的：验证化合物6、PD-1抗体、乐伐替尼甲磺酸盐单独使用及化合物6与乐伐替尼甲磺酸盐联合使用、乐伐替尼甲磺酸盐与PD-1抗体联合使用、化合物6与PD-1抗体及乐伐替尼甲磺酸盐三药联合使用对移植肝癌细胞(H22细胞)小鼠的生存期的影响。
2.实验材料和方法
实验方法、实验步骤和实验材料与实施例3相同。唯一不同之处在于，在给药期间，当动物的肿瘤体积达到2000立方毫米时，动物被判为死亡。在同一组内，当小鼠死亡达到一半的天数定义为50％生存期。
3.实验结果
如图4所示，在溶媒组，小鼠的50％生存期为19天；化合物6单独给药组为26天；PD-1抗体单独给药组为24天；乐伐替尼甲磺酸盐单独给药组为35天；PD-1抗体与乐伐替尼甲磺酸盐联用组中小鼠的50％生存期为49天；化合物6与乐伐替尼甲磺酸盐联用组中小鼠的50％生存期为52天；化合物6与PD-1抗体和乐伐替尼甲磺酸盐的联用组中小鼠的50％生存期大于62天。由此可见，化合物6与PD-1抗体和乐伐替尼甲磺酸盐的联用疗法可显著延长被治疗个体的生存期。
除本文中描述的那些外，根据前述描述，本发明的各种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (25)

  1. 治疗、遏制个体的癌症、降低其严重性、降低其风险或抑制其转移，或者增强针对癌症的细胞介导的免疫应答的方法，所述方法包括向所述个体给药治疗有效量的EP4受体拮抗剂以及治疗有效量的乐伐替尼或其药学上可接受的盐。
  2. 权利要求1的方法，其中所述EP4受体拮抗剂为式(I)的化合物：
    Figure PCTCN2022095115-appb-100001
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式，或其药学上可接受的盐，
    其中：
    M 1、M 2、M 3、M 5、M 6和M 7各自独立地为N原子或C-R 4；
    M 4选自N原子和C原子；
    环A选自C 6-10芳基、C 3-6环烷基、5-10元杂芳基和3-6元杂环基；
    X为
    Figure PCTCN2022095115-appb-100002
    Y选自一个键、C 1-4亚烷基、-CR 5R 6-、-O-、-OC 1-4亚烷基-、-NR 9C 1-4亚烷基-和-NR 9-，所述C 1-4亚烷基任选被选自H原子、D原子、卤素、羟基、氰基、氨基、硝基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；
    R 1和R 2相同或不同，且各自独立地选自H原子、D原子、氰基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3-6元杂环基、-C(O)OR 4、C(O)NR 7R 8、-COR 4、-S(O) mR 4、-NR 7R 8、C 6-10芳基和5-10元杂芳基，所述C 1-4烷基和C 1-4烷氧基各自独立地任选被选自H原子、D原子、卤素、羟基、氰基、氨基、硝基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、C 3-6环烷基、3-6元杂环基、-C(O)OR 4、C(O)NR 7R 8、-COR 4、-NR 4C(O)NR 7R 8、-OC(O)NR 7R 8、-NR 7C(O)OR 4、-S(O) mR 4、-NR 7R 8、C 6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；或者R 1和R 2与其相连接的原子一起形成C 3-6环烷基或3-6元杂环基，其中所述C 3-6环烷基和3-6元杂环基各自独立地任选被选自D原子、卤素、羟基、氰基、氨基、硝基、-C(O)OR 4、C(O)NR 7R 8、-COR 4、-NR 4C(O)NR 7R 8、-OC(O)NR 7R 8、-NR 7C(O)OR 4、-S(O) mR 4、-NR 7R 8、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；
    R 3相同或不同，且各自独立地选自H原子、D原子、卤素、羟基、氰基、氨基、硝基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3-6元杂环基、C 6-10芳基、5-10元杂芳基、-C(O)R 4、-C(O)OR 4、-OC(O)NR 7R 8、-NR 7C(O)OR 4、-S(O) mR 4、-NR 7R 8和-C(O)NR 7R 8，其中所述C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基各自独立地任选被选自C 1-4烷基、羟基C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤素、羟基、氰基、氨基和硝基中的一个或多个取代基所取代；
    R 4选自H原子、D原子、卤素、羟基、氨基、C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基，其中所述C 1-4烷基、C 1-4烷氧基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基各自独立地任选被选自C 1-4烷基、羟基C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤素、羟基、氰基、氨基和硝基中的一个或多个取代基所取代；
    R 5和R 6各自独立地选自H原子、D原子、C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基，其中所述C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基各自独 立地任选被选自C 1-4烷基、羟基C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤素、羟基、氰基、氨基和硝基中的一个或多个取代基所取代；或者R 5和R 6与其相连接的原子一起形成C 3-6环烷基或3-6元杂环基，其中所述C 3-6环烷基或3-6元杂环基各自独立地任选被选自卤素、羟基、氰基、氨基、硝基、C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、羟基C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基中的一个或多个取代基所取代；
    R 7和R 8各自独立地选自H原子、D原子、C 1-4烷基、卤代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基，其中所述C 1-4烷基、卤代C 1-4烷基、C 3-6环烷基、3-6元杂环基、C 6-10芳基和5-10元杂芳基各自独立地任选被选自C 1-4烷基、羟基C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤素、羟基、氰基、氨基和硝基中的一个或多个取代基所取代；
    R 9选自H原子、D原子和C 1-4烷基，其中所述C 1-4烷基任选被选自羟基C 1-4烷基、C 1-4烷氧基、卤代C 1-4烷基、卤代C 1-4烷氧基、卤素、羟基、氰基、氨基和硝基中的一个或多个取代基所取代；
    m为0、1或2；以及
    n为0、1、2、3或4。
  3. 权利要求1或2的方法，其中所述化合物为式(II)所示的化合物：
    Figure PCTCN2022095115-appb-100003
    其中M 1、M 3、M 5和M 6各自独立地为CH或C-卤素，M 2为C-R 4或N原子，M 7为N原子，M 4为C原子，环A、R 1、R 2、R 3、R 4、X、Y和n如权利要求2中所定义。
  4. 权利要求1-3中任一项的方法，其中所述化合物为式(III)所示的化合物：
    Figure PCTCN2022095115-appb-100004
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，
    其中：
    R 1和R 2相同或不同，且各自独立地选自H原子、D原子和C 1-4烷基；或者R 1和R 2与其相连接的原子一起形成C 3-6环烷基，优选环丙基；
    M 2为N原子或C-R 4；
    R 4选自H原子、D原子和卤素；
    X、环A、R 3和n如权利要求2中所定义。
  5. 权利要求1-4中任一项的方法，其中所述化合物选自：
    Figure PCTCN2022095115-appb-100005
    Figure PCTCN2022095115-appb-100006
    Figure PCTCN2022095115-appb-100007
  6. 权利要求1-5中任一项的方法，其还包括向所述个体给药其它抗肿瘤药物；优选地，向所述个体给药PD-1途径抑制剂。
  7. 权利要求1-6中任一项的方法，其中所述PD-1途径抑制剂是抗PD-1抗体，其选自派姆单抗(Pembrolizumab，Keytruda)、Nivolumba(Opdivo)、西米普利单抗(Cemiplimab，Libtayo，REGN-2810)、特瑞普利单抗、信迪利单抗、卡瑞丽珠单抗、替雷利珠单抗(Tislelizumab，BeiGen)、杰诺单抗(Genolimzumab，GB226，亚盛)、JTX-4014(Jounce)、AMP-224、AMP-514、PDR-001(Spartalizumab，Novartis)、BCD-100、TSR-042、JNJ-63723283、Sasanlimab(PF-06801591)、BI-754091、GLS-010、LZM009、HX008、MDX-1106，Merck 3745和CT-011；或者
    所述PD-1途径抑制剂是抗PD-L1抗体，其选自阿特朱单抗(Atezolizumab)、德瓦鲁单抗(Durvalumab，Imfinzi，AZ)、阿维单抗(Avelumab，Bavencio，EMD)、度伐利尤单抗(KN035)、GLS-010、CS1001、M7824、CX-071、LY-3300054、CA-170、SHR-1316、ZKAB001、BAT1306、BMS1166、MAX-10181、YW243.55.S70、MPDL3280A和MDX-1105。
  8. 权利要求1-7中任一项的方法，其中所述癌症选自膀胱癌、乳腺癌、子宫癌、子宫内膜癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、尿道癌、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、胶质母细胞瘤、髓母细胞瘤，以及恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；
    优选地，所述癌症为耐药性肿瘤(优选为乐伐替尼耐药性肿瘤、EP4受体拮抗剂耐药性肿瘤或PD-1途径抑制剂耐药性肿瘤)。
  9. 权利要求1-8中任一项的方法，其中将所述EP4受体拮抗剂以约0.005mg/日至约5000mg/日的量，例如约0.005、0.05、0.5、5、10、20、30、40、50、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1500、2000、2500、3000、3500、4000、4500或5000mg/日的量给药。
  10. 权利要求1-9中任一项的方法，其中将所述EP4受体拮抗剂以每日约1ng/kg至约200mg/kg、约1μg/kg至约100mg/kg或者约1mg/kg至约50mg/kg体重的量给药，例如以每日约1μg/kg、约10μg/kg、约25μg/kg、约50μg/kg、约75μg/kg、约100μg/kg、约125μg/kg、约150μg/kg、约175μg/kg、约200μg kg、约225μg/kg、约250μg kg、约275μg kg、约300μg/kg、约325μg kg、约350μg/kg、约375μg/kg、约400μg/kg、约425μg/kg、约450μg/kg、约475μg/kg、约500μg/kg、约525μg kg、约550μg/kg、约575μg kg、约600μg/kg、约625μg/kg、约650μg/kg、约675μg/kg、约700μg/kg、约725μg/kg、约750μg/kg、约775μg/kg、约800μg/kg、约825μg/kg、约850μg/kg、约875μg/kg、约900μg/kg、约925μg/kg、约950μg/kg、约975μg/kg、约1mg/kg、约5mg/kg、约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约60mg/kg、约70mg/kg、约80mg/kg、约90mg/kg、约100mg/kg、约125mg/kg、约150mg/kg、约175mg/kg、约200mg/kg体重的量给药。
  11. 权利要求1-10中任一项的方法，其中将乐伐替尼或其药学上可接受的盐以0.005mg/日至约5000mg/日的量，例如约0.005、0.05、0.5、5、10、20、30、40、50、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1500、2000、2500、 3000、3500、4000、4500或5000mg/日的量给药。
  12. 权利要求1-11中任一项的方法，其中将乐伐替尼或其药学上可接受的盐以每日约1ng/kg至约200mg/kg、约1μg/kg至约100mg/kg或者约1mg/kg至约50mg/kg体重的量给药，例如以每日约1μg/kg、约10μg/kg、约25μg/kg、约50μg/kg、约75μg/kg、约100μg/kg、约125μg/kg、约150μg/kg、约175μg/kg、约200μg kg、约225μg/kg、约250μg kg、约275μg kg、约300μg/kg、约325μg kg、约350μg/kg、约375μg/kg、约400μg/kg、约425μg/kg、约450μg/kg、约475μg/kg、约500μg/kg、约525μg kg、约550μg/kg、约575μg kg、约600μg/kg、约625μg/kg、约650μg/kg、约675μg/kg、约700μg/kg、约725μg/kg、约750μg/kg、约775μg/kg、约800μg/kg、约825μg/kg、约850μg/kg、约875μg/kg、约900μg/kg、约925μg/kg、约950μg/kg、约975μg/kg、约1mg/kg、约5mg/kg、约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约60mg/kg、约70mg/kg、约80mg/kg、约90mg/kg、约100mg/kg、约125mg/kg、约150mg/kg、约175mg/kg、约200mg/kg体重的量给药。
  13. 权利要求6-12中任一项的方法，其中将所述其它抗肿瘤药物(优选PD-1途径抑制剂)以0.005mg/日至约5000mg/日的量，例如约0.005、0.05、0.5、5、10、20、30、40、50、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1500、2000、2500、3000、3500、4000、4500或5000mg/日的量给药。
  14. 权利要求6-13中任一项的方法，其中将所述其它抗肿瘤药物(优选PD-1途径抑制剂)以每日约1ng/kg至约200mg/kg、约1μg/kg至约100mg/kg或者约1mg/kg至约50mg/kg体重的量给药，例如以每日约1μg/kg、约10μg/kg、约25μg/kg、约50μg/kg、约75μg/kg、约100μg/kg、约125μg/kg、约150μg/kg、约175μg/kg、约200μg kg、约225μg/kg、约250μg kg、约275μg kg、约300μg/kg、约325μg kg、约350μg/kg、约375μg/kg、约400μg/kg、约425μg/kg、约450μg/kg、约475μg/kg、约500μg/kg、约525μg kg、约550μg/kg、约575μg kg、约600μg/kg、约625μg/kg、约650μg/kg、约675μg/kg、约700μg/kg、约725μg/kg、约750μg/kg、约775μg/kg、约800μg/kg、约825μg/kg、约850μg/kg、约875μg/kg、约900μg/kg、约925μg/kg、约950μg/kg、约975μg/kg、约1mg/kg、约5mg/kg、约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约60mg/kg、约70mg/kg、约80mg/kg、约90mg/kg、约100mg/kg、约125mg/kg、约150mg/kg、约175mg/kg、约200mg/kg体重的量给药。
  15. 权利要求1-14中任一项的方法，其中将所述EP4受体拮抗剂与乐伐替尼或其药学上可接受的盐以及任选存在的其它抗肿瘤药物(优选PD-1途径抑制剂)一起、同时、顺序或交替给药。
  16. 权利要求1-15中任一项的方法，其中将所述EP4受体拮抗剂、乐伐替尼或其药学上可接受的盐和/或任选存在的其它抗肿瘤药物(优选PD-1途径抑制剂)连续给药至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少30天、至少35天、至少40天、至少45天或至少50天。
  17. 权利要求1-16中任一项的方法，其中将所述EP4受体拮抗剂、乐伐替尼或其药学上可接受的盐和/或任选存在的其它抗肿瘤药物(优选PD-1途径抑制剂)给药一个或多个(例如1、2、3、4、5、6、7、8、9或10个)疗程，其中每个疗程持续至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少30天、至少35天、至少40天、至少45天或至少50天；并且每两个疗程之间间隔0、1、2、3、4、5、6、7、8、9、10天、两周、三周或四周。
  18. 权利要求1-17中任一项的方法，其中将所述EP4受体拮抗剂、乐伐替尼或其药学上可接受的盐以及任选存在的其它抗肿瘤药物(优选PD-1途径抑制剂)以相同(例如口服)或不同途径(例如分别以口服及肠胃外(如注射))给药；
    优选地，将所述EP4受体拮抗剂和乐伐替尼或其药学上可接受的盐口服给药；
    优选地，将PD-1途径抑制剂注射给药。
  19. 权利要求1-18中任一项的方法，其中将乐伐替尼或其药学上可接受的盐以比当将乐伐替尼或其药学上可接受的盐单独给药或在未给药所述EP4受体拮抗剂时所给药的量更低的量给药；和/或
    将其它抗肿瘤药物(优选PD-1途径抑制剂)以比当将所述其它抗肿瘤药物(优选PD-1途径抑制剂)单独给药或在未给药所述EP4受体拮抗剂时所给药的量更低的量给药。
  20. 权利要求1-19中任一项的方法，其中所述EP4受体拮抗剂增强乐伐替尼或其药学上可接受的盐在治疗癌症中的疗效和/或降低乐伐替尼或其药学上可接受的盐在治疗癌症中的副作用；和/或
    所述EP4受体拮抗剂增强所述其它抗肿瘤药物(优选PD-1途径抑制剂)在治疗癌症中的疗效和/或降低所述其它抗肿瘤药物(优选PD-1途径抑制剂)在治疗癌症中的副作用。
  21. 权利要求1-20中任一项的方法，其中所述个体患有晚期癌症、难治性癌症、复发性癌症或耐药性癌症，特别是患有对于包含乐伐替尼或其药学上可接受的盐的癌症疗法和/或包含PD-1途径抑制剂的癌症疗法耐药的癌症。
  22. 药物组合物，其包含EP4受体拮抗剂和乐伐替尼或其药学上可接受的盐以及药学上可接受的载体；
    优选地，所述EP4受体拮抗剂如权利要求2-5中任一项所定义。
  23. 药物组合物，其包含EP4受体拮抗剂、乐伐替尼或其药学上可接受的盐和PD-1途径抑制剂以及药学上可接受的载体；
    优选地，所述EP4受体拮抗剂如权利要求2-5中任一项所定义；
    优选地，所述PD-1途径抑制剂如权利要求7中所定义。
  24. 药盒，其包含：
    (a)位于第一容器中的第一组分，所述第一组分包含EP4受体拮抗剂(其优选如权利要求2-5中任一项所定义)和任选存在的药学上可接受的载体；
    (b)位于第二容器中的第二组分，所述第二组分包含乐伐替尼或其药学上可接受的盐和任选存在的药学上可接受的载体；以及
    (c)任选存在的说明书。
  25. 药盒，其包含：
    (a)位于第一容器中的第一组分，所述第一组分包含EP4受体拮抗剂(其优选如权利要求2-5中任一项所定义)和任选存在的药学上可接受的载体；
    (b)位于第二容器中的第二组分，所述第二组分包含乐伐替尼或其药学上可接受的盐和任选存在的药学上可接受的载体；
    (c)位于第三容器中的第三组分，所述第三组分包含其它抗肿瘤药物(优选为PD-1途径抑制剂，所述PD-1途径抑制剂优选如权利要求7中所定义)和任选存在的药学上可接受的载体；以及
    (d)任选存在的说明书。
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