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WO2022037601A1 - 作为ep4受体拮抗剂的吡唑酰胺衍生物及其在制备治疗癌症和炎症药物中的用途 - Google Patents

作为ep4受体拮抗剂的吡唑酰胺衍生物及其在制备治疗癌症和炎症药物中的用途 Download PDF

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WO2022037601A1
WO2022037601A1 PCT/CN2021/113207 CN2021113207W WO2022037601A1 WO 2022037601 A1 WO2022037601 A1 WO 2022037601A1 CN 2021113207 W CN2021113207 W CN 2021113207W WO 2022037601 A1 WO2022037601 A1 WO 2022037601A1
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cancer
compound
disease
antibody therapy
acid
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PCT/CN2021/113207
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English (en)
French (fr)
Inventor
张学军
臧杨
李莉娥
李群
赵双
刘哲
常少华
孙红娜
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武汉人福创新药物研发中心有限公司
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Publication of WO2022037601A1 publication Critical patent/WO2022037601A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings

Definitions

  • the present invention relates to the fields of chemistry and medicine, in particular, the present invention relates to pyrazole amide derivatives and uses thereof.
  • Prostaglandin E 2 is an endogenous bioactive lipid, and PGE 2 induces a wide range of upstream and downstream-dependent biological responses by activating prostaglandin receptors (Legler, DF et al, hit. J Biochem .Cell Biol.2010,42,p.198-201), involved in the regulation of many physiological and pathological processes including inflammation, pain, renal function, cardiovascular system, lung function and cancer.
  • PGE 2 is reported to be highly expressed in cancerous tissues of various cancers, and it has been demonstrated that PGE 2 is associated with the occurrence, growth and progression of cancer and disease conditions in patients. It is widely believed that PGE 2 is associated with the activation of cell proliferation and cell death (apoptosis) and plays an important role in the processes of cancer cell proliferation, disease progression and cancer metastasis.
  • EP4 receptor antagonists are promising as anti-inflammatory and/or analgesic drugs to treat diseases related to the PGE 2 -EP4 pathway, such as inflammatory diseases, diseases accompanied by various pains, and the like.
  • EP4 is a major receptor involved in arthritic pain in rodent models of rheumatoid arthritis and osteoarthritis (see eg, J. Pharmacol. Exp. Ther., 325, 425 (2008)), which upon activation leads to intracellular The signaling molecule cAMP accumulates. EP4 receptor expression has been detected on peripheral nerve endings of pain receptors, macrophages, and neutrophils, and these cell types have been shown to be extremely important in endometriosis. Studies have reported that oral EP4 antagonists can alleviate proteinuria in type 2 diabetic mice and inhibit the progression of diabetic nephropathy.
  • EP4 antagonists are useful in the treatment of arthritis, including arthritic pain as well as endometriosis, diabetic nephropathy, and overactive bladder.
  • Existing treatments for arthritis are dominated by traditional NSAIDs (non-steroidal anti-inflammatory drugs) or selective COX-2 inhibitors, which can produce cardiovascular and/or gastrointestinal side effects.
  • Selective EP4 antagonists are less likely to produce cardiovascular side effects.
  • PGE 2 persistently activates EP receptors in the tumor microenvironment (produced abundantly by tumor cells) in the tumor microenvironment (Ochs et al, J Neurochem. 2016, 136, p. 1142-1154; Zelenay, S. et al, Cell 2015, 162, p. 1257-1270), promotes the accumulation and enhances the activity of a variety of immunosuppressive cells, including type 2 tumor-associated macrophages (TAMS), Treg cells, and myeloid-derived suppressor cells (MDSCs) .
  • TAMS type 2 tumor-associated macrophages
  • Treg cells Treg cells
  • MDSCs myeloid-derived suppressor cells
  • One of the main features of the immunosuppressive tumor microenvironment is the presence of abundant MDSCs and TAMs, which in turn correlate with the development of cancers in patients with gastric, ovarian, breast, bladder, hepatocellular (HCC), head and neck, and other types of cancer. was closely related to poor overall survival.
  • PGE 2 has been reported to induce immune tolerance by inhibiting the accumulation of antigen-presenting dendritic cells (DCs) in tumors and inhibiting the activation of tumor-infiltrating DCs (Wang et al, Trends in Molecular Medicine 2016, 22, p. .1-3). All of these PGE2 - mediated actions will collectively help tumor cells evade immune surveillance.
  • PGE 2 plays an important role in promoting tumorigenesis and development.
  • EP2 and EP4 have been found to be elevated in various malignant tumors, including colon cancer, lung cancer, breast cancer, and head and neck cancer, and are often closely related to poor prognosis (Bhooshan, N. et al. al. Lung Cancer 101, 88-91). Therefore, selectively blocking the EP2 and EP4 signaling pathways can inhibit the occurrence and development of tumors by changing the tumor microenvironment and regulating tumor immune cells.
  • E7046 an EP4 antagonist developed by Eisai
  • Phase Ib Phase Ib clinical trial in combination with radiotherapy or chemoradiotherapy for rectal cancer in 2017.
  • ONO-4578 developed by Ono Pharmaceutical was launched in 2017 for a phase I clinical study of advanced or metastatic solid tumors, and in 2018, a phase I/II clinical trial for the treatment of advanced solid tumors as a single agent or in combination with nivolumab was launched.
  • EP4 antagonists have made certain progress in the treatment of inflammatory diseases, pain, cancer and other fields, but there is still a need to further develop new drugs as improvements or replacements of current drugs.
  • the present invention aims to provide a compound that can effectively antagonize EP4, which can be used as an improvement or replacement of current drugs or EP4 antagonists.
  • the present invention proposes a compound, which is a compound represented by formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable compound represented by formula (I)
  • R 1 is selected from H or halogen; halogen is selected from F, Cl, Br, I.
  • the compounds according to the embodiments of the present invention can effectively antagonize EP4 receptors, have better pharmacokinetic properties, higher in vivo exposure, lower administration doses, and better compliance, as EP4 receptor antagonists for EP4
  • the scientific research of receptors and the prevention and treatment of related diseases are of great significance and application prospects.
  • the compound represented by formula (I) may be further preferably any of the following compounds:
  • the pharmaceutically acceptable salt is selected from at least one of the following: sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, benzene Acetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, ethylene sulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionate acid, lactic acid, maleic acid, malic acid, mandelic acid, mucilic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid , oxalic acid,
  • the present invention can also employ other salt types that can be used as intermediates or useful in the purification of compounds or in the preparation of other pharmaceutically acceptable salts for the identification, characterization or purification of the compounds of the present invention.
  • the present invention provides a pharmaceutical composition.
  • the pharmaceutical composition comprises: a pharmaceutically acceptable excipient and the aforementioned compound.
  • the pharmaceutical compositions according to the embodiments of the present invention can effectively antagonize EP4 receptors, have better pharmacokinetic properties, higher in vivo exposure, lower dosages, and better compliance, as EP4 receptor antagonists It has important significance and application prospects for the scientific research of EP4 receptor and the prevention and treatment of related diseases.
  • the present invention proposes the use of the aforementioned compound or the aforementioned pharmaceutical composition in the preparation of a medicament.
  • the medicament is used for treating or preventing EP4-related diseases.
  • the compounds or pharmaceutical compositions according to the embodiments of the present invention can effectively antagonize EP4 receptors, so that they can be used to prevent or treat EP4 receptor-related diseases.
  • the use may further include at least one of the following additional technical features:
  • the medicament is used to treat or prevent a disease selected from at least one of the following: inflammatory disease, pain, cancer, metabolic disease, and urinary system disease.
  • the inflammatory disease includes at least one selected from the group consisting of arthritis, rheumatoid arthritis.
  • the pain includes osteoarthritis pain, pain caused by endometriosis.
  • the medicament is administered in combination with radiotherapy and/or antibody therapy, wherein the antibody therapy is selected from one or a combination of CTLA4 antibody therapy, PDL1 antibody therapy and PD1 antibody therapy.
  • the cancer comprises solid cancer.
  • the cancer includes breast cancer, cervical cancer, colorectal cancer, endometrial cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer, Cancer of the pancreas, prostate, skin and/or urethra.
  • the metabolic disease includes diabetes
  • the urinary system disease includes overactive bladder.
  • the drug is suitable for inhibiting EP4 receptor calcium flux; the drug is suitable for binding to EP4 receptor.
  • the present invention proposes a series of EP4 antagonists with novel structure, better pharmacokinetic properties, better efficacy and good druggability, which can effectively treat EP4-related diseases or conditions.
  • the present invention provides a method for treating or preventing EP4 receptor-related diseases.
  • the method comprises: administering to a subject a compound or pharmaceutical composition as previously described.
  • the methods according to the embodiments of the present invention can have a better effect of preventing or treating EP4-related diseases.
  • the EP4 receptor-related disease is selected from at least one of the following diseases: inflammatory disease, pain, cancer, metabolic disease, and urinary system disease.
  • the inflammatory disease is selected from arthritis, rheumatoid arthritis; the pain is selected from osteoarthritis pain, pain caused by endometriosis; the cancer is selected from solid cancer;
  • the metabolic disease is diabetes, and the urinary system disease is selected from overactive bladder.
  • the cancer is selected from breast cancer, cervical cancer, colorectal cancer, endometrial cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer , pancreatic, prostate, skin and/or urethral cancer.
  • the subject is administered radiation therapy and/or antibody therapy in combination.
  • the antibody therapy is selected from one or a combination of CTLA4 antibody therapy, PDL1 antibody therapy and PD1 antibody therapy.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts derived from inorganic bases include but are not limited to metal salts formed from Al, Ca, Li, Mg, K, Na and Zn; salts derived from organic bases include but are not limited to salts of primary, secondary or tertiary amines, including Naturally occurring substituted or unsubstituted amines, cyclic amines and basic ion exchange resins such as ammonium, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, Dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, benzyl penicillin, ethylenediamine, glucos
  • salts are also contemplated by the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or may be used in the identification, characterization or purification of the compounds of the present invention.
  • stereoisomer refers to isomers that result from different arrangements of atoms in a molecule in space.
  • Stereochemistry definitions and conventions used herein are generally in accordance with SP Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds”, defined by John Wiley & Sons, Inc., New York, 1994.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers.
  • a 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method Spin body.
  • the compounds of the present invention may exist as one of the possible isomers or as a mixture thereof, for example, as pure optical isomers, or as mixtures of isomers, such as racemic and non-isomeric isomers.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques.
  • the substituent may be of E or Z configuration; if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may be cis or trans (cis- or trans-) structure.
  • Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active salt-forming organic acids. Suitable resolving agents for the fractional recrystallization process are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic acid.
  • optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic
  • resolving agents suitable for fractional crystallization methods include ⁇ -methyl-benzylamine in stereoisomerically pure form (eg, S and R forms or diastereomerically pure form), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.
  • Resolution of the racemic mixture can also be performed by elution on a column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). It can be carried out by high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).
  • tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present invention may exhibit tautomerism.
  • Tautomeric compounds can exist as two or more interconvertible species.
  • Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms.
  • Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
  • the ketone form predominates; in phenols, the enol form predominates.
  • the present invention encompasses all tautomeric forms of the compounds.
  • composition means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
  • solvate means that a compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces, and when the solvent is water, it is a hydrate.
  • prodrug refers to a compound of the invention that can be converted under physiological conditions or by solvolysis to a biologically active compound.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds, which modifications can be removed by conventional procedures or in vivo to yield the parent compounds.
  • Prodrugs include compounds formed by connecting a hydroxyl or amino group in the compounds of the present invention to any group. When the prodrugs of the compounds of the present invention are administered to mammalian individuals, the prodrugs are cleaved to form free hydroxyl, free the amino group.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • classes of the term “excipient” include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flowability and/or stickiness.
  • Examples of typical "pharmaceutically acceptable carriers" suitable for use in the above formulations are: carbohydrates such as lactose, sucrose, mannitol and sorbitol; starches such as corn starch, tapioca starch and potato starch; cellulose and derivatives thereof compounds such as sodium carboxymethylcellulose, ethylcellulose and methylcellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid ; alkaline earth metal stearate salts such as magnesium stearate and calcium stearate; stearic acid; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; nonionic, cationic and anionic surfactants Glycol polymers; fatty alcohols; and cereal hydrolyzed solids and other non-toxic compatible fillers, binders, disintegrants, buffers, pre
  • the compounds or pharmaceutical compositions of the present invention can effectively antagonize EP4 receptor activity, have better pharmacokinetic properties, higher in vivo exposure, lower dosage and better compliance . It has broad application prospects in the scientific research of EP4 receptor and the preparation of drugs for preventing or treating EP4-related diseases.
  • the compounds of the present invention are identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the units of NMR shifts are 10-6 (ppm).
  • the solvents for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
  • Liquid-mass spectrometry was determined by Waters Acquity H-class UPLC-SQD2 mass spectrometer and monitored using Ultimate UHPLC XB C18 1.8um 2.1mm*50mm chromatographic column.
  • Gradient elution condition 1 run at a flow rate of 0.6 mL/min for 3.0 min, start with 5% solvent B1 for 0.2 min, increase from 5% solvent B1 to 95% solvent B1 within 1.3 min, and then keep 95% solvent B1 for 1.0 min, 0.1 It is reduced to 5% solvent B1 within min, and then 5% solvent B1 is maintained for 0.4min, and the percentage is the volume percentage of a certain solvent in the total solvent volume.
  • solvent A1 an aqueous solution of 0.05% formic acid
  • solvent B1 an acetonitrile solution of 0.05% formic acid.
  • the percentage is the volume percent of the solute in the solution.
  • Injection volume determined by the concentration of the reaction solution, generally 1.0mg/mL concentration sample, injection 1 ⁇ L; detection wavelength: 254/214/280nm; chromatographic column temperature: 40°C; sample tray temperature 25°C; Source: ESI source; molecular weight scan range: 150-1000; capillary voltage: 3.5kV; desolvation temperature: 650°C; ion source temperature: 150°C; cone voltage: 30V.
  • DIPEA can also be written as DIEA, diisopropylethylamine, that is, N,N-diisopropylethylamine
  • HATU 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • IC 50 the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
  • the reference compound was synthesized with reference to patent application WO2012039972A1.
  • control compounds in the following test examples all refer to the compounds described in Control Example 1.
  • the first step the preparation of 5-(3-bromophenol)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (I-2B)
  • the third step (3-(difluoromethyl)-1-methyl-5-(3-(propane-1-yn-1-yl)phenoxy)-1H-pyrazole-4-carboxylic acid (I -2D) preparation
  • Preparation conditions Welch, Ultimate C18 column, 10 nm, 21.2 nm x 250 mm.
  • Mobile phase A is 1 ⁇ trifluoroacetic acid pure aqueous solution
  • mobile phase B is 1 ⁇ trifluoroacetic acid acetonitrile solution.
  • Gradient conditions 0 to 3 minutes, mobile phase A maintained at 90%, 3 to 18 minutes for gradient elution, from 90% to 5%, and 18 to 22 minutes to maintain 5%.
  • Test Example 1 Determination of Inhibitory Effect on EP4 Receptor Calcium Flux
  • Inhibition rate (%) 100-(test group-EP4 complete antagonist group)/(DMSO group-EP4 complete antagonist group)*100
  • the IC50 values of the compounds for the inhibition of EP4 calcium flux ie, the drug concentration when the intracellular Ca 2+ flux is inhibited by half after the overexpression of human EP4 receptors
  • Test Example 2 Radioligand EP4 Receptor Binding Assay
  • Radioligand EP4 binding assays were performed using recombinant human EP4 receptor membrane protein (prepared from 293 cells overexpressing human EP4 receptor). Compounds to be tested and PGE 2 were prepared as 10 mM stock solutions in DMSO solvent, and then 8 concentration point 4x working solutions were serially diluted in buffer (50 mM HBSS, 0.1% BSA, 500 mM NaCl).
  • the reaction mixture was filtered through a GF/C plate using a Perkin Elmer Filtermate Harvester, then the filter plate was washed and dried at 50°C for 1 hour. After drying, the bottom of the filter plate wells were sealed using Perkin Elmer Unifilter-96 sealing tape, and 50 ⁇ L of MicroScint TM -20 cocktail (Perkin Elmer) was added to seal the top of the filter plate. 3H counts captured on the filters were read using a Perkin Elmer MicroBeta2 Reader.
  • Inhibition rate (%) 100-(test group-PGE 2 group)/(DMSO group-PGE 2 group)*100
  • the IC50 and Ki values of the compounds determined by the binding of the radioligand EP4 were calculated.
  • test compound IC50 (nM) Ki(nM) control compound 30 16 Compound I-1 9.1 5.0
  • the experimental results show that, compared with the control compound, the compound of the present invention has better affinity with the EP4 receptor, and is better than the control compound, and the compound of the present invention shows a better affinity for the EP4 receptor.
  • mice Pharmacokinetic test in mice, using male ICR mice, 20-25 g, fasted overnight. Three mice were taken and administered orally orally at 5 mg/kg. Blood was collected before administration and at 15, 30 minutes and 1, 2, 4, 8, and 24 hours after administration; another 3 mice were taken and administered 1 mg/kg intravenously, before and after administration Blood was collected at 15, 30 minutes and 1, 2, 4, 8, and 24 hours. Blood samples were centrifuged at 6800g at 2-8°C for 6 minutes, and plasma was collected and stored at -80°C.
  • the experimental results show that, compared with the control compound, the compound of the present invention has a lower or equivalent clearance rate by intravenous administration, and a higher or equivalent exposure by oral administration, and the exposure in mice after oral administration is about 4 times that of the control compound, After oral administration to dogs, the exposure is about twice that of the control compound, and the compound of the present invention exhibits better pharmacokinetic properties and good druggability.

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Abstract

一种有效拮抗EP4受体的化合物，其为式(I)所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中，R 1选自H或卤素；卤素选自F、Cl、Br、I。

Description

[根据细则37.2由ISA制定的发明名称]　作为EP4受体拮抗剂的吡唑酰胺衍生物及其在制备治疗癌症和炎症药物中的用途
本申请要求享有申请人于2020年8月18日向中国国家知识产权局提交的，专利申请号为202010835348.8，发明名称为“作为EP4受体拮抗剂的吡唑酰胺衍生物及其在癌症和炎症中的用途”的在先申请的优先权。该在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明涉及化学及医药领域，具体地，本发明涉及吡唑酰胺衍生物及其用途。
背景技术
前列腺素E 2(Prostaglandin E 2，PGE 2)是一种内源性生物活性脂质，PGE 2通过激活前列腺素受体引起广泛的上下游依赖性生物应答(Legler,D.F.et al,hit.J Biochem.Cell Biol.2010,42,p.198-201)，参与调控包括炎症、疼痛、肾功能、心血管系统、肺功能以及癌症等诸多生理和病理过程。据报道，PGE 2在各种癌症的癌变组织中高度表达，并且已证实PGE 2与患者的癌症和疾病状况的发生、成长和发展相关。普遍认为，PGE 2与细胞增殖和细胞死亡(凋亡)的激活相关，并且在癌细胞增殖、疾病进展和癌症转移的过程中起重要作用。
PGE 2的受体中，存在EP1、EP2、EP3和EP4这4个种类的亚型，它们广泛分布于各种组织中。这些亚型之中，PGE 2介由EP4受体干预炎症反应(包括免疫炎症反应)、平滑肌的松弛、发痛、淋巴细胞分化、血管系膜细胞的肥大或增殖、肠胃粘液的分泌等。因而，可以认为EP4受体拮抗剂有希望作为消炎和/或镇痛药治疗与PGE 2-EP4通路相关的疾病，例如炎症性疾病、伴有各种疼痛的疾病等。
EP4是类风湿性关节炎和骨关节炎啮齿动物模型中关节炎性疼痛中涉及的主要受体(参见例如J.Pharmacol.Exp.Ther.,325,425(2008))，其在活化后导致细胞内信号分子cAMP累积。已有研究在痛觉感受器的外周神经末梢、巨噬细胞及嗜中性球上检测到EP4受体的表达，经证实这些细胞类型对于子宫内膜异位症极其重要。有研究报道口服EP4拮抗剂可减轻2型糖尿病小鼠的蛋白尿，抑制糖尿病肾病的进展。另有研究报道膀胱粘膜中EP4的激活和PGE 2的产生增加可能是前列腺炎引起膀胱过度活动的重要原因，膀胱内注射EP4拮抗剂可有效改善前列腺炎后的膀胱过度活动。因此，选择性EP4拮抗剂可用于治疗关节炎、包括关节炎疼痛以及子宫内膜异位症、糖尿病肾病、膀胱过度活动症。现有关节炎的治疗药以传统NSAID(非甾体抗炎药)或选择性COX-2抑制剂为主，它们可产生心血管和/或胃肠副作用。而选择性EP4拮抗剂产生心血管副作用的可能较小。
PGE 2在肿瘤微环境中持续地激活肿瘤微环境中的EP受体(由肿瘤细胞大量产生)(Ochs et al,J Neurochem.2016,136,p.1142-1154；Zelenay,S.et al,Cell 2015,162,p.1257-1270)，会促进多种免疫抑制细胞的积累并增强其活性，包括2型肿瘤相关巨噬细胞(TAMS)、Treg细胞和髓系来源的抑制细胞(MDSCs)。免疫抑制肿瘤微环境的主要特征之一是存在大量的MDSCs和TAM，它们反过来又与胃癌、卵巢癌、乳腺癌、膀胱癌、肝细胞癌(HCC)、头颈癌和其他类型的癌症患者的总体生存率低密切相关。此外，据报道PGE 2通过抑制抗原提呈树突状细胞(DC)在肿瘤中的积聚以及抑制肿瘤浸润性DC的激活来诱导免疫耐受(Wang et al,Trends in Molecular Medicine 2016,22,p.1-3)。所有这些PGE 2介导的作用将共同帮助肿瘤细胞逃避免疫监视。PGE 2在促进肿瘤发生发展中发挥十分重要的作用。在包括结肠癌、肺癌、乳腺癌、和头颈癌等各类恶性肿瘤中都发现PGE 2及其相关受体EP2、EP4的表达水平升高，并往往和不良预后密切相关(Bhooshan,N.et al.Lung Cancer 101,88-91)。因此，选择性阻断EP2和EP4信号通路可以通过改变肿瘤微环境、调控肿瘤免疫细胞抑制肿瘤发生发展。
现有的临床前研究数据显示，EP2和EP4特异性拮抗剂在结肠癌、食道癌、肺癌和乳腺癌等动物模型中可以不同程度的预防或抑制肿瘤的生长。在进入临床的PGE 2受体药物中，辉瑞公司研发的EP4拮抗剂Grapiprant已被FDA批准用于狗的关节炎的治疗，同时于2015年进入抗肿瘤的临床II期研究，用于治疗前列腺癌、非小细胞肺癌和乳腺癌等多种类型的实体肿瘤(De Vito,V.et al.J Pharm Biomed Anal 118,251-258)。卫材公司研发的EP4拮抗剂E7046也于2015年展开临床I期的相关研究，2017年开展联合放疗或放化疗治疗直肠癌的Ib期临床试验。Ono Pharmaceutical研发的ONO-4578于2017年开展晚期或转移性实体瘤的临床I期研究，2018年开展单药或联合nivolumab治疗晚期实体瘤的I/II期临床试验。
目前EP4拮抗剂在炎性疾病、疼痛、癌症等领域的治疗取得了一定的进展，但仍有待进一步开发新型的药物，以作为目前药物的改进或者替换。
发明内容
本发明旨在提出一种能够有效拮抗EP4的化合物，其能够作为目前药物或者EP4拮抗剂的改进或者替换。
为此，本发明提出了一种化合物，其为式(I)所示化合物，或者式(I)所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学可接受的盐或前药：
Figure PCTCN2021113207-appb-000001
其中，R 1选自H或卤素；卤素选自F、Cl、Br、I。
根据本发明实施例的化合物可以有效地拮抗EP4受体，具有更好的药代动力学性质，在体内暴露量更高，给药量低、顺应性更好，作为EP4受体拮抗剂对于EP4受体的科学研究和相关疾病的预防和治疗具有重要意义和应用前景。
根据本发明示例性的实施方案，式(I)所示化合物可以进一步优选为如下任一化合物：
Figure PCTCN2021113207-appb-000002
根据本发明的实施例，所述药学上可以接受的盐选自下列的至少之一：硫酸、磷酸、硝酸、氢溴酸、盐酸、甲酸、乙酸、丙酸、苯磺酸、苯甲酸、苯乙酸、水杨酸、褐藻酸、氨茴酸、樟脑酸、柠檬酸、乙烯磺酸、蚁酸、富马酸、糠酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、乙醇酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、粘液酸、双羟萘酸、泛酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、对甲苯磺酸、丙二酸、2-羟基丙酸、草酸、羟乙酸、葡萄糖醛酸、半乳糖醛酸、枸橼酸、赖氨酸、精氨酸、门冬氨酸、肉桂酸、对甲苯磺酸、甲磺酸、乙磺酸或三氟甲磺酸。本领域技术人员能够理解的是，除了药学可接受的盐外，本发明还可以采用其他的盐类型，可以用于在化合物纯化中或在制备其它药学上可以接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。
在本发明的第二方面，本发明提出了一种药物组合物。根据本发明的实施例，所述药物组合物包含：药学上可接受的赋形剂以及前面所述的化合物。根据本发明实施例的药物组合物可以有效地拮抗EP4受体，具有更好的药代动力学性质，在体内暴露量更高，给药量低、顺应性更好，作为EP4受体拮抗剂对于EP4受体的科学研究和相关疾病的预防和治疗具有重要意义和应用前景。
在本发明的第三方面，本发明提出了前面所述的化合物或者前面所述的药物组合物在制备药物中的用途。根据本发明的实施例，所述药物用于治疗或者预防EP4相关疾病。如前所述，根据本发明实施例的化合物或药物组合物可以有效地拮抗EP4受体，从而可以用于预防或治疗EP4受体相关疾病。
根据本发明的实施例，所述用途还可以进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述药物用于治疗或者预防选自下列至少之一的疾病：炎性疾病、疼痛、癌症、代谢疾病、泌尿系统疾病。
根据本发明的实施例，所述炎性疾病包括选自下列的至少之一：关节炎、类风湿关节炎。
根据本发明的实施例，所述疼痛包括骨关节炎疼痛、子宫内膜异位导致的疼痛。
根据本发明的实施例，所述药物与放射疗法和/或抗体疗法联合施用，其中所述抗体疗法选自CTLA4抗体疗法、PDL1抗体疗法和PD1抗体疗法之一或其组合。
根据本发明的实施例，所述癌症包括实体癌。
根据本发明的实施例，所述癌症包括乳腺癌、宫颈癌、结直肠癌、子宫内膜癌、胶质母细胞瘤、头颈癌、肾癌、肝癌、肺癌、髓母细胞瘤、卵巢癌、胰腺癌、前列腺癌、皮肤癌和/或尿道癌。
根据本发明的实施例，所述代谢疾病包括糖尿病，所述泌尿系统疾病包括膀胱过动症。
根据本发明的实施例，所述药物适于抑制EP4受体钙流；所述药物适于与EP4受体结合。
根据本发明的实施例，利用本发明的化合物或者药物组合物，可以为有需要的患者提供更优、更有效的临床治疗药物或方案。根据本发明的实施例，本发明提出了一系列结构新颖、药代动力学性质更优良、药效更好、成药性好的EP4拮抗剂，能够有效治疗EP4相关的疾病或病症。
在本发明的第四方面，本发明提出了一种治疗或者预防EP4受体相关疾病的方法。根据本发明的实施例，所述方法包括：给予受试者施用前面所述化合物或药物组合物。由此，根据本发明实施例的方法可以起到较好的预防或治疗EP4相关的疾病的效果。
根据本发明的实施例，所述EP4受体相关疾病选自下列至少之一的疾病：炎性疾病、疼痛、癌症、代谢疾病、泌尿系统疾病。
根据本发明的实施例，所述炎性疾病选自关节炎、类风湿关节炎；所述疼痛选自骨关节炎疼痛、子宫内膜异位导致的疼痛；所述癌症选自实体癌；所述代谢疾病为糖尿病，所述泌尿系统疾病选自膀胱过动症。
根据本发明的实施例，所述癌症选自乳腺癌、宫颈癌、结直肠癌、子宫内膜癌、胶质母细胞瘤、头颈癌、肾癌、肝癌、肺癌、髓母细胞瘤、卵巢癌、胰腺癌、前列腺癌、皮肤癌和/或尿道癌。
根据本发明的实施例，对所述受试者联合施用放射疗法和/或抗体疗法。
根据本发明的实施例，所述抗体疗法选自CTLA4抗体疗法、PDL1抗体疗法和PD1抗体疗法之一或其组合。
术语定义和说明
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
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”或者“其药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。衍生自无机碱的盐包括但不限于Al、Ca、Li、Mg、K、Na和Zn形成的金属盐；衍生自有机碱的盐包括但不限于伯胺、仲胺或叔胺的盐，包括天然存在的取代或未取代的胺、环胺和碱性离子交换树脂，例如铵、异丙基胺、三甲基胺、二乙胺、三乙胺、三丙基胺、二乙醇胺、乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己基胺、咖啡碱、普鲁卡因、胆碱、甜菜碱、苯明青霉素、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶或聚胺树脂形成的有机盐；衍生自无机酸和有机酸的盐包括但不限于硫酸、磷酸、硝酸、氢溴酸、盐酸、甲酸、乙酸等形成的有机盐。
除了药学可接受的盐外，本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体。本发明使用的立体化学定义和惯例大体上按照S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994来定义。 本发明化合物可含有不对称中心或手性中心，因此以不同的立体异构形式存在。所预期的是，本发明化合物的所有立体异构体形式，包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomer)和几何(或构象)异构体及它们的混合物，如外消旋混合物，均在本发明的范围之内。
许多有机化合物以光学活性形式存在，即它们具有使平面偏振光的平面发生旋转的能力。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。就给定的化学结构而言，除了这些立体异构体互为镜像外，这些立体异构体是相同的。具体的立体异构体也可称为对映异构体，并且所述异构体的混合物通常称作对映异构体的混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或方法中没有立体选择性或立体特异性时，可出现所述外消旋混合物或外消旋体。
依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。旋光性的(R)-或(S)-异构体可使用手性合成子或手性制剂制备，或使用常规技术拆分。如果此化合物含有一个双键，取代基可能为E或Z构型；如果此化合物中含有二取代的环烷基，环烷基的取代基可能为顺式或反式(cis-或trans-)构型。
当将本发明式中与手性碳的键描写直成线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。
含有不对称取代的碳原子的本发明化合物能够以旋光活性形式或外消旋形式分离。化合物的外消旋混合物的拆分可以通过本领域已知的许多方法中的任一种来进行。示例性方法包括使用手性拆分酸的分级重结晶，该手性拆分酸是旋光活性的成盐有机酸。用于分级重结晶方法的适合的拆分剂例如是旋光活性酸，例如酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸或各种旋光活性樟脑磺酸如β-樟脑磺酸的D和L形式。适合于分级结晶方法的其它的拆分剂包括立体异构纯形式的α-甲基-苄胺(例如，S和R形式或者非对映异构纯形式)、2-苯基甘氨醇、降麻黄碱、麻黄碱、N-甲基麻黄碱、环己基乙胺、1，2-二氨基环己烷等。外消旋混合物的拆分还可以通过在填充有旋光活性拆分剂(例如，二硝基苯甲酰基苯基甘氨酸)的柱子上洗脱来进行。可以采用高效液相色谱(HPLC)法也 可以采用超临界流体色谱法(SFC)进行。具体方法的选择以及洗脱条件、色谱柱的选择可以由本领域技术人员根据化合物的结构以及试验结果选择。进一步的，还可以使用已知构型的光学纯的起始原料或试剂，通过立体有机合成，获得本发明所描述化合物的任何对映体或非对映体。
烯烃、C＝N双键等的许多几何异构体也可以存在于本文所述的化合物中，且所有这种稳定的异构体在本发明中均被考虑。当本文所描述化合物含有烯双键时，除非另外说明，否则，这种双键包括E和Z几何异构体。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。
术语“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物，其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。
术语“溶剂化物”指本发明化合物或其盐包括以分子间非共价力结合的化学计量或非化学计量的溶剂，当溶剂为水时，则为水合物。
术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。
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)。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。
术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。适用于上述制剂的典型的“药学上可接受的载体”的实例为：糖类，例如乳糖、蔗糖、甘露醇和山梨醇；淀粉类，例如玉 米淀粉、木薯淀粉和土豆淀粉；纤维素及其衍生物，例如羧甲基纤维素钠，乙基纤维素和甲基纤维素；磷酸钙类，例如磷酸二钙和磷酸三钙；硫酸钠；硫酸钙；聚乙烯吡咯烷酮；聚乙烯醇；硬脂酸；硬脂酸碱土金属盐，例如硬脂酸镁和硬脂酸钙；硬脂酸；植物油类，例如花生油、棉籽油、芝麻油、橄榄油和玉米油；非离子、阳离子和负离子表面活性剂；乙二醇聚合物；脂肪醇类；和谷物水解固形物以及其它无毒的可相容的填充剂、粘合剂、崩解剂、缓冲剂、防腐剂、抗氧剂、润滑剂、着色剂等在药物制剂中常用到的辅料。
有益效果
根据本发明的实施例，本发明所述化合物或药物组合物能够有效拮抗EP4受体活性，具有更好的药代动力学性质，在体内暴露量更高，给药量低、顺应性更好。在EP4受体的科学研究和制备预防或治疗与EP4相关疾病的药物方面具有广阔的应用前景。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
具体实施方式
下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
如无特别说明，本发明的化合物均是通过核磁共振(NMR)和/或质谱(MS)来确定。NMR位移的单位为10 -6(ppm)。NMR测定的溶剂为氘代二甲基亚砜、氘代氯仿、氘代甲醇等，内标为四甲基硅烷(TMS)。
液质联用(LC-MS)由Waters Acquity H-class UPLC-SQD2质谱仪测定，使用Ultimate UHPLC XB C18 1.8um 2.1mm*50mm色谱柱监测。梯度洗脱条件一：以0.6mL/min流速运行3.0min，开始5％溶剂B1保持0.2min，1.3min内由5％溶剂B1升至95％溶剂B1，然后95％溶剂B1保持1.0min，0.1min内降为5％溶剂B1,然后5％溶剂B1保持0.4min，百分数为某一溶剂占总溶剂体积的体积百分数。其中溶剂A1：0.05％甲酸的水溶液；溶剂B1：0.05％甲酸的乙腈溶液。百分数为溶质占溶液的体积百分数。进样量：由反应液浓度决定，一般的1.0mg/mL浓度样品，进样1μL；检测波长：254/214/280nm；色谱柱温度：40℃；样品盘温度25℃；SQD2质谱参数：离子源：ESI源；分子量扫描范围：150～1000；毛细管电压：3.5kV；脱溶剂温度：650℃；离子源温度：150℃；锥孔电压：30V。
本发明的缩写定义如下：
CuI：碘化亚铜
DIPEA：也可写为DIEA，二异丙基乙胺，亦即N,N-二异丙基乙胺
DMF：N,N-二甲基甲酰胺
DMSO：二甲基亚砜
Et 3N：三乙胺
HATU：2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
SFC：超临界流体色谱
THF：四氢呋喃
IC 50：半数抑制浓度，指达到最大抑制效果一半时的浓度。
除非作出相反的指示，本文例举的化合物使用ChemBioDraw Ultra 13.0命名和编号。
对照例1：对照化合物的制备
Figure PCTCN2021113207-appb-000003
对照化合物参考专利申请WO2012039972A1合成。
下文测试例的对照化合物均指对照例1所述化合物。
实施例1：化合物I-1的制备
(S)-4-(1-(3-(二氟甲基)-5-(4-氟-3-(丙烷-1-炔-1-基)苯氧基)-1-甲基-1H-吡唑-4-甲酰胺)乙基)苯甲酸(化合物I-1)
(S)-4-(1-(3-(difluoromethyl)-5-(4-fluoro-3-(prop-1-yn-1-yl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-1)
Figure PCTCN2021113207-appb-000004
化合物I-1的合成路线如下所示：
Figure PCTCN2021113207-appb-000005
第一步：(S)-4-(1-(5-(3-溴-4-氟苯氧基)-3-(二氟甲基)-1-甲基-1H-吡唑-4-甲酰胺)乙基)苯甲酸甲酯(I-1B)的制备
methyl(S)-4-(1-(5-(3-bromo-4-fluorophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(I-1B)
Figure PCTCN2021113207-appb-000006
室温下将化合物(S)-4-(1-(5-氯-3-(二氟甲基)-1-甲基-1H-吡唑-4-甲酰胺)乙基)苯甲酸甲酯(3.0g，8.1mmol)加入到DMF(40mL)中，加入3-溴-4-氟苯酚(3.1g，16.2mmol)，碳酸铯(7.9g，24.3mmol)，碘化亚铜(308mg，1.62mmol)，1,10-菲罗啉(583mg，3.24mmol)，加热至110℃，搅拌16h。冷却至室温，加入水(200mL)稀释，用乙酸乙酯(60mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝2:1)得白色固体(S)-4-(1-(5-(3-溴-4-氟苯氧基)-3-(二氟甲基)-1-甲基-1H- 吡唑-4-甲酰胺)乙基)苯甲酸甲酯(I-1B)(1.4g，产率32.9％)。
LC-MS,M/Z(ESI):525.6[M+H] +
第二步：(S)-4-(1-(3-(二氟甲基)-5-(4-氟-3-(丙烷-1-炔-1-基)苯氧基)-1-甲基-1H-吡唑-4-甲酰胺)乙基)苯甲酸甲酯(I-1C)的制备
methyl(S)-4-(1-(3-(difluoromethyl)-5-(4-fluoro-3-(prop-1-yn-1-yl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoate(I-1C)
Figure PCTCN2021113207-appb-000007
室温下将化合物(S)-4-(1-(5-(3-溴-4-氟苯氧基)-3-(二氟甲基)-1-甲基-1H-吡唑-4-甲酰胺)乙基)苯甲酸甲酯(1.28g，2.4mmol)加入到DMF(30mL)中，氮气保护下加入1mol/L丙炔的DMF溶液(7.2ml，7.2mmol)，三乙胺(7.3g，7.2mmol)，碘化亚铜(91mg，0.48mmol)，二三苯基膦二氯化钯(168mg，0.24mmol)，加热至100℃，搅拌12h。冷却至室温，加入水(200mL)稀释，用乙酸乙酯(60mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝2:1)得白色固体(S)-4-(1-(3-(二氟甲基)-5-(4-氟-3-(丙烷-1-炔-1-基)苯氧基)-1-甲基-1H-吡唑-4-甲酰胺)乙基)苯甲酸甲酯(I-1C)(1.0g，产率84.5％)。
LC-MS,M/Z(ESI):486.4[M+H] +
第三步：(S)-4-(1-(3-(二氟甲基)-5-(4-氟-3-(丙烷-1-炔-1-基)苯氧基)-1-甲基-1H-吡唑-4-甲酰胺)乙基)苯甲酸(I-1)的制备
(S)-4-(1-(3-(difluoromethyl)-5-(4-fluoro-3-(prop-1-yn-1-yl)phenoxy)-1-methyl-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(I-1)
Figure PCTCN2021113207-appb-000008
室温下将原料(S)-4-(1-(3-(二氟甲基)-5-(4-氟-3-(丙烷-1-炔-1-基)苯氧基)-1-甲基-1H-吡 唑-4-甲酰胺)乙基)苯甲酸甲酯(970mg，2.0mmol)加入到THF(5mL)中，加入水(5mL)，氢氧化锂(144mg，6.0mmol)，室温搅拌16h。反应液浓缩，制备得白色固体(S)-4-(1-(3-(二氟甲基)-5-(4-氟-3-(丙烷-1-炔-1-基)苯氧基)-1-甲基-1H-吡唑-4-甲酰胺)乙基)苯甲酸(600mg，产率36.2％)
1H NMR(400m Hz,DMSO-d 6)δ12.8(s,1H),8.15(d,1H),7.78(d,2H),7.27(t,1H),7.15(d,2H),7.09(d,1H),7.05(d,1H),7.02(t,1H),4.93-4.86(m,1H),3.73(s,3H),2.08(s,3H),1.29(d,3H).
LCMS(ESI)m/z:472.4[M+H] +
实施例2：化合物I-2的制备
(S)-4-(1-(3-(二氟甲基)-1-甲基-5-(3-(丙烷-1-炔-1-基)苯氧基)-1H-吡唑-4-甲酰胺)乙基)苯甲酸(化合物I-2)
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(prop-1-yn-1-yl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(化合物I-2)
Figure PCTCN2021113207-appb-000009
化合物I-2的合成路线如下所示：
Figure PCTCN2021113207-appb-000010
第一步：5-(3-溴苯酚)-3-(二氟甲基)-1-甲基-1H-吡唑-4-甲醛(I-2B)的制备
5-(3-bromophenoxy)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde(I-2B)
Figure PCTCN2021113207-appb-000011
室温下将化合物5-氯-3-(二氟甲基)-1-甲基-1H-吡唑-4-甲醛(194mg，1.0mmol)(参照专利申请WO2011151369A1合成)加入到DMSO(3mL)中，加入3-溴苯酚(346mg，2.0mmol)，氢氧化钾(118mg，3.0mmol)，加热至130℃，搅拌1h。冷却至室温，加入水(20mL)稀释，用乙酸乙酯(15mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1)得无色液体5-(3-溴苯酚)-3-(二氟甲基)-1-甲基-1H-吡唑-4-甲醛(I-2B)(140mg，产率42.3％)。
LC-MS,M/Z(ESI):331.2[M+H] +。
第二步：3-(二氟甲基)-1-甲基-5-(3-(丙烷-1-炔-1-基)苯氧基)-1H-吡唑-4-甲醛(I-2C)的制备
3-(difluoromethyl)-1-methyl-5-(3-(prop-1-yn-1-yl)phenoxy)-1H-pyrazole-4-carbaldehyde(I-2C)
Figure PCTCN2021113207-appb-000012
室温下将5-(3-溴苯酚)-3-(二氟甲基)-1-甲基-1H-吡唑-4-甲醛(330mg，1.0mmol)加入到DMF(5mL)中，加入CuI(38mg，0.20mmol)，二三苯基磷二氯化钯(70mg，0.10mmol)，三乙胺(305mg，3.0mmol)，丙炔的DMF溶液(1mol/L，3mL)，氮气保护下微波加热至110℃，搅拌4h。冷却至室温，加入水(20mL)稀释，用乙酸乙酯(20mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝5:1)得无色液体3-(二氟甲基)-1-甲基-5-(3-(丙烷-1-炔-1-基)苯氧基)-1H-吡唑-4-甲醛(I-2C)(220mg，产率75.8％)。
LC-MS,M/Z(ESI):291.4[M+H] +。
第三步：(3-(二氟甲基)-1-甲基-5-(3-(丙烷-1-炔-1-基)苯氧基)-1H-吡唑-4-甲酸(I-2D)的制备
3-(difluoromethyl)-1-methyl-5-(3-(prop-1-yn-1-yl)phenoxy)-1H-pyrazole-4-carboxylic acid(I-2D)
Figure PCTCN2021113207-appb-000013
室温下将化合物3-(二氟甲基)-1-甲基-5-(3-(丙烷-1-炔-1-基)苯氧基)-1H-吡唑-4-甲醛(220mg，0.76mmol)加入到叔丁醇(10mL)和水(5mL)中，加入2-甲基-2-丁烯(160mg，2.28mmol)，亚氯酸钠(206mg，2.28mmol)，磷酸二氢钠(228mg，1.9mmol)，室温搅拌16h。加入水(5mL)稀释，用乙酸乙酯(20mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，得白色固体粗品(3-(二氟甲基)-1-甲基-5-(3-(丙烷-1-炔-1-基)苯氧基)-1H-吡唑-4-甲酸(I-2D)(230mg，产率99.0％)。
LC-MS,M/Z(ESI):307.6[M+H] +。
第四步：(S)-4-(1-(3-(二氟甲基)-1-甲基-5-(3-(丙烷-1-炔-1-基)苯氧基)-1H-吡唑-4-甲酰胺)乙基)苯甲酸甲酯(I-2E)的制备
methyl(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(prop-1-yn-1-yl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoate(I-2E)
Figure PCTCN2021113207-appb-000014
室温下将化合物(3-(二氟甲基)-1-甲基-5-(3-(丙烷-1-炔-1-基)苯氧基)-1H-吡唑-4-甲酸(100mg，0.30mmol)加入到DMF(5mL)中，加入(S)-4-(1-氨基乙基)苯甲酸甲酯(64mg，0.36mmol)，HATU(171mg，0.45mmol)，DIEA(58mg，0.45mmol)，室温搅拌16h，加入水(20mL)稀释，用乙酸乙酯(10mL×3)萃取，分液，合并有机相，有机相用无水硫酸钠干燥，过滤，浓缩，残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(V/V)＝3:1)得白色固体(S)-4-(1-(3-(二 氟甲基)-1-甲基-5-(3-(丙烷-1-炔-1-基)苯氧基)-1H-吡唑-4-甲酰胺)乙基)苯甲酸甲酯(I-2E)(110mg，产率72.0％)。
LC-MS,M/Z(ESI):468.5[M+H] +。
第五步：(S)-4-(1-(3-(二氟甲基)-1-甲基-5-(3-(丙烷-1-炔-1-基)苯氧基)-1H-吡唑-4-甲酰胺)乙基)苯甲酸(I-2)的制备
(S)-4-(1-(3-(difluoromethyl)-1-methyl-5-(3-(prop-1-yn-1-yl)phenoxy)-1H-pyrazole-4-carboxamido)ethyl)benzoic acid(I-2)
Figure PCTCN2021113207-appb-000015
室温下将原料(S)-4-(1-(3-(二氟甲基)-1-甲基-5-(3-(丙烷-1-炔-1-基)苯氧基)-1H-吡唑-4-甲酰胺)乙基)苯甲酸甲酯(110mg，0.24mmol)加入到THF(5mL)和水(5mL)中，加入氢氧化锂(17mg，0.72mmol)，室温下搅拌16h。反应液浓缩，制备得白色固体(S)-4-(1-(3-(二氟甲基)-1-甲基-5-(3-(丙烷-1-炔-1-基)苯氧基)-1H-吡唑-4-甲酰胺)乙基)苯甲酸(18.5mg，产率17.3％)。
1H NMR(400m Hz,DMSO-d6)δ12.8(s,1H),8.08(d,1H),7.75(d,2H),7.39(t,1H),7.24(d,1H),7.13(d,2H),7.11(t,1H),7.11-6.96(m,2H),4.92(t,1H),3.73(s,3H),2.03(s,3H),1.24(d,3H).
LC-MS,M/Z(ESI):454.5[M+H] +
制备条件：Welch，Ultimate C18柱，10nm，21.2nm×250mm。流动相A为1‰的三氟醋酸纯水溶液，流动相B为1‰的三氟醋酸乙腈溶液。梯度条件：0～3分钟，流动相A保持90％，3～18分钟梯度洗脱，由90％变为5％，18～22分钟保持5％。
生物学活性及相关性质测试例
测试例1：对EP4受体钙流抑制效果测定
化合物对EP4钙流抑制效果的测定在过表达人EP4受体的293细胞中进行。在37℃水浴中迅速解冻细胞，离心、重悬、计数。将细胞悬浮液以20μL/孔接种于2块384孔板(20,000个细胞/孔)，置于37℃，5％CO 2培养箱中过夜。准备2X Fluo-4 Direct TM(Invitrogen,Cat# F10471)上样缓冲液：向1mL FLIPR缓冲液中加入77mg丙磺舒，浓度为250mM。每管Fluo-4 Direct TM crystals(F10471)加入10mL FLIPR缓冲液，和0.2mL 250mM的丙磺舒。
从培养箱中取出一块细胞板并去除培养基，加入20μL分析缓冲液和2X Fluo-4 Direct TM免洗上样缓冲液至384孔细胞培养板，最终体积为40μL。在37℃，5％CO 2培养箱中孵育50分钟，室温孵育10分钟，放入FLIPR。将10μL缓冲液转移至细胞板，读取荧光信号。将激动剂PGE 2在DMSO溶剂中配制成10mM的储备液，使用缓冲液梯度稀释10个浓度点的6X工作液。将10μL激动剂PGE 2转移至细胞板，读取荧光信号，计算EC 80值。
准备6X EC 80浓度的激动剂PGE 2，并将待测化合物在DMSO溶剂中配制成10mM的储备液，使用缓冲液梯度稀释10个浓度点6X化合物工作液。
另取一块细胞板去除培养基，加入20μL分析缓冲液和2X Fluo-4 Direct TM免洗上样缓冲液。在37℃，5％CO 2培养箱中孵育50分钟，室温孵育10分钟，放入FLIPR。将10μL化合物工作液、DMSO、EP4完全拮抗剂转移至细胞板，读取荧光信号。将10μL 6X EC 80浓度的激动剂PGE 2转移至细胞板，读取荧光信号，计算抑制率：
抑制率(％)＝100-(测试组-EP4完全拮抗剂组)/(DMSO组-EP4完全拮抗剂组)*100
根据化合物不同浓度的抑制率，计算化合物对EP4钙流抑制的IC 50值(即过表达人EP4受体后细胞内Ca 2+流动被抑制一半时的药物浓度)。
表1测试化合物对EP4钙流抑制作用
测试化合物 IC 50(nM)
对照化合物 21
化合物I-1 10.9
化合物I-2 12.36
实验结果表明，本发明化合物对EP4钙流显示较好抑制作用，且优于对照化合物，本发明化合物显示出更优异的EP4钙流抑制作用。
测试例2：放射性配体EP4受体结合测定
使用重组人EP4受体膜蛋白(从过表达人EP4受体的293细胞制备)进行放射性配体EP4结合测定。将待测化合物和PGE 2在DMSO溶剂中配制成10mM的储备液，然后使用缓冲液(50mM HBSS,0.1％BSA,500mM NaCl)梯度稀释8个浓度点的4×工作液。将1μL化合物工作液、DMSO、PGE 2工作液分别加到测定板中，加入100μL的EP4受体膜蛋白(20μg/孔)和100μL放射性配体[ 3H]-PGE 2(PerkinElmer,Cat:NET428250UC,Lot:2469552)(终浓度1.5nM)，密封室温下孵育1小时。在室温下，用0.5％BSA，50μL/每孔浸泡 Unifilter-96 GF/C滤板(Perkin Elmer)至少30min。结合完成后，使用Perkin Elmer Filtermate Harvester通过GF/C板过滤反应混合物，然后清洗滤板，在50℃下将滤板干燥1小时。干燥后，使用Perkin Elmer Unifilter-96密封胶带密封滤板孔的底部，加入50μL的MicroScint TM-20 cocktail(Perkin Elmer)，密封滤板顶部。使用Perkin Elmer MicroBeta2 Reader读取过滤器上捕获的 3H计数。
使用GraphPad Prism 5分析数据，按以下公式计算抑制率：
抑制率(％)＝100-(测试组-PGE 2组)/(DMSO组-PGE 2组)*100
根据化合物不同浓度的抑制率，计算化合物通过放射性配体EP4结合测定的IC 50和Ki值。
表2测试化合物通过放射性配体EP4结合测定的IC 50和Ki值
测试化合物 IC 50(nM) Ki(nM)
对照化合物 30 16
化合物I-1 9.1 5.0
实验结果表明，与对照化合物相比，本发明化合物与EP4受体具有更好的亲和力，且优于对照化合物，本发明化合物显示出更优异的EP4受体的亲和作用。
测试例3：药代动力学试验
小鼠药代动力学试验，使用雄性ICR小鼠，20-25g，禁食过夜。取3只小鼠，口服灌胃给药5mg/kg。在给药前和在给药后15、30分钟以及1、2、4、8、24小时采血；取另外3只小鼠，静脉注射给药1mg/kg，在给药前和在给药后15、30分钟以及1、2、4、8、24小时采血。血液样品6800g，2-8℃离心6分钟，收集血浆，于-80℃保存。取各时间点血浆，加入3-5倍量含内标的乙腈溶液混合，涡旋混合1分钟，13000转/分钟4℃离心10分钟，取上清液加入3倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。
犬药代动力学试验，使用雄性Beagle犬，8-10kg，禁食过夜。取3只Beagle犬，口服灌胃给药3mg/kg。取另外3只Beagle犬，静脉注射给药1mg/kg。其余操作同小鼠药代动力学试验。
表3小鼠药代动力学试验结果
Figure PCTCN2021113207-appb-000016
Figure PCTCN2021113207-appb-000017
表4犬药代动力学试验结果
Figure PCTCN2021113207-appb-000018
实验结果表明，与对照化合物相比，本发明化合物的静脉给药清除率更低或相当，口服给药暴露量更高或者相当，小鼠口服给药后暴露量约为对照化合物的4倍，犬口服给药后暴露量约为对照化合物的2倍，本发明化合物表现出更为优良的药代动力学性质，成药性好。

Claims (16)

  1. 一种化合物，其特征在于，其为式(I)所示化合物，或者式(I)所示化合物的互变异构体、立体异构体、水合物、溶剂化物、药学可接受的盐或前药：
    Figure PCTCN2021113207-appb-100001
    其中，R 1选自H或卤素；
    卤素选自F、Cl、Br、I。
  2. 如权利要求1所述的化合物，其特征在于，所述的式(I)所示化合物为如下任一化合物：
    Figure PCTCN2021113207-appb-100002
  3. 一种药物组合物，其特征在于，包含：药学上可接受的赋形剂以及权利要求1～2中任一项所述的化合物。
  4. 权利要求1～2中任一项所述的化合物，或者如权利要求3所述的药物组合物在制备药物中的用途，其特征在于，所述药物用于治疗或者预防EP4受体相关疾病。
  5. 如权利要求4所述的用途，其特征在于，所述EP4受体相关疾病选自下列至少之一的疾病：炎性疾病、疼痛、癌症、代谢疾病、泌尿系统疾病。
  6. 如权利要求5所述的用途，其特征在于，所述炎性疾病选自关节炎、类风湿关节炎；所述疼痛选自骨关节炎疼痛、子宫内膜异位导致的疼痛；所述癌症选自实体癌；所述代谢疾病为糖尿病，所述泌尿系统疾病选自膀胱过动症。
  7. 如权利要求5所述的用途，其特征在于，所述癌症选自乳腺癌、宫颈癌、结直肠癌、子宫内膜癌、胶质母细胞瘤、头颈癌、肾癌、肝癌、肺癌、髓母细胞瘤、卵巢癌、胰腺癌、前列腺癌、皮肤癌和/或尿道癌。
  8. 如权利要求5所述的用途，其特征在于，所述药物与放射疗法和/或抗体疗法联合施用。
  9. 如权利要求8所述的用途，其特征在于，所述抗体疗法选自CTLA4抗体疗法、PDL1抗体疗法和PD1抗体疗法之一或其组合。
  10. 如权利要求5所述的用途，其特征在于，所述药物适于抑制EP4受体钙流；
    所述药物适于与EP4受体结合。
  11. 一种治疗或者预防EP4受体相关疾病的方法，其特征在于，包括：
    给予受试者施用权利要求1或2所述化合物或权利要求3所述药物组合物。
  12. 如权利要求11所述的方法，其特征在于，所述EP4受体相关疾病选自下列至少之一的疾病：炎性疾病、疼痛、癌症、代谢疾病、泌尿系统疾病。
  13. 如权利要求12所述的方法，其特征在于，所述炎性疾病选自关节炎、类风湿关节炎；所述疼痛选自骨关节炎疼痛、子宫内膜异位导致的疼痛；所述癌症选自实体癌；所述代谢疾病为糖尿病，所述泌尿系统疾病选自膀胱过动症。
  14. 如权利要求12所述的方法，其特征在于，所述癌症选自乳腺癌、宫颈癌、结直肠癌、子宫内膜癌、胶质母细胞瘤、头颈癌、肾癌、肝癌、肺癌、髓母细胞瘤、卵巢癌、胰腺癌、前列腺癌、皮肤癌和/或尿道癌。
  15. 如权利要求11所述的方法，其特征在于，对所述受试者联合施用放射疗法和/或抗体疗法。
  16. 如权利要求15所述的方法，其特征在于，所述抗体疗法选自CTLA4抗体疗法、PDL1抗体疗法和PD1抗体疗法之一或其组合。
PCT/CN2021/113207 2020-08-18 2021-08-18 作为ep4受体拮抗剂的吡唑酰胺衍生物及其在制备治疗癌症和炎症药物中的用途 WO2022037601A1 (zh)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1950333A (zh) * 2004-05-04 2007-04-18 辉瑞大药厂 取代的甲基芳基或杂芳基酰胺化合物
CN103097358A (zh) * 2010-09-21 2013-05-08 卫材R&D管理有限公司 药物组合物
CN106572993A (zh) * 2014-05-23 2017-04-19 卫材R&D管理有限公司 用于治疗癌症的组合疗法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1950333A (zh) * 2004-05-04 2007-04-18 辉瑞大药厂 取代的甲基芳基或杂芳基酰胺化合物
CN103097358A (zh) * 2010-09-21 2013-05-08 卫材R&D管理有限公司 药物组合物
CN106572993A (zh) * 2014-05-23 2017-04-19 卫材R&D管理有限公司 用于治疗癌症的组合疗法

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