WO2020156568A1 - 作为pd-l1免疫调节剂的氟乙烯基苯甲酰胺基化合物 - Google Patents

作为pd-l1免疫调节剂的氟乙烯基苯甲酰胺基化合物 Download PDF

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WO2020156568A1
WO2020156568A1 PCT/CN2020/074206 CN2020074206W WO2020156568A1 WO 2020156568 A1 WO2020156568 A1 WO 2020156568A1 CN 2020074206 W CN2020074206 W CN 2020074206W WO 2020156568 A1 WO2020156568 A1 WO 2020156568A1
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compound
pharmaceutically acceptable
present
acid
tumor
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PCT/CN2020/074206
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English (en)
French (fr)
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张杨
夏远峰
孙德恒
左剑
陈正霞
戴美碧
黎健
陈曙辉
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南京明德新药研发有限公司
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Priority to AU2020214518A priority Critical patent/AU2020214518B2/en
Priority to EP20749071.5A priority patent/EP3919477A4/en
Priority to MX2021009261A priority patent/MX2021009261A/es
Priority to CA3128282A priority patent/CA3128282A1/en
Priority to JP2021544927A priority patent/JP7237169B2/ja
Priority to KR1020217027880A priority patent/KR20210124328A/ko
Priority to US17/427,710 priority patent/US20220119368A1/en
Priority to CN202080005329.0A priority patent/CN112752749B/zh
Publication of WO2020156568A1 publication Critical patent/WO2020156568A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a PD-L1 immunomodulator, in particular to a compound represented by formula (I), a pharmaceutically acceptable salt or an isomer thereof as a PD-L1 immunomodulator.
  • the occurrence of tumor cell immune escape is a complex process involving multiple factors and multi-mechanism regulation.
  • the role of PD-1/PD-L1 in promoting tumor occurrence and development has attracted much attention.
  • methods such as immunohistochemistry, flow cytometry, and cellular immunofluorescence have been used in liver cancer, melanoma, renal cell carcinoma, breast cancer and other types of tumor patients in local lesions, peripheral blood immune cells and even circulating tumor cells.
  • High expression of PD-L1 is detected, and the combination of lymphocytes or dendritic cells expressing PD-1 molecules can inhibit the function of immune cells, thereby weakening the body's anti-tumor immune response.
  • PD-L1 on the surface of tumor cells can act as a molecular barrier that prevents immune effector cells and other immune killing tumor cells.
  • the single-agent immunotherapy that blocks the PD-1/PD-L1 pathway has shown strong anti-cancer activity, there are still some patients with poor therapeutic effect.
  • Many patients with advanced malignant tumors have large tumor burden, immune tolerance and Factors such as the formation of the anti-tumor immunosuppressive microenvironment in the body make the body insensitive to single-agent immunotherapy, and even resistance. Therefore, compared with single-agent therapy, the combined treatment of anti-PD-1/PD-L1 immunotherapy may be able to obtain better results.
  • the research of the present invention found that a series of small molecules with novel structures have unique pharmacological properties, which can significantly reduce the expression of PD-L1 and enhance the efficacy of immune checkpoint drugs. It can be combined with PD-1/PD-L1 Achieve synergistic anti-tumor effect. This is extremely valuable for clinical application, and can enhance the response of patients who have weak or non-response to the original immune checkpoint drugs, and increase the patient population.
  • the compound of the present invention has potential therapeutic significance for various types of tumors such as melanoma, breast cancer, lung cancer, liver cancer and gastric cancer.
  • the present invention provides a compound represented by formula (I), its isomers or pharmaceutically acceptable salts thereof,
  • R 1 is selected from H, F, Cl, Br, I, OH and NH 2 ;
  • R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and a C 1-3 alkyl group optionally substituted with 1, 2 or 3 Ra;
  • R a is each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN and CH 3 .
  • R 2 and R 3 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , said CH 3 and CH 2 CH 3 optionally substituted by 1, 2 or 3 R a, the other variables are as defined in the present invention.
  • R 2 and R 3 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention .
  • the above-mentioned compound, its isomers or pharmaceutically acceptable salts thereof are selected from
  • R 2 and R 3 are as defined in the present invention.
  • the present invention also provides a compound represented by the following formula, an isomer thereof or a pharmaceutically acceptable salt thereof, and the compound is selected from
  • the above-mentioned compound, its isomers or pharmaceutically acceptable salts thereof are selected from
  • the present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of the above-mentioned compound, its isomer or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.
  • the present invention also provides the application of the above-mentioned compound, its isomer or pharmaceutically acceptable salt or the above-mentioned composition in the preparation of PD-L1 immunomodulator-related drugs.
  • the above-mentioned PD-L1 immunomodulator-related drugs are drugs for solid tumors.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • the base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acids include such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing an acid radical or a base by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds provided by the present invention also exist in prodrug forms.
  • the prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to transform into the compounds of the invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated form is equivalent to the unsolvated form, and both are included in the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, and diastereomers Conformers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomeric enriched mixtures, all of these mixtures belong to Within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
  • diastereomer refers to a stereoisomer in which a molecule has two or more chiral centers and the relationship between the molecules is non-mirror-image relationship.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a three-dimensional center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dotted key Or use wavy lines Represents a straight solid line key And straight dashed key
  • the compound of the present invention may be specific.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be transformed into each other quickly. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomer also called prototropic tautomer
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers include some recombination of bonding electrons to carry out mutual transformation.
  • keto-enol tautomerization is the tautomerization between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • radioisotopes such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary based on chemically achievable.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent is absent. For example, when X in AX is vacant, it means that the structure is actually A.
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
  • Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Example C 1- 3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n- propyl and isopropyl) and the like.
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4, C 5, C 6, C 7, C 8, C 9, C 10, C 11, and C 12, also including any one of n + m to n ranges, for example C 1- 3 comprises a C 1-12 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; in the same way, from n to n +m means the number of atoms in the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring , 10-membered ring, 11-member
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (B°C ); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fm°C); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1 -Di-(4'-methoxyphenyl)methyl; silyl group, such as trimethylsilyl (TMS) and tert-butyld
  • hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (P
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • SXRD single crystal X-ray diffraction
  • the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations: aq stands for water; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent amount; CDI stands for Carbonyl diimidazole; DCM stands for dichloromethane; PE stands for PE; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate ; EtOH represents ethanol; MeOH represents methanol; CBz represents benzy
  • the compound of the present invention has a high-efficiency down-regulation effect on PD-L1 gene expression; the compound of the present invention has a high-efficiency down-regulation effect on the expression level of PD-L1 protein; the compound of the present invention is in a CT26 model Reflects excellent anti-tumor effect, and combined with PD-L1 antibody to enhance its anti-tumor performance.
  • Figure 1 The effect of the compound of the present invention on the expression level of PD-L1 gene on CT26 cells.
  • Figure 2 The effect of the compound of the present invention on the expression level of PD-L1 gene on MCF7 cells.
  • Figure 3 Results of PD-L1 protein expression level of the compound of the present invention.
  • GAPDH (glyceraldehyde-3-phosphate dehydrogenase)
  • Figure 4 The effect of the compound of the present invention on the tumor volume of a mouse CT26 colon cancer tumor model.
  • Comparative example 1 And control example 2 Prepared according to Example 32 and Example 47 of patent WO2017024968A1.
  • NIS 88 g, 0.4 mol
  • a solution of compound 1e 90 g, 0.36 mol
  • dichloromethane 1.2 L
  • the reaction solution was stirred at 10°C for 2 hours.
  • the reaction was quenched with 10% sodium sulfite solution (100 mL), the organic layer was washed with saturated brine (300 mL ⁇ 2), the organic phases were combined and then dried over anhydrous sodium sulfate, filtered and evaporated.
  • the residue was purified by flash chromatography on silica gel column chromatography to obtain compound 1f.
  • a tetrahydrofuran solution (0.35L, 0.35mol, 1mol/L) of tetrabutylammonium fluoride was added to a tetrahydrofuran (1.4L) solution of 1g (132g, 0.29mol) of the compound at a time.
  • the mixed solution was stirred at 10°C for 2 hours.
  • the reaction solution was poured into 1.5 liters of ice water, and fully stirred for 20 minutes.
  • the aqueous phase was extracted with ethyl acetate (400 mL ⁇ 3), the combined organic phase was washed with saturated brine (200 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and evaporated.
  • the residue was purified by flash chromatography on silica gel column chromatography to obtain compound 1h.
  • hydrazine hydrate (2.38 g, 47.6 mmol) was added to a solution of compound 1j (10 g, 23.8 mmol) in ethanol (180 mL), and then the mixture was stirred at 20°C for 3 hours.
  • Add ethylenediamine (2.86g, 47.6mmol) and cuprous chloride (2.35.6g, 23.8mmol) 10 minutes later, at 0°C, slowly add tribromofluoromethane (16.1g, 59.6mmol) After the addition is complete, stir at 20°C for 16 hours.
  • the TLC plate detects the completion of the reaction. 1mol of citric acid is added dropwise to quench the reaction.
  • Pd(dppf)Cl 2 15mg, 0.02mmol
  • anhydrous potassium phosphate 165mg, 0.78mmol
  • nitrogen gas was exchanged three times, heated to 100°C, and reacted for 3 hours; the reaction solution was cooled and water (5mL) was added, It was extracted with ethyl acetate (5 mL ⁇ 2), the combined organic phases were washed with saturated brine (4 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by TLC plate to obtain 1L of compound.
  • N-Boc-piperazine (90mg, 0.48mmol) was added to a thumb bottle (10mL) containing a DMF (3mL) solution of compound 1m (90mg, crude); then HATU (57mg, 0.24mmol) and DIEA (30mg , 0.24 mmol) was added, and the reaction solution was stirred at room temperature for 16 hours.
  • Water (5mL) was added to the reaction solution, extracted with ethyl acetate (5mL ⁇ 3), the combined organic phase was washed with saturated brine (9mL), dried over anhydrous sodium sulfate, filtered, and spin-dried in vacuo. The residue was passed through a thin layer preparation layer Purification by plate analysis gave compound 1n LCMS (ESI) m/z: 724.6 [M+H] + .
  • the effect of the compound on PD-L1 of MCF7 cells and CT26 cells was detected by qPCR experiment to evaluate the down-regulation effect of the compound on PD-L1 gene.
  • MCF7 cells Human breast cancer (source: ATCC) and mouse colon cancer (CT26) cells (source: ATCC) were stimulated with 250nM compound and interferon gamma respectively, cultured for 48 hours, collected samples, and detected by qPCR; The content of DMSO in the detection reaction is 0.1%.
  • test compound was dissolved in 100% DMSO system and diluted to 10mM for use.
  • Interferon gamma was diluted with phosphate buffered saline (PBS), and the final concentration of the treatment was 100ng/mL.
  • PBS phosphate buffered saline
  • RNA of the cells was extracted with the RNeasy kit, and then converted into cDNA with the Takara reversal kit. Take cDNA and add gene primers and SYBR TM Green reagent to detect the relative content of the target gene by qPCR method.
  • the effect of the compound on the PD-L1 of CT26 cells was detected by immunoblotting experiment to evaluate the down-regulation effect of the compound on the PD-L1 gene.
  • CT26 cells were stimulated with 250nM compound and interferon gamma respectively, samples were collected after 48 hours of culture, and detected by western blotting; the content of DMSO in the detection reaction was 0.1%.
  • Rabbit anti-mouse PD-L1 antibody Abcam-ab213480.
  • test compound was dissolved in 100% DMSO system and diluted to 10mM for use.
  • Interferon gamma was diluted with PBS, and the final concentration was 100 ng/mL.
  • Each compound and interferon gamma were added to the cell sample to make the final concentration of 250 nM and 100 ng/mL, respectively. After 48 hours of incubation, the cells were lysed to extract the whole protein, and the content of the target protein was detected by Western blotting.
  • the compound of the present invention has a high-efficiency down-regulating effect on the expression level of PD-L1 protein.
  • mice Female Balb/c mice were subcutaneously inoculated with CT26 (source: ATCC) mouse colon cancer cell lines, and then randomly grouped according to body weight after inoculation, and the administration was performed as described below.
  • CT26 source: ATCC
  • Group 1 (control group): The administration was started in the afternoon of the day of inoculation, and vehicle 1 (0.5% MC (methyl cellulose) + 0.2% Tween-80) was administered intragastrically at a dose of 0.1 mL/10 g body weight twice a day. On the 4th, 7th, 10th and 13th days after vaccination, vehicle 2 (DPBS) was given by intraperitoneal injection at a dose of 0.1 mL/10 g body weight respectively.
  • vehicle 1 (0.5% MC (methyl cellulose) + 0.2% Tween-80
  • Group 2 Anti-mouse PD-L1 antibody (B7-H1) (source: BioX Cell) was given intraperitoneally at a dose of 8 mg/kg body weight on the 4th, 7th, 10th and 13th days after vaccination.
  • B7-H1 Anti-mouse PD-L1 antibody
  • Group 3 Administration was started in the afternoon on the day of inoculation, and Example 2 (suspended in 0.5% MC (methyl cellulose) + 0.2% Tween-80) was administered intragastrically at a dose of 5 mg/kg body weight twice a day.
  • Group 4 Administration started in the afternoon on the day of inoculation, and Example 2 (suspended in 0.5% MC+0.2% Tween-80) was administered intragastrically at a dose of 10 mg/kg body weight twice a day.
  • Group 5 Administration was started in the afternoon on the day of inoculation, and Example 2 (suspended in 0.5% MC+0.2% Tween-80) was administered intragastrically at a dose of 5 mg/kg body weight twice a day.
  • the anti-mouse PD-L1 antibody (B7-H1) was given by intraperitoneal injection at a dose of 8 mg/kg body weight on the 4th, 7th, 10th and 13th days after vaccination.
  • the tumor volume (TV) calculation formula is as follows:
  • T/C tumor growth rate
  • RTV T represents the RTV of the treatment group
  • RTV C represents the RTV of the solvent control group.
  • the calculation formula of tumor inhibition rate (%) is:
  • TV t(T) represents the tumor volume measured on day T in the treatment group; Indicates the tumor volume measured on day T in the solvent control group.
  • q tumor inhibition rate of the combination group/(antibody single-use group tumor inhibition rate + compound 2 (hydrochloride) low-dose group tumor inhibition rate-antibody single-use group tumor inhibition rate ⁇ Compound 2 (hydrochloride) low-dose group tumor inhibition rate), q ⁇ 0.85 is antagonistic effect, 0.85 ⁇ q ⁇ 1.15 is additive, q>1.15 is combined effect
  • the hydrochloride salt of compound 2 showed anti-tumor activity in both low-dose (5mg/kg) or high-dose (10mg/kg).
  • the tumor growth rate on day 22 Respectively: 36.21% (p ⁇ 0.05) and 37.03% (p ⁇ 0.05).
  • the combination group showed obvious anti-tumor activity, and the tumor proliferation rate (T/C) on the 22nd day was 11.73% (p ⁇ 0.01).
  • the compound of the present invention exhibits excellent anti-tumor effects in the CT26 model, and is combined with PD-L1 antibody to enhance its anti-tumor performance.

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Abstract

涉及一种PD-L1免疫调节剂，具体公开了作为PD-L1免疫调节剂的式(I)所示化合物、药学上可接受的盐或其异构体。

Description

作为PD-L1免疫调节剂的氟乙烯基苯甲酰胺基化合物
相关申请的引用
本申请主张如下优先权：
CN201910107946.0，申请日：2019-02-02。
技术领域
本发明涉及一种PD-L1免疫调节剂，具体涉及作为PD-L1免疫调节剂的式(I)所示化合物、药学上可接受的盐或其异构体。
背景技术
肿瘤细胞免疫逃逸的发生是一个多因素参与、多机制调控的复杂过程。PD-1/PD-L1在促进肿瘤发生、发展过程中的作用备受关注。近年来，运用免疫组化、流式细胞术以及细胞免疫荧光等方法已在肝癌、黑素瘤、肾细胞癌以及乳腺癌等多种类型肿瘤患者病灶局部、外周血免疫细胞甚至循环肿瘤细胞中检测到PD-L1的高表达，表达PD-1分子的淋巴细胞或树突状细胞与其结合可抑制免疫细胞的功能，从而削弱机体抗肿瘤免疫应答。肿瘤细胞表面的PD-L1可作为阻碍免疫效应细胞等免疫杀伤肿瘤细胞的分子屏障。
尽管阻断PD-1/PD-L1通路的单药免疫治疗已显示出强大的抗癌活性，但仍有部分患者治疗效果欠佳，许多晚期恶性肿瘤患者由于肿瘤负荷较大、免疫耐受以及体内抗肿瘤免疫抑制微环境形成等因素导致机体对单药免疫治疗不敏感，甚至产生抵抗。因此，与单药治疗相比，联合抗PD-1/PD-L1免疫疗法的综合治疗也许能获得更好的疗效。
本发明研究发现一系列结构新颖的小分子具有独特的药理学性质独特，可以显著地降低PD-L1的表达，增敏免疫检查点药物的药效，与PD-1/PD-L1联用可以达到协同抗肿瘤效果。这极其具有临床应用价值，能够使原先免疫检查点药物弱应答或不应答的患者增强应答，提高患者适用人群。本发明化合物对黑素瘤、乳腺癌、肺癌、肝癌、胃癌等多种类型的肿瘤具有潜在的治疗意义。
发明内容
本发明提供了式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2020074206-appb-000001
其中，
R 1选自H、F、Cl、Br、I、OH和NH 2；
R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R a取代C 1-3烷基；
R a分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3。
本发明的一些方案中，上述R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R a取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3，其他变量如本发明所定义。
本发明还有一些方案是由上述各变量任意组合而来。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2020074206-appb-000002
其中，
R 2和R 3如本发明所定义。
本发明还提供了下式所示化合物、其异构体或其药学上可接受的盐，所述化合物选自
Figure PCTCN2020074206-appb-000003
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2020074206-appb-000004
本发明还提供了一种药物组合物，包括治疗有效量的上述化合物、其异构体或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
本发明还提供了上述化合物、其异构体或其药学上可接受的盐或者上述组合物在制备PD-L1免疫调节剂相关药物上的应用。
本发明的一些方案中，上述PD-L1免疫调节剂相关药物是用于实体瘤的药物。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、 异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2020074206-appb-000005
和楔形虚线键
Figure PCTCN2020074206-appb-000006
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2020074206-appb-000007
和直形虚线键
Figure PCTCN2020074206-appb-000008
表示立体中心的相对构型，用波浪线
Figure PCTCN2020074206-appb-000009
表示楔形实线键
Figure PCTCN2020074206-appb-000010
或楔形虚线键
Figure PCTCN2020074206-appb-000011
或用波浪线
Figure PCTCN2020074206-appb-000012
表示直形实线键
Figure PCTCN2020074206-appb-000013
和直形虚线键
Figure PCTCN2020074206-appb-000014
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例 是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2020074206-appb-000015
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2020074206-appb-000016
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2020074206-appb-000017
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(B℃)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fm℃)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻 止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2020074206-appb-000018
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表PE；DIAD代表偶氮二羧酸二异丙酯；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；B℃代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；BOC 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表N-氯代丁二酰亚胺；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；DIEA代表N,N-二异丙基乙胺，Pd(PPh 3) 2Cl 2代表双三苯基膦二氯化钯；TBSCl代表叔丁基二甲基氯硅烷；NIS代表N-碘代丁二酰亚胺。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2020074206-appb-000019
软件命名，市售化合物采用供应商目录名称。技术效果：与对照例1和2相比，本发明化合物对PD-L1基因表达具有高效的下调作用；本发明化合物对PD-L1蛋白表达水平具有高效的下调作用；本发明化合物在CT26模型中体现出优异的抗肿瘤作用，并且与PD-L1抗体联用增强其抗肿瘤性能。
附图说明
图1：本发明化合物在CT26细胞上对PD-L1基因表达水平的影响。
图2：本发明化合物在MCF7细胞上对PD-L1基因表达水平的影响。
图3：本发明化合物PD-L1蛋白表达水平结果。
GAPDH:(甘油醛-3-磷酸脱氢酶(glyceraldehyde-3-phosphate dehydrogenase)
图4：本发明化合物对小鼠CT26结肠癌肿瘤模型瘤体积的影响。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
对照例1和2的制备说明
对照例1
Figure PCTCN2020074206-appb-000020
和对照例2
Figure PCTCN2020074206-appb-000021
根据专利WO2017024968A1实施例32和实施例47制备。
中间体1d的制备
Figure PCTCN2020074206-appb-000022
步骤一
20℃下，向1-(3,5-二氯吡啶-4-)乙醇(85.60g,445.74mmol)，三乙胺(90.21g,891.47mmol)的二氯甲烷(1.50L)溶液中，滴加乙酰氯(41.99g,534.88mmol)，在20℃下搅拌1小时后，减压蒸干溶剂，残余物通过柱快速硅胶柱纯化得到化合物1a。
1H NMR(400MHz,CDCl 3)δ8.44(s,2H),6.25(q,J＝6.8Hz,1H),2.09(s,3H),1.63(d,J＝7.2Hz,3H)。
步骤二
20℃下，向化合物1a(31g,243mmol)、DMSO(78mL)与1M NaH 2PO 4/Na 2HPO 4缓冲液(pH 7.5,775mL)的混合溶液中加入诺维信脂肪酶435(31.78g)。在51℃下搅拌129小时后，加水(1L)稀释，用乙酸乙酯(1L×5)萃取。合并的有机层用水(500mL)，盐水(500mL×2)洗涤后，经无水硫酸钠干燥，过滤，滤液浓缩得到的残余物通过快速硅胶柱纯化得到化合物1b。
LCMS(ESI)m/z:233.9[M+1] +。
步骤三
20℃下，向化合物1b(12.00g,51.26mmol)的四氢呋喃(50mL)和甲醇(50mL)混合溶液中，滴加1M氢氧化钠溶液(51.26mL,51.26mmol)，在20℃下搅拌半小时后，加水(30mL)稀释，用乙酸乙酯(100mL×3)萃取。合并的有机层用盐水(20mLx2)洗涤后，经无水硫酸钠干燥减压蒸干溶剂得到化合物1c。
LCMS(ESI)m/z:191.8[M+1] +。
步骤四
0℃冰浴下，向化合物1c(18g,94mmol)和三乙胺(28.45g,281mmol)的二氯甲烷(400mL)混合溶液中缓慢加入甲烷磺酰氯(32.21g,281.2mmol)。反应液在室温条件下搅拌4个小时。反应完成后，加水淬灭反应并用二氯甲烷(500mL×3)萃取。合并有机相，用无水硫酸钠干燥，蒸干得到残留物，通过柱层析得到化合物1d。
中间体1h的制备
Figure PCTCN2020074206-appb-000023
步骤五
室温下，向1-氢-吲唑-5-羟基(54g,0.4mol)和咪唑(40g,0.6mol)的DMF(1L)溶液中分批加入TBSCl(90g,0.6mol)。加完后，反应在15℃下搅拌5个小时。最终反应液加入3升水稀释，用乙酸乙酯(0.8L×3)萃取，合并的有机相用水(0.8L×3)洗涤，有机层用无水硫酸钠干燥，过滤并蒸发。残余物通过快速硅胶柱层析纯化得到化合物1e。
LCMS(ESI)m/z:249[M+1] +。
步骤六
10℃下，向化合物1e(90g,0.36mol)的二氯甲烷(1.2L)的溶液中分批加入NIS(88g,0.4mol)。反应液在10℃下搅拌2个小时。用10％的亚硫酸钠溶液(100mL)淬灭反应，有机层用饱和食盐水洗涤(300mL×2)，合并有机相然后用无水硫酸钠干燥，过滤并蒸发。残留物通过快速色谱法硅胶柱层析纯化得到化合物1f。
LCMS(ESI)m/z:375[M+1] +。
步骤七
先将化合物1f(125g,334mmol)溶解到二氯甲烷(1L)和四氢呋喃(0.4L)的混合溶剂里面，然后把甲基磺酸(6.0g,60mmol)加进去，最后将3,4-四氢化-2-氢-吡喃(124.2g,0.92mol)分批加入反应液中。加完后，在12℃下搅拌5个小时。反应完的反应液用二氯甲烷(500mL)稀释，用饱和的碳酸氢钠溶液(300mL)洗涤。有机层用饱和食盐水再次洗涤并用无水硫酸钠干燥，过滤蒸干。残留物通过快速色谱法硅胶柱层析纯化得到化合物1g。
LCMS(ESI)m/z:459[M+1] +。
步骤八
10℃下，向化合物1g(132g,0.29mol)的四氢呋喃(1.4L)溶液中一次性加入四丁基氟化铵的四氢呋喃溶液(0.35L,0.35mol,1mol/L)。混合溶液在10℃下搅拌2个小时。将反应液倒入1.5升的冰水中，充分搅拌20分钟。水相用乙酸乙酯(400mL×3)萃取，合并有机相用饱和食盐水(200mL×2)洗涤，并用无水硫酸钠干燥，过滤蒸发。残留物通过快速色谱法硅胶柱层析纯化得到化合物1h。
LCMS(ESI)m/z:345[M+1] +。
中间体1k的制备
Figure PCTCN2020074206-appb-000024
步骤九
氮气保护下，化合物1h(24g,88.9mmol)，化合物1d(35g,101.7mmol)和碳酸铯(57.9g,177.7mmol)的乙腈(1000mL)溶液在油浴下加热到110℃并搅拌反应12个小时。反应完成后，过滤，取滤液蒸干得到残留物，通过柱层析得到化合物1i。
LCMS(ESI)m/z:518.0[M+1] +；
1H NMR(400MHz,CD 3OD)δ8.44(s,2H),7.46(dd,J＝2.8,8.8Hz,1H),7.17(dd,J＝2.4,9.2Hz,1H),6.71(s,1H),6.08(d,J＝6.8Hz,1H),5.64～5.59(m,1H),4.01～3.97(m,1H),3.73～3.69(m,1H),2.48～2.47(m,1H),2.13～2.11(m,2H),1.83(d,J＝6.8Hz,3H),1.75～1.64(m,3H)。
步骤十
室温氮气下，向化合物1i(24g,46.3mmol)的DMF(500mL)溶液中加入Pd(PPh 3) 2Cl 2(1.63g,2.32mmol)和甲酸钠(9.5g,139.0mmol)。然后氢化瓶用一氧化碳气体置换，使瓶内充满一氧化碳气体。反应 液在一氧化碳(50psi)及80℃下搅拌反应12个小时。过滤，滤液浓缩干，残留物通过柱层析得到化合物1j。
LCMS(ESI)m/z:420.1[M+1] +。
步骤十一
0℃条件下，向化合物1j(10g,23.8mmol)的乙醇(180mL)溶液中加入水合肼(2.38g,47.6mmol)，然后该混合物在20℃下搅拌3小时。加入乙二胺(2.86g,47.6mmol)和氯化亚铜(2.35.6g,23.8mmol)，10分钟之后，在0℃条件下，慢慢滴加三溴氟甲烷(16.1g,59.6mmol)，滴加完毕之后，在20℃下搅拌16小时。薄层色谱板检测反应完成，滴加1mol柠檬酸淬灭反应，水层用乙酸乙酯(50mL×3)萃取，结合有机层用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，真空浓缩，残余物通过快速色谱法硅胶柱纯化得到化合物1k。
1H NMR(400MHz,CDCl 3)δ8.41(s,2H),7.46-7.43(m,1H),7.13-7.10(dd,J＝2.3,9.0Hz,1H),6.98(d,J＝2.5Hz,1H),6.33(d,J＝2.5Hz,1H),6.25(d,J＝20Hz 1H),6.02(q,J＝6.7Hz,1H),5.69-5.57(m,1H),4.04-3.92(m,1H),3.74-3.65(m,1H),2.54-2.40(m,1H),2.19-2.06(m,1H),2.04-1.93(m,1H),1.80(d,J＝6.5Hz,3H),1.76-1.60(m,2H)。
实施例1
Figure PCTCN2020074206-appb-000025
步骤一
将二氧六环(4mL)和水(1mL)加入到装有化合物1k(200mg,0.39mmol)和1-羧酸甲酯4-苯硼酸嚬哪醇酯(105mg，0.58mmol)的圆底烧瓶中。将Pd(dppf)Cl 2(15mg，0.02mmol)和无水磷酸钾(165mg,0.78mmol)加入；氮气换气三次，加热到100℃，反应3小时；反应液冷却，加入水(5mL)，乙酸乙酯(5mL×2)萃取，合并有机相用饱和食盐水(4mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残余物通过薄层制备层析板纯化得到化合物1L。
LCMS(ESI)m/z:570.0[M+H] +。
步骤二
将甲醇(3mL)，四氢呋喃(6mL)和水(2mL)加入到装有化合物1L(200mg,0.35mmol)和一水合氢氧化锂(74mg,1.75mmol)的单口烧瓶(50mL)中；反应烧瓶室温下搅拌6小时。加入水(5mL)，盐酸水溶液(1M)调解反应液pH到5，二氯甲烷(5mL×3)萃取，合并有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，真空旋干，得到化合物1m。
LCMS(ESI)m/z:556.4[M+H] +。
步骤三
将N-Boc-哌嗪(90mg，0.48mmol)加入到装有化合物1m(90mg，粗品)的DMF(3mL)溶液的拇指瓶(10mL)中；然后HATU(57mg，0.24mmol)和DIEA(30mg，0.24mmol)加入，该反应液在室温下搅拌16小时。向反应液中加入水(5mL)，乙酸乙酯(5mL×3)萃取，合并有机相饱和食盐水(9mL)洗涤，无水硫酸钠干燥，过滤，真空旋干，残余物通过薄层制备层析板纯化得到化合物1n LCMS(ESI)m/z:724.6[M+H] +。
步骤四
向化合物1n(60mg，0.08mmol)的乙醇(2mL)溶液中加入氯化氢乙酸乙酯(0.5mL,4N)；该反应液在40℃下搅拌30分钟。反应液直接真空旋干，残余物通过制备柱(盐酸体系)纯化得到化合物1的盐酸盐。化合物1的盐酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物1。
LCMS(ESI)m/z:540.4[M+H] +；
1H NMR(400MHz,CD 3OD)δ8.59(s,2H),7.97(d,J＝8.28Hz,2H),7.59-7.75(m,3H),7.45(dd,J＝2.26,9.29Hz,1H),7.33(s,1H),7.01-7.17(m,1H),6.21(q,J＝6.53Hz,1H),3.94(br s,4H),3.37(br s,4H),1.86(d,J＝6.78Hz,3H)。
实施例2
Figure PCTCN2020074206-appb-000026
步骤一
将顺式-2,6-二甲基哌嗪(50mg，0.44mmol)加入到装有化合物1m(80mg，粗品)的DMF(3mL)溶液的拇指瓶(10mL)中；然后HATU(52mg，0.22mmol)和DIEA(28mg，0.22mmol)加入，该反应液在室温下搅拌16小时。向反应液中加入水(5mL)，乙酸乙酯(5mL×3)萃取，合并有机相用饱和食盐水(6mL)洗涤，无水硫酸钠干燥，过滤，真空旋干，残余物通过薄层制备层析板纯化得到化合物2a。
LCMS(ESI)m/z:652.6[M+H] +。
步骤二
0℃条件下，将乙酰氯(1mL)加入到装有无水甲醇(4mL)的单口烧瓶(50mL)中，然后升到室温搅拌10分钟；将上述搅拌好的混合溶液(1mL)加入到装有化合物2a(60mg，0.09mmol)的甲醇(1mL)单口反应瓶(50mL)中；反应烧瓶加热到40℃，搅拌1小时。冷却，真空浓缩，制备柱分离纯化，得到化合物2的盐酸盐。化合物2的盐酸盐加入碳酸氢钠溶液中，乙酸乙酯萃取，有机相用无水硫酸钠干燥，减压下浓缩得到化合物2。
LCMS(ESI)m/z:568.6[M+H] +；
1H NMR(400MHz,CD 3OD)δ8.56(s,2H),7.95(d,J＝8.03Hz,2H),7.69(d,J＝8.03Hz,2H),7.59(d,J＝9.03Hz,1H),7.39(dd,J＝2.26,9.03Hz,1H),7.30(s,1H),6.98-7.12(m,1H),6.19(q,J＝6.69Hz,1H),3.45-3.59(m,2H),3.32-3.33(m,4H),1.81-1.91(m,3H),1.39(br s,6H)。
实验例1
生物测试数据：
实验例1：本发明化合物对PD-L1基因表达影响
实验目的：
通过qPCR实验检测化合物对MCF7细胞和CT26细胞的PD-L1影响，来评价化合物对PD-L1基因的下调作用。
实验方法：
人源乳腺癌(MCF7)细胞(来源：ATCC)和小鼠结肠癌(CT26)细胞(来源：ATCC)分别加入250nM的化合物及干扰素γ刺激，培养48小时后收样，利用qPCR法检测；DMSO在检测反应中的含量为0.1％。试剂：
Takara PrimeScript TM RT Master Mix Kit-RR036A
Thermo Power SYBR TM Green PCR Master Mix Kit-4367659
QIAGEN RNeasy Mini Kit-74106。
化合物：
待测化合物溶解在100％的DMSO体系中稀释成10mM待用。干扰素γ以磷酸盐缓冲液(PBS)稀释，处理终浓度为100ng/mL。
实验过程：
向细胞样品中分别添加各化合物和干扰素γ，使其终浓度分别为250nM和100ng/mL。加药孵育48小时后利用RNeasy试剂盒抽提细胞的RNA，并用Takara反转试剂盒反转为cDNA。取cDNA并添加基因引物、SYBR TM Green试剂通过qPCR方法检测目的基因的相对含量。
反应检测：
利用QuantStudio 7仪器读板得到目的基因的相对丰度。
实验结果见图1(CT26细胞)和图2(MCF7细胞)。
实验结论：与对照例1和2相比，本发明化合物对PD-L1基因表达具有高效的下调作用。
实验例2
生物测试数据：
实验例2：本发明化合物的对PD-L1蛋白水平影响
实验目的：
通过免疫印迹实验检测化合物对CT26细胞(来源：ATCC)的PD-L1影响，来评价化合物对PD-L1基因的下调作用。
实验方法：
CT26细胞分别加入250nM的化合物及干扰素γ刺激，培养48小时后收样，利用免疫印迹实验检测；DMSO在检测反应中的含量为0.1％。
试剂：
兔抗鼠PD-L1抗体：Abcam-ab213480。
化合物：
待测化合物溶解在100％的DMSO体系中稀释成10mM待用。干扰素γ以PBS稀释，处理终浓度为100ng/mL。
实验过程：
向细胞样品中分别添加各化合物和干扰素γ，使其终浓度分别为250nM和100ng/mL。加药孵育48小时后裂解细胞抽提全蛋白，并通过免疫印迹实验方法检测目的蛋白的含量。
反应检测：
利用Bio-Rad仪器扫描得到目的蛋白的图像。
实验结果见图3。
实验结论：
与对照例1和2相比，本发明化合物对PD-L1蛋白表达水平具有高效的下调作用。
实验例3
实验例3：本发明化合物在动物体内肿瘤模型上的抗肿瘤活性测试
实验目的：
在小鼠结肠癌CT26体内肿瘤模型上考察待测化合物的单用以及与小鼠抗PD-L1抗体联用的抑瘤效果
实验方法：
在雌性Balb/c小鼠皮下接种CT26(来源：ATCC)小鼠结肠癌细胞株，接种后按照体重随机分组，并且按照下列描述进行给药处理。
第1组(对照组)：接种当天下午开始给药，每天两次按照0.1mL/10g体重的剂量灌胃给药溶媒1(0.5％MC(甲基纤维素)+0.2％Tween-80)。接种后第4,7,10以及13天分别按照0.1mL/10g体重的剂量腹腔注射给予溶媒2(DPBS)一次。
第2组：接种后第4,7,10以及13天分别按照8mg/kg体重的剂量腹腔注射给予抗小鼠PD-L1抗体(B7-H1)(来源：BioX Cell)一次。
第3组：接种当天下午开始给药，每天两次按照5mg/kg体重的剂量灌胃给药实施例2(混悬于0.5％MC(甲基纤维素)+0.2％Tween-80)。
第4组：接种当天下午开始给药，每天两次按照10mg/kg体重的剂量灌胃给药实施例2(混悬于0.5％MC+0.2％Tween-80)。
第5组：接种当天下午开始给药，每天两次按照5mg/kg体重的剂量灌胃给药实施例2(混悬于0.5％MC+0.2％Tween-80)。同时接种后第4,7,10以及13天分别按照8mg/kg体重的剂量腹腔注射给予抗小鼠PD-L1抗体(B7-H1)一次。
实验期间每周三次称量小鼠体重，肿瘤成瘤后，与体重同步每周三次测量瘤体积，按照如下计算瘤体积：肿瘤体积(TV)计算公式如下：
TV(mm 3)＝l×w 2/2
其中，l表示肿瘤长径(mm)；w表示肿瘤短径(mm)。
肿瘤增殖率(T/C)的计算公式为：T/C＝100％×(RTV T/RTV C)
其中，RTV T表示治疗组RTV；RTV C表示溶剂对照组RTV。
肿瘤抑瘤率(％)的计算公式为：
Figure PCTCN2020074206-appb-000027
其中，TV t(T)表示治疗组第T天测量的肿瘤体积；
Figure PCTCN2020074206-appb-000028
表示溶剂对照组第T天测量的肿瘤体积。
组间用Student’s t-test进行统计学分析，p<0.05为有显著性差异。
联合作用效果用金氏公式进行评估：q＝联用组抑瘤率/(抗体单用组抑瘤率+化合物2(盐酸盐)低剂量组抑瘤率-抗体单用组抑瘤率×化合物2(盐酸盐)低剂量组抑瘤率)，q<0.85为拮抗作用，0.85<q<1.15为加和作用，q>1.15为联合作用
实验结果见图4。
实验结论：
在小鼠CT26肿瘤模型上，化合物2的盐酸盐无论是低剂量(5mg/kg)还是高剂量(10mg/kg)都有表现出了抗肿瘤活性，第22天的肿瘤增殖率(T/C)分别为：36.21％(p<0.05)和37.03％(p<0.05)。而联用组表现出了明显的抗肿瘤活性，在第22天的肿瘤增殖率(T/C)为11.73％(p<0.01)。不仅如此，抗PD-L1小鼠抗体联用化合物2表现出了明显的增效作用(q值＝1.14)。
本发明化合物在CT26模型中体现出优异的抗肿瘤作用，并且与PD-L1抗体联用增强其抗肿瘤性能。

Claims (9)

  1. 式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2020074206-appb-100001
    其中，
    R 1选自H、F、Cl、Br、I、OH和NH 2；
    R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和任选被1、2或3个R a取代C 1-3烷基；
    R a分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN和CH 3；
  2. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3，所述CH 3和CH 2CH 3任选被1、2或3个R a取代。
  3. 根据权利要求2所述化合物、其异构体或其药学上可接受的盐，其中，R 2和R 3分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3和CH 2CH 3。
  4. 根据权利要求1～3任意一项所述化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2020074206-appb-100002
    其中，
    R 2和R 3如权利要求1、2和3任意一项所定义。
  5. 下式所示化合物、其异构体或其药学上可接受的盐，所述化合物选自
    Figure PCTCN2020074206-appb-100003
  6. 根据权利要求5所述化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2020074206-appb-100004
  7. 一种药物组合物，包括治疗有效量的根据权利要求1～6任意一项所述的化合物、其异构体或其药学上可接受的盐作为活性成分以及药学上可接受的载体。
  8. 根据权利要求1～6任意一项所述的化合物、其异构体或其药学上可接受的盐或者权利要求7所述的组合物在制备PD-L1免疫调节剂相关药物上的应用。
  9. 根据权利要求8所述的应用，其特征在于，所述PD-L1免疫调节剂相关药物是用于实体瘤的药物。
PCT/CN2020/074206 2019-02-02 2020-02-03 作为pd-l1免疫调节剂的氟乙烯基苯甲酰胺基化合物 WO2020156568A1 (zh)

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