WO2020221236A1 - Trk激酶抑制剂及其用途 - Google Patents

Trk激酶抑制剂及其用途 Download PDF

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WO2020221236A1
WO2020221236A1 PCT/CN2020/087411 CN2020087411W WO2020221236A1 WO 2020221236 A1 WO2020221236 A1 WO 2020221236A1 CN 2020087411 W CN2020087411 W CN 2020087411W WO 2020221236 A1 WO2020221236 A1 WO 2020221236A1
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group
alkyl
compound
formula
pharmaceutically acceptable
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PCT/CN2020/087411
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French (fr)
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秦引林
苏梅
王德忠
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江苏柯菲平医药股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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]

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  • the present invention relates to a new compound, a pharmaceutical combination containing the compound, a method for preparing the compound, and the use of the compound in cancer prevention and treatment. More specifically, the present invention relates to a variety of oncogenic fusion kinase inhibitors and can be used to treat cancer.
  • TRK Tropomyosin
  • the TRK receptor family has three members: TRKA, TRKB and TRKC.
  • TRKA nerve growth factor
  • TRKB brain-derived growth factor
  • BDNF brain-derived growth factor
  • NT3 NT3 which activates TRKC.
  • Each TRK receptor contains an extracellular domain (ligand binding), a transmembrane domain, and an intracellular domain (including kinase domain). Upon ligand binding, the kinase catalyzes autophosphorylation and triggers downstream signal transduction pathways.
  • the overexpression, activation, amplification and/or mutation of TRK are associated with many cancers, including neuroblastoma, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, multiple myeloma, astrocytoma and neuroblastoma Tubuloma, glioma, melanoma, lung adenocarcinoma, large cell neuroendocrine tumor, bowel cancer.
  • non-selective small molecule inhibitors of TRKA, B and C, and TRK/Fc chimera are effective in inhibiting tumor growth and preventing tumor metastasis.
  • the present invention provides novel tropomyosin-related kinase (TRK) inhibitors and preparation methods, pharmaceutical compositions containing these kinase inhibitors and their use in the prevention and treatment of cancer.
  • TRK tropomyosin-related kinase
  • the present invention relates to a compound represented by formula (I), or a crystal form, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or a solvate thereof, or Prodrugs, or their metabolites:
  • Y is selected from a substituted or unsubstituted 3- to 10-membered heterocyclic ring or spiro ring, which has a ring heteroatom selected from N, O, and S, and Y is preferably a substituted or unsubstituted 4- to 6-membered heterocyclic ring;
  • the group is H, halogen, hydroxy, amino, carbonyl, amide, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 3 alkoxy C 1 -C 3 alkyl, C 1 -C 6 alkyl ester group, C 1 -C 6 amide group, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl.
  • the substituent is H, halogen, hydroxy, amino, carbonyl, amide, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 hydroxyalkyl, C 1- C 3 alkoxy group, C 1 -C 3 alkylamino group, C 1 -C 3 alkoxy group C 1 -C 3 alkyl group, C 1 -C 3 alkyl ester group, C 1 -C 3 amide group, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl.
  • the substituents are hydroxy, amide, C 1 -C 3 alkyl.
  • the substituent is selected from H, halogen, hydroxy, amino, carbonyl, amido, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, methyl Oxy, ethoxy, propoxy, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -CF 3 , -CHF 2 , vinyl, propenyl.
  • Y is selected from 5-membered heterocycloalkanes substituted with at least two substituents other than H.
  • Y is selected from substituted or unsubstituted 4-membered heterocycloalkanes.
  • the aforementioned compound represented by formula I is represented by formula Ia, Y is a 5-membered heterocyclic ring selected from N, and its structure is as follows:
  • R 11 , R 12 , R 13 , and R 14 are independently selected from H, halogen, OH, NH 2 , carbonyl, amido, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyl Alkyl group, C 1 -C 6 alkoxy group, C 1 -C 6 alkylamino group, C 1 -C 3 alkoxy group C 1 -C 3 alkyl group, C 1 -C 6 alkyl ester group, -C 1- C 6 alkyl amide, C 3 -C 6 cycloalkyl or C 2 -C 6 alkenyl.
  • R 11 , R 12 , R 13 , and R 14 are independently selected from H, hydroxyl, carbonyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 hydroxy alkane base.
  • R 11 , R 12 , R 13 , and R 14 are independently selected from H, halogen, hydroxyl, amino, carbonyl, amide, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylamino, C 1 -C 3 alkoxy C 1 -C 3 alkyl, C 1 -C 3 alkyl ester group , C 1 -C 3 amido, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl.
  • R 11 , R 12 , R 13 , and R 14 are independently selected from H, halogen, hydroxy, carbonyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclic Butyl, cyclopentyl, methoxymethyl, methoxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -CF 3 , -CHF 2 , vinyl, propenyl, amide.
  • At least two of R 11 , R 12 , R 13 , and R 14 are not H.
  • the aforementioned compound represented by formula Ia is represented by Ia-1,
  • R 12 , R 13 and R 14 are as defined above.
  • the compound represented by the aforementioned formula Ia is:
  • the aforementioned compound represented by formula I is represented by formula Ib, Y is a 4-membered heterocyclic ring selected from N, and its structure is as follows:
  • R 21 and R 22 are independently selected from H, halogen, OH, NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 alkyl ester Group, C 1 -C 6 amide group, or C 1 -C 6 hydroxyalkyl group.
  • R 21 and R 22 are independently selected from H, halogen, hydroxyl, amino, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylamino, C 1- C 3 alkyl ester group, C 1 -C 3 amide group or C 1 -C 3 hydroxyalkyl group; in some more specific embodiments, R 21 and R 22 are independently selected from H, halogen, -OH, amino, Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy or propoxy.
  • the compound represented by the aforementioned formula Ib is:
  • the present invention also provides a method for preparing the compound of formula I,
  • the synthetic route of INT-1 can be synthesized according to conventional methods in the art.
  • a synthetic route is provided as follows:
  • the compound of formula (I) above is trifluoroacetate, sulfate or hydrochloride.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula I according to the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
  • the present invention also provides the compound represented by formula (I), or its crystal form, or its stereoisomer, tautomer or its pharmaceutically acceptable salt or its solvate or its prodrug, or Application of metabolites as TRK inhibitors.
  • the present invention also provides the compound represented by formula (I) of the present invention, or its crystal form, or its stereoisomer, tautomer or its pharmaceutically acceptable salt or its solvate or its prodrug, Application of its metabolites in preparation of drugs for treating pain, inflammation, neurodegenerative diseases or cancer in mammals.
  • the cancer in the present invention includes but is not limited to human colon cancer.
  • a method for treating pain, inflammation, neurodegenerative disease or cancer in a mammal comprising administering to the mammal a therapeutically effective amount of the compound represented by any one of the above formula (I), Or its crystal form, its stereoisomer, tautomer or its pharmaceutically acceptable salt or its solvate or its prodrug, or its metabolite.
  • substitution refers to the replacement of a hydrogen atom or molecule in a molecule, including one substituent or multiple substituents.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br), iodine (I), or astatine (At) ion.
  • alkyl refers to a linear or branched saturated hydrocarbon group having the stated number of carbon atoms.
  • C 1 -C 6 alkyl refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms.
  • C 1 -C 6 alkyl groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl Group, isohexyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl, etc.
  • C 1 -C 3 alkyl refers to a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms.
  • alkoxy means O-alkyl.
  • C 1 -C 6 alkoxy refers to having an OC 1 to C 6 alkyl group.
  • alkylamino means N-alkyl.
  • C 1 -C 6 alkylamino refers to having an NC 1 to C 6 alkyl group.
  • haloalkyl refers to an alkyl group having more than one (including one) halogen substituent.
  • hydroxyalkyl refers to an alkyl group having more than one (including one) hydroxy group substituent.
  • alkoxyalkyl means alkyl-O-alkyl.
  • C 1 -C 3 alkoxy C 1 -C 3 alkyl group refers to having a C 1 -C 3 alkyl group-OC 1 -C 6 alkyl group.
  • alkyl ester group means a -OC(O)- group
  • C 1 -C 6 alkyl ester group means a -OC(O)-C 1 to C 6 alkyl group
  • cycloalkyl refers to a saturated monocyclic or polycyclic ring structure of all carbon atoms.
  • C 3 -C 6 cycloalkyl refers to a saturated monocyclic or polycyclic ring structure having a total of 3 to 6 carbon atoms.
  • C 3 -C 6 cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • amide group means -C(O)NH 2 or -NH-C(O)- group
  • C 1 -C 6 amide group means -NH-C(O)-C 1 ⁇ C 6 alkyl Or -C(O)-NH-C 1 to C 6 alkyl.
  • alkenyl refers to a linear, branched or cyclic non-aromatic hydrocarbon group containing 12 to 18 carbon atoms in the main chain and at least one carbon-carbon double bond. Therefore, "C 2 -C 6 alkenyl” refers to an alkenyl having 2 to 6 carbon atoms in the main chain. Alkenyl groups include vinyl, propenyl, butenyl, 2-methylbutenyl, cyclohexenyl and the like. The linear, branched or cyclic part of the alkenyl group may contain a double bond and this part may be substituted if a substituted alkenyl group is indicated.
  • heterocyclic ring refers to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom, wherein the heteroatom refers to a nitrogen atom, an oxygen atom, and a sulfur atom.
  • pharmaceutically acceptable refers to a carrier, carrier, diluent, excipient, and/or the salt formed is usually chemically or physically compatible with other ingredients constituting a pharmaceutical dosage form, and physiologically Compatible with the receptor.
  • salts and “pharmaceutically acceptable salts” refer to the above-mentioned compounds or other stereoisomers, and acid and/or basic salts formed with infinite and/or organic acids and bases, and also include zwitterionic salts (internal Salt), also including quaternary ammonium salts, such as alkyl ammonium salts. These salts can be directly obtained in the final isolation and purification of the compound. It can also be obtained by mixing the above-mentioned compounds, or their stereoisomers, with a certain amount of acid or base appropriately (for example, equivalent).
  • salts may form a precipitate in the solution and be collected by filtration, or recovered after evaporation of the solvent, or prepared by freeze-drying after reaction in an aqueous medium.
  • the salt in the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, butane Acid salt, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
  • one or more compounds of the present invention may be used in combination with each other.
  • the compound of the present invention can be used in combination with any other active agent to prepare drugs or pharmaceutical compositions for regulating cell function or treating diseases. If a group of compounds are used, these compounds can be administered to the subject simultaneously, separately or sequentially.
  • M means mol/L
  • nM means nmol/L
  • ⁇ M means ⁇ mol/L
  • room temperature means 25 ⁇ 5°C.
  • the new compound represented by formula I disclosed in the present invention exhibits good TRK inhibitory activity and anti-tumor effect, and provides a new option for clinical treatment of diseases related to abnormal TRK activity.
  • Figure 1 shows the tumor growth curve of small molecule antitumor drugs on human colon cancer KM12 xenograft tumor model mice after administration of small molecule antitumor drugs
  • Figure 2 shows the body weight of human colon cancer KM12 subcutaneous xenograft tumor model mice during administration.
  • the synthetic route is as follows:
  • compound 2 700 mg, 4.14 mmol
  • phosphorus oxychloride 5 mL
  • the excess phosphorus oxychloride is removed by rotary evaporation under reduced pressure, and the residue is adjusted to alkaline with 3mol/L sodium hydroxide aqueous solution.
  • the aqueous solution was extracted three times with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried.
  • the residue was purified with a silica gel column to obtain the product compound 3 (500 mg, yield 56%) as a white solid.
  • compound 5 (70 mg, 0.22 mmol) was dissolved in trifluoroacetic acid (1 mL) to obtain a transparent pale yellow solution, and then nitric acid (0.15 mL, 1.1 mmol) was added dropwise to the solution while stirring rapidly. After the addition, the reaction mixture was stirred at room temperature for another 15 minutes, and then poured onto ice for quenching with rapid stirring. The resulting pale yellow suspension was filtered, washed with water, then the solid was ground with methanol, and filtered under vacuum to obtain compound 6 (70 mg, yield 88%) as an off-white fine powder as a pale yellow solid.
  • the synthetic route is as follows:
  • the compound SM2 (3g, 12.24mol) was dissolved in N,N-dimethylformamide (30mL), the temperature was reduced to 0°C, and sodium hydrogen (1.03g, 25.68mmol) was added. The reaction was carried out at this temperature for half an hour. , Add benzyl bromide (2.72g, 15.90mmol). After reacting at room temperature for 2 hours, the reaction solution was quenched with water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure to obtain compound 7 (2.05 g, 50%) by column chromatography, white solid.
  • Example EXP-1 using commercially available compounds or the preparation methods of the intermediate compounds shown in the reference, the example compounds in Table 1 below were prepared.
  • the compounds of the above examples are applied to the detection and screening of TRK kinase inhibitory activity.
  • the inhibition percentage is calculated based on the following formula:
  • Inhibition % (Ratio max -Ratio compound )/(Ratio max -Ratio min )] ⁇ 100%
  • Ratio compound is the HTRF ratio at a given compound concentration
  • Ratio min is the HTRF ratio added to the blank hole
  • Ratio max is the HTRF ratio without adding the compound.
  • LOXO-101 represents a compound with the following structure:
  • Example 3 Inhibitory activity of the compound on the proliferation of KM12 cells
  • Adenosine Tri-Phosphate is an energy carrier shared by various life activities in nature, and is the smallest unit of energy storage and transfer.
  • the CellTiter-Glo TM live cell detection kit uses luciferase as the detection substance, and luciferase needs ATP to participate in the process of luminescence. Add CellTiter-Glo TM reagent to the cell culture medium to measure the luminescence value. The light signal is proportional to the amount of ATP in the system, and ATP is positively related to the number of living cells. Therefore, by using the CellTiter-Glo kit to detect ATP content, cell proliferation can be detected.
  • Cell plating Collect cultured KM12 cells (supplier: ATCC) and use Vi-Cell XR cell counter to count live cells. Adjust the cell suspension to an appropriate concentration with culture medium and add it to a 384-well cell culture plate. Add 54 ⁇ L of cell suspension to each well on a 384-well cell culture plate. The cell plating density depends on the growth rate of the cells. Cultivate in the corresponding incubator.
  • the cell survival rate is calculated by the formula: T/C ⁇ 100%.
  • T is the luminescence reading of the drug treatment group
  • C is the average luminescence reading of the solvent control group.
  • EXP-4 2.0 EXP-5 8.3 EXP-6 13.1 EXP-7 13.0 EXP-8 14.8 EXP-9 3.8 EXP-10 9.0 EXP-11 6.8 EXP-12 591.6 EXP-13 26.0 EXP-14 12 EXP-15 4.1 EXP-16 7.3 LOXO-101 7.8
  • the results show that the multiple compounds of the present invention exhibit higher cell proliferation inhibitory activity against human colon cancer KM12 cell line, and the inhibitory activity is better than LOXO-101.
  • the compounds of the above examples are applied to the detection and screening of CYP kinase inhibitory activity.
  • CYP 1A2 paracetamol
  • CVP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 Hydroxybupropion
  • CYP 2B6 4-Hydroxydiclofenac
  • CYP 2C9 Hydroxymephenytoin
  • CYP 2C19 Hydroxymephenytoin
  • CYP 2D6 1-Hydroxybufurol
  • Salaminophen CYP 3A4
  • Hydroxy Midazolam CYP 3A4
  • phenacetin (CYP 1A2), bupropion (CYP 2B6), diclofenac (CYP 2C9), s-mephenytoin (CYP 2C19), Bufurolol (CYP 2D6), testosterone (CYP 3A4), midazolam (CYP 3A4), mixed human liver microsomes 0.2mg protein/mL as a reaction solution, add human liver microsomes, 0.1M potassium phosphate buffer and add nicotinamide adenine as a coenzyme Dinucleoside phosphate, which initiates the reaction.
  • the above metabolites were quantified by LC/MS method.
  • the concentration of the compound of the present invention is 0, 0.014, 0.04, 0.12, 0.37, 1.11, 3.33, 10 ⁇ mol/L (8 points).
  • the concentration and the inhibition rate are calculated based on the following formula:
  • Inhibition % Bottom+(Top-Bottom)/(1+10 ⁇ ((LogEC50-X)*HillSlope))
  • IC 50 (nM) values measured for the compounds of the present invention are shown in Table 4 below.
  • cisapride was used as a positive control, and HEK293 cells expressing human ether-a-go related gene (hERG) channels were used to study the effect of the compound of the present invention on the ventricular
  • hERG human ether-a-go related gene
  • LC-MS/MS was used to determine the drug concentration of the compound in plasma at different times after intravenous (IV)/ or intragastric (PO) administration of the compound.
  • IV intravenous
  • PO intragastric
  • Drug preparation Compound EXP-1 was prepared into a clear solution with 10% DMSO+90% water as a solvent, and used for IV (intravenous injection) and PO (gavage) groups.
  • the dosage of each compound is: IV5mL/kg (administration concentration 0.2mg/mL), PO10mL/kg (administration concentration 1mg/mL).
  • AUC is 1011h*ng/mL
  • Cmax is 1296ng/mL
  • T 1/2 is 1.3h.
  • AUC is 361.7h*ng/mL
  • Cmax is 716.7ng/mL
  • T 1/2 is 0.73h.
  • the equilibrium dialysis method was used to evaluate the protein binding rate of the compound EXP-1 of the present invention in human plasma.
  • Preparation of plasma buffer apply 100 microliters of blank dialysis buffer to the receiver side of the dialysis chamber, and then add 1 ⁇ M test compound, 100 microliters of plasma, warfarin and quinine to the donor side of the dialysis chamber D is the control compound.
  • the device was placed in a shaker (60 rpm) at 37°C and incubated for 5 hours. The samples were quenched with 200 ⁇ L of acetonitrile containing internal standard (IS). After the experiment, the LC/MS/MS method was used for analysis.
  • %Bound 100 ⁇ ([Donor] 5h -[Receiver] 5h )/[Donor] 5h
  • the plasma protein binding rate of compound EXP-1 was 92.8%.
  • the compound EXP-1 of the above example was applied to the proliferation model test of KM12 cells.
  • the tumor diameter was measured with vernier calipers twice a week.
  • the anti-tumor efficacy of the compound is evaluated by TGI (%) or relative tumor growth rate T/C (%).
  • Relative tumor proliferation rate T/C(%) TRTV/CRTV ⁇ 100% (TRTV: treatment group RTV; CRTV: negative control group RTV).
  • RTV relative tumor volume
  • TGI (%) reflects the tumor growth inhibition rate.
  • TGI(%) [(1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the beginning of the treatment group))/(Average tumor volume at the end of treatment in the solvent control group-start treatment in the solvent control group Average tumor volume at time)] ⁇ 100%.
  • Tweight and Cweight represent the tumor weight of the administration group and the vehicle control group, respectively.
  • the statistical analysis is based on the RTV data at the end of the experiment using SPSS software.
  • the treatment group showed the best treatment effect on the 14th day after administration at the end of the trial, so statistical analysis was performed based on this data to evaluate the differences between the groups.
  • the comparison between two groups is analyzed by T-test, and the comparison between three or more groups is analyzed by one-way ANOVA. If the variances are uniform (the F value is not significantly different), the Dunnett method is used for analysis. If the variances are not uniform (F Values are significantly different), using Games-Howell method to test. p ⁇ 0.05 considered a significant difference.
  • the p value is obtained by analyzing the relative tumor volume value (RTV) using one-way ANOVA.
  • the p value is obtained by analyzing the tumor weight by one-way ANOVA and the vehicle treatment group, and the F value is significantly different (p ⁇ 0.05), and the Games-Howell method is used for analysis.
  • EXP-1 at a dose of 60-400mg/kg has a significant inhibitory effect on the growth of human colon cancer KM12 model nude mice, and high doses have better anti-tumor effects and are dose-dependently inhibited
  • Human colon cancer KM12 cells were transplanted subcutaneously in nude mice. The animals had no significant weight loss at all doses, and the animals were well tolerated and had no disease. The preliminary indications that these compounds have relatively small side effects.

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Abstract

本发明公开一种TRK激酶抑制剂及其用途，本发明所述的TRK激酶抑制剂如式(I)所示，还提供了所述化合物的制备方法、包含有这些激酶抑制剂的药物组合物及其在预防与治疗癌症中的用途；本发明公开的式I所示的新化合物，表现出了良好的TRK抑制活性，为临床治疗与TRK活性异常相关的疾病提供了一种新的选择。

Description

TRK激酶抑制剂及其用途 技术领域
本发明涉及新的化合物、包含该化合物的药物组合、制备该化合物的方法和该化合物在癌症预防与治疗中的用途。更具体而言，本发明涉及多种致癌性融合激酶抑制剂且可用于治疗癌症。
背景技术
原肌球蛋白(TRK)是由神经营养因子(NT)的可溶性生长因子活化的高亲合力受体。该TRK受体家族有三个成员：TRKA、TRKB和TRKC。再NT中，有(1)激活TRKA的神经生长因子(NGF)，(2)激活TRKB的脑衍生生长因子(BDNF)和NT-4/5和(3)激活TRKC的NT3。各TRK受体包含胞外域(配体结合)、跨膜区域和胞内域(包括激酶区域)。在配体结合时，该激酶催化了自磷酸化作用并触发下游信号转导途径。
TRK的过度表达、激活、扩增和/或突变与许多癌症有关，该癌症包括成神经细胞瘤、卵巢癌、前列腺癌、乳腺癌、胰腺癌、多发性骨髓瘤、星形细胞瘤与成神经管细胞瘤、神经胶质瘤、黑素瘤、肺腺癌、大细胞神经内分泌瘤、肠癌。具体而言，TRKA、B和C以及TRK/Fc嵌合体的非选择性小分子抑制剂在抑制肿瘤生长和阻止肿瘤转移中有效。
发明内容
本发明提供新颖的原肌球蛋白有关的激酶(TRK)抑制剂及制备方法、包含有这些激酶抑制剂的药物组合物及其在预防与治疗癌症中的用途。
更具体地，本发明涉及结构如式(I)所示的化合物、或其晶型、或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或其前药、或其代谢物：
Figure PCTCN2020087411-appb-000001
其中，
Y选自被取代或未取代的3至10元杂环或螺环，其具有选自N、O、S的环杂原子，Y优选为被取代或未取代的4至6元杂环；取代基为H、卤素、羟基、氨基、羰基、酰胺基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6羟基烷基、C 1-C 6烷氧基、C 1-C 6烷氨基、C 1-C 3 烷氧基C 1-C 3烷基、C 1-C 6烷基酯基、C 1-C 6酰胺基、C 3-C 6环烷基、C 2-C 6烯基。
在一些实施例中，取代基为H、卤素、羟基、氨基、羰基、酰胺基、C 1-C 3烷基、C 1-C 3卤代烷基、C 1-C 3羟基烷基、C 1-C 3烷氧基、C 1-C 3烷氨基、C 1-C 3烷氧基C 1-C 3烷基、C 1-C 3烷基酯基、C 1-C 3酰胺基、C 3-C 6环烷基、C 2-C 4烯基。
在一些更为具体的实施例中，取代基为羟基、酰胺基、C 1-C 3烷基。
在一些实施例中，取代基选自H、卤素、羟基、氨基、羰基、酰胺基、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、甲氧基、乙氧基、丙氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基、乙氧基乙基、羟甲基、羟乙基、羟丙基、-CF 3、-CHF 2、乙烯基、丙烯基。
在一些实施例中，Y选自至少被两个不为H的取代基取代的5元杂环烷。
在一些实施例中，Y选自被取代或未取代的4元杂环烷。
在一些实施例中，前述式I所示的化合物如式Ia所示，Y是具有选自N的5元杂环，其结构如下：
Figure PCTCN2020087411-appb-000002
式中，
R 11、R 12、R 13、R 14独立选自H、卤素、OH、NH 2、羰基、酰胺基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6羟基烷基、C 1-C 6烷氧基、C 1-C 6烷氨基、C 1-C 3烷氧基C 1-C 3烷基、C 1-C 6烷基酯基、-C 1-C 6烷基酰胺基、C 3-C 6环烷基或C 2-C 6烯基。
在一些实施例中，R 11、R 12、R 13、R 14独立选自H、羟基、羰基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6羟基烷基。
在一些实施例中，R 11、R 12、R 13、R 14独立选自H、卤素、羟基、氨基、羰基、酰胺基、C 1-C 3烷基、C 1-C 3卤代烷基、C 1-C 3羟基烷基、C 1-C 3烷氧基、C 1-C 3烷氨基、C 1-C 3烷氧基C 1-C 3烷基、C 1-C 3烷基酯基、C 1-C 3酰胺基、C 3-C 6环烷基、C 2-C 4烯基。
在一些更具体的实施例中，R 11、R 12、R 13、R 14独立选自H、卤素、羟基、羰基、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、甲氧基甲基、甲氧基乙基、羟甲基、羟乙基、羟丙基、-CF 3、-CHF 2、乙烯基、丙烯基、酰胺基。
在一些实施例中，R 11、R 12、R 13、R 14中至少两个不为H。
在一些更具体的实施例中，前述式Ia所示化合物如Ia-1所示，
Figure PCTCN2020087411-appb-000003
式中，R 12、R 13、R 14定义如上。
在一些更具体的实施例中，前述式Ia所示化合物为：
Figure PCTCN2020087411-appb-000004
在一些实施例中，前述式I所示的化合物如式Ib所示，Y是具有选自N的4元杂环，其结构如下：
Figure PCTCN2020087411-appb-000005
式中，
R 21、R 22独立选自H、卤素、OH、NH 2、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氨基、C 1-C 6烷基酯基、C 1-C 6酰胺基、或C 1-C 6羟基烷基。
在一些实施例中，R 21、R 22独立选自H、卤素、羟基、氨基、C 1-C 3烷基、C 1-C 3烷氧基，C 1-C 3烷氨基、C 1-C 3烷基酯基、C 1-C 3酰胺基或C 1-C 3羟基烷基；在一些更具体的实施例中，R 21、R 22独立选自H、卤素、-OH、氨基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基或丙氧基。
在一些更具体的实施例中，前述式Ib所示化合物为：
Figure PCTCN2020087411-appb-000006
本发明还提供一种式I所述化合物的制备方法，
Figure PCTCN2020087411-appb-000007
其中Y的定义如上。
在一些实施例中，INT-1的合成路线可以按照本领域常规方法合成，在本发明中，提供一种合成路线如下：
Figure PCTCN2020087411-appb-000008
在一种些实施例中，上述式(I)所述化合物，其是三氟乙酸盐、硫酸盐或盐酸盐。
本发明还提供一种药物组合物，其包含本发明所述的式I的化合物，或其药学上可接受的盐和药学上可接受的稀释剂或载体。
本发明还提供式(I)所示的化合物、或其晶型、或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或其前药、或其代谢物作为TRK抑制剂的应用。
本发明还提供本发明式(I)所示的化合物、或其晶型、或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或其前药、或其代谢物在用于制备治疗哺乳动物的疼痛、炎症、神经变性疾病或癌症药物中的应用。
在本发明的癌症包括但不限于人结肠癌。
一种用于治疗哺乳动物的疼痛、炎症、神经变性疾病或癌症的方法，所述方法包括向所述哺乳动物施用治疗有效量的上述任一项所述的式(I)所示的化合物、或其晶型、或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或其前药、或其代谢物。
关于本发明的使用术语的定义：除非另有说明，本文中的基团或者术语提供的初始定义用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予的含义。
术语“取代”是指分子中的氢原子或分子所替换，包括一个取代基或多个取代基的情况。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)、碘(I)或砹(At)离子。
术语“烷基”表示具有所述数目之碳原子的直链或支链饱和烃基。术语“C 1-C 6烷基”是指具有1-6个碳原子的直链或支链饱和烃基。C 1-C 6烷基包括但不限于甲基、乙基、 正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基、2,2-二甲基丁基和2,3-二甲基丁基等。术语“C 1-C 3烷基”是指具有1-3个碳原子的直链或支链饱和烃基。
术语“烷氧基”表示O-烷基。术语“C 1-C 6烷氧基”是指具有O-C 1～C 6烷基。
术语“烷氨基”表示N-烷基。术语“C 1-C 6烷氨基”是指具有N-C 1～C 6烷基。
术语“卤代烷基”表示具有一个以上(包含一个)卤素取代基的烷基。
术语“羟基烷基”表示具有一个以上(包含一个)羟素取代基的烷基。
术语“烷氧基烷基”表示烷基-O-烷基。术语“C 1-C 3烷氧基C 1-C 3烷基”是指具有C 1～C 3烷基-O-C 1～C 6烷基。
术语“烷基酯基”表示-O-C(O)-基团，“C 1-C 6烷基酯基”表示-O-C(O)-C 1～C 6烷基。
术语“环烷基”表示全部为碳原子的饱和的单环或多环的环结构。术语“C 3-C 6环烷基”是指具有总共3至6个碳原子的饱和的单环或多环环结构。C 3-C 6环烷基包括但不限于环丙基、环丁基、环戊基、环己基。
术语“酰胺基”表示-C(O)NH 2或-NH-C(O)-基团，“C 1-C 6酰胺基”表示-NH-C(O)-C 1～C 6烷基或-C(O)-NH-C 1～C 6烷基。
术语“烯基”指直链、支链或环状的，主链含有12～18个碳原子及至少一个碳-碳双键的非芳香烃基。因此，“C 2-C 6烯基”指主链具有2～6个碳原子的烯基。烯基包括乙烯基、丙烯基、丁烯基、2-甲基丁烯基和环己烯基等。烯基的直链、支链或环状部分可含有双键且如果指明了取代的烯基则此部分可被取代。
本发明取代基为“羰基”表示取代基与被取代的C形成“C＝O”。
本发明中“杂环”指包含至少一个杂原子的饱和环或非芳香性的不饱和环，其中杂原子指氮原子、氧原子、硫原子。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其他成分相兼容，并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其他立体异构体，与无极和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，在一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质 中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
在某些实施方式中，本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其他的活性试剂结合使用，用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物，则可将这些化合物同时、分别或有序地对受试对象进行给药。
本发明中“M”是指mol/L；“nM”是指nmol/L；“μM”是指μmol/L。
本发明中所述“室温”是指25±5℃。
本发明公开的式I所示的新化合物，表现出了良好的TRK抑制活性和抗肿瘤效果，为临床治疗与TRK活性异常相关的疾病提供了一种新的选择。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其他多种形式的修改、替换或变更。
附图说明
图1为小分子抗肿瘤药对人结肠癌KM12异种移植瘤模型荷瘤鼠在给予小分子抗肿瘤药后的肿瘤生长曲线；
图2为人结肠癌KM12皮下异种移植瘤模型荷瘤鼠在给药过程中的体重。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围，凡在本发明的构思前提下对本发明制备方法的简单改进都属于本发明的保护范围之内。下面实施例未注明具体条件的实验方法，通常按照本领域的公知手段。下述实施例中所用的试验材料，如无特殊说明，均为自常规生化试剂商店购买得到的。
1.制备中间体INT-1
Figure PCTCN2020087411-appb-000009
合成路线如下：
Figure PCTCN2020087411-appb-000010
步骤1.1化合物1的制备
室温下，原料SM1(3.8g，27.9mmol)和钯碳(3.8g，27.9mmol)溶于甲醇(50mL)中，氢气球条件下搅拌1小时。反应液用硅藻土过滤，滤液真空浓缩得到化合物1(6.0g，收率96％)，白色油状物。
LCMS：t R＝0.343min in 5-95AB_2.6min_214&254_Shimadzu.lcm，chromatography(SunFire C18 50*4.6mm)，MS(ESI)m/z＝84.1[M+H] +
步骤1.2化合物2的制备
化合物1(500mg，6.02mmol)和原料SM2(1.07g，14.4mmol)溶于乙醇(10mL)中，室温下加入乙醇钠(819mg，12.05mmol)，加完后升温至回流并保持此温度搅拌16小时。反应液冷却至室温，过滤，滤饼用冷的5mol/L稀盐酸洗，剩余固体真空干燥得到化合物2(700mg，收率68％)，白色固体。
LCMS：t R＝0.607min in 5-95AB_2.6min_214&254_Shimadzu.lcm，chromatography(SunFire C18 50*4.6mm)，MS(ESI)m/z＝170.0[M+H] +
步骤1.3化合物3的制备
在氮气保护下，化合物2(700mg，4.14mmol)和三氯氧磷(5mL)升温至100℃，并保持16小时。多余的三氯氧磷减压旋蒸除去，剩余物用3mol/L氢氧化钠水溶液调至碱性。该水溶液用乙酸乙酯萃取三次。有机层用无水硫酸钠干燥，过滤，滤液旋干。剩余物用硅胶柱纯化得到产物化合物3(500mg，收率56％)，白色固体。
LCMS：t R＝1.832min in 5-95AB_2.6min_214&254_Shimadzu.lcm，chromatography(SunFire C18 50*4.6mm).
步骤1.4化合物4的制备
室温下，向含有化合物3(500mg，2.44mmol)的冰醋酸(0.5mL)，甲醇(6mL)和四氢呋喃(6mL)的混合溶液中一次性添加锌铜试剂(1.58g，12.2mmol)。混合物升温至50℃并保持该温度搅拌3小时。经硅藻土过滤后，滤液旋干，剩余物用硅胶柱纯化得到化合物4(100mg，收率24％)。
LCMS：t R＝1.590min in 5-95AB_2.6min_214&254_Shimadzu.lcm，chromatography(SunFire C18 50*4.6mm).
步骤1.5化合物5的制备
在压力反应管中添加化合物4(100mg，0.58mmol)、化合物SM3(166mg，0.76mmol)、无水正丁醇(5mL)和二异丙基乙胺(226mg，1.75mmol)。将此溶液密封并在油浴160℃中加热过夜。冷却至室温，用乙酸乙酯稀释，用水和盐水洗涤，有机相经无水硫酸钠干燥。过滤，滤液旋干得粗产品化合物5(70mg，收率26％)，淡黄色固体，该粗产品直接用于下一步反应。
LCMS：t R＝1.995min in 5-95AB_2.6min_214&254_Shimadzu.lcm，chromatography(SunFire C18 50*4.6mm)，MS(ESI)m/z＝319.2[M+H] +
步骤1.6化合物6的制备
室温下，将化合物5(70mg，0.22mmol)溶解于三氟醋酸(1mL)中，得到透明淡黄色溶液，然后向该溶液中滴加硝酸(0.15mL，1.1mmol)，同时快速搅拌。在添加后，在室温下将反应混合物再搅拌15分钟，然后在快速搅拌下倒至冰上淬灭。过滤所得浅黄色悬浮液，用水冲洗，然后用甲醇研磨固体，并真空过滤，得到呈灰白色细粉末的化合物6(70mg，收率88％)，淡黄色固体。
LCMS：t R＝2.016min in 5-95AB_2.6min_214&254_Shimadzu.lcm，chromatography(SunFire C18 50*4.6mm)，MS(ESI)m/z＝364.1[M+H] +
步骤1.7化合物INT-1的制备
在室温和搅拌条件下，向含有化合物6(70mg，0.19mmol)的甲醇/二氯甲烷(1mL/1mL)的混合物中添加锌粉(127mg，1.95mmol)。在快速搅拌下，向该悬浮液中滴加饱和氯化铵水溶液(3mL)。在氯化铵添加完成后，使反应混合物冷却至室温，并再搅拌15分钟。用二氯甲烷稀释反应并通过滤纸过滤，用二氯甲烷冲洗滤饼。分离滤液有机层，并用二氯甲烷萃取水层。合并有机层，用饱和食盐水洗涤，经无水硫酸钠干燥并浓缩得 粗产物化合物INT-1(60mg，收率94％)，浅褐色固体，该粗产物直接用于下一步反应。
LCMS：t R＝0.965min in 30-95AB_2.6min_214&254_Shimadzu.lcm，chromatography(SunFire C18 50*4.6mm)，MS(ESI)m/z＝334.1[M+H] +
实施例1：化合物EXP-1的制备
Figure PCTCN2020087411-appb-000011
合成路线如下：
Figure PCTCN2020087411-appb-000012
步骤1-1化合物7的制备
将化合物SM2(3g，12.24mol)溶于N,N-二甲基甲酰胺(30mL)中，降温至0℃，加入纳氢(1.03g，25.68mmol)，反应在该温度下反应半小时后，加入苄溴(2.72g，15.90mmol)。室温反应2小时后，反应液用水淬灭，乙酸乙酯萃取，有机相合并，无水硫酸钠干燥，有机相减压浓缩，通过柱层析得到的化合物7(2.05g，50％)，白色固体。
LCMS:t R＝1.066min in A10B90_2.6min_214&254_Shimadzu.lcm,chromatography(SunFire C18 50*4.6mm 5um),MS(ESI)m/z 236.0[M-56+H] +.
步骤1-2化合物8的制备
将化合物7(2.05g，6.12mmol)溶于四氢呋喃(30mL)中，控温0℃加入四氢铝 锂(487.7mg，12.85mmol)，在0℃下反应3小时。用饱和的亚硫酸钠液淬灭，乙酸乙酯萃取，有机相合并，无水硫酸钠干燥，有机相减压浓缩，用硅胶柱色谱层析法纯化得到化合物8(1.55g，82.5％)，淡黄色油状。
步骤1-3化合物9的制备
将化合物8(1.18g，3.84mmol)，加入到含有N,N-二甲基甲酰胺(10mL)的体系中，体系降温至0℃，之后往体系加入纳氢(538.1mg，13.44mmol)，反应半小时后，加入对甲苯磺酰氯(1.1g，5.76mmol)，在室温下反应2小时。加入100mL水淬灭，并用乙酸乙酯萃取，依次用水和饱和食盐水洗涤，无水硫酸钠干燥过滤，减压浓缩，用硅胶柱色谱层析法(乙酸乙酯：石油醚)纯化得到化合物9(1.29g，总收率73％)，透明油状物。
LCMS:t R＝2.151min in A10B90_2.6min_214&254_Shimadzu.lcm,chromatography(SunFire C18 50*4.6mm 5um),MS(ESI)m/z 362.0[M-100+H] +.
步骤1-4化合物10的制备
将化合物9(1.2g，2.60mmol)溶解于二甲基亚砜的10mL体系中，加入硼氢化钠(246.2mg，6.5mmol)，升高温度至100℃反应过夜。反应结束后加入水100mL并用乙酸乙酯萃取，有机相干燥旋干，通过柱层析得到化合物10(263mg，总收率35％)。
LCMS:t R＝1.958min in A50B50_2.6min_214&254_Shimadzu.lcm,chromatography(SunFire C18 50*4.6mm 5um),MS(ESI)m/z＝236.3[M+H] +.
步骤1-5化合物11的制备
将化合物10(150mg，0.52mmol)加入到含有甲醇5mL和浓盐酸0.02mL的体系中，体系在3个大气压的条件下反应3小时。反应完后，硅藻土过滤旋干得到化合物11(100mg)，透明油状物。
LCMS:t R＝0.276min in A70B30_2.6min_214&254_Shimadzu.lcm,chromatography(SunFire C18 50*4.6mm 5um),MS(ESI)m/z 102.2[M-100+H] +.
步骤1-6化合物12的制备
将化合物11(100mg，0.50mmol)加入到含有甲醇/盐酸的5mL体系中，在室温下反应过夜。反应完后直接旋干得到化合物12(40mg)。
LCMS:t R＝0.287min in A70B30_2.6min_214&254_Shimadzu.lcm,chromatography(SunFire C18 50*4.6mm 5um),MS(ESI)m/z 102.1[M+H] +.
步骤1-7：化合物EXP-1的制备
将中间体INT-1(50mg，0.15mmol)，N,N-二异丙基乙胺(60.10mg,0.465mmol)，N,N'-羰基二咪唑(51.08mg,0.315mmol)加入到含有二氯甲烷10mL的体系中。体系升温至30℃搅拌30分钟。之后往该体系中加入化合物12(26.64mg,0.195mmol)，反应2小时。反应结束后直接浓缩得到粗产品，该粗品经Prep-HPLC纯化后得到化合物EXP-1(51.39mg,收率74％)
LCMS:t R＝1.474min in A70B30_2.6min_214&254_Shimadzu.lcm,chromatography(SunFire C18 50*4.6mm 5um),MS(ESI)m/z＝461.2[M+H] +.
1H NMR(400MHz,DMSO-d 6)δ8.95(d,J＝8.4Hz,1H),7.84(s,1H),7.23(td,J＝9.2,4.4Hz,1H),7.14–6.89(m,3H),5.54(d,J＝4.8Hz,1H),4.96(d,J＝4.0Hz,1H),4.32(m,J＝8.9,4.3Hz,1H),4.15–4.04(m,1H),3.97(m,J＝13.0,6.3Hz,1H),3.89–3.75(m,1H),3.49(m,J＝10.4,5.1Hz,1H),3.25(m,J＝10.4,3.4Hz,1H),2.44–2.31(m,1H),1.97(td,J＝12.5,6.9Hz,3H),1.85(m,J＝11.4,5.2Hz,1H),1.72–1.61(m,1H),1.15(d,J＝6.2Hz,3H).
依据与上述实施例EXP-1的方法，使用市售化合物或参考所示的中间化合物的制备方法而制备以下表1的实施例化合物。
【表1】
Figure PCTCN2020087411-appb-000013
Figure PCTCN2020087411-appb-000014
Figure PCTCN2020087411-appb-000015
Figure PCTCN2020087411-appb-000016
实施例2：化合物对TRK激酶抑制活性检测
将上述实施例的化合物应用于对TRK激酶抑制活性的检测和筛选。
96孔板上每孔加入相应体积DMSO。每孔分别加入20～30μL的100～200μM不同供试化合物储存液。震荡混合3min。对所有化合物进行3X系列稀释。在第二块96孔板上每孔加入60～80μL Kinase buffer，从第一块96孔板每孔取1～2μL溶液加入在第二块96孔板相应孔中。震荡混合3min。从第二块化合物稀释板每孔取5μL化合物稀释液转移到384孔测试板相应孔。在测试板每孔加1～2μL TK Substrate–biotin。每孔加1～2μL酶混合液。同时设置不加酶的blank孔。每孔加1～2μL ATP溶液，封好板子后室温进行反应。反应时间分别为：TRKA、TRKB和TRKC：30～40min。每孔加3～5μL of Streptavidin-XL665，3～5μL of TK Antibody-cryptate，封好板子后室温放置30分钟以结束反应。PerkinElmer EnVision机器上读取665nm和620nm的fluorescence。
IC50计算：
计算每个孔的HTRF ratio：(665signal/620signal)x 10*4.
抑制百分率基于以下公式计算：
抑制％＝(Ratio max-Ratio 化合物)/(Ratio max-Ratio min)]×100％
其中Ratio 化合物为给定化合物浓度下的HTRF ratio，Ratio min为加入blank孔的HTRF ratio，Ratio max为不加入化合物的情况下的HTRF ratio。通过使用GraphPad Prism 5.0软件，使用非线性回归模型绘制S型剂量-抑制率曲线并计算IC 50值。
LOXO-101表示具有如下结构的化合物：
Figure PCTCN2020087411-appb-000017
实验结果：
化合物测得的IC 50(nM)检测值如下表2所示。
【表2】化合物对TRK激酶抑制活性实验结果
Figure PCTCN2020087411-appb-000018
Figure PCTCN2020087411-appb-000019
结果表明：本发明的多个化合物在TRK激酶中展现了较高的激酶抑制活性，活性优于LOXO-101。
实施例3：化合物对KM12细胞增殖的抑制活性
三磷酸腺苷(Adenosine Tri-Phosphate,ATP)是自然界中各种生命活动中共用的能量载体，是能量储存和转移的最小单位。CellTiter-Glo TM活细胞检测试剂盒采用萤光素酶作检测物，发光过程中萤光素酶需要ATP的参与。向细胞培养基中加入CellTiter-Glo TM试剂，测量发光值，光信号和体系中ATP量成正比，而ATP又和活细胞数正相关。因此 通过使用CellTiter-Glo试剂盒检测ATP含量，可以检测出细胞的增殖情况。
3.1试验步骤
第1天：细胞铺板
1)细胞铺板：收集培养的KM12细胞(供应商：ATCC)并用Vi-Cell XR细胞计数仪进行活细胞计数。用培养基将细胞悬液调整到适当的浓度后加入384-孔细胞培养板中，每孔加54μL细胞悬液于384-孔细胞培养板，细胞铺板密度取决于细胞的生长速度，细胞置于相应的培养箱中培养。
第0天：药物处理
2)首先用DMSO配制3倍梯度稀释的系列测试化合物浓度(work solution-1)，再用RPMI1640+10％FBS对其进行100倍稀释得到work solution-2；用RPMI1640+10％FBS配制Cisplatin的work solution-2，然后从work solution-2中各取6μL加入到步骤1)准备好的含培养基的细胞孔中。这样每孔的体积为60μL，测试化合物处理孔与相应对照孔的DMSO终浓度为0.1％。细胞置相应的培养箱中培养。储存液配制及稀释图详情见附录“化合物稀释和终浓度图”。
第3天：读板
3)每孔加入30μL预先融化并平衡到室温的CTG溶液，用微孔板震荡器混匀2分钟，于室温放置10分钟后用Envision2104读板仪测定luminescence信号。
3.2数据处理
细胞存活率用公式：T/C×100％计算。其中T为药物处理组的luminescence读数，C为溶剂对照组的luminescence读数平均值。应用GraphPad Prism 5.0软件,使用非线性回归模型绘制S型剂量-抑制率曲线并计算IC50(T/C×100％＝50％)值。
3.3实验结果
【表3】化合物对细胞增殖抑制活性实验结果
Code ID KM12(IC 50,nM)
EXP-1 0.3
EXP-2 17.9
EXP-3 107.1
EXP-4 2.0
EXP-5 8.3
EXP-6 13.1
EXP-7 13.0
EXP-8 14.8
EXP-9 3.8
EXP-10 9.0
EXP-11 6.8
EXP-12 591.6
EXP-13 26.0
EXP-14 12
EXP-15 4.1
EXP-16 7.3
LOXO-101 7.8
结果表明：本发明的多个化合物对人结肠癌KM12细胞株展现了较高的细胞增殖抑制活性，抑制活性优于LOXO-101。
实施例4：CYP抑制试验
将上述实施例的化合物应用于对CYP激酶抑制活性的检测和筛选。
使用市售的混合人肝细胞微粒体，以作为人类主要CYP 7分子种类(CVP1A2，CYP2B6，CYP2C8，CYP2C9，CYP2C19，CYP2D6，CYP3A4)的典型底物代谢反应的对乙酰氨基苯酚(CYP 1A2)、羟基安非他酮(CYP 2B6)、4-羟基双氯芬酸(CYP 2C9)、羟基美芬妥英(CYP 2C19)、1-羟基丁呋洛尔(CYP 2D6)、柳胺酚(CYP 3A4)、羟基咪达唑仑(CYP 3A4)为指标，用LC/MS法测定各个探针药物的代谢产物的生成量被本发明化合物抑制的程度进行评价。
以底物、非那西丁(CYP 1A2)、安非他酮(CYP 2B6)、双氯芬酸(CYP 2C9)、s-美芬妥英(CYP 2C19)、丁呋洛尔(CYP 2D6)、睾丸素(CYP 3A4)、咪达唑仑(CYP 3A4)、混合人肝微粒体0.2mg蛋白质/mL作为反应溶液，加入含有人肝微粒体、0.1M磷酸钾缓冲液且添加作为辅酶的烟酰胺腺嘌呤二核苷磷酸盐，引发反应。利用LC/MS方法定量上述代谢物。本发明化合物浓度0,0.014,0.04,0.12,0.37,1.11,3.33,10μmol/L(8点)。
根据本发明化合物各浓度下的残存活性(％)，使用浓度与抑制率基于以下公式计算：
抑制％＝Bottom+(Top-Bottom)/(1+10^((LogEC50-X)*HillSlope))
实验结果：
本发明化合物测得的IC 50(nM)检测值如下表4所示。
【表4】
Figure PCTCN2020087411-appb-000020
结果表明：本发明的EXP-1对CYP酶的抑制作用较弱，避免引起与其他药物的药物药物相互作用。
备注：
1.如果10μM时代谢物生成百分比在50-70％之间，则使用外推法计算IC50。
2.如果0.014μM时代谢物生成百分比小于50％，则使用外推法计算IC50。
实施例5：hERG试验
将上述实施例的化合物EXP-1应用于对hERG试验。
以本发明化合物的心电图QT间隔延长危险性评价为目的，以西沙比利作为阳性对照品，使用表达出human ether-a-go related gene(hERG)通道的HEK293细胞，而研究本发明化合物对于心室再极化过程中发挥重要作用的延迟整流K+电流(Ikr)的作用。
使用全自动膜片钳仪系统(PC-505B，MP—225，PC-10(Narishige，Japan))，并通过全细胞膜片钳仪法，将细胞钳制在–80mV，然后用持续4秒方波去极化到40mV，再用持续2秒方波超极化到-40mV，以得到hERG尾电流，这一程序每20秒重复一次。hERG尾电流是纯hERG电流。检测第二个方波引发的最大尾电流，待其稳定后，将以 目标浓度溶解有本发明化合物的细胞外液(NaCl：137mM；KCl：4mM；CaCl 2：1.8mM；MgCl 2：1mM；4-(2-羟基乙基)-1-哌嗪乙磺酸：10mM；葡萄糖：10mM；pH＝7.4)于室温下作用10分钟。根据所获得的Ikr，以保持膜电位中的电流值为基准而对最大尾电流的绝对值进行测量。进一步算出本发明化合物前的对最大尾电流的抑制率，与介质应用组(0.1％二甲亚砜溶液)进行对比，评价本发明化合物对Ikr的影响。
试验结果：EXP-1:IC 50大于30μM。
实施例6：本发明化合物EXP-1的药物代谢动力学试验
以雄性BALB/c nude小鼠为受试动物，应用LC-MS/MS测定单词静脉注射(IV)/及灌胃(PO)给予化合物后，不同时刻血浆中化合物的药物浓度，研究本发明的化合物在小鼠体内的药代动力学行为，评价其药动学特征。
药物配制：化合物EXP-1以10％DMSO+90％水为溶媒配成澄清溶液，用于IV(静注)和PO(灌胃)组给药。每个化合物的给药剂量为：IV5mL/kg(给药浓度0.2mg/mL)，PO10mL/kg(给药浓度1mg/mL)。
实验结果：
采用
Figure PCTCN2020087411-appb-000021
8.1计算药代动力学参数，结果如下表示。
化合物EXP-1药代动力学参数：
口服：AUC是1011h*ng/mL,Cmax是1296ng/mL,T 1/2是1.3h.
静注：AUC是361.7h*ng/mL,Cmax是716.7ng/mL,T 1/2是0.73h.
实施例7：血浆蛋白结合率试验
用平衡透析法评价本发明化合物EXP-1在人血浆中的蛋白结合率。
血浆缓冲液的制备：将100微升空白透析缓冲液涂在透析室的接收器侧，然后在透析室的供体侧加入含有1μM的受试化合物，100微升的血浆，以华法林和奎尼丁为对照化合物。在96孔样品制备板中加入25微升的血浆和供试品及对照品，作为T 0血浆样品。将装置置于在37℃的摇床(60rpm)中，培育5小时。用含内标物(IS)的200μL乙腈对样品进行淬火。试验结束后，采用LC/MS/MS方法分析。
计算公式：
％Bound＝100×([Donor] 5h-[Receiver] 5h)/[Donor] 5h
％Recovery＝100×([Donor] 5h+[Receiver] 5h)/[Initial] 0h
Fu(％)＝100-％Bound
实验结果：
化合物EXP-1的血浆蛋白结合率92.8％。
实施例8：化合物的动物体内药效试验
将上述实施例的化合物EXP-1应用于对KM12细胞增殖模型试验。
8.1试验方法
准备6～8周雌性裸小鼠(上海灵畅生物科技有限公司)，在SPF级动物房以IVC(独立送风系统，恒温恒湿)笼具饲养(每笼4只)饲养。将0.1mL KM12细胞(5×10 6个)皮下接种于每只小鼠的右后背，肿瘤平均体积达到约120mm 3分组(每组6只)和给药(口服给药，QD)，给药剂量EXP-1：60mg/kg、200mg/kg、400mg/kg，LOXO-101：200mg/kg。
8.2瘤测量和实验指标
每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b2，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。相对肿瘤增殖率T/C(％)＝TRTV/CRTV×100％(TRTV：治疗组RTV；CRTV：阴性对照组RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝Vt/V0，其中V0是分组给药时(即D0)测量所得平均肿瘤体积，Vt为某一次测量时的平均肿瘤体积，TRTV与CRTV取同一天数据。
TGI(％)，反映肿瘤生长抑制率。TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积))/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。
在实验结束后将检测肿瘤重量，并计算T/Cweight百分比，Tweight和Cweight分别表示给药组和溶媒对照组的瘤重。
8.3统计分析
统计分析基于试验结束时RTV的数据运用SPSS软件进行分析。治疗组在试验结束时给药后第14天表现出最好的治疗效果，因此基于此数据进行统计学分析评估组间差异。两组间比较用T-test进行分析，三组或多组间比较用one-way ANOVA进行分析，如果方差齐(F值无显著性差异)，应用Dunnett法进行分析，如果方差不齐(F值有显著性差异)，应用Games-Howell法进行检验。p<0.05认为有显著性差异。
8.4试验结果
8.4.1EXP-1对人结肠癌KM12皮下异种移植肿瘤生长的抑制作用，结果如表5、表6和图1所示。
表5小分子抗肿瘤药对人结肠癌KM12皮下异种移植瘤模型的抑瘤效果(PG-D12)
Figure PCTCN2020087411-appb-000022
注：a.平均值±SEM，n＝6。
b.肿瘤生长抑制由T/C和TGI(TGI(％)＝[1-(T 12-T 0)/(V 12-V 0)]×100)计算。
c.p值运用one-way ANOVA进行分析肿瘤体积相对值(RTV)所得。
表6各组肿瘤重量
Figure PCTCN2020087411-appb-000023
注：a.平均值±SEM，n＝6
b.肿瘤生长抑制由T/C weight＝TW treatment/TW 溶媒计算。
c.p值运用one-way ANOVA与溶媒治疗组进行分析肿瘤重量所得，F值有显著性差异(p<0.05)，应用Games-Howell法进行分析。
8.4.2 EXP-1对动物体重的影响
实验动物的体重作为间接测定药物毒性的参考指标。在此模型中所有给药组均未显示有显著性体重下降(图2)。无发病现象。
8.5结论
本试验条件下，EXP-1在60-400mg/kg剂量下，对人结肠癌KM12模型裸鼠移植瘤生长有显著抑制作用，且高剂量的具有更好的抗肿瘤效果，呈剂量依赖性抑制人结肠癌KM12细胞裸鼠皮下移植瘤生长，动物在所有剂量下均无明显体重下降，动物耐受性良好且无发病现象，初步显示这些化合物具有比小的副作用。

Claims (10)

  1. 式(I)所示的化合物、或其晶型、或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或其前药、或其代谢物：
    Figure PCTCN2020087411-appb-100001
    其中，
    Y选自被取代或未取代的3至10元杂环或螺环，其具有选自N、O、S的环杂原子，Y优选为被取代或未取代的4至6元杂环；
    取代基为H、卤素、羟基、氨基、羰基、酰胺基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6羟基烷基、C 1-C 6烷氧基、C 1-C 6烷氨基、C 1-C 3烷氧基C 1-C 3烷基、C 1-C 6烷基酯基、C 1-C 6酰胺基、C 3-C 6环烷基、C 2-C 6烯基；优选的，取代基为H、卤素、羟基、氨基、羰基、酰胺基、C 1-C 3烷基、C 1-C 3卤代烷基、C 1-C 3羟基烷基、C 1-C 3烷氧基、C 1-C 3烷氨基、C 1-C 3烷氧基C 1-C 3烷基、C 1-C 3烷基酯基、C 1-C 3酰胺基、C 3-C 6环烷基、C 2-C 4烯基；进一步优选的，羟基、酰胺基、C 1-C 3烷基。
    在一些实施例中，取代基选自H、卤素、羟基、氨基、羰基、酰胺基、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、甲氧基、乙氧基、丙氧基、甲氧基甲基、乙氧基甲基、甲氧基乙基、乙氧基乙基、羟甲基、羟乙基、羟丙基、-CF 3、-CHF 2、乙烯基、丙烯基。
  2. 根据权利要求1所述的式(I)所示的化合物、或其晶型、或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或其前药、或其代谢物，其特征在于，Y选自至少被两个不为H的取代基取代的5元杂环烷，或者Y选自被取代或未取代的4元杂环烷。
  3. 根据权利要求1所述的式(I)所示的化合物、或其晶型、或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或其前药、或其代谢物，其特征在于，式I所示的化合物如式Ia所示：
    Figure PCTCN2020087411-appb-100002
    式中，
    R 11、R 12、R 13、R 14独立选自H、卤素、OH、NH 2、羰基、酰胺基、C 1-C 6烷基、C 1-C 6卤代烷基、C 1-C 6羟基烷基、C 1-C 6烷氧基、C 1-C 6烷氨基、C 1-C 3烷氧基C 1-C 3烷基、C 1-C 6烷基酯基、-C 1-C 6烷基酰胺基、C 3-C 6环烷基或C 2-C 6烯基；优选的，R 11、R 12、R 13、R 14独立选自H、羟基、羰基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6羟基烷基；优选的，R 11、R 12、R 13、R 14独立选自H、卤素、羟基、氨基、羰基、酰胺基、C 1-C 3烷基、C 1-C 3卤代烷基、C 1-C 3羟基烷基、C 1-C 3烷氧基、C 1-C 3烷氨基、C 1-C 3烷氧基C 1-C 3烷基、C 1-C 3烷基酯基、C 1-C 3酰胺基、C 3-C 6环烷基、C 2-C 4烯基；优选的，R 11、R 12、R 13、R 14独立选自H、卤素、羟基、羰基、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、甲氧基甲基、甲氧基乙基、羟甲基、羟乙基、羟丙基、-CF 3、-CHF 2、乙烯基、丙烯基、酰胺基；优选的，R 11、R 12、R 13、R 14中至少两个不为H。
  4. 根据权利要求3所述的式(I)所示的化合物、或其晶型、或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或其前药、或其代谢物，其特征在于，式Ia所示化合物如Ia-1所示：
    Figure PCTCN2020087411-appb-100003
    式中，R 12、R 13、R 14定义如权利要求3所述。
  5. 根据权利要求1所述的式(I)所示的化合物、或其晶型、或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或其前药、或其代谢物，其特征在于，式I所示的化合物如式Ib所示：
    Figure PCTCN2020087411-appb-100004
    式中，
    R 21、R 22独立选自H、卤素、OH、NH 2、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷氨基、C 1-C 6烷基酯基、C 1-C 6酰胺基、或C 1-C 6羟基烷基；优选的，R 21、R 22独立选自H、卤素、羟基、氨基、C 1-C 3烷基、C 1-C 3烷氧基，C 1-C 3烷氨基、C 1-C 3烷基酯基、C 1-C 3酰胺基或C 1-C 3羟基烷基；更优选的，R 21、R 22独立选自H、卤素、-OH、氨基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基或丙氧基。
  6. 化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药，所述化合物选自：
    Figure PCTCN2020087411-appb-100005
    Figure PCTCN2020087411-appb-100006
  7. 一种权利要求1所述的式I所述化合物的制备方法，
    Figure PCTCN2020087411-appb-100007
    其中Y的定义如权利要求1所述。
  8. 一种药物组合物，其包含权利要求1～6任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药和药学上可接受的稀释剂或载体。
  9. 权利要求1～6任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药和药学上可接受的稀释剂或载体作为TRK抑制剂的应用。
  10. 权利要求1～6任一项所述的化合物或其立体异构体、互变异构体或其药学上可接受的盐或其溶剂合物或者前药和药学上可接受的稀释剂或载体在用于制备治疗哺乳动物的疼痛、炎症、神经变性疾病或癌症药物中的应用。
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