CN111848626B - TRK kinase inhibitor and application thereof - Google Patents

TRK kinase inhibitor and application thereof Download PDF

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CN111848626B
CN111848626B CN202010337981.4A CN202010337981A CN111848626B CN 111848626 B CN111848626 B CN 111848626B CN 202010337981 A CN202010337981 A CN 202010337981A CN 111848626 B CN111848626 B CN 111848626B
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group
trk
tumor
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CN111848626A (en
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秦引林
苏梅
王德忠
王伟
娄雅静
田雪芹
王姗
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Jiangsu Carephar Pharmaceutical Co ltd
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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]

Abstract

The invention discloses a TRK kinase inhibitor and application thereof, wherein the TRK kinase inhibitor is shown as a formula (I), and also provides a preparation method of the compound, a pharmaceutical composition containing the kinase inhibitors and application thereof in preventing and treating cancers; the novel compound shown in the formula I shows good TRK inhibitory activity, provides a new choice for clinically treating diseases related to TRK activity abnormity,

Description

TRK kinase inhibitor and application thereof
Technical Field
The present invention relates to novel compounds, pharmaceutical combinations comprising the compounds, processes for preparing the compounds and the use of the compounds in the prevention and treatment of cancer. More particularly, the invention relates to various oncogenic fusion kinase inhibitors and may be used to treat cancer.
Background
Tropomyosin (TRK) is a high affinity receptor activated by soluble growth factors for neurotrophic factor (NT). There are three members of the TRK receptor family: TRKA, TRKB, and TRKC. Among the further NTs are (1) Nerve Growth Factor (NGF) which activates TRKA, (2) brain-derived growth factor (BDNF) which activates TRKB and NT-4/5 and (3) NT3 which activates TRKC. Each TRK receptor comprises an extracellular domain (ligand binding), a transmembrane region, and an intracellular domain (including a kinase region). Upon ligand binding, the kinase catalyzes autophosphorylation and triggers downstream signal transduction pathways.
Over-expression, activation, amplification and/or mutation of TRK is associated with many cancers, including neuroblastoma, ovarian cancer, prostate cancer, breast cancer, pancreatic cancer, multiple myeloma, astrocytoma and medulloblastoma, glioma, melanoma, lung adenocarcinoma, large cell neuroendocrine tumor, intestinal cancer. In particular, non-selective small molecule inhibitors of TRKA, B and C and TRK/Fc chimeras are effective in inhibiting tumor growth and preventing tumor metastasis.
Disclosure of Invention
The present invention provides novel tropomyosin-related kinase (TRK) inhibitors, methods of preparation, pharmaceutical compositions comprising these kinase inhibitors and their use in the prevention and treatment of cancer.
More specifically, the invention relates to a compound with a structure shown as a formula (I), or a crystal form thereof, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof:
Figure GDA0003049122780000011
wherein the content of the first and second substances,
y is selected from a substituted or unsubstituted 3 to 10 membered heterocyclic ring or spirocyclic ring having a ring heteroatom selected from N, O, S, preferably Y is a substituted or unsubstituted 4 to 6 membered heterocyclic ring; the substituent is H, halogen, hydroxyl, amino, carbonyl, amido, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C1-C6Alkylamino radical, C1-C3Alkoxy radical C1-C3Alkyl radical, C1-C6Alkyl ester group, C1-C6Amide group, C3-C6Cycloalkyl radical, C2-C6An alkenyl group.
In some embodiments, the substituent is H, halogen, hydroxy, amino, carbonyl, amido, C1-C3Alkyl radical, C1-C3Haloalkyl, C1-C3Hydroxyalkyl radical, C1-C3Alkoxy radical, C1-C3Alkylamino radical, C1-C3Alkoxy radical C1-C3Alkyl radical, C1-C3Alkyl ester group, C1-C3Amide group, C3-C6Cycloalkyl radical, C2-C4An alkenyl group.
In some more specific embodiments, the substituent is hydroxyl, amido, C1-C3An alkyl group.
In some embodiments, the substituent is selected from the group consisting of H, halogen, hydroxy, amino, carbonyl, amido, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxy, ethoxy, propoxy, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -CF3、-CHF2Vinyl, propenyl.
In some embodiments, Y is selected from a 5-membered heterocycloalkyl substituted with at least two substituents other than H.
In some embodiments, Y is selected from a substituted or unsubstituted 4 membered heterocycloalkyl.
In some embodiments, the compound of formula I is of formula Ia, Y is a 5-membered heterocycle having a structure selected from N, which is as follows:
Figure GDA0003049122780000021
in the formula (I), the compound is shown in the specification,
R11、R12、R13、R14independently selected from H, halogen, OH, NH2Carbonyl group, amide group, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C1-C6Alkylamino radical, C1-C3Alkoxy radical C1-C3Alkyl radical, C1-C6Alkyl ester group, -C1-C6Alkylamide group, C3-C6Cycloalkyl or C2-C6An alkenyl group.
In some embodiments, R11、R12、R13、R14Independently selected from H, hydroxy, carbonyl, C1-C6Alkyl radical, C3-C6Cycloalkyl radical, C1-C6A hydroxyalkyl group.
In some embodiments, R11、R12、R13、R14Independently selected from H, halogen, hydroxyl, amino, carbonyl, amido and C1-C3Alkyl radical, C1-C3Haloalkyl, C1-C3Hydroxyalkyl radical, C1-C3Alkoxy radical, C1-C3Alkylamino radical, C1-C3Alkoxy radical C1-C3Alkyl radical, C1-C3Alkyl ester group, C1-C3Amide group, C3-C6Cycloalkyl radical, C2-C4An alkenyl group.
In some more specific embodiments, R11、R12、R13、R14Independently selected from H, halogen, hydroxy, carbonyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxymethyl, methoxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, -CF3、-CHF2Vinyl, propenyl, amido.
In some embodiments, R11、R12、R13、R14At least two of which are not H.
In some more specific embodiments, the compound of formula Ia above is represented by Ia-1,
Figure GDA0003049122780000031
in the formula, R12、R13、R14As defined above.
In some more specific embodiments, the compound of formula Ia is:
Figure GDA0003049122780000032
in some embodiments, the compound of formula I is of formula Ib, Y is a 4-membered heterocycle having N, and is of the structure:
Figure GDA0003049122780000041
in the formula (I), the compound is shown in the specification,
R21、R22independently selected from H, halogen, OH, NH2、C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkylamino radical, C1-C6Alkyl ester group, C1-C6Amide group, or C1-C6A hydroxyalkyl group.
In some embodiments, R21、R22Independently selected from H, halogen, hydroxyl, amino and C1-C3Alkyl radical, C1-C3Alkoxy radical, C1-C3Alkylamino radical, C1-C3Alkyl ester group, C1-C3Amide group or C1-C3A hydroxyalkyl group; in some more specific embodiments, R21、R22Independently selected from H, halogen, -OH, amino, methyl, ethyl, n-propyl, isopropyl, methoxy, ethylOxy or propoxy.
In some more specific embodiments, the compound of formula Ib is:
Figure GDA0003049122780000042
the invention also provides a preparation method of the compound shown in the formula I,
Figure GDA0003049122780000043
wherein Y is as defined above.
In some embodiments, the synthetic route for INT-1 can be synthesized according to methods conventional in the art, and in the present invention, one synthetic route is provided as follows:
Figure GDA0003049122780000051
in some embodiments, the compound of formula (I) above is a trifluoroacetate, sulfate or hydrochloride salt.
The present invention also provides a pharmaceutical composition comprising a compound of formula I as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
The invention also provides application of the compound shown in the formula (I), or a crystal form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, or a metabolite thereof as a TRK inhibitor.
The invention also provides application of the compound shown in the formula (I) or a crystal form, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, or a metabolite thereof in preparing a medicament for treating pain, inflammation, neurodegenerative diseases or cancer of mammals.
Cancers in the present invention include, but are not limited to, human colon cancer.
A method for treating pain, inflammation, neurodegenerative disease or cancer in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I) as described in any one of the above, or a crystalline form thereof, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof.
Definitions of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for by a group or term herein apply to that group or term throughout the specification; for terms not specifically defined herein, the meanings that would be afforded to one skilled in the art should be given in light of the disclosure and the context.
The term "substituted" refers to the replacement of a hydrogen atom or molecule in a molecule, including the case of a substituent or substituents.
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), iodine (I), or astatine (At) ions.
The term "alkyl" denotes a straight or branched chain saturated hydrocarbon group having the stated number of carbon atoms. The term "C1-C6Alkyl "refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. C1-C6Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 2-dimethylbutyl, and 2, 3-dimethylbutyl, and the like. The term "C1-C3Alkyl "refers to a straight or branched chain saturated hydrocarbon group having 1 to 3 carbon atoms.
The term "alkoxy" denotes an O-alkyl group. The term "C1-C6Alkoxy "means having O-C1～C6An alkyl group.
The term "alkylamino" denotes N-alkyl. The term "C1-C6Alkylamino means having N-C1～C6An alkyl group.
The term "haloalkyl" denotes an alkyl group having more than one (including one) halogen substituent.
The term "hydroxyalkyl" denotes an alkyl group having more than one (including one) hydroxy substituent.
The term "alkoxyalkyl" denotes alkyl-O-alkyl. The term "C1-C3Alkoxy radical C1-C3Alkyl "means having C1～C3alkyl-O-C1～C6An alkyl group.
The term "alkyl ester group" denotes the group-O-C (O) -, C1-C6The alkyl ester group "represents-O-C (O) -C1～C6An alkyl group.
The term "cycloalkyl" denotes a saturated monocyclic or polycyclic ring structure of all carbon atoms. The term "C3-C6Cycloalkyl "refers to a saturated monocyclic or polycyclic ring structure having a total of 3 to 6 carbon atoms. C3-C6Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
The term "amido" denotes-C (O) NH2Or a-NH-C (O) -group, "C1-C6Amido "represents-NH-C (O) -C1～C6Alkyl or-C (O) -NH-C1～C6An alkyl group.
The term "alkenyl" refers to a straight, branched or cyclic non-aromatic hydrocarbon group having a main chain containing 12 to 18 carbon atoms and at least one carbon-carbon double bond. Thus, "C2-C6The alkenyl group means an alkenyl group having 2 to 6 carbon atoms in the main chain. Alkenyl groups include ethenyl, propenyl, butenyl, 2-methylbutenyl, cyclohexenyl and the like. The straight, branched, or cyclic portion of an alkenyl group can contain a double bond and this portion can be substituted if a substituted alkenyl group is indicated.
The substituent "carbonyl" in the present invention means that the substituent forms "C ═ O" with the substituted C.
The term "heterocyclic ring" as used herein refers to a saturated or non-aromatic unsaturated ring containing at least one heteroatom, wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of the above compounds or other stereoisomers, with non-polar and/or organic acids and bases, as well as zwitterionic salts (inner salts), and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by mixing the above-mentioned compounds with a certain amount of an acid or a base as appropriate (for example, an equivalent amount). These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salts described in the present invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate salts of the compounds.
In certain embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
In the present invention, "M" means mol/L; "nM" refers to nmol/L; "μ M" means μmol/L.
The term "room temperature" as used herein means 25. + -. 5 ℃.
The novel compound shown in the formula I shows good TRK inhibitory activity and anti-tumor effect, and provides a new choice for clinically treating diseases related to TRK activity abnormity.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
Drawings
FIG. 1 is a tumor growth curve of a tumor-bearing mouse of a human colon carcinoma KM12 xenograft tumor model with a small molecule antitumor drug after administration of the small molecule antitumor drug;
FIG. 2 is the body weight of tumor-bearing mice in the human colon cancer KM12 subcutaneous xenograft tumor model during administration.
Detailed Description
The present invention is further described with reference to the following examples, which are not intended to limit the scope of the present invention, and all simple modifications of the preparation method of the present invention based on the concept of the present invention are within the scope of the present invention. The following examples are experimental methods without specifying specific conditions, and generally follow the methods known in the art. The test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified.
1. Preparation of intermediate INT-1
Figure GDA0003049122780000071
The synthetic route is as follows:
Figure GDA0003049122780000081
step 1.1 preparation of Compound 1
The starting materials SM1(3.8g, 27.9mmol) and palladium on carbon (3.8g, 27.9mmol) were dissolved in methanol (50mL) at room temperature and stirred under a hydrogen balloon for 1 hour. The reaction solution was filtered through celite, and the filtrate was concentrated in vacuo to give compound 1(6.0g, yield 96%) as a white oil.
LCMS：tR＝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]+
Step 1.2 preparation of Compound 2
Compound 1(500mg, 6.02mmol) and starting material SM2(1.07g, 14.4mmol) were dissolved in ethanol (10mL), sodium ethoxide (819mg, 12.05mmol) was added at room temperature, after which time the mixture was warmed to reflux and stirred for 16 h while maintaining this temperature. The reaction was cooled to room temperature, filtered, the filter cake washed with cold 5mol/L dilute HCl and the remaining solid dried under vacuum to give Compound 2(700mg, yield 68%) as a white solid.
LCMS：tR＝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]+
Step 1.3 preparation of Compound 3
Under nitrogen, compound 2(700mg, 4.14mmol) and phosphorus oxychloride (5mL) were warmed to 100 ℃ and held for 16 hours. Excess phosphorus oxychloride is removed by reduced pressure rotary evaporation, and the residue is adjusted to be alkaline by 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 by silica gel column to give the product compound 3(500mg, yield 56%) as a white solid.
LCMS：tR＝1.832min in 5-95AB_2.6min_214&254_Shimadzu.lcm，chromatography(SunFire C18 50*4.6mm).
Step 1.4 preparation of Compound 4
To a mixed solution of glacial acetic acid (0.5mL), methanol (6mL) and tetrahydrofuran (6mL) containing compound 3(500mg, 2.44mmol) was added zinc copper reagent (1.58g, 12.2mmol) at room temperature in one portion. The mixture was warmed to 50 ℃ and kept stirring at this temperature for 3 hours. After filtration through celite, the filtrate was spin-dried, and the residue was purified by silica gel column to give compound 4(100mg, yield 24%).
LCMS：tR＝1.590min in 5-95AB_2.6min_214&254_Shimadzu.lcm，chromatography(SunFire C18 50*4.6mm).
Step 1.5 preparation of Compound 5
Compound 4(100mg, 0.58mmol), compound SM3(166mg, 0.76mmol), n-butanol anhydrous (5mL), and diisopropylethylamine (226mg, 1.75mmol) were added to a pressure reaction tube. The solution was sealed and heated in an oil bath at 160 ℃ overnight. Cooled to room temperature, diluted with ethyl acetate, washed with water and brine and the organic phase dried over anhydrous sodium sulfate. Filtration and spin-drying of the filtrate gave the crude compound 5(70mg, 26% yield) as a pale yellow solid which was used directly in the next reaction.
LCMS：tR＝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]+
Step 1.6 preparation of Compound 6
Compound 5(70mg, 0.22mmol) was dissolved in trifluoroacetic acid (1mL) at room temperature to give a clear pale yellow solution, to which was then added dropwise nitric acid (0.15mL, 1.1mmol) with rapid stirring. After addition, the reaction mixture was stirred at room temperature for a further 15 minutes and then quenched by pouring onto ice with rapid stirring. The resulting pale yellow suspension was filtered, washed with water, then the solid was triturated with methanol and filtered under vacuum to give compound 6(70mg, yield 88%) as an off-white fine powder as a pale yellow solid.
LCMS：tR＝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]+
Step 1.7 preparation of Compound INT-1
To a mixture of compound 6(70mg, 0.19mmol) in methanol/dichloromethane (1mL/1mL) was added zinc powder (127mg, 1.95mmol) at room temperature with stirring. To the suspension was added dropwise saturated aqueous ammonium chloride (3mL) with rapid stirring. After the ammonium chloride addition was complete, the reaction mixture was allowed to cool to room temperature and stirred for an additional 15 minutes. The reaction was diluted with dichloromethane and filtered through filter paper, rinsing the filter cake with dichloromethane. The organic layer of the filtrate was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the crude compound INT-1(60mg, yield 94%) as a pale brown solid, which was used directly in the next reaction.
LCMS：tR＝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]+
Example 1: preparation of Compound EXP-1
Figure GDA0003049122780000101
The synthetic route is as follows:
Figure GDA0003049122780000102
step 1-1 preparation of Compound 7
Compound SM2(3g, 12.24mol) was dissolved in N, N-dimethylformamide (30mL), cooled to 0 deg.C, and after addition of sodium hydride (1.03g, 25.68mmol) reacted at this temperature for half an hour, benzyl bromide (2.72g, 15.90mmol) was added. After 2 hours reaction at room temperature, the reaction was quenched with water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound 7(2.05g, 50%) was obtained by column chromatography as a white solid.
LCMS:tR＝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]+.
Step 1-2 preparation of Compound 8
Compound 7(2.05g, 6.12mmol) was dissolved in tetrahydrofuran (30mL), and lithium aluminum hydride (487.7mg, 12.85mmol) was added thereto at a temperature of 0 ℃ to react at 0 ℃ for 3 hours. Quenching with saturated sodium sulfite solution, extracting with ethyl acetate, combining the organic phases, drying over anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, and purifying by silica gel column chromatography to give compound 8(1.55g, 82.5%) as a pale yellow oil.
Steps 1-3 preparation of Compound 9
Compound 8(1.18g, 3.84mmol) was added to a system containing N, N-dimethylformamide (10mL), the system was cooled to 0 ℃ and then sodium hydrogen (538.1mg, 13.44mmol) was added to the system, and after reaction for half an hour, p-toluenesulfonyl chloride (1.1g, 5.76mmol) was added and the reaction was carried out at room temperature for 2 hours. After quenching with 100mL of water and extraction with ethyl acetate, the mixture was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate: petroleum ether) to obtain compound 9(1.29g, total yield: 73%) as a transparent oil.
LCMS:tR＝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]+.
Steps 1-4 preparation of Compound 10
Compound 9(1.2g, 2.60mmol) was dissolved in 10mL of dimethylsulfoxide, sodium borohydride (246.2mg, 6.5mmol) was added, and the temperature was raised to 100 ℃ for reaction overnight. After completion of the reaction, 100mL of water was added and extracted with ethyl acetate, the organic phase was dried and dried, and compound 10(263mg, 35% total yield) was obtained by column chromatography.
LCMS:tR＝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]+.
Steps 1-5 preparation of Compound 11
Compound 10(150mg, 0.52mmol) was added to a system containing 5mL of methanol and 0.02mL of concentrated hydrochloric acid, and the system was reacted under 3 atmospheres for 3 hours. After completion of the reaction, celite was filtered and spin-dried to give compound 11(100mg) as a clear oil.
LCMS:tR＝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]+.
Steps 1-6 preparation of Compound 12
Compound 11(100mg, 0.50mmol) was added to a 5mL system containing methanol/hydrochloric acid and reacted at room temperature overnight. After completion of the reaction, compound 12(40mg) was obtained by direct spin-drying.
LCMS:tR＝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]+.
Step 1-7: preparation of Compound EXP-1
Intermediate INT-1(50mg, 0.15mmol), N, N-diisopropylethylamine (60.10mg,0.465mmol), N, N' -carbonyldiimidazole (51.08mg,0.315mmol) were added to a system containing 10mL of dichloromethane. The system was warmed to 30 ℃ and stirred for 30 minutes. Thereafter, compound 12(26.64mg,0.195mmol) was added to the system, and reacted for 2 hours. After the reaction was complete, the reaction mixture was directly concentrated to give a crude product which was purified by Prep-HPLC to give the compound EXP-1(51.39mg, 74% yield)
LCMS:tR＝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-d6)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).
The example compounds of Table 1 below were prepared according to the method similar to that of example EXP-1 above, using commercially available compounds or the preparation method referenced to the intermediate compounds shown.
[ TABLE 1 ]
Figure GDA0003049122780000121
Figure GDA0003049122780000131
Figure GDA0003049122780000141
Figure GDA0003049122780000151
Example 2: detection of TRK kinase inhibitory Activity of Compounds
The compounds of the above examples were applied to the detection and screening of TRK kinase inhibitory activity.
The corresponding volume of DMSO was added to each well of the 96-well plate. Each well is filled with 20-30 μ L of 100-200 μ M stock solutions of different test compounds. Mix for 3min with shaking. All compounds were diluted 3X serially. Adding 60-80 mu L of Kinase buffer into each hole of the second 96-hole plate, and taking 1-2 mu L of solution from each hole of the first 96-hole plate and adding the solution into the corresponding hole of the second 96-hole plate. Mix for 3min with shaking. From the second compound dilution plate, 5. mu.L of compound dilution per well was transferred to the corresponding well of the 384-well test plate. 1-2 μ L TK Substrate-biotin was added to each well of the test plate. Adding 1-2 mu L of enzyme mixed solution into each hole. Blank wells were also provided with no enzyme added. Adding 1-2 mu L of ATP solution into each hole, sealing the plate, and reacting at room temperature. The reaction time is respectively as follows: TRKA, TRKB and TRKC: 30-40 min. Adding 3-5 muL of Streptavidin-XL665 and 3-5 muL of TK Antibody-cryptate into each well, sealing the plate, and standing at room temperature for 30 minutes to finish the reaction. Fluorescences at 665nm and 620nm were read on a Perkinelmer EnVision machine.
IC50 calculates:
calculate the HTRF ratio for each well: (665signal/620signal) x 10 x 4.
Percent inhibition was calculated based on the following equation:
inhibition% (% Ratio)max-RatioCompound (I))/(Ratiomax-Ratiomin)]×100％
Wherein RatioCompound (I)Is the HTRF Ratio, Ratio at a given compound concentrationminHTRF Ratio, Ratio for adding blank wellmaxIs the HTRF ratio without the addition of a compound. Sigmoidal dose-inhibition curves were plotted using a non-linear regression model and IC was calculated by using GraphPad Prism 5.0 software50The value is obtained.
LOXO-101 represents a compound having the structure:
Figure GDA0003049122780000161
the experimental results are as follows:
IC determined by Compound50The (nM) values are shown in Table 2 below.
[ TABLE 2 ] test results of TRK kinase inhibitory Activity of Compounds
Figure GDA0003049122780000162
Figure GDA0003049122780000171
The results show that: a plurality of compounds of the invention show higher kinase inhibition activity in TRK kinase, and the activity is better than LOXO-101.
Example 3: inhibitory Activity of Compound on KM12 cell proliferation
Adenosine Triphosphate (ATP) is an energy carrier commonly used in various life activities in nature, and is the minimum unit for energy storage and transfer. CellTiter-GloTMThe living cell detection kit adopts luciferase as a detection object, and the luciferase needs participation of ATP in the luminescence process. Adding CellTiter-Glo to cell culture mediumTMThe reagent is used for measuring the luminous value, the light signal is in direct proportion to the amount of ATP in the system, and the ATP is positively correlated with the number of living cells. Therefore, the proliferation of the cells can be detected by detecting the ATP content using the CellTiter-Glo kit.
3.1 test procedure
Day 1: cell plating
1) Cell plating: cultured KM12 cells (supplier: ATCC) were collected and subjected to viable Cell counting using a Vi-Cell XR Cell counter. The cell suspension was adjusted to the appropriate concentration with the medium and added to 384-well cell culture plates, 54. mu.L of cell suspension per well was added to the 384-well cell culture plates, the cell plating density was determined by the growth rate of the cells, and the cells were cultured in the corresponding incubator.
Day 0: drug treatment
2) Firstly, preparing 3 times of gradient diluted series test compound concentration (work solution-1) by DMSO, and then diluting the series test compound concentration (work solution-1) by RPMI1640+ 10% FBS for 100 times to obtain work solution-2; cisplatin's work solution-2 was prepared with RPMI1640+ 10% FBS, and then 6. mu.L each of the work solution-2 was added to the well containing the culture medium prepared in step 1). Thus the volume per well was 60 μ L and the final DMSO concentration in the test compound treated wells and the corresponding control wells was 0.1%. The cells are cultured in corresponding incubators.
Day 3: reading board
3) mu.L of CTG solution previously melted and equilibrated to room temperature was added to each well, mixed by a microplate shaker for 2 minutes, left at room temperature for 10 minutes, and then assayed for luminescense signal by an Envision2104 plate reader.
3.2 data processing
Cell viability using the formula: T/C × 100% calculation. Where T is the luminence reading for the drug treated group and C is the mean luminence reading for the solvent control group. Sigmoidal dose-inhibition curves were plotted using a non-linear regression model using GraphPad Prism 5.0 software and IC50(T/C × 100% ═ 50%) values were calculated.
3.3 results of the experiment
[ TABLE 3 ] results of experiments on the cell proliferation inhibitory activity of the Compounds
Figure GDA0003049122780000181
Figure GDA0003049122780000191
The results show that: the compounds of the invention show higher cell proliferation inhibition activity on human colon cancer KM12 cell strain, and the inhibition activity is better than LOXO-101.
Example 4: CYP inhibition assay
The compounds of the above examples were applied to the detection and screening of CYP kinase inhibitory activity.
The degree of inhibition of the metabolite production of each probe drug by the compound of the present invention was evaluated by an LC/MS method using commercially available mixed human hepatocyte microsomes as indicators for acetaminophen (CYP 1a2), hydroxyamphetanone (CYP 2B6), 4-hydroxydiclofenac (CYP 2C9), hydroxymetryin (CYP 2C19), 1-hydroxybutylol (CYP 2D6), salidroside (CYP 3A4), and hydroxymidazolam (CYP 3A4), which are typical substrate metabolic reactions of human major CYP 7 molecular species (CVP1a2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3 A4).
The reaction is initiated by adding nicotinamide adenine dinucleotide phosphate containing human liver microsome and 0.1M potassium phosphate buffer solution as well as coenzyme to a reaction solution of substrate, phenacetin (CYP 1A2), bupropion (CYP 2B6), diclofenac (CYP 2C9), s-mephenytoin (CYP 2C19), bufalol (CYP 2D6), testosterone (CYP 3A4), midazolam (CYP 3A4) and mixed human liver microsome of 0.2mg protein/mL. The metabolites were quantified by LC/MS method. The concentration of the compound of the present invention was 0,0.014,0.04,0.12,0.37,1.11,3.33, 10. mu. mol/L (point 8).
The residual activity (%) at each concentration of the compound according to the present invention was calculated using the concentration and the inhibition ratio based on the following formula:
inhibition [% ]. about ] - (% Top-Bottom + ]) (1+10^ LogEC50-X) [% ] HillSlope) ]
The experimental results are as follows:
IC determination of the Compounds of the invention50The (nM) measurements are shown in Table 4 below.
[ TABLE 4 ]
Figure GDA0003049122780000201
The results show that: the EXP-1 of the invention has weak inhibition effect on CYP enzyme, and avoids causing drug-drug interaction with other drugs.
Remarking:
1. if the percentage metabolite production is between 50-70% at 10. mu.M, then IC50 is calculated using extrapolation.
2. If the percentage of metabolite production at 0.014 μ M is less than 50%, then the IC50 is calculated using extrapolation.
Example 5: hERG assay
The compound EXP-1 of the above example was used in the hERG assay.
With the object of evaluating the risk of QT interval prolongation in an electrocardiogram of the compound of the present invention, the effect of the compound of the present invention on the delayed rectification K + current (Ikr) that plays an important role in the ventricular repolarization process was investigated using HEK293 cells expressing human ether-a-related gene (hERG) as a positive control.
Using a fully automated patch clamp system (PC-505B, MP-225, PC-10(Narishige, Japan)) and by whole cell patch clamp method, cells were clamped at-80 mV, then depolarized to 40mV with a4 second duration square wave, and then hyperpolarized to-40 mV with a2 second duration square wave to obtain hERG tail current, this procedure was repeated every 20 seconds. The hERG tail current is pure hERG current. The second square wave-induced maximum tail current was measured and, after stabilization, the extracellular fluid (NaCl: 137 mM; KCl: 4 mM; CaCl) in which the compound of the invention was dissolved at the target concentration was used2：1.8mM；MgCl2: 1 mM; 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid: 10 mM; glucose: 10 mM; pH 7.4) at room temperature for 10 minutes. From the obtained Ikr, the absolute value of the maximum tail current was measured with reference to the current value in the retained membrane potential. The inhibition rate of the compound of the present invention on the maximum tail current before use was further calculated and compared with the vehicle application group (0.1% dimethylsulfoxide solution) to evaluate the effect of the compound of the present invention on Ikr.
And (3) test results: EXP-1: IC50Greater than 30 μ M.
Example 6: pharmacokinetic testing of Compound EXP-1 of the invention
A male BALB/c nude mouse is taken as a test animal, LC-MS/MS is used for measuring the drug concentration of the compound in plasma at different moments after the compound is administered by intravenous Injection (IV) and intragastric administration (PO), the pharmacokinetic behavior of the compound in the mouse is researched, and the pharmacokinetic characteristic of the compound is evaluated.
Preparing the medicine: compound EXP-1 was formulated as a clear solution in 10% DMSO + 90% water as vehicle for IV (intravenous) and PO (intragastric) administration. The dose of each compound administered was: IV5mL/kg (administration concentration 0.2mg/mL), PO10mL/kg (administration concentration 1 mg/mL).
The experimental results are as follows:
by using
Figure GDA0003049122780000211
8.1 calculation of pharmacokinetic parameters, the results are presented below.
Compound EXP-1 pharmacokinetic parameters:
oral administration: AUC was 1011h ng/mL, Cmax was 1296ng/mL, T1/2Is 1.3h.
Intravenous injection: AUC was 361.7h ng/mL, Cmax was 716.7ng/mL, T1/2Is 0.73h.
Example 7: plasma protein binding Rate assay
The protein binding rate of EXP-1 of the present invention in human plasma was evaluated by equilibrium dialysis.
Preparation of plasma buffer: 100 microliters of blank dialysis buffer was applied to the receiver side of the dialysis chamber, and then the donor side of the dialysis chamber was loaded with the test compound at 1 μ M, 100 microliters of plasma, with warfarin and quinidine as control compounds. To a 96 well sample preparation plate, 25 microliters of plasma and test and control were added as T0Plasma samples. The device was placed in a shaker (60rpm) at 37 ℃ and incubated for 5 hours. The sample was quenched with 200 μ L acetonitrile containing Internal Standard (IS). After the test is finished, the LC/MS/MS method is adopted for analysis.
Calculating the formula:
％Bound＝100×([Donor]5h-[Receiver]5h)/[Donor]5h
％Recovery＝100×([Donor]5h+[Receiver]5h)/[Initial]0h
Fu(％)＝100-％Bound
the experimental results are as follows:
the plasma protein binding rate of EXP-1 compound was 92.8%.
Example 8: in vivo efficacy testing of compounds in animals
The compound EXP-1 of the above example was used in a cell proliferation model test for KM 12.
8.1 test methods
Female nude mice (shanghai ling-biotechnology limited) were prepared for 6-8 weeks and were kept in SPF-level animal houses in IVC (independent air supply system, constant temperature and humidity) cages (4 mice per cage). 0.1mL of KM12 cells (5X 10)6Individual) were subcutaneously inoculated in the right hind dorsal aspect of each mouse and the mean tumor volume reached about 120mm3Grouping (6 per group) and dosing (oral dosing, QD), dosing EXP-1: 60mg/kg, 200mg/kg, 400mg/kg, LOXO-101: 200 mg/kg.
8.2 tumor measurement and Experimental indices
Tumor diameters were measured twice weekly using a vernier caliper. The formula for tumor volume is: v ═ 0.5a × b2, with a and b indicating the major and minor diameters of the tumor, respectively.
The tumor suppressor therapeutic effect of the compound was evaluated as TGI (%) or relative tumor proliferation rate T/C (%). The relative tumor proliferation rate T/C (%) ═ TRTV/CRTV × 100% (TRTV: treatment group RTV; CRTV: negative control group RTV). Relative Tumor Volume (RTV) is calculated from the tumor measurement results, and the calculation formula is RTV ═ Vt/V0, where V0 is the mean tumor volume measured at the time of group administration (i.e. D0), Vt is the mean tumor volume at a certain time of measurement, and TRTV and CRTV take the same day data.
TGI (%), reflecting the rate of tumor growth inhibition. TGI (%) × (1- (average tumor volume at the end of administration of a certain treatment group-average tumor volume at the start of administration of the treatment group))/(average tumor volume at the end of treatment in the solvent control group-average tumor volume at the start of treatment in the solvent control group) ] × 100%.
Tumor weights will be measured at the end of the experiment and the percent T/cwight calculated, Tweight and cwight indicating tumor weights in the dosing and vehicle control groups, respectively.
8.3 statistical analysis
Statistical analysis was performed using SPSS software based on RTV data at the end of the experiment. Treatment groups showed the best treatment effect at day 14 after dosing at the end of the trial, so statistical analysis was performed based on this data to assess differences between groups. The comparisons between the two groups were analyzed by T-test, the comparisons between the three or more groups were analyzed by one-way ANOVA, and if the variances were uniform (no significant difference in F-values), the Dunnett method was used for the analyses, and if the variances were not uniform (significant difference in F-values), the Games-Howell method was used for the tests. Significant differences were considered with p < 0.05.
8.4 test results
8.4.1 inhibition of EXP-1 on the growth of human colon carcinoma KM12 subcutaneous xenograft tumors, the results are shown in Table 5, Table 6 and FIG. 1.
TABLE 5 tumor-inhibiting effect of small-molecule antitumor drugs on human colon carcinoma KM12 subcutaneous xenograft tumor model (PG-D12)
Figure GDA0003049122780000231
Note: a. mean ± SEM, n ═ 6.
b. Tumor growth inhibition is mediated by T/C and TGI (%) - [1- (T)12-T0)/(V12-V0)]X 100).
c.p values were obtained by analyzing the Relative Tumor Volume (RTV) using one-way ANOVA.
TABLE 6 tumor weights of the groups
Figure GDA0003049122780000232
Note: a. mean. + -. SEM, n ═ 6
b. Tumor growth inhibition by T/Cweight＝TWtreatment/TWSolventAnd (4) calculating.
c.p values were obtained by analyzing tumor weights using one-way ANOVA and vehicle treated groups, and F values were significantly different (p <0.05) and analyzed using the Games-Howell method.
8.4.2 Effect of EXP-1 on animal body weight
The body weight of the experimental animal is used as a reference index for indirectly measuring the toxicity of the medicament. All dosing groups showed no significant weight loss in this model (figure 2). Has no disease phenomenon.
8.5 conclusion
Under the test condition, the EXP-1 has obvious inhibiting effect on the growth of the transplanted tumor of a nude mouse model of the human colon cancer KM12 under the dosage of 60-400mg/kg, has better anti-tumor effect under the high dosage, inhibits the growth of the subcutaneous transplanted tumor of the nude mouse model of the human colon cancer KM12 in a dosage-dependent manner, has no obvious weight reduction of animals under all dosages, has good animal tolerance and no disease occurrence phenomenon, and preliminarily shows that the compounds have small side effect.

Claims (4)

1. Compound EXP-1 or a pharmaceutically acceptable salt thereof:
Figure DEST_PATH_IMAGE001
。
2. a pharmaceutical composition comprising compound EXP-1 of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
3. Use of the compound EXP-1 of claim 1 or a pharmaceutically acceptable salt thereof or the composition of claim 2 for the preparation of a TRK inhibitor medicament.
4. Use of the compound EXP-1 of claim 1 or a pharmaceutically acceptable salt thereof or the composition of claim 2 for the manufacture of a medicament for treating pain, inflammation, neurodegenerative disease or cancer in a mammal.
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