WO2024083120A1 - Composé de benzyl-aminoquinoléine et son procédé de préparation - Google Patents

Composé de benzyl-aminoquinoléine et son procédé de préparation Download PDF

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WO2024083120A1
WO2024083120A1 PCT/CN2023/124976 CN2023124976W WO2024083120A1 WO 2024083120 A1 WO2024083120 A1 WO 2024083120A1 CN 2023124976 W CN2023124976 W CN 2023124976W WO 2024083120 A1 WO2024083120 A1 WO 2024083120A1
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compound
present
alkyl
pharmaceutically acceptable
stereoisomer
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PCT/CN2023/124976
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Chinese (zh)
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贺海鹰
李鹏
代天资
师凯旋
陈曙辉
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南京明德新药研发有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a class of benzylaminoquinoline compounds and a preparation method thereof, and in particular to a compound represented by formula (II), a stereoisomer thereof and a pharmaceutically acceptable salt thereof.
  • RAS protein is a guanine nucleoside binding protein with guanosine triphosphate hydrolase (GTPase) activity, mainly including three subtypes, KRAS, NRAS and HRAS.
  • GTPase guanine nucleoside binding protein with guanosine triphosphate hydrolase
  • KRAS guanosine triphosphate hydrolase
  • HRAS HRAS
  • GTP-RAS active GTP-bound state
  • GDP-RAS inactive GDP-bound state
  • SOS1 (Son of Sevenless 1) is a type of GEF that regulates the GDP/GTP cycle of RAS proteins. After the cell surface receptor is activated and binds to intracellular Grb2, Grb2 recruits SOS1 to the cell membrane, and then SOS1 catalyzes RAS-GDP/GTP exchange, thereby activating downstream signaling pathways. Small molecule SOS1 inhibitors that bind to the catalytic site can block the binding of SOS1 to RAS proteins, thereby effectively reducing the abnormal activation of RAS downstream signaling pathways in cancer cells and playing a role in treating cancer.
  • AMG-510 is a potent, orally bioavailable, selective KRAS G12C covalent inhibitor developed by Amgen for the treatment of locally advanced or metastatic non-small cell lung cancer carrying KRAS G12C mutations. Its structure is shown below:
  • the present invention provides a compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • T is selected from
  • R 1 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 Ra ;
  • R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 R b ;
  • R 3 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 R c ;
  • the present invention provides a compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • T is selected from
  • R1 is selected from H, F, Cl and Br;
  • R 2 is selected from C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 R b ;
  • R3 is selected from H, F, Cl and Br;
  • Each R b is independently selected from F and -OH.
  • the above compound has a structure shown in formula (II-1):
  • the carbon atom with "*" is a chiral carbon atom, which exists in the form of a single enantiomer (R) or (S) or in the form enriched in one enantiomer.
  • the above compound has a structure shown in formula (II-1):
  • T, R 1 , R 2 and R 3 are as defined in the present invention.
  • the above compound has a structure shown in formula (II-1):
  • T, R 1 , R 2 and R 3 are as defined in the present invention.
  • each R b mentioned above is independently selected from F and -OH, and other variables are as defined in the present invention.
  • R 1 is selected from H, F, Cl, Br and -NH 2 , and other variables are as defined in the present invention.
  • R 1 is selected from H, and other variables are as defined in the present invention.
  • R 2 is selected from H, F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 and -CH 2 CH(CH 3 ) 2 , wherein said -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 and -CH 2 CH(CH 3 ) 2 are each independently optionally substituted by 1, 2, 3 or 4 R b , and R b and other variables are as defined in the present invention.
  • R 2 is selected from -CH 3 and -CH 2 CH(CH 3 ) 2 , wherein said -CH 3 and -CH 2 CH(CH 3 ) 2 are independently optionally substituted by 1, 2, 3 or 4 R b , and R b and other variables are as defined in the present invention.
  • R 2 is selected from -CH 2 CH(CH 3 ) 2 , wherein the -CH 2 CH(CH 3 ) 2 is optionally substituted by 1, 2, 3 or 4 R b , and R b and other variables are as defined in the present invention.
  • R 2 is selected from H, F, Cl, Br, -CN, R b and other variables are as defined herein.
  • R 2 is selected from R b and other variables are as defined herein.
  • R 2 is selected from R b and other variables are as defined herein.
  • R2 is selected from H, F, Other variables are as defined in the present invention.
  • R2 is selected from H, Other variables are as defined in the present invention.
  • R 2 is selected from Other variables are as defined in the present invention.
  • R 3 is selected from H, F, Cl, Br and -NH 2 , and other variables are as defined in the present invention.
  • R 3 is selected from F, and other variables are as defined in the present invention.
  • the present invention provides a compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • R 2 is selected from C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 R b ;
  • R3 is selected from H, F, Cl and Br;
  • Each R b is independently selected from F and -OH.
  • the present invention provides a compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • R2 and R3 are as defined in the present invention.
  • the present invention provides a compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • R 2 is selected from C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 R b ;
  • R3 is selected from H, F, Cl and Br;
  • Each R b is independently selected from F and -OH.
  • the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:
  • the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt the compound is selected from,
  • the present invention also provides the use of the above compound, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating KRAS mutant solid tumors.
  • the present application also provides a method for treating KRAS mutant solid tumors in a subject in need thereof, comprising providing the subject with an effective dose of the above compound, its stereoisomer or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a biological test method for the above compound:
  • Test method 1 H358 cell 3D proliferation inhibition activity test
  • H358 cells with KRAS (G12C) mutation the KRAS signaling pathway is abnormally activated.
  • Small molecule SOS1 inhibitors inhibit the binding of SOS1 to RAS protein, reduce its GEF activity, and reduce the ratio of activated RAS-GTP. Further downregulation of the phosphorylation level of the MEK/ERK pathway downstream of RAS achieves the effect of inhibiting cell proliferation. Small molecules are co-cultured with H358 cells in 3D space, and then cell readouts are used to indirectly reflect the proliferation inhibitory activity of SOS1 inhibitors on H358 cells.
  • RPMI1640 medium fetal bovine serum, penicillin/streptomycin antibiotics were purchased from Vicente, and low melting point agarose was purchased from Sigma.
  • Almar blue reagent was purchased from Invitrogen.
  • NCI-H358 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Nivo multi-label analyzer (PerkinElmer).
  • H358 cells were seeded in a 96-well U-shaped plate.
  • Low melting point agarose was first prepared into a 2% stock solution. When used, the agarose stock solution was first heated in a microwave oven to completely melt it, and then placed in a 42°C water bath to keep the agarose in a liquid state. The gel was added to the serum-containing culture medium to prepare a gel concentration of 0.6% as the bottom layer gel, and 50 ⁇ L was spread into the 96-well U-shaped plate at each well. After the bottom layer gel solidified, 2% gel was added to the cell-containing culture medium to prepare a cell-containing upper layer gel with a gel concentration of 0.4%, and the cell density was 4 ⁇ 10 4 cells/ml. 75 ⁇ L was added to each well of the 96-well U-shaped plate with the bottom layer gel, and the cell density was 3000 per well. After the upper layer gel solidified, the cell plate was placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted 3-fold to the ninth concentration, that is, from 6mM to 0.9 ⁇ M, with a dispenser, and a double-well experiment was set up.
  • the concentration range of the compound transferred to the cell plate is 30 ⁇ M to 4.5 nM.
  • the cell plate is placed in a carbon dioxide incubator and cultured for another 7 days.
  • the cells were incubated for 14 days, and 20 ⁇ L of Almar blue detection reagent was added to each well of the cell plate.
  • the plate with dye was placed on a horizontal shaker for 15 minutes, and then the plate was incubated at room temperature for 5 hours to stabilize the luminescent signal.
  • the reading was performed using a multi-label analyzer.
  • the raw data were converted into inhibition rate using the equation (Sample-Min)/(Max-Min) ⁇ 100%, and the IC50 value was obtained by four-parameter curve fitting (obtained using the "log(inhibitor)vs.response--Variable slope" mode in GraphPad Prism).
  • the compounds of the present invention can inhibit the proliferation of H358 cells under 3D conditions.
  • CD-1 mice male, 7-9 weeks old, Shanghai Slack
  • the pharmacokinetic characteristics of the compounds after intravenous and oral administration in rodents were tested using standard protocols.
  • the candidate compounds were prepared into clear solutions and given to mice as a single intravenous injection and oral administration.
  • the intravenous and oral solvents were a mixed solvent of 10% dimethyl sulfoxide and 90% of a 10% hydroxypropyl ⁇ -cyclodextrin aqueous solution.
  • Four female CD-1 mice were used in this project. Two mice were intravenously injected with the drug at a dose of 1 mg/kg, and plasma samples were collected at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 12 h after administration.
  • mice were orally gavaged with the drug at a dose of 2 mg/kg, and plasma samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 12 h after administration.
  • the samples were stirred at 3,200 x g at 4°C for 10 minutes, and the supernatant was separated to obtain plasma samples.
  • a 20-fold volume of methanol solution containing an internal standard was added to precipitate the protein, and the samples were stirred at 12,000 x g for 15 minutes.
  • the supernatant was centrifuged at 4°C and 50 ⁇ L was transferred to a 96-well plate for a second centrifugation.
  • the supernatant was sampled and quantitatively analyzed for blood drug concentrations using LC-MS/MS analysis methods, and pharmacokinetic parameters such as peak concentration (C max ), clearance (CL), half-life (T 1/2 ), tissue distribution (Vdss), and area under the drug-time curve (AUC 0-last ), bioavailability (F), etc.
  • C max peak concentration
  • CL clearance
  • T 1/2 half-life
  • Vdss tissue distribution
  • AUC 0-last area under the drug-time curve
  • bioavailability F
  • the compounds of the present invention have good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.
  • Human pancreatic cancer cells were cultured in vitro in an adherent monolayer in DMEM medium with 10% fetal bovine serum at 37°C and 5% CO 2. They were routinely digested and passaged with trypsin-EDTA two to three times a week. When the cell saturation reached 80%–90% and the number reached the required level, the cells were harvested, counted, and inoculated.
  • mice Female, 6-7 weeks old, were purchased from Shanghai Xipu-Bikai Experimental Animal Co., Ltd.
  • TGI 0.5a ⁇ b 2 , where a and b are the long diameter and short diameter of the tumor, respectively.
  • the anti-tumor efficacy of the test compound was evaluated by using TGI (%).
  • TGI (%) reflects the tumor growth inhibition rate.
  • TGI (%) [1-(average tumor volume at the end of administration of a treatment group - average tumor volume at the beginning of administration of the treatment group) / (average tumor volume at the end of treatment of the solvent control group - average tumor volume at the beginning of treatment of the solvent control group)] ⁇ 100%.
  • the compound of the present invention has good KRAS (G12C)-SOS1 binding inhibitory activity, and has significant inhibitory activity on DLD-1 cells and KRAS (G12C) mutated H358 cells; safety experimental studies have found that the compound of the present invention has no obvious inhibitory effect on the hERG potassium channel, has a low risk of cardiac toxicity, and thus obtains excellent activity in inhibiting tumor growth.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases.
  • base addition salts can be obtained by contacting such compounds 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 amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds 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, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and 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 functional groups, and thus can be converted into any base or
  • salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.
  • 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, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of one another.
  • cis-trans isomers or “geometric isomers” arises from the inability of a double bond or single bond forming a ring carbon atom to rotate freely.
  • diastereomer refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.
  • the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Denotes a solid wedge bond or dotted wedge key Or use a wavy line Represents a straight solid bond and straight dashed key
  • tautomer or "tautomeric form” means that at room temperature, different functional group isomers are in dynamic equilibrium and can quickly convert to each other. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • Valence isomers include interconversions by the reorganization of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “isomerically enriched”, “enriched in one enantiomer” or “enantiomerically enriched” mean that the content of one isomer or 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 greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 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 enantiomeric 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 one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).
  • the compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound.
  • the compound may be labeled with a radioactive isotope, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes 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 particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permitted only 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.
  • substituent When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom of it. For example, pyridyl as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.
  • linking group L When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example,
  • the connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of the reading order from left to right to form Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds to become a group with a corresponding valence.
  • the chemical bond connecting the site to other groups can be a straight solid bond.
  • the straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group. It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.
  • the number of atoms in a ring is generally defined as the ring member number, for example, "5-7 membered ring” refers to a “ring” having 5-7 atoms arranged around it.
  • Cn-n+m or Cn - Cn+m includes any specific case of n to n+m carbon atoms, for example, C1-12 includes C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , and also includes any range from n to n+m, for example, C1-12 includes C1-3 , C1-6 , C1-9 , C3-6 , C3-9 , C3-12 , C6-9 , C6-12 , and C13 .
  • n-membered to n+m-membered means that the number of atoms in the ring is n to n+m
  • 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-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.
  • alkyl by itself or as part of another substituent refers to a straight or branched saturated hydrocarbon group.
  • the alkyl group may be a C 1-6 alkyl group or a C 1-3 alkyl group.
  • the alkyl group may be optionally substituted with one or more of the following groups: oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy.
  • C 1-4 alkyl is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 1-3 and C 2-3 alkyl groups, etc.; they can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Examples of C 1-4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), etc.
  • C 1-3 alkyl is used to represent a straight or branched saturated hydrocarbon group consisting 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 polyvalent (such as methine).
  • Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction).
  • a substitution reaction e.g., a nucleophilic substitution reaction.
  • representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-brosylate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.
  • protecting group includes, but is not limited to, an "amino protecting group", a “hydroxy protecting group” or a “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methoxycarbon ...oc), 1,1-bis-(4'-methoxyphenyl)methoxycarbonyl (Boc), 1,1-bis-(4'-methoxyphenyl)methoxycarbonyl (Boc), 1,1-bis-(4'-methoxyphenyl)methoxycarbonyl (B
  • hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (such as acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM
  • 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, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.
  • the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction SXRD
  • the light source is CuK ⁇ radiation
  • the scanning mode is ⁇ / ⁇ scanning.
  • the direct method Shelxs97 is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • the volume used in the present invention is commercially available.
  • Alloc represents allyloxycarbonyl
  • SEM represents trimethylsilylethoxymethyl
  • OTs represents 4-toluenesulfonyl
  • Boc represents tert-butyloxycarbonyl
  • DCM dichloromethane
  • DIEA represents N,N-diisopropylethylamine
  • MeI represents iodomethane
  • PE represents petroleum ether
  • EA represents ethyl acetate
  • THF represents tetrahydrofuran
  • EtOH represents ethanol
  • MeOH represents methanol
  • Boc 2 O represents di-tert-butyl dicarbonate
  • NH 4 Cl represents ammonium chloride
  • T 3 P represents 1-propylphosphoric acid tricyclic anhydride
  • Pd/C represents palladium/carbon catalyst
  • TMSN 3 represents azidotrimethylsilane
  • NCS represents N-chlorosuccinimide
  • HBr represents hydrobromic acid
  • AcOH represents ace
  • the present invention is described in detail below by examples, but it is not intended to limit the present invention in any adverse way.
  • 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 the combination thereof with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art, and preferred embodiments include but are not limited to the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and improvements are made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.
  • compound B-3 (677 mg, 1.82 mmol) was dissolved in toluene (10 mL), and methylmagnesium bromide solution (compound B-4) (3M, 2.43 mL) was added at 0 ° C. The reaction solution was stirred at 25 ° C for 2 hours. Saturated ammonium chloride solution (10 mL) was added to quench, and extracted with ethyl acetate (10 mL ⁇ 2). The organic phase was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • compound B-4 methylmagnesium bromide solution
  • compound B-5 (441 mg, 1.56 mmol) was dissolved in toluene (5 mL), and compound B-6 (1.87 g, 5.19 mmol) and bistriphenylphosphine palladium dichloride (109 mg, 0.16 mmol) were added.
  • the reaction solution was stirred at 120 ° C for 12 hours.
  • Saturated potassium fluoride solution (20 mL) was added to quench, and extracted with ethyl acetate (15 mL ⁇ 2). Filtered and concentrated under reduced pressure to obtain compound B-7.
  • intermediate B The hydrochloride of intermediate B was added to 1M NaOH (5 mL), extracted with ethyl acetate (5 mL ⁇ 2), and the organic phase was filtered with anhydrous sodium sulfate, concentrated under reduced pressure, and dried to obtain intermediate B.
  • Small molecule compounds bind to the catalytic site of SOS1 and inhibit the binding of SOS1 to KRAS (G12C).
  • SOS1 small molecule compounds
  • G12C fluorescently labeled SOS1 protein to fluorescently labeled KRAS (G12C) protein
  • the emitted fluorescence changes.
  • a homogeneous time-resolved fluorescence (HTRF) binding assay is used to detect the ability of the compounds of the present invention to inhibit the binding of SOS1 to KRAS (G12C).
  • KRAS (G12C) protein was expressed and purified by Wuhan Pujian Biotechnology Co., Ltd., SOS1 exchange domin (564-1049) protein (H ⁇ man recombinant) was purchased from Cytoskeleton, Mab Anti 6HIS-XL665 and Mab Anti GST-E ⁇ cryptate were purchased from Cisbio. Multifunctional microplate reader Nivo5 was purchased from PerkinElmer.
  • 1X buffer preparation (prepared and used immediately): Hepes: 5mM; NaCl: 150mM; EDTA: 10mM; Igepal: 0.0025%; KF: 100mM; DTT: 1mM; BSA: 005%;
  • test compound was diluted 5-fold with DMSO using a dispenser to the eighth concentration, that is, from 1 mM to 0.064 ⁇ M.
  • Table 1 provides the inhibitory activity of the compounds of the present invention on the binding of KRAS (G12C) and SOS1.
  • DLD-1 cells were purchased from Nanjing Kebai; 1640 culture medium was purchased from Biological Industries; fetal bovine serum was purchased from Biosera; Advanced Phospho-ERK1/2 (THR202/TYR204) KIT was purchased from Cisbio.
  • the composition of Advanced Phospho-ERK1/2 (THR202/TYR204) KIT is shown in Table 2.
  • DLD-1 cells were seeded in a transparent 96-well cell culture plate, with 80 ⁇ L of cell suspension per well, and each well contained 8000 DLD-1 cells.
  • the cell plate was placed in a carbon dioxide incubator and incubated overnight at 37°C;
  • the compound to be tested was diluted to 2 mM with 100% DMSO as the first concentration, and then diluted 5 times with a pipette to the eighth concentration, that is, from 2 mM to 0.026 ⁇ M.
  • 2 ⁇ L of compound was added to 78 ⁇ L of cell starvation medium, mixed, and 20 ⁇ L of compound solution was added to the corresponding cell plate wells.
  • the cell plate was returned to the carbon dioxide incubator and incubated for 1 hour. At this time, the compound concentration was 10 ⁇ M to 0.128 nM, and the DMSO concentration was 0.5%;
  • the raw data were converted into inhibition rate using the equation (Sample-Min)/(Max-Min)*100%, and the IC50 value was obtained by four-parameter curve fitting (derived by log(inhibitor) vs.response--Variable slope mode in GraphPad Prism).
  • Max well The reading value of the positive control well is 1X lysate
  • Min well negative control well reading value is 0.5% DMSO cell well cell lysate
  • the compounds of the present invention have a significant inhibitory effect on the proliferation of p-ERK in DLD-1 cells.
  • CHO-hERG cells were cultured in a 175 cm2 culture flask. When the cell density grew to 60-80%, the culture medium was removed, and the cells were washed once with 7 mL of PBS (phosphate buffered saline), and then 3 mL of cell dissociation reagent was added for digestion. After complete digestion, 7 mL of culture medium was added for neutralization, and then centrifuged, the supernatant was aspirated, and 5 mL of culture medium was added for re-suspending to ensure that the cell density was 2-5 ⁇ 10 6 /mL.
  • PBS phosphate buffered saline
  • Dilute the compound stock solution with DMSO take 10 ⁇ L of the compound stock solution and add it to 20 ⁇ L DMSO solution, and dilute it 3 times continuously to 6 DMSO concentrations.
  • the highest test concentration is 40.00 ⁇ M, and there are 6 concentrations of 40.00, 13.33, 4.44, 1.48, 0.49, and 0.16 ⁇ M respectively.
  • the DMSO content in the final test concentration does not exceed 0.2%, and this concentration of DMSO has no effect on the hERG potassium channel.
  • the compound preparation is completed by the Bravo instrument throughout the dilution process.
  • the Qpatch instrument automatically completes the electrophysiological recording process, single-cell high-impedance sealing and whole-cell pattern formation. After obtaining the whole-cell recording mode, the cell is clamped at -80 mV. Before a 5-second +40 mV depolarizing stimulus is given, a 50-millisecond -50 mV pre-voltage is given, and then repolarizes to -50 mV for 5 seconds, and then returns to -80 mV. This voltage stimulus is applied every 15 seconds. After recording for 2 minutes, the extracellular solution is given for 5 minutes, and then the drug administration process begins. The compound concentration starts from the lowest test concentration, and each test concentration is given for 2.5 minutes. At least 3 cells (n ⁇ 3) are tested for each concentration.
  • the experimental data were analyzed by GraphPad Prism 5.0 software.
  • the compound of the present invention has no obvious inhibitory effect on hERG potassium channel and has a low risk of cardiac toxicity.

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Abstract

La présente invention concerne un composé de benzyl-aminoquinoléine et son procédé de préparation. La présente invention concerne spécifiquement un composé représenté par la formule (II), un stéréoisomère de celui-ci et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2023/124976 2022-10-18 2023-10-17 Composé de benzyl-aminoquinoléine et son procédé de préparation WO2024083120A1 (fr)

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WO2022199670A1 (fr) * 2021-03-26 2022-09-29 南京明德新药研发有限公司 Dérivés cycliques hétéroaryle substitués par un groupe 6-carbamate
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Publication number Priority date Publication date Assignee Title
CN101679384A (zh) * 2007-06-05 2010-03-24 韩美药品株式会社 用于抑制癌细胞生长的新酰胺衍生物
CN102276808A (zh) * 2010-06-13 2011-12-14 中国石油化工股份有限公司 聚对苯二甲酸乙二酸乙二醇共聚酯的制备方法
CN104513229A (zh) * 2013-09-28 2015-04-15 正大天晴药业集团股份有限公司 喹唑啉衍生物及其制备方法
CN106279128A (zh) * 2015-05-19 2017-01-04 四川海思科制药有限公司 环氧乙烷衍生物及其制备方法和在医药上的应用
CN111630046A (zh) * 2017-12-19 2020-09-04 南京明德新药研发有限公司 喹唑啉衍生物及其应用
WO2019201848A1 (fr) * 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-méthyl-aza-quinazolines
WO2021031952A1 (fr) * 2019-08-16 2021-02-25 劲方医药科技(上海)有限公司 Composé de pyrimidine cyclique à six chaînons substitué par oxygène, son procédé de préparation et son utilisation médicale
WO2021180181A1 (fr) * 2020-03-12 2021-09-16 南京明德新药研发有限公司 Composés pyrimidohétérocycliques et leur application
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CN115322158A (zh) * 2022-08-16 2022-11-11 江南大学 作为krasg12c蛋白抑制剂的取代喹唑啉类化合物

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