WO2024083120A1 - 苄氨基喹啉类化合物及其制备方法 - Google Patents
苄氨基喹啉类化合物及其制备方法 Download PDFInfo
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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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- Prior art keywords
- compound
- present
- alkyl
- pharmaceutically acceptable
- stereoisomer
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- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
Classifications
-
- 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
本发明公开了一类苄氨基喹啉类化合物及其制备方法,具体涉及式(Ⅱ)所示化合物、其立体异构体及其药学上可接受的盐。
Description
本申请主张如下优先权:
CN202211276424.1,2022年10月18日;
CN202211497271.3,2022年11月25日。
本发明涉及一类苄氨基喹啉类化合物及其制备方法,具体涉及式(Ⅱ)所示化合物、其立体异构体及其药学上可接受的盐。
RAS蛋白是一种拥有鸟苷三磷酸水解酶(GTPase)活性的鸟嘌呤核苷结合蛋白,主要包含三种亚型,KRAS,NRAS和HRAS。作为GDP/GTP循环控制的二进制分子开关,RAS蛋白可以在活性的GTP结合状态(GTP-RAS)和无活性的GDP结合状态(GDP-RAS)之间循环。这一循环在细胞中具有重要的调控功能,同细胞的增殖,存活,代谢,迁移,免疫和生长密切相关。
SOS1(英文全称Son of Sevenless 1)是一类调控RAS蛋白GDP/GTP循环的GEF。细胞表面受体被激活并与胞内Grb2结合后,Grb2招募SOS1至细胞膜,随后SOS1催化RAS-GDP/GTP交换,进而激活下游信号通路。结合在催化位点的小分子SOS1抑制剂,可以阻断SOS1与RAS蛋白的结合,从而有效降低癌细胞中RAS下游信号通路的异常激活,起到治疗癌症的作用。目前SOS1小分子抑制剂只有勃林格殷格翰公司开发的BI-1701963(WO2018115380,WO2019122129)进入了I期临床实验。拜耳公司(WO2018172250,WO2019201848)开发的SOS1抑制剂仍处于临床前研究阶段。近年来有研究认为,RAS通路的药物在临床应用中很容易产生耐药,部分耐药产生的原因是ERK磷酸化被抑制后会负反馈激活上游RAS通路。而这一负反馈调节机制与SOS1密切相关。因此,开发SOS1小分子抑制剂具有广阔的应用前景。
AMG-510是安进公司开发的一种有效的,口服生物可利用的,选择性的KRAS G12C共价抑制剂,用于治疗携带KRAS G12C突变的局部晚期或转移性非小细胞肺癌。其结构如下所示:
发明内容
本发明提供了式(Ⅱ)所示化合物、其立体异构体或其药学上可接受的盐,
其中,
T选自
R1选自H、F、Cl、Br、I、-OH、-NH2、-CN和C1-4烷基,其中所述C1-4烷基任选被1、2、3或4个Ra取代;
R2选自H、F、Cl、Br、I、-OH、-NH2、-CN和C1-4烷基,其中所述C1-4烷基任选被1、2、3或4个Rb取代;
R3选自H、F、Cl、Br、I、-OH、-NH2、-CN和C1-4烷基,其中所述C1-4烷基任选被1、2、3或4个Rc取代;
各Ra分别独立地选自F、Cl、Br、I、-OH、-NH2、-CN、-COOH、=O和C1-3烷基;
各Rb分别独立地选自F、Cl、Br、I、-OH、-NH2、-CN、-COOH、=O和C1-3烷基;
各Rc分别独立地选自F、Cl、Br、I、-OH、-NH2、-CN、-COOH、=O和C1-3烷基。
本发明提供了式(Ⅱ)所示化合物、其立体异构体或其药学上可接受的盐,
其中,
T选自
R1选自H、F、Cl和Br;
R2选自C1-4烷基,其中所述C1-4烷基任选被1、2、3或4个Rb取代;
R3选自H、F、Cl和Br;
各Rb分别独立地选自F和-OH。
本发明的一些方案中,上述化合物具有式(Ⅱ-1)所示结构:
其中,T、R1、R2和R3如本发明所定义;
带“*”的碳原子为手性碳原子,以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明的一些方案中,上述化合物具有式(Ⅱ-1)所示结构:
其中,T、R1、R2和R3如本发明所定义。
本发明的一些方案中,上述化合物具有式(Ⅱ-1)所示结构:
其中,T、R1、R2和R3如本发明所定义。
本发明的一些方案中,上述各Rb分别独立地选自F和-OH,其他变量如本发明所定义。
本发明的一些方案中,上述R1选自H、F、Cl、Br和-NH2,其他变量如本发明所定义。
本发明的一些方案中,上述R1选自H,其他变量如本发明所定义。
本发明的一些方案中,上述R2选自H、F、Cl、Br、-CN、-CH3、-CH2CH3、-CH(CH3)2和-CH2CH(CH3)2,其中所述-CH3、-CH2CH3、-CH(CH3)2和-CH2CH(CH3)2分别独立地任选被1、2、3或4个Rb取代,Rb及其他变量如本发明所定义。
本发明的一些方案中,上述R2选自-CH3和-CH2CH(CH3)2,其中所述-CH3和-CH2CH(CH3)2分别独立地任选被1、2、3或4个Rb取代,Rb及其他变量如本发明所定义。
本发明的一些方案中,上述R2选自-CH2CH(CH3)2,其中所述和-CH2CH(CH3)2任选被1、2、3或4个Rb取代,Rb及其他变量如本发明所定义。
本发明的一些方案中,上述R2选自H、F、Cl、Br、-CN、
Rb及其他变量如本发明所定义。
本发明的一些方案中,上述R2选自Rb及其他变量如本发明所定义。
本发明的一些方案中,上述R2选自Rb及其他变量如本发明所定义。
本发明的一些方案中,上述R2选自H、F、其他变量如本发明所定义。
本发明的一些方案中,上述R2选自H、其他变量如本发明所定义。
本发明的一些方案中,上述R2选自其他变量如本发明所定义。
本发明的一些方案中,上述R3选自H、F、Cl、Br和-NH2,其他变量如本发明所定义。
本发明的一些方案中,上述R3选自F,其他变量如本发明所定义。
本发明还有一些方案是由上述各变量任意组合而来。
本发明提供了式(Ⅱ)所示化合物、其立体异构体或其药学上可接受的盐,
其中,
R2选自C1-4烷基,其中所述C1-4烷基任选被1、2、3或4个Rb取代;
R3选自H、F、Cl和Br;
各Rb分别独立地选自F和-OH。
本发明提供了式(Ⅱ)所示化合物、其立体异构体或其药学上可接受的盐,
其中,R2和R3如本发明所定义。
本发明提供了式(Ⅱ)所示化合物、其立体异构体或其药学上可接受的盐,
其中,
R2选自C1-4烷基,其中所述C1-4烷基任选被1、2、3或4个Rb取代;
R3选自H、F、Cl和Br;
各Rb分别独立地选自F和-OH。
本发明提供了下式化合物或其药学上可接受的盐,
在本发明的一些方案中,上述化合物、其立体异构体或其药学上可接受的盐,其化合物选自,
本发明还提供了上述化合物、其立体异构体或其药学上可接受的盐在制备治疗KRAS突变实体瘤药物中的应用。
本申请还提供了一种在需要的受试者中治疗KRAS突变实体瘤的方法,包括向受试者提供有效剂量的上述化合物、其立体异构体或其药学上可接受的盐。
本发明还提供了上述化合物的生物试验测试方法:
试验测试方法1:H358细胞3D增殖抑制活性测试
实验原理:
KRAS(G12C)突变的H358细胞中,KRAS信号通路异常激活。小分子SOS1抑制剂通过抑制SOS1与RAS蛋白的结合,降低其GEF活性,减少激活状态RAS-GTP的比例。进一步下调RAS下游的MEK/ERK通路的磷酸化水平,达到抑制细胞增殖的效果。将小分子与H358细胞在3D空间内共培养,然后通过细胞读数,间接反映SOS1抑制剂对H358细胞的增殖抑制活性。
实验材料:
RPMI1640培养基,胎牛血清,盘尼西林/链霉素抗生素购自维森特,低熔点琼脂糖购自Sigma。Almar blue试剂购自Invitrogen。NCI-H358细胞系购自南京科佰生物科技有限公司。Nivo多标记分析仪(PerkinElmer)。
实验方法:
将H358细胞种于96孔U型板中,先将低熔点琼脂糖配成2%的母液,使用时先将琼脂糖母液在微波炉中加热使其完全融化,之后至于42℃水浴锅中使琼脂糖保持液体状态。将凝胶加入含血清的培养基中配成凝胶浓度为0.6%作为底层胶,按照每孔50μL铺到96孔U型板中。待底层胶凝固后,再将2%凝胶加入到含细胞的培养基中,配成凝胶浓度为0.4%的含细胞的上层胶,细胞密度为4×104细胞/毫升,按照每孔75μL加到铺有底层胶的96孔U型板中,细胞密度为3000个每孔。待上层胶凝固后细胞板置于二氧化碳培养箱中过夜培养。
加化合物当天,在铺好细胞的96孔U型板中加入85μL液体培养基。将待测化合物用排枪进行3倍稀释至第9个浓度,即从6mM稀释至0.9μM,设置双复孔实验。向中间板中加入97μL培养基,再按照对应位置,转移2.5μL每孔的梯度稀释化合物至中间板,混匀后转移40μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是30μM至4.5nM。细胞板置于二氧化碳培养箱中培养7天,第8天,将待测化合物用排枪进行3倍稀释至第九个浓度,即从6mM稀释至0.9μM,设置双复孔实验。像中间板中加入198μL培养基,再按照对应位置,转移2μL每孔的梯度稀释化合物至第一块中间板中,再向第二块中间板中加入100μL培养基,取第一块中间板中的混匀化合物100μL加入,混匀后转移40μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是30μM至4.5nM。细胞板置于二氧化碳培养箱中再培养7天。化合物与细
胞共孵育14天,向细胞板中加入每孔20μL的Almar blue检测试剂,将加染料的板子置于水平摇床上震荡15分钟,再将板子至于室温孵育至5小时使发光信号稳定。采用多标记分析仪读数。
数据分析:
利用方程式(Sample-Min)/(Max-Min)×100%将原始数据换算成抑制率,IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。
实验结论:本发明化合物能在3D条件下抑制H358细胞的增殖。
试验测试方法2:化合物药代动力学评价
实验材料:
CD-1小鼠(雄性,7~9周龄,上海斯莱克)
实验操作:
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征,实验中候选化合物配成澄清溶液,给予小鼠单次静脉注射及口服给药。静注及口服溶媒为10%二甲基亚砜与90%的10%的羟丙基β环糊***溶液配成的混合溶媒。该项目使用四只雌性CD-1小鼠,两只小鼠进行静脉注射给药,给药剂量为1mg/kg,收集给药后0.033,0.083,0.25,0.5,1,2,4,8,12h的血浆样品;另外两只小鼠口服灌胃给药,给药剂量为2mg/kg,收集给药后0.083,0.25、0.5,1,2,4,8,12h的血浆样品,在4℃下3,200x g搅拌10分钟,分离上清得血浆样品,加入20倍体积含内标的甲醇溶液沉淀蛋白,12000x g搅拌15min,4℃离心取上清液50μL转移至96-well plate二次离心取上清进样,以LC-MS/MS分析方法定量分析血药浓度,并计算药代参数,如达峰浓度(Cmax),清除率(CL),半衰期(T1/2),组织分布(Vdss),药时曲线下面积(AUC0-last),生物利用度(F)等。
实验结论:本发明化合物具有良好的药代动力学性质,包括良好的口服生物利用度,口服暴露量,半衰期和清除率等。
试验测试方法3:化合物在Miapaca2裸鼠移植瘤模型的体内药效评价
细胞培养:
人胰腺癌细胞(ATCC),体外贴壁单层培养,培养条件为DMEM培养基中加10%胎牛血清,37℃,5%CO2孵箱培养。一周两到三次用胰酶–EDTA进行常规消化处理传代。当细胞饱和度为80%–90%,数量到达要求时,收取细胞,计数,接种。
实验动物:
Balb/c裸小鼠,雌性,6-7周,购自上海西普尔-必凯实验动物有限公司。
模型制备:
将0.2mL(5×106个)Miapaca2细胞(加基质胶,体积比为1:1)皮下接种于每只小鼠的右后背,肿瘤平均体积达到118mm3时开始分组给药。
肿瘤测量和实验指标:
每周两次用游标卡尺测量肿瘤直径,肿瘤体积以立方毫米计量,通过以下的公式计算:V=0.5a×b2,其中a和b分别是肿瘤的长径和短径。受试化合物的抑瘤疗效通过使用TGI(%)来评价。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%。
实验结论:本发明的化合物与AMG-510联用在Miapaca2裸鼠移植瘤模型中展现出优异的抑瘤效果。
技术效果
本发明化合物具有良好的KRAS(G12C)-SOS1结合抑制活性,以及对DLD-1细胞和KRAS(G12C)突变的H358细胞具有显著的抑制活性;安全性实验研究发现,本发明化合物的hERG钾通道没有明显的抑制效果,心脏毒性风险较低进而获得了优良的抑制肿瘤生长的活性。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”,是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸,碳酸氢根,磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸;还包括氨基酸(如精氨酸等)的盐,以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物,包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体,及其外消旋混合物和其他混合物,例如对映异构体或非对映体富集的混合物,所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物,均包括在本发明的范围之内。
除非另有说明,术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明,术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明,术语“非对映异构体”是指分子具有两个或多个手性中心,并且分子间为非镜像的关系的立体异构体。
除非另有说明,“(+)”表示右旋,“(-)”表示左旋,“(±)”表示外消旋。
除非另有说明,用楔形实线键和楔形虚线键表示一个立体中心的绝对构型,用直形实线键和直形虚线键表示立体中心的相对构型,用波浪线表示楔形实线键或楔形虚线键或用波浪线表示直形实线键和直形虚线键
本发明的化合物可以存在特定的。除非另有说明,术语“互变异构体”或“互变异构体形式”是指在室温下,不同官能团异构体处于动态平衡,并能很快的相互转化。若互变异构体是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明,术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100%,并且,该异构体或对映体的含量大于等于60%,或者大于等于70%,或者大于等于80%,或者大于等于90%,或者大于等于95%,或者大于等于96%,或者大于等于97%,或者大于等于98%,或者大于等于99%,或者大于等于99.5%,或者大于等于99.6%,或者大于等于99.7%,或者大于等于99.8%,或者大于等于99.9%。
除非另有说明,术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如,其中一种异构体或对映体的含量为90%,另一种异构体或对映体的含量为10%,则异构体或对映体过量(ee值)为80%。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体,可以通过不对称合成或者具有手性助剂的衍生作用来制备,其中将所得非对映体混合物分离,并且辅助基团裂开以提供纯的所需对映异构体。或者,当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时,与适当的光学活性的酸或碱形成非对映异构体的盐,然后通过本领域所公知的常规方法进行非对映异构体拆分,然后回收得到纯的对映体。此外,对映异构体和非对映异构体的分离通常是通过使用色谱法完成的,所述色谱法采用手性固定相,并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素标记化合物,比如氚(3H),碘-125(125I)或C-14(14C)。又例如,可用重氢取代氢形成氘代药物,氘与碳构成的键比普通氢与碳构成的键更坚固,相比于未氘化药物,氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换,无论放射性与否,都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的,并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代,取代基可以包括重氢和氢的变体,只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即=O)时,意味着两个氢原子被取代。氧取代不会发生在芳香基上。
术语“任选被取代的”是指可以被取代,也可以不被取代,除非另有规定,取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时,其在每一种情况下的定义都是独立的。因此,例如,如果一个基团被0-2个R所取代,则所述基团可以任选地至多被两个R所取代,并且每种情况下的R都有独立的选项。此外,取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时,比如-(CRR)0-,表示该连接基团为单键。
当其中一个变量选自单键时,表示其连接的两个基团直接相连,比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时,表示该取代基是不存在的,比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时,这种取代基可以通过其任何原子相键合,例如,吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向,其连接方向是任意的,例如,中连接基团L为-M-W-,此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定,当某一基团具有一个或多个可连接位点时,该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的,且可连接位点存在H原子时,则连接化学键时,该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键直形虚线键或波浪线表示。例如-OCH3中的直形实线键表示通过该基团中的氧原子与其他基团相连;中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连;中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连。表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连,至少包括
这4种连接方式,即使-N-上画出了H原子,但是仍包括
这种连接方式的基团,只是在连接1个化学键时,该位点的H会对应减少1个变成相应的一价哌啶基。
当某取代基的化学键与连接环上两原子的化学键相交时,说明该取代基可与环上任意原子成键。当某取代基连接的原子并没有指明的时候,该取代基可以与任意原子成键,如果取代基连接的原子在双环或者三环体系中,则说明该取代基可与该体系中任意环的任意原子成键。取代基及/或变量的组合只有在该组合产生稳定的化合物时才被允许。例如,结构单元表示其可在环己基或者环戊基上的任意一个位置发生取代。
除非另有规定,环上原子的数目通常被定义为环的元数,例如,“5-7元环”是指环绕排列5-7个原子的“环”。
除非另有规定,Cn-n+m或Cn-Cn+m包括n至n+m个碳的任何一种具体情况,例如C1-12包括C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、和C12,也包括n至n+m中的任何一个范围,例如C1-12包括C1-
3、C1-6、C1-9、C3-6、C3-9、C3-12、C6-9、C6-12、和C9-12等;同理,n元至n+m元表示环上原子数为n至n+m个,例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环,也包括n至n+m中的任何一个范围,例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
除非另有规定,术语“烷基”本身或作为另一取代基的一部分表示直链或支链的饱和碳氢基团。所述烷基可以为C1-6烷基或C1-3烷基。所述烷基任选地被一个或多个以下基团取代:氧代、羟基、氨基、硝基、卤素、氰基、烯基、炔基、烷氧基、卤代烷氧基、烷基氨基、二烷基氨基、卤代烷基氨基、卤代二烷基氨基、环烷基、环烷基氧基、杂环基、杂环基氧基、杂环烷基、杂环烷基氧基、杂芳基、杂芳基氧基、芳基或芳基氧基。
除非另有规定,术语“C1-4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C1-4烷基包括C1-2、C1-3和C2-3烷基等;其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-4烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基,异丁基,s-丁基和t-丁基)等。
除非另有规定,术语“C1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C1-3烷基包括C1-2和C2-3烷基等;其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-
3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如,代表性的离去基团包括三氟甲磺酸酯;氯、溴、碘;磺酸酯基,如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等;酰氧基,如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于:甲酰基;酰基,例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基);烷氧基羰基,如叔丁氧基羰基(Boc);芳基甲氧羰基,如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc);芳基甲基,如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲
基;甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于:烷基,如甲基、乙基和叔丁基;酰基,例如链烷酰基(如乙酰基);芳基甲基,如苄基(Bn),对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基,DPM);甲硅烷基,如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构,如果本发明涉及化合物的绝对构型,则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD),把培养出的单晶用Bruker D8venture衍射仪收集衍射强度数据,光源为CuKα辐射,扫描方式:φ/ω扫描,收集相关数据后,进一步采用直接法(Shelxs97)解析晶体结构,便可以确证绝对构型。
本发明所使用的容积可经市售获得。
本发明采用下述缩略词:Alloc代表烯丙氧羰基;SEM代表三甲基硅烷基乙氧甲基;OTs代表4-甲苯磺酰基;Boc代表叔丁氧羰基;DCM代表二氯甲烷;DIEA代表N,N-二异丙基乙胺;MeI代表碘甲烷;PE代表石油醚;EA代表乙酸乙酯;THF代表四氢呋喃;EtOH代表乙醇;MeOH代表甲醇;Boc2O代表二碳酸二叔丁酯;NH4Cl代表氯化铵;T3P代表1-丙基磷酸三环酸酐;Pd/C代表钯/碳催化剂;TMSN3代表叠氮基三甲基硅烷;NCS代表N-氯代丁二酰亚胺;HBr代表氢溴酸;AcOH代表醋酸;HATU代表O-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐;DBU代表1,8-二氮杂二环十一碳-7-烯;FA代表甲酸;ACN代表乙腈;TLC代表薄层色谱;HPLC代表高压液相色谱;LCMS代表液质联用色谱。DMSO代表二甲亚砜;DMSO-d6代表氘代二甲亚砜;CD3OD代表氘代甲醇;CDCl3代表氘代氯仿;D2O代表氘水。
化合物依据本领域常规命名原则或者使用软件命名,市售化合物采用供应商目录名称。
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
中间体A
合成路线:
第一步
将化合物A-1(10.0g,47.3mmoL)溶解在乙腈(24mL)中,在25℃下向其中通入干燥氯化氢气体0.5小时,反应液在90℃下搅拌3小时,反应液冷却至25℃,过滤,收集滤饼并溶解在水(100mL)中,溶液用10%碳酸氢钠溶液(100mL)中和,过滤,滤饼用冰水(100mL)洗涤,干燥得到化合物A-2。1H NMR(400MHz,CD3OD)δ7.55(s,1H),7.07(s,1H),3.98(s,3H),3.95(s,3H),2.45(s,3H)。
第二步
将化合物A-2(3.00g,13.6mmol)溶解在甲基磺酸(15mL)中,向化合物中加入DL-蛋氨酸(2.44g,16.4mmol),反应液在110℃下反应12小时,反应液用水(90mL)和氢氧化钠水溶液(2mol/L,150ml)淬灭,反应液过滤,收集滤饼并真空干燥,得到中间体A。1H NMR(400MHz,DMSO-d6)δ7.33(s,1H),7.02(s,1H),3.88(s,3H),2.88(s,3H)。
中间体B
合成路线:
第一步
将B-2(3.37g,16.6mmol)溶于二甲亚砜(20mL)中,加入铜粉(1.06g,16.6mmol)。反应液在25℃搅拌反应1小时。然后再向反应液中加入化合物B-1(2.00g,6.65mmol),在70℃搅拌反应12小时。将反应液倒入20mL冰水中,加入乙酸乙酯(20mL),过滤,滤液用乙酸乙酯(20mL×3)萃取。有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,1/0~20/1,V/V)分离纯化得到化合物B-3。1H NMR(400MHz,CDCl3)δ7.75-7.68(m,1H),7.64-7.57(m,1H),7.16(t,J=8.0Hz,1H),4.38(m,2H),1.34(t,J=8.0Hz,3H)。
第二步
在氮气保护下,将化合物B-3(677mg,1.82mmol)溶于甲苯(10mL)中,0℃下加入甲基溴化镁溶液(化合物B-4)(3M,2.43mL)。反应液在25℃搅拌反应2小时。加入饱和氯化铵溶液(10mL)淬灭,用乙酸乙酯(10mL×2)萃取。有机相用饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余
物经过硅胶柱层析法(石油醚/乙酸乙酯,1/0~10/1,V/V)分离纯化得到化合物B-5。1H NMR(400MHz,CDCl3)δ7.66(t,J=6.4Hz,1H),7.51-7.34(m,1H),7.16-6.93(m,1H),2.01(s,1H),1.35(s,6H)。
第三步
在氮气保护下,将化合物B-5(441mg,1.56mmol)溶于甲苯(5mL)中,加入化合物B-6(1.87g,5.19mmol)和双三苯基磷二氯化钯(109mg,0.16mmol),反应液在120℃搅拌反应12小时。加入饱和氟化钾溶液(20mL)淬灭,用乙酸乙酯(15mL×2)萃取。过滤,减压浓缩得化合物B-7。
第四步
在氮气保护下,将化合物B-7(425mg,1.55mmol)溶于丙酮(10mL)中,0℃下逐滴加入盐酸溶液(12M,1.03mL),在25℃搅拌反应1小时。加入饱和碳酸氢钠溶液中和至pH=8,用乙酸乙酯(10mL)萃取。有机相用饱和食盐水(10mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,20/1~4/1,V/V)分离纯化得到化合物B-8。MS-ESI计算值[M+H]+247,实测值247。
第五步
在25℃下将化合物B-8(346mg,1.41mmol)溶于四氢呋喃(5mL)中,加入化合物B-9(511mg,4.22mmol)和四乙氧基钛(2.00g,7.03mmol)。反应液在80℃搅拌反应36小时。然后在-5℃下向反应液中加入硼氢化钠(64.0mg,1.69mmol),在25℃搅拌反应1小时。将反应液倒入20mL冰水中,过滤,滤液用乙酸乙酯(5mL×2)萃取。有机相用饱和食盐水(5mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,2/1~0/1,V/V)分离纯化得到化合物B-10。MS-ESI计算值[M+H]+352,实测值352。
第六步
将化合物B-10(366mg,1.04mmol)溶于二氧六环(2.5mL)中,加入氯化氢二氧六环溶液(4M,1.15mL)。反应液在25℃搅拌反应6小时。反应液减压浓缩,剩余物经过硅胶柱层析法(二氯甲烷/甲醇,1/0~8/1,V/V)分离纯化得到中间体B的盐酸盐。将中间体B的盐酸盐加入1M NaOH(5mL)中,乙酸乙酯萃取(5mL×2),有机相用无水硫酸钠,过滤,减压浓缩,干燥得到中间体B。
MS-ESI计算值[M+H]+248,实测值248。
实施例1
合成路线:
第一步
将中间体A(300mg,2.91mmol)溶于四氢呋喃(5mL)中,然后加入化合物1-1(674mg,3.35mmol)和N,N-二异丙基乙胺(1.13g,8.73mmol),反应液在25℃下搅拌反应1小时。将反应液倒入水(20mL)中,过滤,滤液用乙酸乙酯(20mL×3)萃取,有机相用无水硫酸钠干燥,减压浓缩得到化合物1-2。
第二步
将化合物1-2(500mg,1.35mmol)溶于N,N-二甲基甲酰胺(5mL)中,滴加三乙胺(940μL,6.75mmol)和化合物1-3(541mg,2.70mmol),在25℃下搅拌反应12小时。反应液过滤,减压浓缩,剩余物用硅胶柱色谱法(二氯甲烷/甲醇,100/1~10/1,V/V),得到化合物1-4。MS-ESI计算值[M+H]+433,实测值433。
第三步
将化合物1-4(460mg,1.06mmol)溶于二氯甲烷(10mL)中,加入化合物1-5(387mg,1.28mmol),4-二甲基氨基吡啶(13.0mg,106μmol)和N,N-二异丙基乙胺(556μL,3.19mmol),在25℃下搅拌反应12小时。反应液过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,100/1~10/1,V/V),得到化合物1-6。MS-ESI计算值[M+H]+699,实测值699。
第四步
将化合物1-6(620mg,887μmol)溶于二甲基亚砜(10mL)中,加入中间体B(219mg,887μmol)和三乙胺(370μL,2.66mmol),在90℃下搅拌反应12小时。降至室温后,向反应液中缓慢加入水(100mL),用乙酸乙酯(100mL×3)萃取,有机相用饱和食盐水(100mL×5)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(二氯甲烷/甲醇,100/1~10/1,V/V),得到化合物1-7。MS-ESI计算值[M+H]+662,实测值662。
第五步
将化合物1-7(540mg,816μmol)溶于乙酸乙酯(5mL)中,加入氯化氢/乙酸乙酯溶液(4mol/L,8.31mL),在25℃下搅拌反应1小时。反应液减压浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex C18 150mm×40mm×5μm;流动相:0.05%盐酸水溶液-乙腈;梯度:乙腈10%-40%,10min)得到化合物1的盐酸盐。1H NMR(400MHz,CD3OD)δ8.45(s,1H),7.70-7.57(m,1H),7.48-7.37(m,1H),7.29-7.21(m,1H),7.20(s,1H),6.08-5.94(m,1H),4.79-4.14(m,2H),4.04(s,3H),3.66-3.44(m,2H),3.44-3.35(m,2H),3.29-3.15(m,1H),2.62(s,3H),1.74(d,J=6.8Hz,3H),1.51(d,J=6.0Hz,3H),1.37-1.21(m,6H)。
MS-ESI计算值[M+H]+562,实测值562。
生物学活性:
实验例1:KRAS(G12C)和SOS1结合实验
实验原理:
小分子化合物结合在SOS1的催化位点,而抑制SOS1与KRAS(G12C)的结合。荧光标记的SOS1蛋白与荧光标记的KRAS(G12C)蛋白的结合被抑制时,发出的荧光发生改变。通过检测荧光改变,可以测试小分子阻止SOS1与KRAS(G12C)结合的能力。采用均相时间分辨荧光(HTRF)结合试验来检测本发明的化合物抑制SOS1与KRAS(G12C)相互结合的能力。
实验材料:
KRAS(G12C)蛋白由武汉普健生物科技有限公司表达纯化,SOS1 exchange domin(564-1049)protein(Hμman recombinant)购自Cytoskeleton,Mab Anti 6HIS-XL665和Mab Anti GST-Eμcryptate购自Cisbio。多功能酶标仪Nivo5购自于PerkinElmer。
实验方法:
1X buffer配制(现配现用):Hepes:5mM;NaCl:150mM;EDTA:10mM;Igepal:0.0025%;KF:100mM;DTT:1mM;BSA:005%;
用DMSO将待测化合物用排枪进行5倍稀释至第8个浓度,即从1mM稀释至0.064μM。
用1X buffer将待测化合物各梯度稀释成DMSO为2%的工作液,5μL/孔加到对应孔中,对应浓度梯度为20μM至0.00128nM,置双复孔实验。1000转,离心1分钟。
用1X buffer配制KRAS(G12C)(200nM)和Mab Anti GST-Eμcryptate(1ng/μL)的混和工作液,将该混合工作液放置25℃中孵育5分钟,2.5μL/孔加入到对应孔。
用1X buffer配制SOS1(80nM)和Mab Anti 6HIS-XL665(8g/μL)的混和工作液,2.5μL/孔加入到对应孔中,Blank孔中加入2.5μL Mab Anti 6HIS-XL665(8g/μL)稀释液,此时化合物终浓度梯度为10μM稀释至0.64nM,KRAS(G12C)(500nM),MAb Anti GST-Eu cryptate(0.25ng/μL),SOS1(20nM),Mab Anti 6HIS-XL665(2g/μL),反应体系置于25℃反应60分钟。反应结束后采用多标记分析仪读取HTRF。
数据分析:
利用方程式(Sample-Min)/(Max-Min)×100%将原始数据换算成抑制率,IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中log(inhibitor)vs.response--Variable slope模式得出)。表1提供了本发明的化合物对KRAS(G12C)和SOS1结合的抑制活性。
表1本发明化合物对KRAS(G12C)和SOS1结合的IC50值测试结果
实验结论:本发明化合物对KRAS(G12C)和SOS1结合有显著的抑制效果。
实验例2:DLD-1细胞p-ERK增殖抑制活性测试
实验材料:
DLD-1细胞购自南京科佰;1640培养基购自Biological Industries;胎牛血清购自Biosera;Advanced Phospho-ERK1/2(THR202/TYR204)KIT购自Cisbio。Advanced Phospho-ERK1/2(THR202/TYR204)KIT成分表见表2。
表2 Advanced Phospho-ERK1/2(THR202/TYR204)KIT成分表
实验方法:
DLD-1细胞种于透明96孔细胞培养板中,80μL细胞悬液每孔,每孔包含8000个DLD-1细胞,细胞板放入二氧化碳培养箱,37℃过夜孵育;
将待测化合物用100%DMSO稀释到2mM作为第一个浓度,然后再用移液器进行5倍稀释至第8个浓度,即从2mM稀释至0.026μM。取2μL化合物加入78μL细胞饥饿培养基,混匀后,取20μL化合物溶液加入到对应细胞板孔中,细胞板放回二氧化碳培养箱继续孵育1小时,此时化合物浓度为10μM至0.128nM,DMSO浓度为0.5%;
结束孵育后,弃掉细胞上清加入50μL细胞裂解液每孔,室温摇晃孵育30分钟;
使用检测缓冲液将铕穴状化合物(Eu Cryptate)标记的磷酸化ERK1/2抗体和磷酸化ERK1/2d2抗体稀释20倍;
取16μL细胞裂解物上清每孔到新的384白色微孔板中,再加入2μL铕穴状化合物(Eu Cryptate)标记的磷酸化ERK1/2抗体稀释液和2μL磷酸化ERK1/2d2抗体稀释液,常温孵育4小时;
孵育结束后使用多标记分析仪读取HTRF激发波长:320nm,发射波长:615nm,665nm。
数据分析:
利用方程式(Sample-Min)/(Max-Min)*100%将原始数据换算成抑制率,IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中log(inhibitor)vs.response--Variable slope模式得出)。
Max孔:阳性对照孔读值为1X裂解液
Min孔:阴性对照孔读值为0.5%DMSO细胞孔细胞裂解液
本发明的化合物对DLD-1细胞p-ERK的抑制活性结果见表3。
表3本发明化合物对DLD-1细胞p-ERK增殖的IC50值测试结果
实验结论:本发明化合物对DLD-1细胞p-ERK增殖有显著的抑制效果。
实验例3:hERG钾通道作用全自动膜片钳(Qpatch)测试
实验方法:
CHO-hERG细胞培养于175cm2培养瓶中,待细胞密度生长到60~80%,移走培养液,用7mL PBS(磷酸盐缓冲液)洗一遍,然后加入3mL细胞解离试剂消化。待消化完全后加入7mL培养液中和,然后离心,吸走上清液,再加入5mL培养液重悬,以确保细胞密度为2~5×106/mL。
将化合物母液用DMSO进行稀释,取10μL化合物母液加入至20μL DMSO溶液中,3倍连续稀释至6个DMSO浓度。分别取4μL 6个DMSO浓度的化合物,加入至396μL的细胞外液中,100倍稀释至6个中间浓度,再分别取80μL的6个中间浓度化合物,加入至320μL的细胞外液中,5倍稀释至需要测试的最终浓度。最高测试浓度为40.00μM,依次分别为40.00,13.33,4.44,1.48,0.49,0.16μM共6个浓度。最终测试浓度中的DMSO含量不超过0.2%,此浓度的DMSO对hERG钾通道没有影响。化合物准备由Bravo仪器完成整个稀释过程。
记录电生理过程,单细胞高阻抗封接和全细胞模式形成过程全部由Qpatch仪器自动完成,在获得全细胞记录模式后,细胞钳制在-80毫伏,在给予一个5秒的+40毫伏去极化刺激前,先给予一个50毫秒的-50毫伏前置电压,然后复极化到-50毫伏维持5秒,再回到-80毫伏。每15秒施加此电压刺激,记录2分钟后给予细胞外液记录5分钟,然后开始给药过程,化合物浓度从最低测试浓度开始,每个测试浓度给予2.5分钟。每个浓度至少测试3个细胞(n≥3)。
数据分析:
实验数据由GraphPad Prism 5.0软件进行分析。
本发明的化合物对hERG钾通道的抑制活性结果见表3。
表3本发明化合物hERG钾通道的IC50值测试结果
实验结论:本发明化合物hERG钾通道没有明显的抑制效果,其心脏毒性风险低。
Claims (11)
- 式(Ⅱ)化合物、其立体异构体或其药学上可接受的盐,
其中,T选自R1选自H、F、Cl、Br、I、-OH、-NH2、-CN和C1-4烷基,其中所述C1-4烷基任选被1、2、3或4个Ra取代;R2选自H、F、Cl、Br、I、-OH、-NH2、-CN和C1-4烷基,其中所述C1-4烷基任选被1、2、3或4个Rb取代;R3选自H、F、Cl、Br、I、-OH、-NH2、-CN和C1-4烷基,其中所述C1-4烷基任选被1、2、3或4个Rc取代;各Ra分别独立地选自F、Cl、Br、I、-OH、-NH2、-CN、-COOH、=O和C1-3烷基;各Rb分别独立地选自F、Cl、Br、I、-OH、-NH2、-CN、-COOH、=O和C1-3烷基;各Rc分别独立地选自F、Cl、Br、I、-OH、-NH2、-CN、-COOH、=O和C1-3烷基。 - 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐,其中所述化合物具有式(Ⅱ-1)所示结构:
其中,T、R1、R2和R3如权利要求1所定义;带“*”的碳原子为手性碳原子,以(R)或(S)单一对映体形式或富含一种对映体形式存在。 - 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐,其中,各Rb分别独立地选自F和-OH。
- 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐,其中,R1选自H、F、Cl、Br和-NH2。
- 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐,其中,R2选自H、F、Cl、Br、 -CN、-CH3、-CH2CH3、-CH(CH3)2和-CH2CH(CH3)2,其中所述-CH3、-CH2CH3、-CH(CH3)2和-CH2CH(CH3)2分别独立地任选被1、2、3或4个Rb取代。
- 根据权利要求5所述的化合物、其立体异构体或其药学上可接受的盐,其中,R2选自H、F、
- 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐,其中,R3选自H、F、Cl、Br和-NH2。
- 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐,其化合物选自:
其中,R2选自C1-4烷基,其中所述C1-4烷基任选被1、2、3或4个Rb取代;R3选自H、F、Cl和Br;各Rb分别独立地选自F和-OH。 - 下式化合物、其立体异构体或其药学上可接受的盐,其化合物选自:
- 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐,其化合物选自:
- 根据权利要求1~9任意一项所述的化合物、其立体异构体或其药学上可接受的盐在制备治疗KRAS突变实体瘤药物中的应用。
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